Andrew D. Bowser

MILAN – Among the dermatologic adverse effects of immune checkpoint inhibitor therapy, bullous disorders are relatively infrequent but associated with a high likelihood of treatment interruption, according to results of a single-center study described at the World Congress of Dermatology.

Bullous disorders were seen in about 1% of patients receiving anti-PD-1 or anti-PD-L1 therapy in the single-center retrospective review, and nearly all required systemic steroids and were associated with interruptions and discontinuations of the anti-cancer treatment, reported Jonathan Leventhal, MD, director of the oncodermatology clinic at Yale University, New Haven, Conn.

“This series highlights a very important, clinically relevant, cutaneous immune-related adverse event,” Dr. Leventhal said in an oral presentation at the congress. “These disorders manifested in most patients as bullous pemphigoid, occurred several months after starting therapy, and at a frequency rate of 1%” among all patients treated with these agents, “at least in our institution.”

The retrospective review presented by Dr. Leventhal was based on medical records of patients evaluated at Yale New Haven Hospital between 2016 and 2018. This included a total of 853 patients who received anti-PD-1/PD-L1 therapy, of whom 98 (11.5%) were evaluated at the oncodermatology clinic or inpatient consultative service.

Nine patients – five men, four women – developed bullous disorders, representing about 1% of patients treated with PD-1/PD-L1 blocking therapy, according to Dr. Leventhal. The mean age of the patients was 67.4 years. Seven of the nine patients had received PD-1 inhibitors, while two received PD-L1 inhibitors, for tumors of the lung in four cases, melanoma in two, genitourinary tumors in two, and acute myeloid leukemia in one.

“The time from rash onset to first administration of the drug was over 6 months, which is quite long compared to a lot of the other (checkpoint inhibitor–associated) toxicities that we see more commonly, which often occur in several weeks to just a few months,” Dr. Leventhal said.

Of the 853 patients in this retrospective study, 463 (54.3%) were treated with nivolumab (Opdivo) and 242 (28.4%) were treated with pembrolizumab (Keytruda), both PD-1 blockers. Of the remainder, 112 (13.1%) received the PD-L1 blockers atezolizumab (Tecentriq), 29 (3.4%) received durvalumab (Imfinzi), and 7 (0.8%) received avelumab (Bavencio), Dr. Leventhal reported.

All these patients presented with both pruritus and vesiculobullous eruptions seen mainly on the trunk and extremities, while two patients had oral ulcerations. Other presentations included urticarial-predominant bullous pemphigoid, dyshidrosiform pemphigoid, and lichenoid papules and vesicles. The diagnosis was bullous pemphigoid in seven of nine cases, Dr. Leventhal said.

The best management approach for immune-related bullous disorders would be use of high-potency topical steroids to avoid systemic steroids and avoid interruptions in checkpoint inhibitor therapy, he pointed out. However, eight of the nine patients in this retrospective series required systemic steroids due to progression of the bullae, he added.

Several notable cases were described, including one patient refractory to prednisone and omalizumab who eventually achieved control with methotrexate, a second patient who was well controlled with omalizumab monotherapy and able to resume treatment with an anti PD-1 inhibitor, and another patient who responded to prednisone and dapsone maintenance therapy.

The immunotherapy treatment for cancer was interrupted in four of nine patients due to the bullous disorders, and was permanently discontinued in another four, Dr. Leventhal said.

It’s not clear why patients receiving cancer immunotherapy treatment develop bullous pemphigoid. However, the 180-kd bullous pemphigoid antigen (BP180) is expressed in melanoma and non-small cell lung cancer, which may lead to production of antibodies against tumor cell antigens that also impact the skin, according to Dr. Leventhal.

Further studies are needed to evaluate whether immune-related bullous disorders have any prognostic significance in cancer patients, he added.

Dr. Leventhal reported that he had no relevant disclosures.

MILAN – Among the dermatologic adverse effects of immune checkpoint inhibitor therapy, bullous disorders are relatively infrequent but associated with a high likelihood of treatment interruption, according to results of a single-center study described at the World Congress of Dermatology.

Bullous disorders were seen in about 1% of patients receiving anti-PD-1 or anti-PD-L1 therapy in the single-center retrospective review, and nearly all required systemic steroids and were associated with interruptions and discontinuations of the anti-cancer treatment, reported Jonathan Leventhal, MD, director of the oncodermatology clinic at Yale University, New Haven, Conn.

“This series highlights a very important, clinically relevant, cutaneous immune-related adverse event,” Dr. Leventhal said in an oral presentation at the congress. “These disorders manifested in most patients as bullous pemphigoid, occurred several months after starting therapy, and at a frequency rate of 1%” among all patients treated with these agents, “at least in our institution.”

The retrospective review presented by Dr. Leventhal was based on medical records of patients evaluated at Yale New Haven Hospital between 2016 and 2018. This included a total of 853 patients who received anti-PD-1/PD-L1 therapy, of whom 98 (11.5%) were evaluated at the oncodermatology clinic or inpatient consultative service.

Nine patients – five men, four women – developed bullous disorders, representing about 1% of patients treated with PD-1/PD-L1 blocking therapy, according to Dr. Leventhal. The mean age of the patients was 67.4 years. Seven of the nine patients had received PD-1 inhibitors, while two received PD-L1 inhibitors, for tumors of the lung in four cases, melanoma in two, genitourinary tumors in two, and acute myeloid leukemia in one.

