Lung Cancer Updates

Screening high-risk populations for lung cancer saves lives. The National Lung Screening Trial (NLST) demonstrated a 20% relative reduction in lung cancer mortality with annual screening over 3 years with low-dose CT as compared with x-rays. The NELSON trial found a higher benefit: Men at high risk for lung cancer had a 26% reduced risk of dying from lung cancer and women had a 61% reduced risk over 10 years. However, the 2022 American Lung Association State of Lung Cancer report shows that less than 6% of eligible people get screened. Why is this?

There are many reasons, but I submit that at least one hurdle is related to the difficulties associated with ordering the low-dose CT in the electronic medical record (EMR) and following the results. The rules and regulations around lung cancer screening are complex. First, the ordering provider must be able to determine if the patient is eligible for screening and has insurance coverage – a complicated procedure, which is constantly in flux, and is based on age, smoking history, smoke-free interval, and type of insurance coverage. Most EMRs do not have a way of flagging high-risk individuals, and clinic coordinators (for those practices that have one) are often put in charge of determining eligibility.

Secondly, the health care provider must order the scan. Unlike mammography, people must have a prescreening visit with a physician or other health care provider – a visit which is poorly compensated, and often must be supported by the institution. Many EMRs also do not have a smooth mechanism to make sure all the “boxes have been checked” before the scan can be ordered. Is there a complete smoking history? Has the patient had their prescreening visit? Has the patient been counseled regarding tobacco use? Has eligibility for insurance payment been confirmed?

Coordinating follow-up is cumbersome. Abnormal findings are common and usually nonmalignant, but must be followed up, and the follow-up recommendations are complicated and are based upon the appearance of the finding. This may be difficult for a general practitioner, so referrals to pulmonologists are often scheduled. Best practices state the patient be followed in a multidisciplinary pulmonary module clinic, but again, most multidisciplinary pulmonary module clinics are found in the academic setting.

All this involves a lot of back-and-forth for the patient: First to see their primary care physician, then to see a pulmonologist or other health care provider for the counseling regarding risks and benefits of screening and the importance of smoking cessation, and then a visit to a radiologist as well as a visit to a smoking cessation clinic, then a return follow-up visit. Academic medical centers and NCI-approved cancer centers often have these procedures worked out, but many private or smaller practices do not. Yes, the local IT folks can modify an EMR, but in a small practice, there are other “more important” problems that take precedence.

Would coupling lung cancer screening with breast cancer scanning help? One study followed 874 women who attended mammographic screening and found that over 11% were at high risk for lung cancer. This would appear to be an ideal “teaching moment” to educate the importance of lung cancer screening to women. It could also cut down on some of the logistical issues associated with lung cancer screening, particularly if a health care provider and coordinator were immediately available for counseling and eligibility determination at the time of the mammography visit. The radiology clinic staff could schedule a scan and return visit while the patient was still in the mammography suite.

Of course, the logistical hassle is just one of many associated with lung cancer screening. The internal stigma the patient may experience about their smoking history, the unconscious bias on the part of many health professionals, the many other screening and prevention regulations providers are now required to follow, the institution’s reluctance to support a screening program, the rushed pace in many clinics: These all certainly contribute to the problem. However, we have overcome all of these issues when it comes to mammography, such as work flow, stigma, logistical issues, seamless incorporation of ordering scans and referrals to specialists in the EMR, etc. We can and must do the same for our patients at high risk for lung cancer, and routine scheduling of mammograms and low-dose CTs may help.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation. Ivy Elkins, cofounder of EGFR Resisters, a patient, survivor, and caregiver advocacy group, contributed to this article.

Screening high-risk populations for lung cancer saves lives. The National Lung Screening Trial (NLST) demonstrated a 20% relative reduction in lung cancer mortality with annual screening over 3 years with low-dose CT as compared with x-rays. The NELSON trial found a higher benefit: Men at high risk for lung cancer had a 26% reduced risk of dying from lung cancer and women had a 61% reduced risk over 10 years. However, the 2022 American Lung Association State of Lung Cancer report shows that less than 6% of eligible people get screened. Why is this?

There are many reasons, but I submit that at least one hurdle is related to the difficulties associated with ordering the low-dose CT in the electronic medical record (EMR) and following the results. The rules and regulations around lung cancer screening are complex. First, the ordering provider must be able to determine if the patient is eligible for screening and has insurance coverage – a complicated procedure, which is constantly in flux, and is based on age, smoking history, smoke-free interval, and type of insurance coverage. Most EMRs do not have a way of flagging high-risk individuals, and clinic coordinators (for those practices that have one) are often put in charge of determining eligibility.

Secondly, the health care provider must order the scan. Unlike mammography, people must have a prescreening visit with a physician or other health care provider – a visit which is poorly compensated, and often must be supported by the institution. Many EMRs also do not have a smooth mechanism to make sure all the “boxes have been checked” before the scan can be ordered. Is there a complete smoking history? Has the patient had their prescreening visit? Has the patient been counseled regarding tobacco use? Has eligibility for insurance payment been confirmed?

Coordinating follow-up is cumbersome. Abnormal findings are common and usually nonmalignant, but must be followed up, and the follow-up recommendations are complicated and are based upon the appearance of the finding. This may be difficult for a general practitioner, so referrals to pulmonologists are often scheduled. Best practices state the patient be followed in a multidisciplinary pulmonary module clinic, but again, most multidisciplinary pulmonary module clinics are found in the academic setting.

All this involves a lot of back-and-forth for the patient: First to see their primary care physician, then to see a pulmonologist or other health care provider for the counseling regarding risks and benefits of screening and the importance of smoking cessation, and then a visit to a radiologist as well as a visit to a smoking cessation clinic, then a return follow-up visit. Academic medical centers and NCI-approved cancer centers often have these procedures worked out, but many private or smaller practices do not. Yes, the local IT folks can modify an EMR, but in a small practice, there are other “more important” problems that take precedence.

Would coupling lung cancer screening with breast cancer scanning help? One study followed 874 women who attended mammographic screening and found that over 11% were at high risk for lung cancer. This would appear to be an ideal “teaching moment” to educate the importance of lung cancer screening to women. It could also cut down on some of the logistical issues associated with lung cancer screening, particularly if a health care provider and coordinator were immediately available for counseling and eligibility determination at the time of the mammography visit. The radiology clinic staff could schedule a scan and return visit while the patient was still in the mammography suite.

Of course, the logistical hassle is just one of many associated with lung cancer screening. The internal stigma the patient may experience about their smoking history, the unconscious bias on the part of many health professionals, the many other screening and prevention regulations providers are now required to follow, the institution’s reluctance to support a screening program, the rushed pace in many clinics: These all certainly contribute to the problem. However, we have overcome all of these issues when it comes to mammography, such as work flow, stigma, logistical issues, seamless incorporation of ordering scans and referrals to specialists in the EMR, etc. We can and must do the same for our patients at high risk for lung cancer, and routine scheduling of mammograms and low-dose CTs may help.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation. Ivy Elkins, cofounder of EGFR Resisters, a patient, survivor, and caregiver advocacy group, contributed to this article.

Screening high-risk populations for lung cancer saves lives. The National Lung Screening Trial (NLST) demonstrated a 20% relative reduction in lung cancer mortality with annual screening over 3 years with low-dose CT as compared with x-rays. The NELSON trial found a higher benefit: Men at high risk for lung cancer had a 26% reduced risk of dying from lung cancer and women had a 61% reduced risk over 10 years. However, the 2022 American Lung Association State of Lung Cancer report shows that less than 6% of eligible people get screened. Why is this?

There are many reasons, but I submit that at least one hurdle is related to the difficulties associated with ordering the low-dose CT in the electronic medical record (EMR) and following the results. The rules and regulations around lung cancer screening are complex. First, the ordering provider must be able to determine if the patient is eligible for screening and has insurance coverage – a complicated procedure, which is constantly in flux, and is based on age, smoking history, smoke-free interval, and type of insurance coverage. Most EMRs do not have a way of flagging high-risk individuals, and clinic coordinators (for those practices that have one) are often put in charge of determining eligibility.

Secondly, the health care provider must order the scan. Unlike mammography, people must have a prescreening visit with a physician or other health care provider – a visit which is poorly compensated, and often must be supported by the institution. Many EMRs also do not have a smooth mechanism to make sure all the “boxes have been checked” before the scan can be ordered. Is there a complete smoking history? Has the patient had their prescreening visit? Has the patient been counseled regarding tobacco use? Has eligibility for insurance payment been confirmed?

Coordinating follow-up is cumbersome. Abnormal findings are common and usually nonmalignant, but must be followed up, and the follow-up recommendations are complicated and are based upon the appearance of the finding. This may be difficult for a general practitioner, so referrals to pulmonologists are often scheduled. Best practices state the patient be followed in a multidisciplinary pulmonary module clinic, but again, most multidisciplinary pulmonary module clinics are found in the academic setting.

All this involves a lot of back-and-forth for the patient: First to see their primary care physician, then to see a pulmonologist or other health care provider for the counseling regarding risks and benefits of screening and the importance of smoking cessation, and then a visit to a radiologist as well as a visit to a smoking cessation clinic, then a return follow-up visit. Academic medical centers and NCI-approved cancer centers often have these procedures worked out, but many private or smaller practices do not. Yes, the local IT folks can modify an EMR, but in a small practice, there are other “more important” problems that take precedence.

Would coupling lung cancer screening with breast cancer scanning help? One study followed 874 women who attended mammographic screening and found that over 11% were at high risk for lung cancer. This would appear to be an ideal “teaching moment” to educate the importance of lung cancer screening to women. It could also cut down on some of the logistical issues associated with lung cancer screening, particularly if a health care provider and coordinator were immediately available for counseling and eligibility determination at the time of the mammography visit. The radiology clinic staff could schedule a scan and return visit while the patient was still in the mammography suite.

Of course, the logistical hassle is just one of many associated with lung cancer screening. The internal stigma the patient may experience about their smoking history, the unconscious bias on the part of many health professionals, the many other screening and prevention regulations providers are now required to follow, the institution’s reluctance to support a screening program, the rushed pace in many clinics: These all certainly contribute to the problem. However, we have overcome all of these issues when it comes to mammography, such as work flow, stigma, logistical issues, seamless incorporation of ordering scans and referrals to specialists in the EMR, etc. We can and must do the same for our patients at high risk for lung cancer, and routine scheduling of mammograms and low-dose CTs may help.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation. Ivy Elkins, cofounder of EGFR Resisters, a patient, survivor, and caregiver advocacy group, contributed to this article.

Several decades ago, a new patient came to my office with her family. She was elderly, in good health, spoke no English, and her extended family translated for her. Their request: “Don’t tell her that she has cancer.” Sharing her diagnosis with her would cause too much stress, they said. Their mother would not be able to tolerate the bad news, they said. She would “give up.”

I asked her (through her family and an interpreter) how much she wanted to know about what was going on, or would she prefer I confine my remarks to her family? It turns out that she did want to know her diagnosis and prognosis, and after a thorough discussion in front of her family about her treatment options, she decided she did not want to proceed with additional therapy. She wanted to focus on quality of life. I did not get the impression that this is what her family would have opted for.

