Immunotherapy

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

In the not-too-distant future, immunotherapy might be administered to cancer patients in their homes.

The possibility is being driven by the development of subcutaneous formulations of commonly used immune checkpoint inhibitors for non–small cell lung cancer (NSCLC) and other indications, including pembrolizumab, nivolumab, durvalumab, atezolizumab, and amivantamab.

Instead of waiting anywhere from 30 minutes to several hours for infusions into their veins, patients would spend just a few minutes being injected under the loose skin of their abdomens or thighs. Clinicians would save time and money, and patients would leave the clinic much sooner than normal. The ease of subcutaneous injections also opens up an opportunity for home treatment, a potential boon for people who don’t want to spend their remaining time on hospital visits.

“In the future, I hope we can deliver these medicines at home,” said Hazel O’Sullivan, MBBCh, a medical lung cancer oncologist at Cork University, Ireland, who explained the issues during a session at the 2024 European Lung Cancer Congress.

She was the discussant on two studies at the meeting that highlighted the latest developments in the field, the IMscin002 study of subcutaneous atezolizumab and the PALOMA study of subcutaneous amivantamab, both mostly in NSCLC patients.

Subcutaneous atezolizumab was approved recently in Europe after its maker, Genentech/Roche, made a convincing case that its pharmacokinetics, efficacy, and safety are comparable to the intravenous (IV) version. The U.S. Food and Drug Administration is considering approval; Genentech/Roche anticipates a decision in 2024.

IMscin002 randomized 179 stage 2-4 NSCLC patients evenly to IV or subcutaneous atezolizumab for the first three cycles, then switched them for three more cycles.

Participants were then asked what version they preferred and what they wanted to continue with.

Seventy-one percent said they liked the subcutaneous version better and 80% opted to continue with it. Their main reasons were because they spent less time in the clinic and it was more comfortable.

When asked about the potential for home administration, presenter Federico Cappuzzo, MD, PhD, a medical lung cancer oncologist in Rome, said that it could be “an important option in the future,” particularly in isolated areas far away from hospitals.

The authors of new research are currently evaluating whether home administration is possible. Nurses are administering atezolizumab to patients in their homes with telemedicine monitoring.

The other subcutaneous study presented at the meeting, the PALOMA trial with amivantamab, had only 19 subjects. Administration took no more than 10 minutes, versus potentially hours, especially for the first dose. Subcutaneous amivantamab was given once a month, versus every 2 weeks for the IV formulation, during the maintenance phase of treatment.

The take-home from PALOMA is that the risk of infusion reactions is lower with subcutaneous administration (16% versus 67%) but the risk of mostly mild skin rashes is higher (79% versus 36%).

Investigation is ongoing to confirm safety, pharmacokinetic, and efficacy equivalence with the IV formulation, including in combination with other medications.

When asked about home administration of amivantamab, PALOMA lead investigator Natasha Leighl, MD, a lung, and breast cancer medical oncologist at the University of Toronto, stated that patients probably need to be watched in the clinic for the first 4 months.

The atezolizumab study was funded by maker Genentech/Roche. The amivantamab study was funded by its maker, Janssen. The amivantamab investigator, Dr. Leighl, reported grants, honoraria, and travel payments from Janssen. Dr. Cappuzzo, the investigator on the atezolizumab study, reported speaker and adviser payments from Genentech/Roche. The discussant, Dr. O’Sullivan, wasn’t involved with either company but reported payments from Amgen and AstraZeneca and travel costs covered by Takeda.

In the not-too-distant future, immunotherapy might be administered to cancer patients in their homes.

The possibility is being driven by the development of subcutaneous formulations of commonly used immune checkpoint inhibitors for non–small cell lung cancer (NSCLC) and other indications, including pembrolizumab, nivolumab, durvalumab, atezolizumab, and amivantamab.

Instead of waiting anywhere from 30 minutes to several hours for infusions into their veins, patients would spend just a few minutes being injected under the loose skin of their abdomens or thighs. Clinicians would save time and money, and patients would leave the clinic much sooner than normal. The ease of subcutaneous injections also opens up an opportunity for home treatment, a potential boon for people who don’t want to spend their remaining time on hospital visits.

“In the future, I hope we can deliver these medicines at home,” said Hazel O’Sullivan, MBBCh, a medical lung cancer oncologist at Cork University, Ireland, who explained the issues during a session at the 2024 European Lung Cancer Congress.

She was the discussant on two studies at the meeting that highlighted the latest developments in the field, the IMscin002 study of subcutaneous atezolizumab and the PALOMA study of subcutaneous amivantamab, both mostly in NSCLC patients.

Subcutaneous atezolizumab was approved recently in Europe after its maker, Genentech/Roche, made a convincing case that its pharmacokinetics, efficacy, and safety are comparable to the intravenous (IV) version. The U.S. Food and Drug Administration is considering approval; Genentech/Roche anticipates a decision in 2024.

IMscin002 randomized 179 stage 2-4 NSCLC patients evenly to IV or subcutaneous atezolizumab for the first three cycles, then switched them for three more cycles.

Participants were then asked what version they preferred and what they wanted to continue with.

Seventy-one percent said they liked the subcutaneous version better and 80% opted to continue with it. Their main reasons were because they spent less time in the clinic and it was more comfortable.

When asked about the potential for home administration, presenter Federico Cappuzzo, MD, PhD, a medical lung cancer oncologist in Rome, said that it could be “an important option in the future,” particularly in isolated areas far away from hospitals.

The authors of new research are currently evaluating whether home administration is possible. Nurses are administering atezolizumab to patients in their homes with telemedicine monitoring.

The other subcutaneous study presented at the meeting, the PALOMA trial with amivantamab, had only 19 subjects. Administration took no more than 10 minutes, versus potentially hours, especially for the first dose. Subcutaneous amivantamab was given once a month, versus every 2 weeks for the IV formulation, during the maintenance phase of treatment.

The take-home from PALOMA is that the risk of infusion reactions is lower with subcutaneous administration (16% versus 67%) but the risk of mostly mild skin rashes is higher (79% versus 36%).

Investigation is ongoing to confirm safety, pharmacokinetic, and efficacy equivalence with the IV formulation, including in combination with other medications.

When asked about home administration of amivantamab, PALOMA lead investigator Natasha Leighl, MD, a lung, and breast cancer medical oncologist at the University of Toronto, stated that patients probably need to be watched in the clinic for the first 4 months.

The atezolizumab study was funded by maker Genentech/Roche. The amivantamab study was funded by its maker, Janssen. The amivantamab investigator, Dr. Leighl, reported grants, honoraria, and travel payments from Janssen. Dr. Cappuzzo, the investigator on the atezolizumab study, reported speaker and adviser payments from Genentech/Roche. The discussant, Dr. O’Sullivan, wasn’t involved with either company but reported payments from Amgen and AstraZeneca and travel costs covered by Takeda.

In the not-too-distant future, immunotherapy might be administered to cancer patients in their homes.

The possibility is being driven by the development of subcutaneous formulations of commonly used immune checkpoint inhibitors for non–small cell lung cancer (NSCLC) and other indications, including pembrolizumab, nivolumab, durvalumab, atezolizumab, and amivantamab.

Instead of waiting anywhere from 30 minutes to several hours for infusions into their veins, patients would spend just a few minutes being injected under the loose skin of their abdomens or thighs. Clinicians would save time and money, and patients would leave the clinic much sooner than normal. The ease of subcutaneous injections also opens up an opportunity for home treatment, a potential boon for people who don’t want to spend their remaining time on hospital visits.

“In the future, I hope we can deliver these medicines at home,” said Hazel O’Sullivan, MBBCh, a medical lung cancer oncologist at Cork University, Ireland, who explained the issues during a session at the 2024 European Lung Cancer Congress.

She was the discussant on two studies at the meeting that highlighted the latest developments in the field, the IMscin002 study of subcutaneous atezolizumab and the PALOMA study of subcutaneous amivantamab, both mostly in NSCLC patients.

Subcutaneous atezolizumab was approved recently in Europe after its maker, Genentech/Roche, made a convincing case that its pharmacokinetics, efficacy, and safety are comparable to the intravenous (IV) version. The U.S. Food and Drug Administration is considering approval; Genentech/Roche anticipates a decision in 2024.