The patient’s voice can take multiple directions, such as making informed decisions about their own care. When empowered, patients can and will express their wants, needs, feelings, and priorities to their providers, and they’ll participate in directing their own care. There is a growing body of evidence that shows patients who are more engaged and share decision-making with their health care professionals have better health outcomes and care experiences. Engaged patients feel more empowered and are more motivated to take action. They’re also more likely to follow treatment plans, take their medications, and heed their provider’s recommendations. By virtue of better treatments for lung cancer, many patients are living longer and better lives. Some of these patients even become “experts” on their own care, often bringing questions about research and clinical trials to the attention of their providers.
 

The patient’s voice in research and advocacy

The patient’s perspective is also key to a meaningful, successful clinical research project. Rather than being carried out to, about, or for the patient, patient involvement means research being carried out with or by patients. A patient and researcher may have different research goals. For example, patients may value being able to work, be with family, and live without pain, whereas a clinical researcher’s goal may be inducing responses. Patient involvement is important in both laboratory research and clinical research. The best-designed projects involve patient advocates from the beginning of the project to help make research relevant and meaningful to patients and include these perspectives through project completion.

More and more pharmaceutical companies are actively involving patients at all levels of protocol development, including protocol design and selection of relevant outcomes to patients. Benefits of engaging patients as partners in research include inclusion of real-world data, increased study enrollment, and translation of results to the cancer community in an understandable and accessible manner.
 

Accelerated research

Advocating for accelerated research is another area where the patient’s voice is important. Patients can and do identify research priorities for researchers, funding agencies, and pharma. Patients who support research advocacy are frequently part of meetings and panel discussions with researchers, the Food and Drug Administration, and the National Cancer Institute. And, they serve on advisory boards for pharmaceutical companies. They participate in grant reviews and institutional review boards, review manuscripts, and are active members of the cooperative groups and other professional societies. In fact, patient-led advocacy groups are raising money to help fund research they feel is most important to them. In lung cancer, for example, there are many groups organized around biomarkers, including the EGFR Resisters, ALK Positive, ROS1ders, MET Crusaders, and KRAS Kickers, who have raised hundreds of thousands of dollars to fund investigator-led translational research that would not have occurred without their involvement.

It is important to recognize that all patients are different and have different values and motivations that are important to them and influence their life decisions. Some patients want to know more about their condition and their preferences should be respected. Similarly, it’s critical to understand that not every patient is an advocate and not every advocate is a research advocate. Research advocates have more in-depth knowledge about the science of lung cancer and focus on representing the patient perspective for all lung cancer patients.

So, getting back to my original story: Did my patient “give up” by choosing palliative care without chemotherapy? Perhaps, but I don’t think she considered her decision “giving up.” Instead, she made the best decision possible for herself. What would have happened had she not been told of her diagnosis? She probably would not have spent extra quality time with her family, as they tried to ignore the obvious. And, after all, quality time with her family was all she wanted.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation. Ivy Elkins, cofounder of EGFR Resisters, a patient, survivor, and caregiver advocacy group, contributed to this article.

Several decades ago, a new patient came to my office with her family. She was elderly, in good health, spoke no English, and her extended family translated for her. Their request: “Don’t tell her that she has cancer.” Sharing her diagnosis with her would cause too much stress, they said. Their mother would not be able to tolerate the bad news, they said. She would “give up.”

I asked her (through her family and an interpreter) how much she wanted to know about what was going on, or would she prefer I confine my remarks to her family? It turns out that she did want to know her diagnosis and prognosis, and after a thorough discussion in front of her family about her treatment options, she decided she did not want to proceed with additional therapy. She wanted to focus on quality of life. I did not get the impression that this is what her family would have opted for.

The patient’s voice can take multiple directions, such as making informed decisions about their own care. When empowered, patients can and will express their wants, needs, feelings, and priorities to their providers, and they’ll participate in directing their own care. There is a growing body of evidence that shows patients who are more engaged and share decision-making with their health care professionals have better health outcomes and care experiences. Engaged patients feel more empowered and are more motivated to take action. They’re also more likely to follow treatment plans, take their medications, and heed their provider’s recommendations. By virtue of better treatments for lung cancer, many patients are living longer and better lives. Some of these patients even become “experts” on their own care, often bringing questions about research and clinical trials to the attention of their providers.
 

The patient’s voice in research and advocacy

The patient’s perspective is also key to a meaningful, successful clinical research project. Rather than being carried out to, about, or for the patient, patient involvement means research being carried out with or by patients. A patient and researcher may have different research goals. For example, patients may value being able to work, be with family, and live without pain, whereas a clinical researcher’s goal may be inducing responses. Patient involvement is important in both laboratory research and clinical research. The best-designed projects involve patient advocates from the beginning of the project to help make research relevant and meaningful to patients and include these perspectives through project completion.

More and more pharmaceutical companies are actively involving patients at all levels of protocol development, including protocol design and selection of relevant outcomes to patients. Benefits of engaging patients as partners in research include inclusion of real-world data, increased study enrollment, and translation of results to the cancer community in an understandable and accessible manner.
 

Accelerated research

Advocating for accelerated research is another area where the patient’s voice is important. Patients can and do identify research priorities for researchers, funding agencies, and pharma. Patients who support research advocacy are frequently part of meetings and panel discussions with researchers, the Food and Drug Administration, and the National Cancer Institute. And, they serve on advisory boards for pharmaceutical companies. They participate in grant reviews and institutional review boards, review manuscripts, and are active members of the cooperative groups and other professional societies. In fact, patient-led advocacy groups are raising money to help fund research they feel is most important to them. In lung cancer, for example, there are many groups organized around biomarkers, including the EGFR Resisters, ALK Positive, ROS1ders, MET Crusaders, and KRAS Kickers, who have raised hundreds of thousands of dollars to fund investigator-led translational research that would not have occurred without their involvement.

It is important to recognize that all patients are different and have different values and motivations that are important to them and influence their life decisions. Some patients want to know more about their condition and their preferences should be respected. Similarly, it’s critical to understand that not every patient is an advocate and not every advocate is a research advocate. Research advocates have more in-depth knowledge about the science of lung cancer and focus on representing the patient perspective for all lung cancer patients.

So, getting back to my original story: Did my patient “give up” by choosing palliative care without chemotherapy? Perhaps, but I don’t think she considered her decision “giving up.” Instead, she made the best decision possible for herself. What would have happened had she not been told of her diagnosis? She probably would not have spent extra quality time with her family, as they tried to ignore the obvious. And, after all, quality time with her family was all she wanted.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation. Ivy Elkins, cofounder of EGFR Resisters, a patient, survivor, and caregiver advocacy group, contributed to this article.

Several decades ago, a new patient came to my office with her family. She was elderly, in good health, spoke no English, and her extended family translated for her. Their request: “Don’t tell her that she has cancer.” Sharing her diagnosis with her would cause too much stress, they said. Their mother would not be able to tolerate the bad news, they said. She would “give up.”

I asked her (through her family and an interpreter) how much she wanted to know about what was going on, or would she prefer I confine my remarks to her family? It turns out that she did want to know her diagnosis and prognosis, and after a thorough discussion in front of her family about her treatment options, she decided she did not want to proceed with additional therapy. She wanted to focus on quality of life. I did not get the impression that this is what her family would have opted for.

The patient’s voice can take multiple directions, such as making informed decisions about their own care. When empowered, patients can and will express their wants, needs, feelings, and priorities to their providers, and they’ll participate in directing their own care. There is a growing body of evidence that shows patients who are more engaged and share decision-making with their health care professionals have better health outcomes and care experiences. Engaged patients feel more empowered and are more motivated to take action. They’re also more likely to follow treatment plans, take their medications, and heed their provider’s recommendations. By virtue of better treatments for lung cancer, many patients are living longer and better lives. Some of these patients even become “experts” on their own care, often bringing questions about research and clinical trials to the attention of their providers.
 

The patient’s voice in research and advocacy

The patient’s perspective is also key to a meaningful, successful clinical research project. Rather than being carried out to, about, or for the patient, patient involvement means research being carried out with or by patients. A patient and researcher may have different research goals. For example, patients may value being able to work, be with family, and live without pain, whereas a clinical researcher’s goal may be inducing responses. Patient involvement is important in both laboratory research and clinical research. The best-designed projects involve patient advocates from the beginning of the project to help make research relevant and meaningful to patients and include these perspectives through project completion.

More and more pharmaceutical companies are actively involving patients at all levels of protocol development, including protocol design and selection of relevant outcomes to patients. Benefits of engaging patients as partners in research include inclusion of real-world data, increased study enrollment, and translation of results to the cancer community in an understandable and accessible manner.
 

Accelerated research

Advocating for accelerated research is another area where the patient’s voice is important. Patients can and do identify research priorities for researchers, funding agencies, and pharma. Patients who support research advocacy are frequently part of meetings and panel discussions with researchers, the Food and Drug Administration, and the National Cancer Institute. And, they serve on advisory boards for pharmaceutical companies. They participate in grant reviews and institutional review boards, review manuscripts, and are active members of the cooperative groups and other professional societies. In fact, patient-led advocacy groups are raising money to help fund research they feel is most important to them. In lung cancer, for example, there are many groups organized around biomarkers, including the EGFR Resisters, ALK Positive, ROS1ders, MET Crusaders, and KRAS Kickers, who have raised hundreds of thousands of dollars to fund investigator-led translational research that would not have occurred without their involvement.

It is important to recognize that all patients are different and have different values and motivations that are important to them and influence their life decisions. Some patients want to know more about their condition and their preferences should be respected. Similarly, it’s critical to understand that not every patient is an advocate and not every advocate is a research advocate. Research advocates have more in-depth knowledge about the science of lung cancer and focus on representing the patient perspective for all lung cancer patients.

So, getting back to my original story: Did my patient “give up” by choosing palliative care without chemotherapy? Perhaps, but I don’t think she considered her decision “giving up.” Instead, she made the best decision possible for herself. What would have happened had she not been told of her diagnosis? She probably would not have spent extra quality time with her family, as they tried to ignore the obvious. And, after all, quality time with her family was all she wanted.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation. Ivy Elkins, cofounder of EGFR Resisters, a patient, survivor, and caregiver advocacy group, contributed to this article.

Because we care about our patients, we need to get involved in the climate change movement. If we want to help prevent cancer and deliver the best possible care to our patients, we need to stop burning fossil fuels. As addressed in an earlier version of this column, burning fossil fuels results in the release of particulate matter and particles measuring 2.5 micrometers in diameter (PM2.5), are classified as group 1 carcinogens by the International Association of Research and Cancer.

Fossil fuels also release greenhouse gases (carbon dioxide, methane, nitrous oxide, and fluorinated gases) which trap solar radiation that would otherwise have been reflected back into space after hitting the earth’s surface. Instead, it is redirected back to earth as infrared radiation warming the planet by 1.1° C since preindustrial times.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Because we care about our patients, we need to get involved in the climate change movement. If we want to help prevent cancer and deliver the best possible care to our patients, we need to stop burning fossil fuels. As addressed in an earlier version of this column, burning fossil fuels results in the release of particulate matter and particles measuring 2.5 micrometers in diameter (PM2.5), are classified as group 1 carcinogens by the International Association of Research and Cancer.

Fossil fuels also release greenhouse gases (carbon dioxide, methane, nitrous oxide, and fluorinated gases) which trap solar radiation that would otherwise have been reflected back into space after hitting the earth’s surface. Instead, it is redirected back to earth as infrared radiation warming the planet by 1.1° C since preindustrial times.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Because we care about our patients, we need to get involved in the climate change movement. If we want to help prevent cancer and deliver the best possible care to our patients, we need to stop burning fossil fuels. As addressed in an earlier version of this column, burning fossil fuels results in the release of particulate matter and particles measuring 2.5 micrometers in diameter (PM2.5), are classified as group 1 carcinogens by the International Association of Research and Cancer.

Fossil fuels also release greenhouse gases (carbon dioxide, methane, nitrous oxide, and fluorinated gases) which trap solar radiation that would otherwise have been reflected back into space after hitting the earth’s surface. Instead, it is redirected back to earth as infrared radiation warming the planet by 1.1° C since preindustrial times.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Decades ago I saw a patient with non–small cell lung cancer (NSCLC) whose tumor was sent out for next-generation sequencing only to find a HER2 mutation. What to do? Had my patient come in today, we may have had other options.

Multiple studies have shown that trastuzumab (Herceptin, Genentech), as assessed by HER2 overexpression or amplification, has been shown to have essentially no efficacy benefit in NSCLC alone or in combination with chemotherapy. In fact, a randomized, phase 2 study of gemcitabine-cisplatin with or without trastuzumab in HER2 mutation–positive NSCLC essentially showed no difference between gemcitabine-cisplatin or gemcitabine-cisplatin with trastuzumab.

NSCLC has become the poster child for targeted therapies. After all, NSCLC makes up about 85% of all lung cancer cases, some of which are driven by gene mutations or other genetic abnormalities like translocation, fusion, or amplification. Seven of these genetic alterations have Food and Drug Administration–approved targeted drugs: EGFR, ALK, ROS1, BRAF V6006, RET, KRAS, MET, and NTRK fusions. And, now we have a new one: HER2.

In August, the FDA granted accelerated approval of trastuzumab deruxtecan (T-DXd) (Enhertu, Daiichi Sankyo) for the second-line treatment of NSCLC patients with HER alterations. T-DXd is a humanized anti-HER antibody linked to a topoisomerase 1 inhibitor. When given intravenously, the antibody portion of the molecule binds to cells with a mutated HER2 on the surface. The molecule is taken up by the cancer cell and the linker between the antibody and the chemotherapy drug is broken, so the drug will be delivered very specifically only to cancer cells that have a mutated HER2. In theory, they will only target cells with HER alterations and thus should have less toxicity.

Unlike other driver mutations, HER mutations are relatively rare. Roughly 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis. Accelerated approved by the FDA was based on data from the DESTINY-Lung 02 phase 2 trial. An interim efficacy analysis of this trial reported an overall response rate to trastuzumab deruxtecan (at 5.4 mg/kg every 3 weeks) of 57.7% in 52 patients. Median duration of response was 8.7 months. Data are also available from the DESTINY-Lung-01 clinical trial, published in the New England Journal of Medicine, in which 91 patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment were treated with T-DXd (at 6.4 mg/kg every 3 weeks). The investigators reported a 55% objective response rate, a median duration of response of 9.3 months, a median progression-free survival (PFS) of 8.2 months, and a median overall survival of almost 18 months.
 

Companion tests

Biomarker testing is obviously a must in these cases. The FDA-approved companion diagnostic tests to detect HER2 mutations: Life Companion tests, Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue, and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that, if no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Other approvals

T-DXd is also approved for advanced breast and gastric patients who are HER-2 positive. Of note, the majority of HER2-positive NSCLC have HER2 mutations, whereas the majority of HER2-positive breast and gastric cancers have HER2 amplification (increased copy number) or overexpression (increased protein expression).

T-DXd is approved for unresectable or metastatic HER2-positive breast cancer patients who have received a prior anti-HER2–based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. DESTINY-Breast01 enrolled breast cancer patients who had received two or more prior anti-HER2 therapies in the metastatic setting, and reported a response rate of 60.3% with a median duration of response of 14.8 months.

For patients with locally advanced or metastatic HER2-positive gastric cancer who have received two or more prior therapies, including a trastuzumab-based regimen, approval was based on a randomized, phase 3 study comparing 6.4 mg/kg of T-DXd with physician’s choice – either irinotecan or paclitaxel. Overall survival was 12.5 months in the T-DXd arm, compared with 8.4 months in the irinotecan or paclitaxel arm (hazard ratio, 0.59). Response rates were 40.5% and 11.3%, respectively. Median PFS was 5.6 months in the T-DXd arm, compared with a median PFS of 3.5 months in the chemotherapy arm.
 

Trastuzumab emtansine vs. trastuzumab deruxtecan

Trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, Kadcyla) is another antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the antimicrotubule agent DM1. It is also approved for advanced breast cancer patients with HER2-positive disease. Although no studies comparing T-DXd with trastuzumab emtansine have been conducted in lung cancer patients, a randomized, phase 3 trial in patients with HER2-positive advanced breast cancer comparing the two reported an overall response rate of 79.7% of the patients who received trastuzumab deruxtecan and 34.2% of those who received trastuzumab emtansine. Drug-related interstitial lung disease (ILD) occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; at 12 months, 75.8% of the patients in the trastuzumab deruxtecan were alive without progression, compared with 34.1% of those receiving trastuzumab emtansine.

ILDs

In DESTINY-Lung01, ILD occurred in 26% of patients and resulted in death in two patients. Increased rates of ILD were more commonly observed at higher dose levels. Of 491 patients with unresectable or metastatic HER2-positive breast cancer treated with 5.4 mg/kg of T-TDx, ILD occurred in 13% of patients. Fatal outcomes caused by ILD and/or pneumonitis occurred in 1.4% of patients. Median time to first onset was 5.5 months (range, 1.1-20.8 months). In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with 6.4 mg/kg, T-DXd ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range, 1.2-21.0 months).

Chemotherapy-like adverse effects

Other adverse events are more typically seen with cytotoxic agents and are presumably related to the release of the topoisomerase inhibitor into the blood stream. Although common (occurring in 97% of patients), these adverse events are generally mild (grade 1 or 2). Nausea was reported in about two-thirds of patients. Other side effects occurring in 20% or more of patients included vomiting, decreased appetite, alopecia, and constipation and diarrhea, musculoskeletal pain, and respiratory infections. Laboratory abnormalities occurred in 20% or more of patients included myelosuppression, increased AST, ALT, alkaline phosphatase, and hypokalemia (28%). Grade 3 or higher drug-related adverse events were observed in 46% of patients, with the most common being neutropenia and anemia which was observed in 19% and 10% of patients in the DESTINY-LUNG-01 trial.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Decades ago I saw a patient with non–small cell lung cancer (NSCLC) whose tumor was sent out for next-generation sequencing only to find a HER2 mutation. What to do? Had my patient come in today, we may have had other options.

Multiple studies have shown that trastuzumab (Herceptin, Genentech), as assessed by HER2 overexpression or amplification, has been shown to have essentially no efficacy benefit in NSCLC alone or in combination with chemotherapy. In fact, a randomized, phase 2 study of gemcitabine-cisplatin with or without trastuzumab in HER2 mutation–positive NSCLC essentially showed no difference between gemcitabine-cisplatin or gemcitabine-cisplatin with trastuzumab.

NSCLC has become the poster child for targeted therapies. After all, NSCLC makes up about 85% of all lung cancer cases, some of which are driven by gene mutations or other genetic abnormalities like translocation, fusion, or amplification. Seven of these genetic alterations have Food and Drug Administration–approved targeted drugs: EGFR, ALK, ROS1, BRAF V6006, RET, KRAS, MET, and NTRK fusions. And, now we have a new one: HER2.

In August, the FDA granted accelerated approval of trastuzumab deruxtecan (T-DXd) (Enhertu, Daiichi Sankyo) for the second-line treatment of NSCLC patients with HER alterations. T-DXd is a humanized anti-HER antibody linked to a topoisomerase 1 inhibitor. When given intravenously, the antibody portion of the molecule binds to cells with a mutated HER2 on the surface. The molecule is taken up by the cancer cell and the linker between the antibody and the chemotherapy drug is broken, so the drug will be delivered very specifically only to cancer cells that have a mutated HER2. In theory, they will only target cells with HER alterations and thus should have less toxicity.

Unlike other driver mutations, HER mutations are relatively rare. Roughly 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis. Accelerated approved by the FDA was based on data from the DESTINY-Lung 02 phase 2 trial. An interim efficacy analysis of this trial reported an overall response rate to trastuzumab deruxtecan (at 5.4 mg/kg every 3 weeks) of 57.7% in 52 patients. Median duration of response was 8.7 months. Data are also available from the DESTINY-Lung-01 clinical trial, published in the New England Journal of Medicine, in which 91 patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment were treated with T-DXd (at 6.4 mg/kg every 3 weeks). The investigators reported a 55% objective response rate, a median duration of response of 9.3 months, a median progression-free survival (PFS) of 8.2 months, and a median overall survival of almost 18 months.
 

Companion tests

Biomarker testing is obviously a must in these cases. The FDA-approved companion diagnostic tests to detect HER2 mutations: Life Companion tests, Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue, and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that, if no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Other approvals

T-DXd is also approved for advanced breast and gastric patients who are HER-2 positive. Of note, the majority of HER2-positive NSCLC have HER2 mutations, whereas the majority of HER2-positive breast and gastric cancers have HER2 amplification (increased copy number) or overexpression (increased protein expression).

T-DXd is approved for unresectable or metastatic HER2-positive breast cancer patients who have received a prior anti-HER2–based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. DESTINY-Breast01 enrolled breast cancer patients who had received two or more prior anti-HER2 therapies in the metastatic setting, and reported a response rate of 60.3% with a median duration of response of 14.8 months.

For patients with locally advanced or metastatic HER2-positive gastric cancer who have received two or more prior therapies, including a trastuzumab-based regimen, approval was based on a randomized, phase 3 study comparing 6.4 mg/kg of T-DXd with physician’s choice – either irinotecan or paclitaxel. Overall survival was 12.5 months in the T-DXd arm, compared with 8.4 months in the irinotecan or paclitaxel arm (hazard ratio, 0.59). Response rates were 40.5% and 11.3%, respectively. Median PFS was 5.6 months in the T-DXd arm, compared with a median PFS of 3.5 months in the chemotherapy arm.
 

Trastuzumab emtansine vs. trastuzumab deruxtecan

Trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, Kadcyla) is another antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the antimicrotubule agent DM1. It is also approved for advanced breast cancer patients with HER2-positive disease. Although no studies comparing T-DXd with trastuzumab emtansine have been conducted in lung cancer patients, a randomized, phase 3 trial in patients with HER2-positive advanced breast cancer comparing the two reported an overall response rate of 79.7% of the patients who received trastuzumab deruxtecan and 34.2% of those who received trastuzumab emtansine. Drug-related interstitial lung disease (ILD) occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; at 12 months, 75.8% of the patients in the trastuzumab deruxtecan were alive without progression, compared with 34.1% of those receiving trastuzumab emtansine.

ILDs

In DESTINY-Lung01, ILD occurred in 26% of patients and resulted in death in two patients. Increased rates of ILD were more commonly observed at higher dose levels. Of 491 patients with unresectable or metastatic HER2-positive breast cancer treated with 5.4 mg/kg of T-TDx, ILD occurred in 13% of patients. Fatal outcomes caused by ILD and/or pneumonitis occurred in 1.4% of patients. Median time to first onset was 5.5 months (range, 1.1-20.8 months). In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with 6.4 mg/kg, T-DXd ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range, 1.2-21.0 months).