IMscin002 randomized 179 stage 2-4 NSCLC patients evenly to IV or subcutaneous atezolizumab for the first three cycles, then switched them for three more cycles.

Participants were then asked what version they preferred and what they wanted to continue with.

Seventy-one percent said they liked the subcutaneous version better and 80% opted to continue with it. Their main reasons were because they spent less time in the clinic and it was more comfortable.

When asked about the potential for home administration, presenter Federico Cappuzzo, MD, PhD, a medical lung cancer oncologist in Rome, said that it could be “an important option in the future,” particularly in isolated areas far away from hospitals.

The authors of new research are currently evaluating whether home administration is possible. Nurses are administering atezolizumab to patients in their homes with telemedicine monitoring.

The other subcutaneous study presented at the meeting, the PALOMA trial with amivantamab, had only 19 subjects. Administration took no more than 10 minutes, versus potentially hours, especially for the first dose. Subcutaneous amivantamab was given once a month, versus every 2 weeks for the IV formulation, during the maintenance phase of treatment.

The take-home from PALOMA is that the risk of infusion reactions is lower with subcutaneous administration (16% versus 67%) but the risk of mostly mild skin rashes is higher (79% versus 36%).

Investigation is ongoing to confirm safety, pharmacokinetic, and efficacy equivalence with the IV formulation, including in combination with other medications.

When asked about home administration of amivantamab, PALOMA lead investigator Natasha Leighl, MD, a lung, and breast cancer medical oncologist at the University of Toronto, stated that patients probably need to be watched in the clinic for the first 4 months.

The atezolizumab study was funded by maker Genentech/Roche. The amivantamab study was funded by its maker, Janssen. The amivantamab investigator, Dr. Leighl, reported grants, honoraria, and travel payments from Janssen. Dr. Cappuzzo, the investigator on the atezolizumab study, reported speaker and adviser payments from Genentech/Roche. The discussant, Dr. O’Sullivan, wasn’t involved with either company but reported payments from Amgen and AstraZeneca and travel costs covered by Takeda.

Widely considered the father of cancer immunotherapy, Steven A. Rosenberg MD, PhD, FAACR, has spent nearly 50 years analyzing the link between patients’ immune reaction and their cancer response.

His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.

To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.

Rosenberg_Steven_A_MD_web.jpg

Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.


As a young boy, did you always want to become a doctor?

Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.


How did that experience impact your aspirations?

Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.


What led to your interest in cancer treatment?

Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.


Were there patients who inspired your research?

Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
 

Was the second patient’s case as impressive?

Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.


From there, how did your work evolve?

Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.


Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?

Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.

Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.


What guidance would you have for other physician-investigators or young doctors who want to follow in your path?

Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.

Widely considered the father of cancer immunotherapy, Steven A. Rosenberg MD, PhD, FAACR, has spent nearly 50 years analyzing the link between patients’ immune reaction and their cancer response.

His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.

To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.

Rosenberg_Steven_A_MD_web.jpg

Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.


As a young boy, did you always want to become a doctor?

Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.


How did that experience impact your aspirations?

Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.


What led to your interest in cancer treatment?

Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.


Were there patients who inspired your research?

Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
 

Was the second patient’s case as impressive?

Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.


From there, how did your work evolve?

Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.


Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?

Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.

Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.


What guidance would you have for other physician-investigators or young doctors who want to follow in your path?

Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.

Widely considered the father of cancer immunotherapy, Steven A. Rosenberg MD, PhD, FAACR, has spent nearly 50 years analyzing the link between patients’ immune reaction and their cancer response.

His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.

To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.

Rosenberg_Steven_A_MD_web.jpg

Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.


As a young boy, did you always want to become a doctor?

Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.


How did that experience impact your aspirations?

Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.


What led to your interest in cancer treatment?

Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.


Were there patients who inspired your research?

Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
 

Was the second patient’s case as impressive?

Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.


From there, how did your work evolve?

Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.


Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?

Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.

Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.


What guidance would you have for other physician-investigators or young doctors who want to follow in your path?

Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.

This transcript has been edited for clarity.

Hi. I’m Brian Rini. I’m an Ingram Professor of Medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. I’m going to talk to you briefly today about some major highlights in renal cancer from the Genitourinary (GU) Cancer Symposium that was just held. I think there’s three main areas: adjuvant therapy in kidney cancer, frontline therapy in advanced disease, and the refractory space.

To open with adjuvant therapy, the biggest news in kidney cancer, and probably all of GU cancer at ASCO GU this year, was the adjuvant pembrolizumab overall survival data. This KEYNOTE study had previously shown disease-free survival advantages over placebo in a population with high-risk resected kidney cancer. There was a trend toward overall survival, but it was not significant in those early analyses.

Now with nearly 5 years of follow-up, we see an overall survival advantage, with a hazard ratio in the 0.6 range — so, about a 40% reduction in the risk for death among these patients receiving adjuvant pembrolizumab (pembro). This was really important for the field. It’s been difficult to show a survival advantage, even in diseases like melanoma, which is considered at least as much, if not more immune responsive, and I think puts into perspective whether to offer this drug to high-risk resected patients. And it certainly needs to be considered for this population.

I think the balance on that — and this came out in some of the questions after the session — was around how many of the placebo recipients got salvage immune therapy, which would be a standard of care. But in the countries where this was done, it’s not really clear how many actually got therapy. We know most patients got some salvage therapy, be it local or systemic, and about half the patients got immune therapy. But some more granular detail would be necessary.

The other thing I would mention is that this was paired with the previous presentation, which was adjuvant nivolumab. It was a very similar study, a similar drug in a similar setting, but it did not show any advantages of either disease-free or overall survival. This comes on the heels of other negative studies and a negative ipilimumab/nivolumab (ipi/nivo) study in this setting, part of the same study.

The reasons for these discrepancies are not entirely clear. There’s differences in populations and duration of therapy and mechanism, and all sorts of things. I don’t think anybody’s really been able to come up with one reason why we have some negative immune trials in kidney cancer and one shiningly positive one. But be that as it may, I think the take-home was that adjuvant pembro is certainly a standard of care in high-risk disease, and a benefit/risk discussion needs to be had with each individual patient. And I think pembro will be the building block for future studies, some of which are ongoing.

The second major area of update was in frontline kidney cancer. There weren’t a lot of new data, but there were updates to the existing trials. As you may know, frontline immune-based doublet is a standard of care in this disease: either ipi/nivo or one of the immuno-oncology/tyrosine kinase inhibitor (IO/TKI) regimens. We had two updates. One was an 8-year update on ipi/nivo. It’s a really long follow-up for these patients now, and what was observed was that these results remain remarkably consistent.

The hazard ratios for benefit in terms of survival and durability of response are really consistent over the past several years — again, a hallmark of immune therapy. Over half the responders are still responding now, many years later. I think that only strengthens the position of ipi/nivo as a choice for advanced clear cell kidney cancer patients. Again, there are good long-term toxicity data, and some patients can remain off treatment in what’s called treatment-free survival. So, an important update. We look forward to future, probably 10-year, data.

The CheckMate 9ER cabozantinib/nivolumab (cabo/nivo) study was updated now with many years of follow-up, as some of the other IO/TKI regimens have as well. And I think there is a similar theme, although a few years behind in maturity from the ipi/nivo data. It shows persistence of benefit. With IO/TKI regimens, a lot of the benefit is up front. It’s high response rates. It’s progression-free survival (PFS). But we’re starting to see some of that durability.

Where it’ll land, if there will be a tail of the curve and where it will be, is unclear, but these updates are important in terms of counseling patients. Patients want to know not just what’s going to happen at their first scan but also years from now. And they’re planning to be around years from now. So, I think these data are important.

The last thing I’ll mention is a health-related quality-of-life update from what was called the 005 trial of belzutifan, an oral HIF inhibitor, compared with everolimus. We heard data at the European Society for Medical Oncology (ESMO) Congress 2023 on a PFS and response-rate advantage. The drug was approved by the US Food and Drug Administration (FDA) in late December, and now we see some quality-of-life data.