Chemotherapy-like adverse effects

Other adverse events are more typically seen with cytotoxic agents and are presumably related to the release of the topoisomerase inhibitor into the blood stream. Although common (occurring in 97% of patients), these adverse events are generally mild (grade 1 or 2). Nausea was reported in about two-thirds of patients. Other side effects occurring in 20% or more of patients included vomiting, decreased appetite, alopecia, and constipation and diarrhea, musculoskeletal pain, and respiratory infections. Laboratory abnormalities occurred in 20% or more of patients included myelosuppression, increased AST, ALT, alkaline phosphatase, and hypokalemia (28%). Grade 3 or higher drug-related adverse events were observed in 46% of patients, with the most common being neutropenia and anemia which was observed in 19% and 10% of patients in the DESTINY-LUNG-01 trial.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Decades ago I saw a patient with non–small cell lung cancer (NSCLC) whose tumor was sent out for next-generation sequencing only to find a HER2 mutation. What to do? Had my patient come in today, we may have had other options.

Multiple studies have shown that trastuzumab (Herceptin, Genentech), as assessed by HER2 overexpression or amplification, has been shown to have essentially no efficacy benefit in NSCLC alone or in combination with chemotherapy. In fact, a randomized, phase 2 study of gemcitabine-cisplatin with or without trastuzumab in HER2 mutation–positive NSCLC essentially showed no difference between gemcitabine-cisplatin or gemcitabine-cisplatin with trastuzumab.

NSCLC has become the poster child for targeted therapies. After all, NSCLC makes up about 85% of all lung cancer cases, some of which are driven by gene mutations or other genetic abnormalities like translocation, fusion, or amplification. Seven of these genetic alterations have Food and Drug Administration–approved targeted drugs: EGFR, ALK, ROS1, BRAF V6006, RET, KRAS, MET, and NTRK fusions. And, now we have a new one: HER2.

In August, the FDA granted accelerated approval of trastuzumab deruxtecan (T-DXd) (Enhertu, Daiichi Sankyo) for the second-line treatment of NSCLC patients with HER alterations. T-DXd is a humanized anti-HER antibody linked to a topoisomerase 1 inhibitor. When given intravenously, the antibody portion of the molecule binds to cells with a mutated HER2 on the surface. The molecule is taken up by the cancer cell and the linker between the antibody and the chemotherapy drug is broken, so the drug will be delivered very specifically only to cancer cells that have a mutated HER2. In theory, they will only target cells with HER alterations and thus should have less toxicity.

Unlike other driver mutations, HER mutations are relatively rare. Roughly 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis. Accelerated approved by the FDA was based on data from the DESTINY-Lung 02 phase 2 trial. An interim efficacy analysis of this trial reported an overall response rate to trastuzumab deruxtecan (at 5.4 mg/kg every 3 weeks) of 57.7% in 52 patients. Median duration of response was 8.7 months. Data are also available from the DESTINY-Lung-01 clinical trial, published in the New England Journal of Medicine, in which 91 patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment were treated with T-DXd (at 6.4 mg/kg every 3 weeks). The investigators reported a 55% objective response rate, a median duration of response of 9.3 months, a median progression-free survival (PFS) of 8.2 months, and a median overall survival of almost 18 months.
 

Companion tests

Biomarker testing is obviously a must in these cases. The FDA-approved companion diagnostic tests to detect HER2 mutations: Life Companion tests, Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue, and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that, if no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Other approvals

T-DXd is also approved for advanced breast and gastric patients who are HER-2 positive. Of note, the majority of HER2-positive NSCLC have HER2 mutations, whereas the majority of HER2-positive breast and gastric cancers have HER2 amplification (increased copy number) or overexpression (increased protein expression).

T-DXd is approved for unresectable or metastatic HER2-positive breast cancer patients who have received a prior anti-HER2–based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. DESTINY-Breast01 enrolled breast cancer patients who had received two or more prior anti-HER2 therapies in the metastatic setting, and reported a response rate of 60.3% with a median duration of response of 14.8 months.

For patients with locally advanced or metastatic HER2-positive gastric cancer who have received two or more prior therapies, including a trastuzumab-based regimen, approval was based on a randomized, phase 3 study comparing 6.4 mg/kg of T-DXd with physician’s choice – either irinotecan or paclitaxel. Overall survival was 12.5 months in the T-DXd arm, compared with 8.4 months in the irinotecan or paclitaxel arm (hazard ratio, 0.59). Response rates were 40.5% and 11.3%, respectively. Median PFS was 5.6 months in the T-DXd arm, compared with a median PFS of 3.5 months in the chemotherapy arm.
 

Trastuzumab emtansine vs. trastuzumab deruxtecan

Trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, Kadcyla) is another antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the antimicrotubule agent DM1. It is also approved for advanced breast cancer patients with HER2-positive disease. Although no studies comparing T-DXd with trastuzumab emtansine have been conducted in lung cancer patients, a randomized, phase 3 trial in patients with HER2-positive advanced breast cancer comparing the two reported an overall response rate of 79.7% of the patients who received trastuzumab deruxtecan and 34.2% of those who received trastuzumab emtansine. Drug-related interstitial lung disease (ILD) occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; at 12 months, 75.8% of the patients in the trastuzumab deruxtecan were alive without progression, compared with 34.1% of those receiving trastuzumab emtansine.

ILDs

In DESTINY-Lung01, ILD occurred in 26% of patients and resulted in death in two patients. Increased rates of ILD were more commonly observed at higher dose levels. Of 491 patients with unresectable or metastatic HER2-positive breast cancer treated with 5.4 mg/kg of T-TDx, ILD occurred in 13% of patients. Fatal outcomes caused by ILD and/or pneumonitis occurred in 1.4% of patients. Median time to first onset was 5.5 months (range, 1.1-20.8 months). In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with 6.4 mg/kg, T-DXd ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range, 1.2-21.0 months).

Chemotherapy-like adverse effects

Other adverse events are more typically seen with cytotoxic agents and are presumably related to the release of the topoisomerase inhibitor into the blood stream. Although common (occurring in 97% of patients), these adverse events are generally mild (grade 1 or 2). Nausea was reported in about two-thirds of patients. Other side effects occurring in 20% or more of patients included vomiting, decreased appetite, alopecia, and constipation and diarrhea, musculoskeletal pain, and respiratory infections. Laboratory abnormalities occurred in 20% or more of patients included myelosuppression, increased AST, ALT, alkaline phosphatase, and hypokalemia (28%). Grade 3 or higher drug-related adverse events were observed in 46% of patients, with the most common being neutropenia and anemia which was observed in 19% and 10% of patients in the DESTINY-LUNG-01 trial.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Shortly after osimertinib was approved for patients with non–small cell lung cancer in 2020 by the Food and Drug Administration, a patient came to me with increasing shortness of breath. He had been on erlotinib (Tarceva) for about 2 years and had done well. Nearly all of his pulmonary lesions had resolved and he was feeling well. He enjoyed boating in the summer and visiting grandkids in California in the winter. However, on this day, it was different. He was losing weight; he was tired and didn’t feel strong enough to put his boat in the water that spring. Long story short: We ordered a CT scan and all of his lesions were progressing. Since osimertinib had just been approved, we got a second biopsy, hoping that his insurance would pay for it. It did and sure enough, a new T790M mutation was present. He was on osimertinib for another 2 years before progressing and starting chemotherapy.

Second biopsies increasingly routine

The practice of ordering a second biopsy for patients with non–small cell lung carcinoma (NSCLC) was not common practice until after 2015 when the Food and Drug Administration approved gefitinib, a tyrosine kinase inhibitor (TKI) for patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

Up until then, second biopsies were not routinely done for lung cancers. But with the advent of targeted therapy and new drugs designed specifically to tackle first- and second-line treatment resistance mutations, rebiopsies have become a necessity for patients with progressive disease.

Epidermal growth factors, including HER2, ErbB2, and MET, are receptors of tyrosine kinases that control cell growth, but when in overdrive, they can lead to the development of cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, colon adenocarcinoma, and NSCLC.

EGFRs date back to 1962 with their discovery by Stanley Cohen. The discovery was so important that in 1986, Mr. Cohen was awarded the Nobel Prize in physiology or medicine for the discovery along with Rita Levi-Montalcini.

Now, many years later, we finally have a string of new approvals for mutations in the EGF family of receptors and several under study.

Sensitizing mutations

The more commonly used strategy for blocking EGFR signaling in lung cancer is the use of tyrosine kinase inhibitors, which compete with adenosine triphosphate (ATP) for binding to the tyrosine kinase portion of the receptor. They are located at chromosome 7p11.2. The most frequent mutations that sensitize patients to EGFR inhibitors include exon 19 deletions and L858R point mutation in exon 21, although multiple other driver mutations also exist.

The first-generation of EGFR TKIs include gefitinib and erlotinib, which bind reversibly to the EGF receptor. Second-generation inhibitors afatinib and dacomitinib bind irreversibly. Osimertinib, a third-generation EGFR TKI, which also binds irreversibly, was approved in 2020 for adjuvant therapy, and first- and second-line treatment in patients with NSCLC who have EGFR mutation–positive disease.
 

First-generation EGFR tyrosine kinase inhibitors

Four randomized, first-line, placebo-controlled phase 3 trials conducted with EGFR TKIs in combination with platinum-based doublet chemotherapy in an EGFR nonselected patient population failed to show a survival benefit with erlotinib or gefitinib (TRIBUTE, Tarceva Lung Cancer Investigation Trial, INTACT 1, INTACT 2).

However, a first-line study randomized patients to gefitinib or chemotherapy with carboplatin-paclitaxel, and included patients with or without an EGFR mutations. In the subgroup of patients with an EGFR mutation, progression-free survival (PFS) was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48), whereas in the subgroup of patients who were negative for the mutation, PFS was significantly longer among those who received chemotherapy (HR for progression or death with gefitinib, 2.85).

Numerous studies have shown that EGFR TKIs used in the first-line setting improved progression free survival, response rates, and quality of life while reducing toxicity. A recent meta-analysis of randomized clinical trials involving EGFR TKIs showed that EGFR TKI improved PFS with a HR of 0.40, compared with standard chemotherapy with fewer serious adverse events, although no benefit on overall survival was observed (HR, 0.96; 95% confidence interval, 0.83-1.10; P = .556).
 

T790M: The most common resistance mutation

T790M is the most common resistance mechanism to develop in patients with EGFR mutations being treated with EGFR TKIs. A randomized phase 3 trial of osimertinib vs. chemotherapy in patients with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy, reported a median duration of progression-free survival that was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; HR, 0.30). In addition, among 144 patients with metastases to the central nervous system, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; HR, 0.32). However, now that osimertinib has moved into the front-line setting, it has left a void for the treatment of patients with advanced disease who have failed osimertinib.

New resistance mechanisms continue to be identified

One of the most common sets of resistance mutations are insertions in exon 20 of the EGF receptor gene. These are a heterogenous group of mutations, many of which do not respond to first-, second-, or third-generation TKIs. Some, such as EGFR-A763_Y764insFQEA, may be sensitive to first- and third-generation EGFR TKIs. Other drugs targeting exon 20 insertion mutations are under development.

Newly approved by the FDA within the last year are mobocertinib and CLN-081 for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.

Savolitinib is a receptor tyrosine kinase (MET) inhibitor currently under development for NSCLC and other cancers. Amivantamab-vmjw was approved by the FDA last year for metastatic NSCLC. It targets EGF and MET receptors in patients with EGFR exon 20 insertion mutations.

We finally have approved drugs for exon 20 insertions and c-Met amplification, even though their approvals are based on small, single arm studies with no definitive claims of improved efficacy over older therapies. Taking a second biopsy will help determine which resistance mechanisms are active to better identify subsequent treatment as in my patient described in this article.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Shortly after osimertinib was approved for patients with non–small cell lung cancer in 2020 by the Food and Drug Administration, a patient came to me with increasing shortness of breath. He had been on erlotinib (Tarceva) for about 2 years and had done well. Nearly all of his pulmonary lesions had resolved and he was feeling well. He enjoyed boating in the summer and visiting grandkids in California in the winter. However, on this day, it was different. He was losing weight; he was tired and didn’t feel strong enough to put his boat in the water that spring. Long story short: We ordered a CT scan and all of his lesions were progressing. Since osimertinib had just been approved, we got a second biopsy, hoping that his insurance would pay for it. It did and sure enough, a new T790M mutation was present. He was on osimertinib for another 2 years before progressing and starting chemotherapy.

Second biopsies increasingly routine

The practice of ordering a second biopsy for patients with non–small cell lung carcinoma (NSCLC) was not common practice until after 2015 when the Food and Drug Administration approved gefitinib, a tyrosine kinase inhibitor (TKI) for patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

Up until then, second biopsies were not routinely done for lung cancers. But with the advent of targeted therapy and new drugs designed specifically to tackle first- and second-line treatment resistance mutations, rebiopsies have become a necessity for patients with progressive disease.

Epidermal growth factors, including HER2, ErbB2, and MET, are receptors of tyrosine kinases that control cell growth, but when in overdrive, they can lead to the development of cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, colon adenocarcinoma, and NSCLC.

EGFRs date back to 1962 with their discovery by Stanley Cohen. The discovery was so important that in 1986, Mr. Cohen was awarded the Nobel Prize in physiology or medicine for the discovery along with Rita Levi-Montalcini.

Now, many years later, we finally have a string of new approvals for mutations in the EGF family of receptors and several under study.

Sensitizing mutations

The more commonly used strategy for blocking EGFR signaling in lung cancer is the use of tyrosine kinase inhibitors, which compete with adenosine triphosphate (ATP) for binding to the tyrosine kinase portion of the receptor. They are located at chromosome 7p11.2. The most frequent mutations that sensitize patients to EGFR inhibitors include exon 19 deletions and L858R point mutation in exon 21, although multiple other driver mutations also exist.

The first-generation of EGFR TKIs include gefitinib and erlotinib, which bind reversibly to the EGF receptor. Second-generation inhibitors afatinib and dacomitinib bind irreversibly. Osimertinib, a third-generation EGFR TKI, which also binds irreversibly, was approved in 2020 for adjuvant therapy, and first- and second-line treatment in patients with NSCLC who have EGFR mutation–positive disease.
 

First-generation EGFR tyrosine kinase inhibitors

Four randomized, first-line, placebo-controlled phase 3 trials conducted with EGFR TKIs in combination with platinum-based doublet chemotherapy in an EGFR nonselected patient population failed to show a survival benefit with erlotinib or gefitinib (TRIBUTE, Tarceva Lung Cancer Investigation Trial, INTACT 1, INTACT 2).

However, a first-line study randomized patients to gefitinib or chemotherapy with carboplatin-paclitaxel, and included patients with or without an EGFR mutations. In the subgroup of patients with an EGFR mutation, progression-free survival (PFS) was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48), whereas in the subgroup of patients who were negative for the mutation, PFS was significantly longer among those who received chemotherapy (HR for progression or death with gefitinib, 2.85).

Numerous studies have shown that EGFR TKIs used in the first-line setting improved progression free survival, response rates, and quality of life while reducing toxicity. A recent meta-analysis of randomized clinical trials involving EGFR TKIs showed that EGFR TKI improved PFS with a HR of 0.40, compared with standard chemotherapy with fewer serious adverse events, although no benefit on overall survival was observed (HR, 0.96; 95% confidence interval, 0.83-1.10; P = .556).
 

T790M: The most common resistance mutation

T790M is the most common resistance mechanism to develop in patients with EGFR mutations being treated with EGFR TKIs. A randomized phase 3 trial of osimertinib vs. chemotherapy in patients with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy, reported a median duration of progression-free survival that was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; HR, 0.30). In addition, among 144 patients with metastases to the central nervous system, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; HR, 0.32). However, now that osimertinib has moved into the front-line setting, it has left a void for the treatment of patients with advanced disease who have failed osimertinib.

New resistance mechanisms continue to be identified

One of the most common sets of resistance mutations are insertions in exon 20 of the EGF receptor gene. These are a heterogenous group of mutations, many of which do not respond to first-, second-, or third-generation TKIs. Some, such as EGFR-A763_Y764insFQEA, may be sensitive to first- and third-generation EGFR TKIs. Other drugs targeting exon 20 insertion mutations are under development.

Newly approved by the FDA within the last year are mobocertinib and CLN-081 for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.

Savolitinib is a receptor tyrosine kinase (MET) inhibitor currently under development for NSCLC and other cancers. Amivantamab-vmjw was approved by the FDA last year for metastatic NSCLC. It targets EGF and MET receptors in patients with EGFR exon 20 insertion mutations.

We finally have approved drugs for exon 20 insertions and c-Met amplification, even though their approvals are based on small, single arm studies with no definitive claims of improved efficacy over older therapies. Taking a second biopsy will help determine which resistance mechanisms are active to better identify subsequent treatment as in my patient described in this article.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Shortly after osimertinib was approved for patients with non–small cell lung cancer in 2020 by the Food and Drug Administration, a patient came to me with increasing shortness of breath. He had been on erlotinib (Tarceva) for about 2 years and had done well. Nearly all of his pulmonary lesions had resolved and he was feeling well. He enjoyed boating in the summer and visiting grandkids in California in the winter. However, on this day, it was different. He was losing weight; he was tired and didn’t feel strong enough to put his boat in the water that spring. Long story short: We ordered a CT scan and all of his lesions were progressing. Since osimertinib had just been approved, we got a second biopsy, hoping that his insurance would pay for it. It did and sure enough, a new T790M mutation was present. He was on osimertinib for another 2 years before progressing and starting chemotherapy.

Second biopsies increasingly routine

The practice of ordering a second biopsy for patients with non–small cell lung carcinoma (NSCLC) was not common practice until after 2015 when the Food and Drug Administration approved gefitinib, a tyrosine kinase inhibitor (TKI) for patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

Up until then, second biopsies were not routinely done for lung cancers. But with the advent of targeted therapy and new drugs designed specifically to tackle first- and second-line treatment resistance mutations, rebiopsies have become a necessity for patients with progressive disease.

Epidermal growth factors, including HER2, ErbB2, and MET, are receptors of tyrosine kinases that control cell growth, but when in overdrive, they can lead to the development of cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, colon adenocarcinoma, and NSCLC.

EGFRs date back to 1962 with their discovery by Stanley Cohen. The discovery was so important that in 1986, Mr. Cohen was awarded the Nobel Prize in physiology or medicine for the discovery along with Rita Levi-Montalcini.

Now, many years later, we finally have a string of new approvals for mutations in the EGF family of receptors and several under study.

Sensitizing mutations

The more commonly used strategy for blocking EGFR signaling in lung cancer is the use of tyrosine kinase inhibitors, which compete with adenosine triphosphate (ATP) for binding to the tyrosine kinase portion of the receptor. They are located at chromosome 7p11.2. The most frequent mutations that sensitize patients to EGFR inhibitors include exon 19 deletions and L858R point mutation in exon 21, although multiple other driver mutations also exist.

The first-generation of EGFR TKIs include gefitinib and erlotinib, which bind reversibly to the EGF receptor. Second-generation inhibitors afatinib and dacomitinib bind irreversibly. Osimertinib, a third-generation EGFR TKI, which also binds irreversibly, was approved in 2020 for adjuvant therapy, and first- and second-line treatment in patients with NSCLC who have EGFR mutation–positive disease.
 

First-generation EGFR tyrosine kinase inhibitors

Four randomized, first-line, placebo-controlled phase 3 trials conducted with EGFR TKIs in combination with platinum-based doublet chemotherapy in an EGFR nonselected patient population failed to show a survival benefit with erlotinib or gefitinib (TRIBUTE, Tarceva Lung Cancer Investigation Trial, INTACT 1, INTACT 2).

However, a first-line study randomized patients to gefitinib or chemotherapy with carboplatin-paclitaxel, and included patients with or without an EGFR mutations. In the subgroup of patients with an EGFR mutation, progression-free survival (PFS) was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48), whereas in the subgroup of patients who were negative for the mutation, PFS was significantly longer among those who received chemotherapy (HR for progression or death with gefitinib, 2.85).

Numerous studies have shown that EGFR TKIs used in the first-line setting improved progression free survival, response rates, and quality of life while reducing toxicity. A recent meta-analysis of randomized clinical trials involving EGFR TKIs showed that EGFR TKI improved PFS with a HR of 0.40, compared with standard chemotherapy with fewer serious adverse events, although no benefit on overall survival was observed (HR, 0.96; 95% confidence interval, 0.83-1.10; P = .556).
 

T790M: The most common resistance mutation

T790M is the most common resistance mechanism to develop in patients with EGFR mutations being treated with EGFR TKIs. A randomized phase 3 trial of osimertinib vs. chemotherapy in patients with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy, reported a median duration of progression-free survival that was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; HR, 0.30). In addition, among 144 patients with metastases to the central nervous system, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; HR, 0.32). However, now that osimertinib has moved into the front-line setting, it has left a void for the treatment of patients with advanced disease who have failed osimertinib.

New resistance mechanisms continue to be identified

One of the most common sets of resistance mutations are insertions in exon 20 of the EGF receptor gene. These are a heterogenous group of mutations, many of which do not respond to first-, second-, or third-generation TKIs. Some, such as EGFR-A763_Y764insFQEA, may be sensitive to first- and third-generation EGFR TKIs. Other drugs targeting exon 20 insertion mutations are under development.

Newly approved by the FDA within the last year are mobocertinib and CLN-081 for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.

Savolitinib is a receptor tyrosine kinase (MET) inhibitor currently under development for NSCLC and other cancers. Amivantamab-vmjw was approved by the FDA last year for metastatic NSCLC. It targets EGF and MET receptors in patients with EGFR exon 20 insertion mutations.

We finally have approved drugs for exon 20 insertions and c-Met amplification, even though their approvals are based on small, single arm studies with no definitive claims of improved efficacy over older therapies. Taking a second biopsy will help determine which resistance mechanisms are active to better identify subsequent treatment as in my patient described in this article.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

We’ve still got some work to do before we can say with authority whether concurrent neoadjuvant chemotherapy and immunotherapy is better than concurrent adjuvant chemotherapy with immunotherapy for non–small cell lung cancer (NSCLC). While there has been some notable progress in this area, we need phase 3 trials that compare the two therapeutic approaches.