Quality-of-life questionnaires and scales have a lot of imperfections. I don’t think they necessarily capture everything we want. But in this case, it was fairly clean in that belzutifan is known to be a well-tolerated agent. The toxicity profile is clean. It’s been used for years in patients with Von Hippel-Lindau syndrome, certainly in the trials for years, and has shown good tolerance over time. So, I view these data as complementary to what we already knew about the drug, but they’re nice to see.

It’s nice to see datasets come together and show the same thing: Not only is the drug active in a refractory renal cell carcinoma (RCC) setting, but also it’s really well tolerated and does not adversely impact patients› quality of life. I use this drug a lot in refractory kidney cancer, and because it’s so well tolerated. That means it’s also combinable. And there are some very large studies in the front-end second-line space combining it, in a space where people believe that it has more activity. But there are some complementary data as we wait for the overall survival signal, hopefully, from this regimen.

So, there have been some exciting updates, mostly in the adjuvant space but also in some other spaces in kidney cancer and building upon some of the clinical advances that we had seen from previous meetings. I’m Brian Rini, and I appreciate you attending.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Brian Rini. I’m an Ingram Professor of Medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. I’m going to talk to you briefly today about some major highlights in renal cancer from the Genitourinary (GU) Cancer Symposium that was just held. I think there’s three main areas: adjuvant therapy in kidney cancer, frontline therapy in advanced disease, and the refractory space.

To open with adjuvant therapy, the biggest news in kidney cancer, and probably all of GU cancer at ASCO GU this year, was the adjuvant pembrolizumab overall survival data. This KEYNOTE study had previously shown disease-free survival advantages over placebo in a population with high-risk resected kidney cancer. There was a trend toward overall survival, but it was not significant in those early analyses.

Now with nearly 5 years of follow-up, we see an overall survival advantage, with a hazard ratio in the 0.6 range — so, about a 40% reduction in the risk for death among these patients receiving adjuvant pembrolizumab (pembro). This was really important for the field. It’s been difficult to show a survival advantage, even in diseases like melanoma, which is considered at least as much, if not more immune responsive, and I think puts into perspective whether to offer this drug to high-risk resected patients. And it certainly needs to be considered for this population.

I think the balance on that — and this came out in some of the questions after the session — was around how many of the placebo recipients got salvage immune therapy, which would be a standard of care. But in the countries where this was done, it’s not really clear how many actually got therapy. We know most patients got some salvage therapy, be it local or systemic, and about half the patients got immune therapy. But some more granular detail would be necessary.

The other thing I would mention is that this was paired with the previous presentation, which was adjuvant nivolumab. It was a very similar study, a similar drug in a similar setting, but it did not show any advantages of either disease-free or overall survival. This comes on the heels of other negative studies and a negative ipilimumab/nivolumab (ipi/nivo) study in this setting, part of the same study.

The reasons for these discrepancies are not entirely clear. There’s differences in populations and duration of therapy and mechanism, and all sorts of things. I don’t think anybody’s really been able to come up with one reason why we have some negative immune trials in kidney cancer and one shiningly positive one. But be that as it may, I think the take-home was that adjuvant pembro is certainly a standard of care in high-risk disease, and a benefit/risk discussion needs to be had with each individual patient. And I think pembro will be the building block for future studies, some of which are ongoing.

The second major area of update was in frontline kidney cancer. There weren’t a lot of new data, but there were updates to the existing trials. As you may know, frontline immune-based doublet is a standard of care in this disease: either ipi/nivo or one of the immuno-oncology/tyrosine kinase inhibitor (IO/TKI) regimens. We had two updates. One was an 8-year update on ipi/nivo. It’s a really long follow-up for these patients now, and what was observed was that these results remain remarkably consistent.

The hazard ratios for benefit in terms of survival and durability of response are really consistent over the past several years — again, a hallmark of immune therapy. Over half the responders are still responding now, many years later. I think that only strengthens the position of ipi/nivo as a choice for advanced clear cell kidney cancer patients. Again, there are good long-term toxicity data, and some patients can remain off treatment in what’s called treatment-free survival. So, an important update. We look forward to future, probably 10-year, data.

The CheckMate 9ER cabozantinib/nivolumab (cabo/nivo) study was updated now with many years of follow-up, as some of the other IO/TKI regimens have as well. And I think there is a similar theme, although a few years behind in maturity from the ipi/nivo data. It shows persistence of benefit. With IO/TKI regimens, a lot of the benefit is up front. It’s high response rates. It’s progression-free survival (PFS). But we’re starting to see some of that durability.

Where it’ll land, if there will be a tail of the curve and where it will be, is unclear, but these updates are important in terms of counseling patients. Patients want to know not just what’s going to happen at their first scan but also years from now. And they’re planning to be around years from now. So, I think these data are important.

The last thing I’ll mention is a health-related quality-of-life update from what was called the 005 trial of belzutifan, an oral HIF inhibitor, compared with everolimus. We heard data at the European Society for Medical Oncology (ESMO) Congress 2023 on a PFS and response-rate advantage. The drug was approved by the US Food and Drug Administration (FDA) in late December, and now we see some quality-of-life data.

Quality-of-life questionnaires and scales have a lot of imperfections. I don’t think they necessarily capture everything we want. But in this case, it was fairly clean in that belzutifan is known to be a well-tolerated agent. The toxicity profile is clean. It’s been used for years in patients with Von Hippel-Lindau syndrome, certainly in the trials for years, and has shown good tolerance over time. So, I view these data as complementary to what we already knew about the drug, but they’re nice to see.

It’s nice to see datasets come together and show the same thing: Not only is the drug active in a refractory renal cell carcinoma (RCC) setting, but also it’s really well tolerated and does not adversely impact patients› quality of life. I use this drug a lot in refractory kidney cancer, and because it’s so well tolerated. That means it’s also combinable. And there are some very large studies in the front-end second-line space combining it, in a space where people believe that it has more activity. But there are some complementary data as we wait for the overall survival signal, hopefully, from this regimen.

So, there have been some exciting updates, mostly in the adjuvant space but also in some other spaces in kidney cancer and building upon some of the clinical advances that we had seen from previous meetings. I’m Brian Rini, and I appreciate you attending.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Brian Rini. I’m an Ingram Professor of Medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. I’m going to talk to you briefly today about some major highlights in renal cancer from the Genitourinary (GU) Cancer Symposium that was just held. I think there’s three main areas: adjuvant therapy in kidney cancer, frontline therapy in advanced disease, and the refractory space.

To open with adjuvant therapy, the biggest news in kidney cancer, and probably all of GU cancer at ASCO GU this year, was the adjuvant pembrolizumab overall survival data. This KEYNOTE study had previously shown disease-free survival advantages over placebo in a population with high-risk resected kidney cancer. There was a trend toward overall survival, but it was not significant in those early analyses.

Now with nearly 5 years of follow-up, we see an overall survival advantage, with a hazard ratio in the 0.6 range — so, about a 40% reduction in the risk for death among these patients receiving adjuvant pembrolizumab (pembro). This was really important for the field. It’s been difficult to show a survival advantage, even in diseases like melanoma, which is considered at least as much, if not more immune responsive, and I think puts into perspective whether to offer this drug to high-risk resected patients. And it certainly needs to be considered for this population.

I think the balance on that — and this came out in some of the questions after the session — was around how many of the placebo recipients got salvage immune therapy, which would be a standard of care. But in the countries where this was done, it’s not really clear how many actually got therapy. We know most patients got some salvage therapy, be it local or systemic, and about half the patients got immune therapy. But some more granular detail would be necessary.

The other thing I would mention is that this was paired with the previous presentation, which was adjuvant nivolumab. It was a very similar study, a similar drug in a similar setting, but it did not show any advantages of either disease-free or overall survival. This comes on the heels of other negative studies and a negative ipilimumab/nivolumab (ipi/nivo) study in this setting, part of the same study.

The reasons for these discrepancies are not entirely clear. There’s differences in populations and duration of therapy and mechanism, and all sorts of things. I don’t think anybody’s really been able to come up with one reason why we have some negative immune trials in kidney cancer and one shiningly positive one. But be that as it may, I think the take-home was that adjuvant pembro is certainly a standard of care in high-risk disease, and a benefit/risk discussion needs to be had with each individual patient. And I think pembro will be the building block for future studies, some of which are ongoing.