Investigators reporting at the 2022 annual meeting of American Society of Clinical Oncology focused primarily on neoadjuvant treatment, which I’ll address here.

In the randomized, phase 2 NADIM II clinical trial reported at the meeting, researchers expanded on the results of NADIM published in 2020 in the Lancet Oncology and in May 2022 in the Journal of Clinical Oncology along with CheckMate 816 results published in the New England Journal of Medicine.

In each of these three studies, researchers compared nivolumab plus chemotherapy versus chemotherapy alone (abstract 8501) as a neoadjuvant treatment for resectable stage IIIA NSCLC. In the study reported at ASCO 2022, patients with resectable clinical stage IIIA-B (per American Joint Committee on Cancer 8th edition) NSCLC and no known EGFR/ALK alterations, were randomized to receive preoperative nivolumab plus chemotherapy (paclitaxel and carboplatin; n = 57) or chemotherapy (n = 29) alone followed by surgery.

The primary endpoint was pathological complete response (pCR); secondary endpoints included major pathological response, safety and tolerability, impact on surgical issues such as delayed or canceled surgeries or length of hospital stay, overall survival and progression free survival. The pCR rate was 36.8% in the neoadjuvant nivolumab plus chemotherapy arm and 6.9% in the chemotherapy alone arm. (P = .0068). 25% of patients on the nivolumab plus chemo arm had grade 3-4 adverse events, compared with 10.3% in the control arm. 93% of patients on the nivolumab plus chemo arm underwent definitive surgery whereas 69.0% of the patients on the chemo alone arm had definitive surgery. (P = .008)
 

What else did we learn about neoadjuvant treatment at the meeting?

Investigators looking at the optimal number of neoadjuvant cycles (abstract 8500) found that three cycles of sintilimab (an investigational PD-1 inhibitor) produced a numerically higher major pathological response rate, compared with two cycles (when given in concert with platinum-doublet chemotherapy). And, neoadjuvant chemoradiotherapy does not result in significant survival benefits when compared with neoadjuvant chemotherapy alone (abstract 8503).

Of course, when it comes to resectable NSCLC, the goal of treatment is to increase the cure rate and improve survival. No randomized studies have reported yet on overall survival, probably because they are too immature. Instead, disease-free survival (DFS) or event-free survival (EFS) are often used as surrogate endpoints. Since none of the studies reported at ASCO reported on DFS or EFS, we need to look elsewhere. CheckMate 816 was a phase 3 study which randomized patients with stages IB-IIIA NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy alone, followed by resection. The median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P = .005). The percentage of patients with a pCR was 24.0% and 2.2%, respectively (P < .001).

We all know one has to be careful when doing cross-trial comparisons as these studies differ by the percentage of patients with various stages of disease, the type of immunotherapy and chemotherapy used, etc. However, I think we can agree that neoadjuvant chemoimmunotherapy results in better outcomes than chemotherapy alone.

Of course, resectable NSCLC is, by definition, resectable. And traditionally, resection is followed by adjuvant chemotherapy to eradicate micrometastases. Unfortunately, the current standard of care for completely resected early-stage NSCLC (stage I [tumor ≥ 4 cm] to IIIA) involves adjuvant platinum-based combination chemotherapy which results in only a modest 4%-5% improvement in survival versus observation.

Given these modest results, as in the neoadjuvant space, investigators have looked at the benefit of adding immunotherapy to adjuvant chemotherapy. One such study has been reported. IMpower 010 randomly assigned patients with completely resected stage IB (tumors ≥ 4 cm) to IIIA NSCLC, whose tumor cells expressed at least 1% PD-L1, to receive adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy. In the stage II-IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells, 3-year DFS rates were 60% and 48% in the atezolizumab and best supportive care arms, respectively (hazard ratio, 0·66 P =·.0039). In all patients in the stage II-IIIA population, the 3-year DFS rates were 56% in the atezolizumab group and 49% in the best supportive care group, (HR, 0.79; P = .020).

KEYNOTE-091, reported at the 2021 annual meeting of the European Society for Medical Oncology, randomized early-stage NSCLC patients following complete resection and adjuvant chemotherapy to pembrolizumab or placebo. Median DFS for the overall population was 53.6 months for patients in the pembro arm versus 42 months in the placebo arm (HR, 0.76; P = .0014). Interestingly, the benefit was not seen in patients with PD-L1 with at least 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm (HR, 0.82; P = .14). Although the contradictory results of PD-L1 as a biomarker is puzzling, I think we can agree that the addition of immunotherapy following adjuvant chemotherapy improves outcomes compared to adjuvant chemotherapy alone.
 

What to do when a patient presents with resectable disease?

Cross-trial comparisons are fraught with danger. Until we have a phase 3 study comparing concurrent neoadjuvant chemo/immunotherapy with concurrent adjuvant chemo/immunotherapy, I do not think we can answer the question “which is better?” However, there are some caveats to keep in mind when deciding on which approach to recommend to our patients: First, neoadjuvant treatment requires biomarker testing to ensure the patient does not have EGFR or ALK mutations. This will necessitate a delay in the operation. Will patients be willing to wait? Will the surgeon? Or, would patients prefer to proceed with surgery while the results are pending? Yes, neoadjuvant therapy gives you information regarding the pCR rate, but does that help you in subsequent management of the patient? We do not know.

Secondly, the two adjuvant studies used adjuvant chemotherapy followed by adjuvant immunotherapy, as contrasted to the neoadjuvant study which used concurrent chemo/immunotherapy. Given the longer duration of treatment in postoperative sequential adjuvant studies, there tends to be more drop off because of patients being unwilling or unfit postoperatively to receive long courses of therapy. In IMpower 010, 1,269 patients completed adjuvant chemotherapy; 1,005 were randomized, and of the 507 assigned to the atezolizumab/chemo group, only 323 completed treatment.

Finally, we must beware of using neoadjuvant chemo/immunotherapy to “down-stage” a patient. KEYNOTE-091 included patients with IIIA disease and no benefit to adjuvant chemotherapy followed by immunotherapy was found in this subgroup of patients, which leads me to wonder if these patients were appropriately selected as surgical candidates. In the NADIM II trials, 9 of 29 patients on the neoadjuvant chemotherapy were not resected.

So, many questions remain. In addition to the ones we’ve raised, there is a clear and immediate need for predictive and prognostic biomarkers. In the NADIM II trial, PD-L1 expression was a predictive biomarker of response. The pCR rate for patients with a PD-L1 tumor expression of less than 1%, 1%-49%, and 50% or higher was 15%, 41.7%, and 61.1%, respectively. However, in KEYNOTE-091, the benefit was not seen in patients with PD-L1 of at least than 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm.

Another possible biomarker: circulating tumor DNA. In the first NADIM study, three low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and overall survival (HR, 0.20 and HR, 0.07, respectively). Although clinical response did not predict survival outcomes, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and overall survival (HR, 0.26 and HR0.04, respectively). Similarly, in CheckMate 816, clearance of ctDNA was associated with longer EFS in patients with ctDNA clearance than in those without ctDNA clearance in both the nivolumab/chemotherapy group (HR, 0.60) and the chemotherapy-alone group (HR, 0.63).

Hopefully, ASCO 2023 will provide more answers.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

We’ve still got some work to do before we can say with authority whether concurrent neoadjuvant chemotherapy and immunotherapy is better than concurrent adjuvant chemotherapy with immunotherapy for non–small cell lung cancer (NSCLC). While there has been some notable progress in this area, we need phase 3 trials that compare the two therapeutic approaches.

Investigators reporting at the 2022 annual meeting of American Society of Clinical Oncology focused primarily on neoadjuvant treatment, which I’ll address here.

In the randomized, phase 2 NADIM II clinical trial reported at the meeting, researchers expanded on the results of NADIM published in 2020 in the Lancet Oncology and in May 2022 in the Journal of Clinical Oncology along with CheckMate 816 results published in the New England Journal of Medicine.

In each of these three studies, researchers compared nivolumab plus chemotherapy versus chemotherapy alone (abstract 8501) as a neoadjuvant treatment for resectable stage IIIA NSCLC. In the study reported at ASCO 2022, patients with resectable clinical stage IIIA-B (per American Joint Committee on Cancer 8th edition) NSCLC and no known EGFR/ALK alterations, were randomized to receive preoperative nivolumab plus chemotherapy (paclitaxel and carboplatin; n = 57) or chemotherapy (n = 29) alone followed by surgery.

The primary endpoint was pathological complete response (pCR); secondary endpoints included major pathological response, safety and tolerability, impact on surgical issues such as delayed or canceled surgeries or length of hospital stay, overall survival and progression free survival. The pCR rate was 36.8% in the neoadjuvant nivolumab plus chemotherapy arm and 6.9% in the chemotherapy alone arm. (P = .0068). 25% of patients on the nivolumab plus chemo arm had grade 3-4 adverse events, compared with 10.3% in the control arm. 93% of patients on the nivolumab plus chemo arm underwent definitive surgery whereas 69.0% of the patients on the chemo alone arm had definitive surgery. (P = .008)
 

What else did we learn about neoadjuvant treatment at the meeting?

Investigators looking at the optimal number of neoadjuvant cycles (abstract 8500) found that three cycles of sintilimab (an investigational PD-1 inhibitor) produced a numerically higher major pathological response rate, compared with two cycles (when given in concert with platinum-doublet chemotherapy). And, neoadjuvant chemoradiotherapy does not result in significant survival benefits when compared with neoadjuvant chemotherapy alone (abstract 8503).

Of course, when it comes to resectable NSCLC, the goal of treatment is to increase the cure rate and improve survival. No randomized studies have reported yet on overall survival, probably because they are too immature. Instead, disease-free survival (DFS) or event-free survival (EFS) are often used as surrogate endpoints. Since none of the studies reported at ASCO reported on DFS or EFS, we need to look elsewhere. CheckMate 816 was a phase 3 study which randomized patients with stages IB-IIIA NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy alone, followed by resection. The median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P = .005). The percentage of patients with a pCR was 24.0% and 2.2%, respectively (P < .001).

We all know one has to be careful when doing cross-trial comparisons as these studies differ by the percentage of patients with various stages of disease, the type of immunotherapy and chemotherapy used, etc. However, I think we can agree that neoadjuvant chemoimmunotherapy results in better outcomes than chemotherapy alone.

Of course, resectable NSCLC is, by definition, resectable. And traditionally, resection is followed by adjuvant chemotherapy to eradicate micrometastases. Unfortunately, the current standard of care for completely resected early-stage NSCLC (stage I [tumor ≥ 4 cm] to IIIA) involves adjuvant platinum-based combination chemotherapy which results in only a modest 4%-5% improvement in survival versus observation.

Given these modest results, as in the neoadjuvant space, investigators have looked at the benefit of adding immunotherapy to adjuvant chemotherapy. One such study has been reported. IMpower 010 randomly assigned patients with completely resected stage IB (tumors ≥ 4 cm) to IIIA NSCLC, whose tumor cells expressed at least 1% PD-L1, to receive adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy. In the stage II-IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells, 3-year DFS rates were 60% and 48% in the atezolizumab and best supportive care arms, respectively (hazard ratio, 0·66 P =·.0039). In all patients in the stage II-IIIA population, the 3-year DFS rates were 56% in the atezolizumab group and 49% in the best supportive care group, (HR, 0.79; P = .020).