The second major area of update was in frontline kidney cancer. There weren’t a lot of new data, but there were updates to the existing trials. As you may know, frontline immune-based doublet is a standard of care in this disease: either ipi/nivo or one of the immuno-oncology/tyrosine kinase inhibitor (IO/TKI) regimens. We had two updates. One was an 8-year update on ipi/nivo. It’s a really long follow-up for these patients now, and what was observed was that these results remain remarkably consistent.

The hazard ratios for benefit in terms of survival and durability of response are really consistent over the past several years — again, a hallmark of immune therapy. Over half the responders are still responding now, many years later. I think that only strengthens the position of ipi/nivo as a choice for advanced clear cell kidney cancer patients. Again, there are good long-term toxicity data, and some patients can remain off treatment in what’s called treatment-free survival. So, an important update. We look forward to future, probably 10-year, data.

The CheckMate 9ER cabozantinib/nivolumab (cabo/nivo) study was updated now with many years of follow-up, as some of the other IO/TKI regimens have as well. And I think there is a similar theme, although a few years behind in maturity from the ipi/nivo data. It shows persistence of benefit. With IO/TKI regimens, a lot of the benefit is up front. It’s high response rates. It’s progression-free survival (PFS). But we’re starting to see some of that durability.

Where it’ll land, if there will be a tail of the curve and where it will be, is unclear, but these updates are important in terms of counseling patients. Patients want to know not just what’s going to happen at their first scan but also years from now. And they’re planning to be around years from now. So, I think these data are important.

The last thing I’ll mention is a health-related quality-of-life update from what was called the 005 trial of belzutifan, an oral HIF inhibitor, compared with everolimus. We heard data at the European Society for Medical Oncology (ESMO) Congress 2023 on a PFS and response-rate advantage. The drug was approved by the US Food and Drug Administration (FDA) in late December, and now we see some quality-of-life data.

Quality-of-life questionnaires and scales have a lot of imperfections. I don’t think they necessarily capture everything we want. But in this case, it was fairly clean in that belzutifan is known to be a well-tolerated agent. The toxicity profile is clean. It’s been used for years in patients with Von Hippel-Lindau syndrome, certainly in the trials for years, and has shown good tolerance over time. So, I view these data as complementary to what we already knew about the drug, but they’re nice to see.

It’s nice to see datasets come together and show the same thing: Not only is the drug active in a refractory renal cell carcinoma (RCC) setting, but also it’s really well tolerated and does not adversely impact patients› quality of life. I use this drug a lot in refractory kidney cancer, and because it’s so well tolerated. That means it’s also combinable. And there are some very large studies in the front-end second-line space combining it, in a space where people believe that it has more activity. But there are some complementary data as we wait for the overall survival signal, hopefully, from this regimen.

So, there have been some exciting updates, mostly in the adjuvant space but also in some other spaces in kidney cancer and building upon some of the clinical advances that we had seen from previous meetings. I’m Brian Rini, and I appreciate you attending.

A version of this article first appeared on Medscape.com.

Clinicians are navigating how to begin treating their patients with lifileucel (Amtagvi, Iovance Biotherapeutics Inc.), a new treatment for melanoma with a hefty price tag.

The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.

Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
 

Insurance Adjustments

The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.

Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.

Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.

The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.

Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.

At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.

Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.

Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.

 

Logistics and Infrastructure

A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.

The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
 

Docs Hope TIL Improves in Several Ways

Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.

More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”

Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.

“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.

“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.

“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”

“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.  

In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.

The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.

The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.

Clinicians are navigating how to begin treating their patients with lifileucel (Amtagvi, Iovance Biotherapeutics Inc.), a new treatment for melanoma with a hefty price tag.

The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.

Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
 

Insurance Adjustments

The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.

Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.

Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.

The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.

Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.

At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.

Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.

Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.

 

Logistics and Infrastructure

A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.

The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
 

Docs Hope TIL Improves in Several Ways

Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.

More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”

Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.

“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.

“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.

“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”

“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.  

In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.

The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.

The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.

Clinicians are navigating how to begin treating their patients with lifileucel (Amtagvi, Iovance Biotherapeutics Inc.), a new treatment for melanoma with a hefty price tag.

The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.

Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
 

Insurance Adjustments

The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.

Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.

Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.

The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.

Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.

At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.

Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.

Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.

 

Logistics and Infrastructure

A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.

The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
 

Docs Hope TIL Improves in Several Ways

Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.

More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”

Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.

“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.

“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.

“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”

“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.  

In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.

The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.

The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This patient showed no evidence of recurrence in the scar where the melanoma was excised, and had no enlarged lymph nodes on palpation. His complete blood count and liver function tests were normal. A positron emission tomography (PET) scan was ordered by Dr. Nasser that revealed hypermetabolic right paratracheal, right hilar, and subcarinal lymph nodes, highly suspicious for malignant lymph nodes. The patient was referred to oncology for metastatic melanoma treatment and has been doing well on ipilimumab and nivolumab.

166695_eyebrow_web.jpg

Vitiligo is an autoimmune condition characterized by the progressive destruction of melanocytes resulting in hypopigmentation or depigmentation of the skin. Vitiligo has been associated with cutaneous melanoma. Patients with melanoma can present with hypopigmentation around the primary lesion and/or bilateral symmetrical lesions similar to vitiligo. Melanoma-associated leukoderma occurs in a portion of patients with melanoma and is correlated with a favorable prognosis. Additionally, leukoderma has been described as a side effect of melanoma treatment itself. However, cases such as this one have also been reported of vitiligo-like depigmentation presenting prior to the diagnosis of metastatic melanoma.

Melanoma, like vitiligo, is considered highly immunogenic, and cytotoxic T lymphocytes (CTLs) can recognize antigens in melanoma. Furthermore, studies have shown a vitiligo-like halo around melanoma tumors, likely caused by T-cell recruitment, and this may lead to tumor destruction, but rarely total clearance. It seems that the CTL infiltrate in both diseases is similar, but regulatory T cells are decreased in vitiligo, whereas they are present in melanomas and may contribute to the immunosuppressive tumor microenvironment found at the margin of these lesions.

Leukoderma is also associated with melanoma immunotherapy which may be described as drug-induced leukoderma. Additionally, the frequency of recognition of melanoma cells by CTLs leading to hypopigmentation appears to be higher in those with metastatic disease. High immune infiltrate with CTLs and interferon-gamma (IFN-gamma) expression by type 1 T helper cells is associated with favorable prognosis. Immunotherapy with checkpoint inhibitors has shown promise in treatment augmentation for melanoma, but not all patients fully respond to therapy. Nonetheless, development of leukoderma with these treatments has been significantly associated with good therapeutic response. Depigmentation of hair and retinal epithelium has also been reported. However, drug-induced leukoderma and vitiligo seem to have clinical and biological differences, including family history of disease and serum chemokine levels. Vaccines are in production to aid in the treatment of melanoma, but researchers must first identify the appropriate antigen(s) to include.

BiluMartin_Donna_FLORIDA_web.jpg

Conversely, vitiligo-like depigmentation has been reported as a harbinger of metastatic melanoma. Patients with previous excision of primary melanoma have presented months or years later with depigmentation and, upon further evaluation, have been diagnosed with metastatic melanoma. The prevalence of depigmentation in melanoma patients is about 3%-6%, and is estimated to be 7-10 times more common in those with melanoma than in the general population. In most cases, hypopigmentation follows the diagnosis of melanoma, with an average of 4.8 years after the initial diagnosis and 1-2 years after lymph node or distant metastases. It is unclear whether hypopigmentation occurs before or after the growth of metastatic lesions, but this clinical finding in a patient with previous melanoma may serve as an important clue to conduct further investigation for metastasis.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida, and Natalie Y. Nasser, MD, Kaiser Permanente Riverside Medical Center; Riverside, California. The column was edited by Donna Bilu Martin, MD.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Cerci FB et al. Cutis. 2017 Jun;99(6):E1-E2. PMID: 28686764.

Cho EA et al. Ann Dermatol. 2009 May;21(2):178-181.

Failla CM et al. Int J Mol Sci. 2019 Nov 15;20(22):5731.

This patient showed no evidence of recurrence in the scar where the melanoma was excised, and had no enlarged lymph nodes on palpation. His complete blood count and liver function tests were normal. A positron emission tomography (PET) scan was ordered by Dr. Nasser that revealed hypermetabolic right paratracheal, right hilar, and subcarinal lymph nodes, highly suspicious for malignant lymph nodes. The patient was referred to oncology for metastatic melanoma treatment and has been doing well on ipilimumab and nivolumab.

166695_eyebrow_web.jpg

Vitiligo is an autoimmune condition characterized by the progressive destruction of melanocytes resulting in hypopigmentation or depigmentation of the skin. Vitiligo has been associated with cutaneous melanoma. Patients with melanoma can present with hypopigmentation around the primary lesion and/or bilateral symmetrical lesions similar to vitiligo. Melanoma-associated leukoderma occurs in a portion of patients with melanoma and is correlated with a favorable prognosis. Additionally, leukoderma has been described as a side effect of melanoma treatment itself. However, cases such as this one have also been reported of vitiligo-like depigmentation presenting prior to the diagnosis of metastatic melanoma.

Melanoma, like vitiligo, is considered highly immunogenic, and cytotoxic T lymphocytes (CTLs) can recognize antigens in melanoma. Furthermore, studies have shown a vitiligo-like halo around melanoma tumors, likely caused by T-cell recruitment, and this may lead to tumor destruction, but rarely total clearance. It seems that the CTL infiltrate in both diseases is similar, but regulatory T cells are decreased in vitiligo, whereas they are present in melanomas and may contribute to the immunosuppressive tumor microenvironment found at the margin of these lesions.

Leukoderma is also associated with melanoma immunotherapy which may be described as drug-induced leukoderma. Additionally, the frequency of recognition of melanoma cells by CTLs leading to hypopigmentation appears to be higher in those with metastatic disease. High immune infiltrate with CTLs and interferon-gamma (IFN-gamma) expression by type 1 T helper cells is associated with favorable prognosis. Immunotherapy with checkpoint inhibitors has shown promise in treatment augmentation for melanoma, but not all patients fully respond to therapy. Nonetheless, development of leukoderma with these treatments has been significantly associated with good therapeutic response. Depigmentation of hair and retinal epithelium has also been reported. However, drug-induced leukoderma and vitiligo seem to have clinical and biological differences, including family history of disease and serum chemokine levels. Vaccines are in production to aid in the treatment of melanoma, but researchers must first identify the appropriate antigen(s) to include.

BiluMartin_Donna_FLORIDA_web.jpg

Conversely, vitiligo-like depigmentation has been reported as a harbinger of metastatic melanoma. Patients with previous excision of primary melanoma have presented months or years later with depigmentation and, upon further evaluation, have been diagnosed with metastatic melanoma. The prevalence of depigmentation in melanoma patients is about 3%-6%, and is estimated to be 7-10 times more common in those with melanoma than in the general population. In most cases, hypopigmentation follows the diagnosis of melanoma, with an average of 4.8 years after the initial diagnosis and 1-2 years after lymph node or distant metastases. It is unclear whether hypopigmentation occurs before or after the growth of metastatic lesions, but this clinical finding in a patient with previous melanoma may serve as an important clue to conduct further investigation for metastasis.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida, and Natalie Y. Nasser, MD, Kaiser Permanente Riverside Medical Center; Riverside, California. The column was edited by Donna Bilu Martin, MD.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Cerci FB et al. Cutis. 2017 Jun;99(6):E1-E2. PMID: 28686764.

Cho EA et al. Ann Dermatol. 2009 May;21(2):178-181.

Failla CM et al. Int J Mol Sci. 2019 Nov 15;20(22):5731.

This patient showed no evidence of recurrence in the scar where the melanoma was excised, and had no enlarged lymph nodes on palpation. His complete blood count and liver function tests were normal. A positron emission tomography (PET) scan was ordered by Dr. Nasser that revealed hypermetabolic right paratracheal, right hilar, and subcarinal lymph nodes, highly suspicious for malignant lymph nodes. The patient was referred to oncology for metastatic melanoma treatment and has been doing well on ipilimumab and nivolumab.

166695_eyebrow_web.jpg

Vitiligo is an autoimmune condition characterized by the progressive destruction of melanocytes resulting in hypopigmentation or depigmentation of the skin. Vitiligo has been associated with cutaneous melanoma. Patients with melanoma can present with hypopigmentation around the primary lesion and/or bilateral symmetrical lesions similar to vitiligo. Melanoma-associated leukoderma occurs in a portion of patients with melanoma and is correlated with a favorable prognosis. Additionally, leukoderma has been described as a side effect of melanoma treatment itself. However, cases such as this one have also been reported of vitiligo-like depigmentation presenting prior to the diagnosis of metastatic melanoma.

Melanoma, like vitiligo, is considered highly immunogenic, and cytotoxic T lymphocytes (CTLs) can recognize antigens in melanoma. Furthermore, studies have shown a vitiligo-like halo around melanoma tumors, likely caused by T-cell recruitment, and this may lead to tumor destruction, but rarely total clearance. It seems that the CTL infiltrate in both diseases is similar, but regulatory T cells are decreased in vitiligo, whereas they are present in melanomas and may contribute to the immunosuppressive tumor microenvironment found at the margin of these lesions.

Leukoderma is also associated with melanoma immunotherapy which may be described as drug-induced leukoderma. Additionally, the frequency of recognition of melanoma cells by CTLs leading to hypopigmentation appears to be higher in those with metastatic disease. High immune infiltrate with CTLs and interferon-gamma (IFN-gamma) expression by type 1 T helper cells is associated with favorable prognosis. Immunotherapy with checkpoint inhibitors has shown promise in treatment augmentation for melanoma, but not all patients fully respond to therapy. Nonetheless, development of leukoderma with these treatments has been significantly associated with good therapeutic response. Depigmentation of hair and retinal epithelium has also been reported. However, drug-induced leukoderma and vitiligo seem to have clinical and biological differences, including family history of disease and serum chemokine levels. Vaccines are in production to aid in the treatment of melanoma, but researchers must first identify the appropriate antigen(s) to include.

BiluMartin_Donna_FLORIDA_web.jpg

Conversely, vitiligo-like depigmentation has been reported as a harbinger of metastatic melanoma. Patients with previous excision of primary melanoma have presented months or years later with depigmentation and, upon further evaluation, have been diagnosed with metastatic melanoma. The prevalence of depigmentation in melanoma patients is about 3%-6%, and is estimated to be 7-10 times more common in those with melanoma than in the general population. In most cases, hypopigmentation follows the diagnosis of melanoma, with an average of 4.8 years after the initial diagnosis and 1-2 years after lymph node or distant metastases. It is unclear whether hypopigmentation occurs before or after the growth of metastatic lesions, but this clinical finding in a patient with previous melanoma may serve as an important clue to conduct further investigation for metastasis.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida, and Natalie Y. Nasser, MD, Kaiser Permanente Riverside Medical Center; Riverside, California. The column was edited by Donna Bilu Martin, MD.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Cerci FB et al. Cutis. 2017 Jun;99(6):E1-E2. PMID: 28686764.

Cho EA et al. Ann Dermatol. 2009 May;21(2):178-181.

Failla CM et al. Int J Mol Sci. 2019 Nov 15;20(22):5731.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

HAMBURG, Germany — The human microbiome comprises 39 to 44 billion microbes. That is ten times more than the number of cells in our body. Hendrik Poeck, MD, managing senior physician of internal medicine at the University Hospital Regensburg, illustrated this point at the annual meeting of the German Society for Hematology and Medical Oncology. If the gut microbiome falls out of balance, then “intestinal dysbiosis potentially poses a risk for the pathogenesis of local and systemic diseases,” explained Dr. Poeck.

Cancers and their therapies can also be influenced in this way. “Microbial diversity affects whether a tumor grows, whether it leads to inflammation, immune escape mechanisms or genomic instability, or whether therapeutic resistances develop,” said Dr. Poeck.

Microbial diversity could be beneficial for cancer therapy, too. The composition of the microbiome varies significantly from host to host and can mutate. These properties make it a target for precision microbiotics, which involves using the gut microbiome as a biomarker to predict various physical reactions and to develop individualized diets.