KEYNOTE-091, reported at the 2021 annual meeting of the European Society for Medical Oncology, randomized early-stage NSCLC patients following complete resection and adjuvant chemotherapy to pembrolizumab or placebo. Median DFS for the overall population was 53.6 months for patients in the pembro arm versus 42 months in the placebo arm (HR, 0.76; P = .0014). Interestingly, the benefit was not seen in patients with PD-L1 with at least 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm (HR, 0.82; P = .14). Although the contradictory results of PD-L1 as a biomarker is puzzling, I think we can agree that the addition of immunotherapy following adjuvant chemotherapy improves outcomes compared to adjuvant chemotherapy alone.
 

What to do when a patient presents with resectable disease?

Cross-trial comparisons are fraught with danger. Until we have a phase 3 study comparing concurrent neoadjuvant chemo/immunotherapy with concurrent adjuvant chemo/immunotherapy, I do not think we can answer the question “which is better?” However, there are some caveats to keep in mind when deciding on which approach to recommend to our patients: First, neoadjuvant treatment requires biomarker testing to ensure the patient does not have EGFR or ALK mutations. This will necessitate a delay in the operation. Will patients be willing to wait? Will the surgeon? Or, would patients prefer to proceed with surgery while the results are pending? Yes, neoadjuvant therapy gives you information regarding the pCR rate, but does that help you in subsequent management of the patient? We do not know.

Secondly, the two adjuvant studies used adjuvant chemotherapy followed by adjuvant immunotherapy, as contrasted to the neoadjuvant study which used concurrent chemo/immunotherapy. Given the longer duration of treatment in postoperative sequential adjuvant studies, there tends to be more drop off because of patients being unwilling or unfit postoperatively to receive long courses of therapy. In IMpower 010, 1,269 patients completed adjuvant chemotherapy; 1,005 were randomized, and of the 507 assigned to the atezolizumab/chemo group, only 323 completed treatment.

Finally, we must beware of using neoadjuvant chemo/immunotherapy to “down-stage” a patient. KEYNOTE-091 included patients with IIIA disease and no benefit to adjuvant chemotherapy followed by immunotherapy was found in this subgroup of patients, which leads me to wonder if these patients were appropriately selected as surgical candidates. In the NADIM II trials, 9 of 29 patients on the neoadjuvant chemotherapy were not resected.

So, many questions remain. In addition to the ones we’ve raised, there is a clear and immediate need for predictive and prognostic biomarkers. In the NADIM II trial, PD-L1 expression was a predictive biomarker of response. The pCR rate for patients with a PD-L1 tumor expression of less than 1%, 1%-49%, and 50% or higher was 15%, 41.7%, and 61.1%, respectively. However, in KEYNOTE-091, the benefit was not seen in patients with PD-L1 of at least than 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm.

Another possible biomarker: circulating tumor DNA. In the first NADIM study, three low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and overall survival (HR, 0.20 and HR, 0.07, respectively). Although clinical response did not predict survival outcomes, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and overall survival (HR, 0.26 and HR0.04, respectively). Similarly, in CheckMate 816, clearance of ctDNA was associated with longer EFS in patients with ctDNA clearance than in those without ctDNA clearance in both the nivolumab/chemotherapy group (HR, 0.60) and the chemotherapy-alone group (HR, 0.63).

Hopefully, ASCO 2023 will provide more answers.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

We’ve still got some work to do before we can say with authority whether concurrent neoadjuvant chemotherapy and immunotherapy is better than concurrent adjuvant chemotherapy with immunotherapy for non–small cell lung cancer (NSCLC). While there has been some notable progress in this area, we need phase 3 trials that compare the two therapeutic approaches.

Investigators reporting at the 2022 annual meeting of American Society of Clinical Oncology focused primarily on neoadjuvant treatment, which I’ll address here.

In the randomized, phase 2 NADIM II clinical trial reported at the meeting, researchers expanded on the results of NADIM published in 2020 in the Lancet Oncology and in May 2022 in the Journal of Clinical Oncology along with CheckMate 816 results published in the New England Journal of Medicine.

In each of these three studies, researchers compared nivolumab plus chemotherapy versus chemotherapy alone (abstract 8501) as a neoadjuvant treatment for resectable stage IIIA NSCLC. In the study reported at ASCO 2022, patients with resectable clinical stage IIIA-B (per American Joint Committee on Cancer 8th edition) NSCLC and no known EGFR/ALK alterations, were randomized to receive preoperative nivolumab plus chemotherapy (paclitaxel and carboplatin; n = 57) or chemotherapy (n = 29) alone followed by surgery.

The primary endpoint was pathological complete response (pCR); secondary endpoints included major pathological response, safety and tolerability, impact on surgical issues such as delayed or canceled surgeries or length of hospital stay, overall survival and progression free survival. The pCR rate was 36.8% in the neoadjuvant nivolumab plus chemotherapy arm and 6.9% in the chemotherapy alone arm. (P = .0068). 25% of patients on the nivolumab plus chemo arm had grade 3-4 adverse events, compared with 10.3% in the control arm. 93% of patients on the nivolumab plus chemo arm underwent definitive surgery whereas 69.0% of the patients on the chemo alone arm had definitive surgery. (P = .008)
 

What else did we learn about neoadjuvant treatment at the meeting?

Investigators looking at the optimal number of neoadjuvant cycles (abstract 8500) found that three cycles of sintilimab (an investigational PD-1 inhibitor) produced a numerically higher major pathological response rate, compared with two cycles (when given in concert with platinum-doublet chemotherapy). And, neoadjuvant chemoradiotherapy does not result in significant survival benefits when compared with neoadjuvant chemotherapy alone (abstract 8503).

Of course, when it comes to resectable NSCLC, the goal of treatment is to increase the cure rate and improve survival. No randomized studies have reported yet on overall survival, probably because they are too immature. Instead, disease-free survival (DFS) or event-free survival (EFS) are often used as surrogate endpoints. Since none of the studies reported at ASCO reported on DFS or EFS, we need to look elsewhere. CheckMate 816 was a phase 3 study which randomized patients with stages IB-IIIA NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy alone, followed by resection. The median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P = .005). The percentage of patients with a pCR was 24.0% and 2.2%, respectively (P < .001).

We all know one has to be careful when doing cross-trial comparisons as these studies differ by the percentage of patients with various stages of disease, the type of immunotherapy and chemotherapy used, etc. However, I think we can agree that neoadjuvant chemoimmunotherapy results in better outcomes than chemotherapy alone.

Of course, resectable NSCLC is, by definition, resectable. And traditionally, resection is followed by adjuvant chemotherapy to eradicate micrometastases. Unfortunately, the current standard of care for completely resected early-stage NSCLC (stage I [tumor ≥ 4 cm] to IIIA) involves adjuvant platinum-based combination chemotherapy which results in only a modest 4%-5% improvement in survival versus observation.

Given these modest results, as in the neoadjuvant space, investigators have looked at the benefit of adding immunotherapy to adjuvant chemotherapy. One such study has been reported. IMpower 010 randomly assigned patients with completely resected stage IB (tumors ≥ 4 cm) to IIIA NSCLC, whose tumor cells expressed at least 1% PD-L1, to receive adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy. In the stage II-IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells, 3-year DFS rates were 60% and 48% in the atezolizumab and best supportive care arms, respectively (hazard ratio, 0·66 P =·.0039). In all patients in the stage II-IIIA population, the 3-year DFS rates were 56% in the atezolizumab group and 49% in the best supportive care group, (HR, 0.79; P = .020).

KEYNOTE-091, reported at the 2021 annual meeting of the European Society for Medical Oncology, randomized early-stage NSCLC patients following complete resection and adjuvant chemotherapy to pembrolizumab or placebo. Median DFS for the overall population was 53.6 months for patients in the pembro arm versus 42 months in the placebo arm (HR, 0.76; P = .0014). Interestingly, the benefit was not seen in patients with PD-L1 with at least 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm (HR, 0.82; P = .14). Although the contradictory results of PD-L1 as a biomarker is puzzling, I think we can agree that the addition of immunotherapy following adjuvant chemotherapy improves outcomes compared to adjuvant chemotherapy alone.
 

What to do when a patient presents with resectable disease?

Cross-trial comparisons are fraught with danger. Until we have a phase 3 study comparing concurrent neoadjuvant chemo/immunotherapy with concurrent adjuvant chemo/immunotherapy, I do not think we can answer the question “which is better?” However, there are some caveats to keep in mind when deciding on which approach to recommend to our patients: First, neoadjuvant treatment requires biomarker testing to ensure the patient does not have EGFR or ALK mutations. This will necessitate a delay in the operation. Will patients be willing to wait? Will the surgeon? Or, would patients prefer to proceed with surgery while the results are pending? Yes, neoadjuvant therapy gives you information regarding the pCR rate, but does that help you in subsequent management of the patient? We do not know.

Secondly, the two adjuvant studies used adjuvant chemotherapy followed by adjuvant immunotherapy, as contrasted to the neoadjuvant study which used concurrent chemo/immunotherapy. Given the longer duration of treatment in postoperative sequential adjuvant studies, there tends to be more drop off because of patients being unwilling or unfit postoperatively to receive long courses of therapy. In IMpower 010, 1,269 patients completed adjuvant chemotherapy; 1,005 were randomized, and of the 507 assigned to the atezolizumab/chemo group, only 323 completed treatment.

Finally, we must beware of using neoadjuvant chemo/immunotherapy to “down-stage” a patient. KEYNOTE-091 included patients with IIIA disease and no benefit to adjuvant chemotherapy followed by immunotherapy was found in this subgroup of patients, which leads me to wonder if these patients were appropriately selected as surgical candidates. In the NADIM II trials, 9 of 29 patients on the neoadjuvant chemotherapy were not resected.

So, many questions remain. In addition to the ones we’ve raised, there is a clear and immediate need for predictive and prognostic biomarkers. In the NADIM II trial, PD-L1 expression was a predictive biomarker of response. The pCR rate for patients with a PD-L1 tumor expression of less than 1%, 1%-49%, and 50% or higher was 15%, 41.7%, and 61.1%, respectively. However, in KEYNOTE-091, the benefit was not seen in patients with PD-L1 of at least than 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm.

Another possible biomarker: circulating tumor DNA. In the first NADIM study, three low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and overall survival (HR, 0.20 and HR, 0.07, respectively). Although clinical response did not predict survival outcomes, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and overall survival (HR, 0.26 and HR0.04, respectively). Similarly, in CheckMate 816, clearance of ctDNA was associated with longer EFS in patients with ctDNA clearance than in those without ctDNA clearance in both the nivolumab/chemotherapy group (HR, 0.60) and the chemotherapy-alone group (HR, 0.63).

Hopefully, ASCO 2023 will provide more answers.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Air pollution is a well-established cause of morbidity and mortality. It largely comes from manmade sources such as particulate matter that arises from burning fossil fuels, which is a major contributor of greenhouse gas emissions.

Acute exposure to fine inhalable particles of as little as 2.5 mcm (PM2.5) in diameter can cause a decrease in lung function leading to respiratory and cardiovascular diseases and even death because of cardiopulmonary conditions and lung cancer.

The 2015 Global Burden of Disease study lists air pollution as the fourth highest–ranking global mortality risk factor. The World Health Organization estimated that 4.2 million deaths were caused by outdoor air pollution in 2016, and another 2.3 million from indoor air pollution.