Microbiome and Pathogenesis

The body’s microbiome fulfills a barrier function, especially where the body is exposed to an external environment: at the epidermis and the internal mucous membranes, in the gastrointestinal tract, and in the lungs, chest, and urogenital system.

Association studies on humans and experimental manipulations on mouse models of cancer showed that certain microorganisms can have either protective or harmful effects on cancer development, on the progression of a malignant disease, and on the response to therapy.

A Master Regulator?

Disruptions of the microbial system in the gut, as occur during antibiotic therapy, can have significant effects on a patient’s response to immunotherapy. Taking antibiotics shortly before or after starting therapy with immune checkpoint inhibitors (ICIs) significantly affected both overall survival (OS) and progression-free survival (PFS), as reported in a recent review and meta-analysis, for example.

Proton pump inhibitors also affect the gut microbiome and reduce the response to immunotherapy; this effect was demonstrated by an analysis of data from more than 2700 cancer patients that was recently presented at the annual meeting of the European Society for Medical Oncology (ESMO).

The extent to which the gut microbiome influences the efficacy of an ICI or predicts said efficacy was examined in a retrospective analysis published in Science in 2018, which Dr. Poeck presented. Resistance to ICI correlated with the relative frequency of the bacteria Akkermansia muciniphila in the gut of patients with cancer. In mouse models, the researchers restored the efficacy of the PD-1 blockade through a stool transplant.

Predicting Immunotherapy Response

If A muciniphila is present, can the composition of the microbiome act as a predictor for an effective ICI therapy?

Laurence Zitvogel, MD, PhD, and her working group at the National Institute of Health and Medical Research in Villejuif, France, performed a prospective study in 338 patients with non–small cell lung cancer and examined the prognostic significance of the fecal bacteria A muciniphila (Akk). The “Akkerman status” (low Akk vs high Akk) in a patient’s stool correlated with an increased objective response rate and a longer OS, independently of PD-L1 expression, antibiotics, and performance status. The OS for low Akk was 13.4 months, vs 18.8 months for high Akk in first-line treatment.

These results are promising, said Dr. Poeck. But there is no one-size-fits-all solution. No conclusions can be drawn from one bacterium on the efficacy of therapies in humans, since “the entirety of the bacteria is decisive,” said Dr. Poeck. In addition to the gut microbiome, the composition of gut metabolites influences the response to immunotherapies, as shown in a study with ICI.

Therapeutic Interventions

One possible therapeutic intervention to restore the gut microbiome is fecal microbiota transplantation (FMT). In a phase 1 study presented by Dr. Poeck, FMT was effective in the treatment of 20 patients with melanoma with ICI in an advanced and treatment-naive stage. Seven days after the patients received FMT, the first cycle with anti-PD-1 immunotherapy was initiated, with a total administration of three to four cycles. After 12 weeks, most patients were in complete or partial remission, as evidenced on imaging.

However, FMT also carries some risks. Two cases of sepsis with multiresistant Escherichia coli occurred, as well as other serious infections. Since then, there has been an FDA condition for extended screening of the donor stool, said Dr. Poeck. Nevertheless, this intervention is promising. A search of the keywords “FMT in cancer/transplant setting” reveals 46 currently clinical studies on clinicaltrials.gov.

Nutritional Interventions

Dr. Poeck advises caution about over-the-counter products. These products usually contain only a few species, such as Lactobacillus and Bifidobacterium. “Over-the-counter probiotics can even delay the reconstitution of the microbiome after antibiotics,” said Dr. Poeck, according to a study. In some studies, the response rates were significantly lower after probiotic intake or led to controversial results, according to Dr. Poeck.

In contrast, Dr. Poeck said prebiotics (that is, a fiber-rich diet with indigestible carbohydrates) were promising. During digestion, prebiotics are split into short-chain fatty acids by bacterial enzymes and promote the growth of certain microbiota.

In this way, just 20 g of extremely fiber-rich food had a significant effect on PFS in 128 patients with melanoma undergoing anti-PD-1 immunotherapy. With 20 g of fiber-rich food per day, the PFS was stable over 60 months. The most significant benefit was observed in patients with a sufficient fiber intake who were not taking probiotics.

What to Recommend?

In summary, Dr. Poeck said that it is important to “budget” well, particularly with antibiotic administration, and to strive for calculated therapy with as narrow a spectrum as possible. For patients who experience complications such as cytokine release syndrome as a reaction to cell therapy, delaying the use of antibiotics is important. However, it is often difficult to differentiate this syndrome from neutropenic fever. The aim should be to avoid high-risk antibiotics, if clinically justifiable. Patients should avoid taking antibiotics for 30 days before starting immunotherapy.

Regarding nutritional interventions, Dr. Poeck referred to the recent Onkopedia recommendation for nutrition after cancer and the 10 nutritional rules of the German Nutrition Society. According to Dr. Poeck, the important aspects of these recommendations are a fiber-rich diet (> 20 g/d) from various plant products and avoiding artificial sweeteners and flavorings, as well as ultraprocessed (convenience) foods. In addition, meat should be consumed only in moderation, and as little processed meat as possible should be consumed. In addition, regular (aerobic and anaerobic) physical activity is important.

“Looking ahead into the future,” said Dr. Poeck, “we need a uniform and functional understanding and we need a randomized prediction for diagnosis.”


This article was translated from the Medscape German edition.

A version of this article appeared on Medscape.com.

HAMBURG, Germany — The human microbiome comprises 39 to 44 billion microbes. That is ten times more than the number of cells in our body. Hendrik Poeck, MD, managing senior physician of internal medicine at the University Hospital Regensburg, illustrated this point at the annual meeting of the German Society for Hematology and Medical Oncology. If the gut microbiome falls out of balance, then “intestinal dysbiosis potentially poses a risk for the pathogenesis of local and systemic diseases,” explained Dr. Poeck.

Cancers and their therapies can also be influenced in this way. “Microbial diversity affects whether a tumor grows, whether it leads to inflammation, immune escape mechanisms or genomic instability, or whether therapeutic resistances develop,” said Dr. Poeck.

Microbial diversity could be beneficial for cancer therapy, too. The composition of the microbiome varies significantly from host to host and can mutate. These properties make it a target for precision microbiotics, which involves using the gut microbiome as a biomarker to predict various physical reactions and to develop individualized diets.

Microbiome and Pathogenesis

The body’s microbiome fulfills a barrier function, especially where the body is exposed to an external environment: at the epidermis and the internal mucous membranes, in the gastrointestinal tract, and in the lungs, chest, and urogenital system.

Association studies on humans and experimental manipulations on mouse models of cancer showed that certain microorganisms can have either protective or harmful effects on cancer development, on the progression of a malignant disease, and on the response to therapy.

A Master Regulator?

Disruptions of the microbial system in the gut, as occur during antibiotic therapy, can have significant effects on a patient’s response to immunotherapy. Taking antibiotics shortly before or after starting therapy with immune checkpoint inhibitors (ICIs) significantly affected both overall survival (OS) and progression-free survival (PFS), as reported in a recent review and meta-analysis, for example.

Proton pump inhibitors also affect the gut microbiome and reduce the response to immunotherapy; this effect was demonstrated by an analysis of data from more than 2700 cancer patients that was recently presented at the annual meeting of the European Society for Medical Oncology (ESMO).

The extent to which the gut microbiome influences the efficacy of an ICI or predicts said efficacy was examined in a retrospective analysis published in Science in 2018, which Dr. Poeck presented. Resistance to ICI correlated with the relative frequency of the bacteria Akkermansia muciniphila in the gut of patients with cancer. In mouse models, the researchers restored the efficacy of the PD-1 blockade through a stool transplant.

Predicting Immunotherapy Response

If A muciniphila is present, can the composition of the microbiome act as a predictor for an effective ICI therapy?

Laurence Zitvogel, MD, PhD, and her working group at the National Institute of Health and Medical Research in Villejuif, France, performed a prospective study in 338 patients with non–small cell lung cancer and examined the prognostic significance of the fecal bacteria A muciniphila (Akk). The “Akkerman status” (low Akk vs high Akk) in a patient’s stool correlated with an increased objective response rate and a longer OS, independently of PD-L1 expression, antibiotics, and performance status. The OS for low Akk was 13.4 months, vs 18.8 months for high Akk in first-line treatment.