Not all oncologists believe that air pollution is a cancer problem, but air pollution and particulate matters are carcinogens and in fact, they have been deemed level 1 carcinogens by the International Association of Research on Cancer.

The research on the link between air pollution, PM2.5 and lung cancer is robust. Numerous epidemiological studies have shown that people living in highly polluted areas are more likely to die of lung cancer than those who do not. For example, Turner and colleagues in CA: A Cancer Journal for Clinicians performed a Cox proportional hazard regression model adjusting for numerous variables – smoking, passive smoking, occupational exposures (asbestos, coal dust, diesel engine exhaust, etc.), an occupational “dirtiness” index, radon exposure, among others – and found a dose-response relationship between PM2.5 concentration and lung cancer mortality (each 10-mg/m increase in PM2.5 concentrations was associated with a 15%-27% increase in lung cancer mortality).

A similar analysis by Coleman and colleagues in Cancer Causes and Control found lung cancer mortality was adversely associated with increases in PM2.5 not only in the overall population that was studied, but also in a never-smoker cohort. A study reported in Environmental Health Perspectives also showed that exposure to air pollution increases the incidence and mortality from lung cancer, with lung cancer risk associated with PM2.5 exposure being greatest for former smokers (hazard ratio, 1.44; 95% CI, 1.04-2.01), followed by never-smokers (HR, 1.18; 95% CI, 1.00-1.39), and then current smokers (HR, 1.06; 95% CI, 0.97-1.15).

A 2020 study reported in Thorax that patients with COPD who have never smoked were more likely to get lung cancer, compared with never-smokers without COPD (HR, 2.67, 95% CI, 2.09-3.40). Other studies (The Lancet Oncology and The Lancet) confirm these findings. A meta-analysis published in Environmental Research of a large number of cohort studies over the past 25 years reported that the estimated HR, adjusted for age, sex, and smoking status, was 1.13 (95% CI, 1.07-1.20) per 10 mcg/m elevation in PM2.5.

Air pollution also affects patients who already have lung cancer. Air pollution exposures after the diagnosis of lung cancer shortens survival. For example, a 2016 study published in the journal Thorax found the median survival for patients with early-stage lung cancer at diagnosis was 2.4 years for those with high PM2.5 exposure (≥ 16 mcg/m³) and 5.7 years for those with low PM2.5 exposure (< 10 mcg/m³).

What does air pollution have to do with climate change? They both come from the burning of fossil fuels

Although the topic of climate change is generally seen through an environmental (and political) lens, it should also be seen through a health lens. In 2021, the New England Journal of Medicine and 229 other publications simultaneously published an editorial calling climate change a health emergency.

The increase in the earth’s temperature causes extreme weather events, such as heat waves, droughts, floods, and rising sea levels, all of which results in multiple health effects. These include conditions associated with water and food contamination, and increased susceptibility to allergens. There are also changes in vector ecology which leads to expanding areas of vector-borne diseases, such as Lyme disease, West Nile, and Zika.

Extreme weather events also have major impacts on the ability of cancer patients to access care and their medication. For example, a recent study published in JAMA found that poorer survival was associated with patients with non–small cell lung cancer receiving definitive radiation therapy during hurricane disasters, compared with a matched cohort of patients who underwent treatment in the absence of a hurricane disaster.

Reducing our dependence on fossil fuels will have two important health benefits: mitigating climate change and its associated effects on health, and decreasing air pollution and its subsequent oncologic consequences.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Air pollution is a well-established cause of morbidity and mortality. It largely comes from manmade sources such as particulate matter that arises from burning fossil fuels, which is a major contributor of greenhouse gas emissions.

Acute exposure to fine inhalable particles of as little as 2.5 mcm (PM2.5) in diameter can cause a decrease in lung function leading to respiratory and cardiovascular diseases and even death because of cardiopulmonary conditions and lung cancer.

The 2015 Global Burden of Disease study lists air pollution as the fourth highest–ranking global mortality risk factor. The World Health Organization estimated that 4.2 million deaths were caused by outdoor air pollution in 2016, and another 2.3 million from indoor air pollution.

Not all oncologists believe that air pollution is a cancer problem, but air pollution and particulate matters are carcinogens and in fact, they have been deemed level 1 carcinogens by the International Association of Research on Cancer.

The research on the link between air pollution, PM2.5 and lung cancer is robust. Numerous epidemiological studies have shown that people living in highly polluted areas are more likely to die of lung cancer than those who do not. For example, Turner and colleagues in CA: A Cancer Journal for Clinicians performed a Cox proportional hazard regression model adjusting for numerous variables – smoking, passive smoking, occupational exposures (asbestos, coal dust, diesel engine exhaust, etc.), an occupational “dirtiness” index, radon exposure, among others – and found a dose-response relationship between PM2.5 concentration and lung cancer mortality (each 10-mg/m increase in PM2.5 concentrations was associated with a 15%-27% increase in lung cancer mortality).

A similar analysis by Coleman and colleagues in Cancer Causes and Control found lung cancer mortality was adversely associated with increases in PM2.5 not only in the overall population that was studied, but also in a never-smoker cohort. A study reported in Environmental Health Perspectives also showed that exposure to air pollution increases the incidence and mortality from lung cancer, with lung cancer risk associated with PM2.5 exposure being greatest for former smokers (hazard ratio, 1.44; 95% CI, 1.04-2.01), followed by never-smokers (HR, 1.18; 95% CI, 1.00-1.39), and then current smokers (HR, 1.06; 95% CI, 0.97-1.15).

A 2020 study reported in Thorax that patients with COPD who have never smoked were more likely to get lung cancer, compared with never-smokers without COPD (HR, 2.67, 95% CI, 2.09-3.40). Other studies (The Lancet Oncology and The Lancet) confirm these findings. A meta-analysis published in Environmental Research of a large number of cohort studies over the past 25 years reported that the estimated HR, adjusted for age, sex, and smoking status, was 1.13 (95% CI, 1.07-1.20) per 10 mcg/m elevation in PM2.5.

Air pollution also affects patients who already have lung cancer. Air pollution exposures after the diagnosis of lung cancer shortens survival. For example, a 2016 study published in the journal Thorax found the median survival for patients with early-stage lung cancer at diagnosis was 2.4 years for those with high PM2.5 exposure (≥ 16 mcg/m³) and 5.7 years for those with low PM2.5 exposure (< 10 mcg/m³).

What does air pollution have to do with climate change? They both come from the burning of fossil fuels

Although the topic of climate change is generally seen through an environmental (and political) lens, it should also be seen through a health lens. In 2021, the New England Journal of Medicine and 229 other publications simultaneously published an editorial calling climate change a health emergency.

The increase in the earth’s temperature causes extreme weather events, such as heat waves, droughts, floods, and rising sea levels, all of which results in multiple health effects. These include conditions associated with water and food contamination, and increased susceptibility to allergens. There are also changes in vector ecology which leads to expanding areas of vector-borne diseases, such as Lyme disease, West Nile, and Zika.

Extreme weather events also have major impacts on the ability of cancer patients to access care and their medication. For example, a recent study published in JAMA found that poorer survival was associated with patients with non–small cell lung cancer receiving definitive radiation therapy during hurricane disasters, compared with a matched cohort of patients who underwent treatment in the absence of a hurricane disaster.

Reducing our dependence on fossil fuels will have two important health benefits: mitigating climate change and its associated effects on health, and decreasing air pollution and its subsequent oncologic consequences.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Air pollution is a well-established cause of morbidity and mortality. It largely comes from manmade sources such as particulate matter that arises from burning fossil fuels, which is a major contributor of greenhouse gas emissions.

Acute exposure to fine inhalable particles of as little as 2.5 mcm (PM2.5) in diameter can cause a decrease in lung function leading to respiratory and cardiovascular diseases and even death because of cardiopulmonary conditions and lung cancer.

The 2015 Global Burden of Disease study lists air pollution as the fourth highest–ranking global mortality risk factor. The World Health Organization estimated that 4.2 million deaths were caused by outdoor air pollution in 2016, and another 2.3 million from indoor air pollution.

Not all oncologists believe that air pollution is a cancer problem, but air pollution and particulate matters are carcinogens and in fact, they have been deemed level 1 carcinogens by the International Association of Research on Cancer.

The research on the link between air pollution, PM2.5 and lung cancer is robust. Numerous epidemiological studies have shown that people living in highly polluted areas are more likely to die of lung cancer than those who do not. For example, Turner and colleagues in CA: A Cancer Journal for Clinicians performed a Cox proportional hazard regression model adjusting for numerous variables – smoking, passive smoking, occupational exposures (asbestos, coal dust, diesel engine exhaust, etc.), an occupational “dirtiness” index, radon exposure, among others – and found a dose-response relationship between PM2.5 concentration and lung cancer mortality (each 10-mg/m increase in PM2.5 concentrations was associated with a 15%-27% increase in lung cancer mortality).

A similar analysis by Coleman and colleagues in Cancer Causes and Control found lung cancer mortality was adversely associated with increases in PM2.5 not only in the overall population that was studied, but also in a never-smoker cohort. A study reported in Environmental Health Perspectives also showed that exposure to air pollution increases the incidence and mortality from lung cancer, with lung cancer risk associated with PM2.5 exposure being greatest for former smokers (hazard ratio, 1.44; 95% CI, 1.04-2.01), followed by never-smokers (HR, 1.18; 95% CI, 1.00-1.39), and then current smokers (HR, 1.06; 95% CI, 0.97-1.15).

A 2020 study reported in Thorax that patients with COPD who have never smoked were more likely to get lung cancer, compared with never-smokers without COPD (HR, 2.67, 95% CI, 2.09-3.40). Other studies (The Lancet Oncology and The Lancet) confirm these findings. A meta-analysis published in Environmental Research of a large number of cohort studies over the past 25 years reported that the estimated HR, adjusted for age, sex, and smoking status, was 1.13 (95% CI, 1.07-1.20) per 10 mcg/m elevation in PM2.5.

Air pollution also affects patients who already have lung cancer. Air pollution exposures after the diagnosis of lung cancer shortens survival. For example, a 2016 study published in the journal Thorax found the median survival for patients with early-stage lung cancer at diagnosis was 2.4 years for those with high PM2.5 exposure (≥ 16 mcg/m³) and 5.7 years for those with low PM2.5 exposure (< 10 mcg/m³).

What does air pollution have to do with climate change? They both come from the burning of fossil fuels

Although the topic of climate change is generally seen through an environmental (and political) lens, it should also be seen through a health lens. In 2021, the New England Journal of Medicine and 229 other publications simultaneously published an editorial calling climate change a health emergency.

The increase in the earth’s temperature causes extreme weather events, such as heat waves, droughts, floods, and rising sea levels, all of which results in multiple health effects. These include conditions associated with water and food contamination, and increased susceptibility to allergens. There are also changes in vector ecology which leads to expanding areas of vector-borne diseases, such as Lyme disease, West Nile, and Zika.

Extreme weather events also have major impacts on the ability of cancer patients to access care and their medication. For example, a recent study published in JAMA found that poorer survival was associated with patients with non–small cell lung cancer receiving definitive radiation therapy during hurricane disasters, compared with a matched cohort of patients who underwent treatment in the absence of a hurricane disaster.

Reducing our dependence on fossil fuels will have two important health benefits: mitigating climate change and its associated effects on health, and decreasing air pollution and its subsequent oncologic consequences.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.