These results are promising, said Dr. Poeck. But there is no one-size-fits-all solution. No conclusions can be drawn from one bacterium on the efficacy of therapies in humans, since “the entirety of the bacteria is decisive,” said Dr. Poeck. In addition to the gut microbiome, the composition of gut metabolites influences the response to immunotherapies, as shown in a study with ICI.

Therapeutic Interventions

One possible therapeutic intervention to restore the gut microbiome is fecal microbiota transplantation (FMT). In a phase 1 study presented by Dr. Poeck, FMT was effective in the treatment of 20 patients with melanoma with ICI in an advanced and treatment-naive stage. Seven days after the patients received FMT, the first cycle with anti-PD-1 immunotherapy was initiated, with a total administration of three to four cycles. After 12 weeks, most patients were in complete or partial remission, as evidenced on imaging.

However, FMT also carries some risks. Two cases of sepsis with multiresistant Escherichia coli occurred, as well as other serious infections. Since then, there has been an FDA condition for extended screening of the donor stool, said Dr. Poeck. Nevertheless, this intervention is promising. A search of the keywords “FMT in cancer/transplant setting” reveals 46 currently clinical studies on clinicaltrials.gov.

Nutritional Interventions

Dr. Poeck advises caution about over-the-counter products. These products usually contain only a few species, such as Lactobacillus and Bifidobacterium. “Over-the-counter probiotics can even delay the reconstitution of the microbiome after antibiotics,” said Dr. Poeck, according to a study. In some studies, the response rates were significantly lower after probiotic intake or led to controversial results, according to Dr. Poeck.

In contrast, Dr. Poeck said prebiotics (that is, a fiber-rich diet with indigestible carbohydrates) were promising. During digestion, prebiotics are split into short-chain fatty acids by bacterial enzymes and promote the growth of certain microbiota.

In this way, just 20 g of extremely fiber-rich food had a significant effect on PFS in 128 patients with melanoma undergoing anti-PD-1 immunotherapy. With 20 g of fiber-rich food per day, the PFS was stable over 60 months. The most significant benefit was observed in patients with a sufficient fiber intake who were not taking probiotics.

What to Recommend?

In summary, Dr. Poeck said that it is important to “budget” well, particularly with antibiotic administration, and to strive for calculated therapy with as narrow a spectrum as possible. For patients who experience complications such as cytokine release syndrome as a reaction to cell therapy, delaying the use of antibiotics is important. However, it is often difficult to differentiate this syndrome from neutropenic fever. The aim should be to avoid high-risk antibiotics, if clinically justifiable. Patients should avoid taking antibiotics for 30 days before starting immunotherapy.

Regarding nutritional interventions, Dr. Poeck referred to the recent Onkopedia recommendation for nutrition after cancer and the 10 nutritional rules of the German Nutrition Society. According to Dr. Poeck, the important aspects of these recommendations are a fiber-rich diet (> 20 g/d) from various plant products and avoiding artificial sweeteners and flavorings, as well as ultraprocessed (convenience) foods. In addition, meat should be consumed only in moderation, and as little processed meat as possible should be consumed. In addition, regular (aerobic and anaerobic) physical activity is important.

“Looking ahead into the future,” said Dr. Poeck, “we need a uniform and functional understanding and we need a randomized prediction for diagnosis.”


This article was translated from the Medscape German edition.

A version of this article appeared on Medscape.com.

HAMBURG, Germany — The human microbiome comprises 39 to 44 billion microbes. That is ten times more than the number of cells in our body. Hendrik Poeck, MD, managing senior physician of internal medicine at the University Hospital Regensburg, illustrated this point at the annual meeting of the German Society for Hematology and Medical Oncology. If the gut microbiome falls out of balance, then “intestinal dysbiosis potentially poses a risk for the pathogenesis of local and systemic diseases,” explained Dr. Poeck.

Cancers and their therapies can also be influenced in this way. “Microbial diversity affects whether a tumor grows, whether it leads to inflammation, immune escape mechanisms or genomic instability, or whether therapeutic resistances develop,” said Dr. Poeck.

Microbial diversity could be beneficial for cancer therapy, too. The composition of the microbiome varies significantly from host to host and can mutate. These properties make it a target for precision microbiotics, which involves using the gut microbiome as a biomarker to predict various physical reactions and to develop individualized diets.

Microbiome and Pathogenesis

The body’s microbiome fulfills a barrier function, especially where the body is exposed to an external environment: at the epidermis and the internal mucous membranes, in the gastrointestinal tract, and in the lungs, chest, and urogenital system.

Association studies on humans and experimental manipulations on mouse models of cancer showed that certain microorganisms can have either protective or harmful effects on cancer development, on the progression of a malignant disease, and on the response to therapy.

A Master Regulator?

Disruptions of the microbial system in the gut, as occur during antibiotic therapy, can have significant effects on a patient’s response to immunotherapy. Taking antibiotics shortly before or after starting therapy with immune checkpoint inhibitors (ICIs) significantly affected both overall survival (OS) and progression-free survival (PFS), as reported in a recent review and meta-analysis, for example.

Proton pump inhibitors also affect the gut microbiome and reduce the response to immunotherapy; this effect was demonstrated by an analysis of data from more than 2700 cancer patients that was recently presented at the annual meeting of the European Society for Medical Oncology (ESMO).

The extent to which the gut microbiome influences the efficacy of an ICI or predicts said efficacy was examined in a retrospective analysis published in Science in 2018, which Dr. Poeck presented. Resistance to ICI correlated with the relative frequency of the bacteria Akkermansia muciniphila in the gut of patients with cancer. In mouse models, the researchers restored the efficacy of the PD-1 blockade through a stool transplant.

Predicting Immunotherapy Response

If A muciniphila is present, can the composition of the microbiome act as a predictor for an effective ICI therapy?

Laurence Zitvogel, MD, PhD, and her working group at the National Institute of Health and Medical Research in Villejuif, France, performed a prospective study in 338 patients with non–small cell lung cancer and examined the prognostic significance of the fecal bacteria A muciniphila (Akk). The “Akkerman status” (low Akk vs high Akk) in a patient’s stool correlated with an increased objective response rate and a longer OS, independently of PD-L1 expression, antibiotics, and performance status. The OS for low Akk was 13.4 months, vs 18.8 months for high Akk in first-line treatment.

These results are promising, said Dr. Poeck. But there is no one-size-fits-all solution. No conclusions can be drawn from one bacterium on the efficacy of therapies in humans, since “the entirety of the bacteria is decisive,” said Dr. Poeck. In addition to the gut microbiome, the composition of gut metabolites influences the response to immunotherapies, as shown in a study with ICI.

Therapeutic Interventions

One possible therapeutic intervention to restore the gut microbiome is fecal microbiota transplantation (FMT). In a phase 1 study presented by Dr. Poeck, FMT was effective in the treatment of 20 patients with melanoma with ICI in an advanced and treatment-naive stage. Seven days after the patients received FMT, the first cycle with anti-PD-1 immunotherapy was initiated, with a total administration of three to four cycles. After 12 weeks, most patients were in complete or partial remission, as evidenced on imaging.

However, FMT also carries some risks. Two cases of sepsis with multiresistant Escherichia coli occurred, as well as other serious infections. Since then, there has been an FDA condition for extended screening of the donor stool, said Dr. Poeck. Nevertheless, this intervention is promising. A search of the keywords “FMT in cancer/transplant setting” reveals 46 currently clinical studies on clinicaltrials.gov.

Nutritional Interventions

Dr. Poeck advises caution about over-the-counter products. These products usually contain only a few species, such as Lactobacillus and Bifidobacterium. “Over-the-counter probiotics can even delay the reconstitution of the microbiome after antibiotics,” said Dr. Poeck, according to a study. In some studies, the response rates were significantly lower after probiotic intake or led to controversial results, according to Dr. Poeck.

In contrast, Dr. Poeck said prebiotics (that is, a fiber-rich diet with indigestible carbohydrates) were promising. During digestion, prebiotics are split into short-chain fatty acids by bacterial enzymes and promote the growth of certain microbiota.

In this way, just 20 g of extremely fiber-rich food had a significant effect on PFS in 128 patients with melanoma undergoing anti-PD-1 immunotherapy. With 20 g of fiber-rich food per day, the PFS was stable over 60 months. The most significant benefit was observed in patients with a sufficient fiber intake who were not taking probiotics.

What to Recommend?

In summary, Dr. Poeck said that it is important to “budget” well, particularly with antibiotic administration, and to strive for calculated therapy with as narrow a spectrum as possible. For patients who experience complications such as cytokine release syndrome as a reaction to cell therapy, delaying the use of antibiotics is important. However, it is often difficult to differentiate this syndrome from neutropenic fever. The aim should be to avoid high-risk antibiotics, if clinically justifiable. Patients should avoid taking antibiotics for 30 days before starting immunotherapy.

Regarding nutritional interventions, Dr. Poeck referred to the recent Onkopedia recommendation for nutrition after cancer and the 10 nutritional rules of the German Nutrition Society. According to Dr. Poeck, the important aspects of these recommendations are a fiber-rich diet (> 20 g/d) from various plant products and avoiding artificial sweeteners and flavorings, as well as ultraprocessed (convenience) foods. In addition, meat should be consumed only in moderation, and as little processed meat as possible should be consumed. In addition, regular (aerobic and anaerobic) physical activity is important.

“Looking ahead into the future,” said Dr. Poeck, “we need a uniform and functional understanding and we need a randomized prediction for diagnosis.”


This article was translated from the Medscape German edition.

A version of this article appeared on Medscape.com.

TOPLINE:

Cutaneous immune-related adverse events are associated with improved overall and progression-free survival among patients treated with immune checkpoint inhibitors (ICIs).

METHODOLOGY:

• Emerging evidence suggests that the presence of cutaneous immune-related adverse events may be linked with favorable outcomes among patients with cancer who receive ICIs.
• Researchers conducted a systematic review and meta-analysis that included 23 studies and a total of 22,749 patients with cancer who received ICI treatment; studies compared outcomes among patients with and those without cutaneous immune-related adverse events.
• The major outcomes evaluated in the analysis were overall survival and progression-free survival (PFS); subgroup analyses assessed cutaneous immune-related adverse event type, cancer type, and other factors.

TAKEAWAY:

• The occurrence of cutaneous immune-related adverse events was associated with improved PFS (hazard ratio, 0.52; P < .001) and overall survival (HR, 0.61; P < .001).
• In the subgroup analysis, patients with eczematous (HR, 0.69), lichenoid or lichen planus–like skin lesions (HR, 0.51), pruritus without rash (HR, 0.70), psoriasis (HR, 0.63), or vitiligo (HR, 0.30) demonstrated a significant overall survival advantage. Vitiligo was the only adverse event associated with a PFS advantage (HR, 0.28).
• Among patients with melanoma, analyses revealed a significant association between the incidence of cutaneous immune-related adverse events and improved overall survival (HR, 0.51) and PFS (HR, 0.45). The authors highlighted similar findings among patients with non–small cell lung cancer (HR, 0.50 for overall survival and 0.61 for PFS).

IN PRACTICE:

“These data suggest that [cutaneous immune-related adverse events] may have useful prognostic value in ICI treatment,” the authors concluded.

SOURCE:

The analysis, led by Fei Wang, MD, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing, China, was published online in JAMA Dermatology.

LIMITATIONS:

Most of the data came from retrospective studies, and there were limited data on specific patient subgroups. The Egger tests, used to assess potential publication bias in meta-analyses, revealed publication bias.

DISCLOSURES:

No disclosures were reported. The study was supported by a grant from the Postgraduate Research and Practice Innovation Program of Jiangsu Province.

A version of this article first appeared on Medscape.com.

TOPLINE:

Cutaneous immune-related adverse events are associated with improved overall and progression-free survival among patients treated with immune checkpoint inhibitors (ICIs).

METHODOLOGY:

• Emerging evidence suggests that the presence of cutaneous immune-related adverse events may be linked with favorable outcomes among patients with cancer who receive ICIs.
• Researchers conducted a systematic review and meta-analysis that included 23 studies and a total of 22,749 patients with cancer who received ICI treatment; studies compared outcomes among patients with and those without cutaneous immune-related adverse events.
• The major outcomes evaluated in the analysis were overall survival and progression-free survival (PFS); subgroup analyses assessed cutaneous immune-related adverse event type, cancer type, and other factors.

TAKEAWAY:

• The occurrence of cutaneous immune-related adverse events was associated with improved PFS (hazard ratio, 0.52; P < .001) and overall survival (HR, 0.61; P < .001).
• In the subgroup analysis, patients with eczematous (HR, 0.69), lichenoid or lichen planus–like skin lesions (HR, 0.51), pruritus without rash (HR, 0.70), psoriasis (HR, 0.63), or vitiligo (HR, 0.30) demonstrated a significant overall survival advantage. Vitiligo was the only adverse event associated with a PFS advantage (HR, 0.28).
• Among patients with melanoma, analyses revealed a significant association between the incidence of cutaneous immune-related adverse events and improved overall survival (HR, 0.51) and PFS (HR, 0.45). The authors highlighted similar findings among patients with non–small cell lung cancer (HR, 0.50 for overall survival and 0.61 for PFS).

IN PRACTICE:

“These data suggest that [cutaneous immune-related adverse events] may have useful prognostic value in ICI treatment,” the authors concluded.

SOURCE:

The analysis, led by Fei Wang, MD, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing, China, was published online in JAMA Dermatology.

LIMITATIONS:

Most of the data came from retrospective studies, and there were limited data on specific patient subgroups. The Egger tests, used to assess potential publication bias in meta-analyses, revealed publication bias.

DISCLOSURES:

No disclosures were reported. The study was supported by a grant from the Postgraduate Research and Practice Innovation Program of Jiangsu Province.

A version of this article first appeared on Medscape.com.

TOPLINE:

Cutaneous immune-related adverse events are associated with improved overall and progression-free survival among patients treated with immune checkpoint inhibitors (ICIs).

METHODOLOGY:

• Emerging evidence suggests that the presence of cutaneous immune-related adverse events may be linked with favorable outcomes among patients with cancer who receive ICIs.
• Researchers conducted a systematic review and meta-analysis that included 23 studies and a total of 22,749 patients with cancer who received ICI treatment; studies compared outcomes among patients with and those without cutaneous immune-related adverse events.
• The major outcomes evaluated in the analysis were overall survival and progression-free survival (PFS); subgroup analyses assessed cutaneous immune-related adverse event type, cancer type, and other factors.

TAKEAWAY:

• The occurrence of cutaneous immune-related adverse events was associated with improved PFS (hazard ratio, 0.52; P < .001) and overall survival (HR, 0.61; P < .001).
• In the subgroup analysis, patients with eczematous (HR, 0.69), lichenoid or lichen planus–like skin lesions (HR, 0.51), pruritus without rash (HR, 0.70), psoriasis (HR, 0.63), or vitiligo (HR, 0.30) demonstrated a significant overall survival advantage. Vitiligo was the only adverse event associated with a PFS advantage (HR, 0.28).
• Among patients with melanoma, analyses revealed a significant association between the incidence of cutaneous immune-related adverse events and improved overall survival (HR, 0.51) and PFS (HR, 0.45). The authors highlighted similar findings among patients with non–small cell lung cancer (HR, 0.50 for overall survival and 0.61 for PFS).

IN PRACTICE:

“These data suggest that [cutaneous immune-related adverse events] may have useful prognostic value in ICI treatment,” the authors concluded.

SOURCE:

The analysis, led by Fei Wang, MD, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing, China, was published online in JAMA Dermatology.

LIMITATIONS:

Most of the data came from retrospective studies, and there were limited data on specific patient subgroups. The Egger tests, used to assess potential publication bias in meta-analyses, revealed publication bias.

DISCLOSURES:

No disclosures were reported. The study was supported by a grant from the Postgraduate Research and Practice Innovation Program of Jiangsu Province.

A version of this article first appeared on Medscape.com.