“The time from rash onset to first administration of the drug was over 6 months, which is quite long compared to a lot of the other (checkpoint inhibitor–associated) toxicities that we see more commonly, which often occur in several weeks to just a few months,” Dr. Leventhal said.

Of the 853 patients in this retrospective study, 463 (54.3%) were treated with nivolumab (Opdivo) and 242 (28.4%) were treated with pembrolizumab (Keytruda), both PD-1 blockers. Of the remainder, 112 (13.1%) received the PD-L1 blockers atezolizumab (Tecentriq), 29 (3.4%) received durvalumab (Imfinzi), and 7 (0.8%) received avelumab (Bavencio), Dr. Leventhal reported.

All these patients presented with both pruritus and vesiculobullous eruptions seen mainly on the trunk and extremities, while two patients had oral ulcerations. Other presentations included urticarial-predominant bullous pemphigoid, dyshidrosiform pemphigoid, and lichenoid papules and vesicles. The diagnosis was bullous pemphigoid in seven of nine cases, Dr. Leventhal said.

The best management approach for immune-related bullous disorders would be use of high-potency topical steroids to avoid systemic steroids and avoid interruptions in checkpoint inhibitor therapy, he pointed out. However, eight of the nine patients in this retrospective series required systemic steroids due to progression of the bullae, he added.

Several notable cases were described, including one patient refractory to prednisone and omalizumab who eventually achieved control with methotrexate, a second patient who was well controlled with omalizumab monotherapy and able to resume treatment with an anti PD-1 inhibitor, and another patient who responded to prednisone and dapsone maintenance therapy.

The immunotherapy treatment for cancer was interrupted in four of nine patients due to the bullous disorders, and was permanently discontinued in another four, Dr. Leventhal said.

It’s not clear why patients receiving cancer immunotherapy treatment develop bullous pemphigoid. However, the 180-kd bullous pemphigoid antigen (BP180) is expressed in melanoma and non-small cell lung cancer, which may lead to production of antibodies against tumor cell antigens that also impact the skin, according to Dr. Leventhal.

Further studies are needed to evaluate whether immune-related bullous disorders have any prognostic significance in cancer patients, he added.

Dr. Leventhal reported that he had no relevant disclosures.

MILAN – Among the dermatologic adverse effects of immune checkpoint inhibitor therapy, bullous disorders are relatively infrequent but associated with a high likelihood of treatment interruption, according to results of a single-center study described at the World Congress of Dermatology.

Bullous disorders were seen in about 1% of patients receiving anti-PD-1 or anti-PD-L1 therapy in the single-center retrospective review, and nearly all required systemic steroids and were associated with interruptions and discontinuations of the anti-cancer treatment, reported Jonathan Leventhal, MD, director of the oncodermatology clinic at Yale University, New Haven, Conn.

“This series highlights a very important, clinically relevant, cutaneous immune-related adverse event,” Dr. Leventhal said in an oral presentation at the congress. “These disorders manifested in most patients as bullous pemphigoid, occurred several months after starting therapy, and at a frequency rate of 1%” among all patients treated with these agents, “at least in our institution.”

The retrospective review presented by Dr. Leventhal was based on medical records of patients evaluated at Yale New Haven Hospital between 2016 and 2018. This included a total of 853 patients who received anti-PD-1/PD-L1 therapy, of whom 98 (11.5%) were evaluated at the oncodermatology clinic or inpatient consultative service.

Nine patients – five men, four women – developed bullous disorders, representing about 1% of patients treated with PD-1/PD-L1 blocking therapy, according to Dr. Leventhal. The mean age of the patients was 67.4 years. Seven of the nine patients had received PD-1 inhibitors, while two received PD-L1 inhibitors, for tumors of the lung in four cases, melanoma in two, genitourinary tumors in two, and acute myeloid leukemia in one.

“The time from rash onset to first administration of the drug was over 6 months, which is quite long compared to a lot of the other (checkpoint inhibitor–associated) toxicities that we see more commonly, which often occur in several weeks to just a few months,” Dr. Leventhal said.

Of the 853 patients in this retrospective study, 463 (54.3%) were treated with nivolumab (Opdivo) and 242 (28.4%) were treated with pembrolizumab (Keytruda), both PD-1 blockers. Of the remainder, 112 (13.1%) received the PD-L1 blockers atezolizumab (Tecentriq), 29 (3.4%) received durvalumab (Imfinzi), and 7 (0.8%) received avelumab (Bavencio), Dr. Leventhal reported.

All these patients presented with both pruritus and vesiculobullous eruptions seen mainly on the trunk and extremities, while two patients had oral ulcerations. Other presentations included urticarial-predominant bullous pemphigoid, dyshidrosiform pemphigoid, and lichenoid papules and vesicles. The diagnosis was bullous pemphigoid in seven of nine cases, Dr. Leventhal said.

The best management approach for immune-related bullous disorders would be use of high-potency topical steroids to avoid systemic steroids and avoid interruptions in checkpoint inhibitor therapy, he pointed out. However, eight of the nine patients in this retrospective series required systemic steroids due to progression of the bullae, he added.

Several notable cases were described, including one patient refractory to prednisone and omalizumab who eventually achieved control with methotrexate, a second patient who was well controlled with omalizumab monotherapy and able to resume treatment with an anti PD-1 inhibitor, and another patient who responded to prednisone and dapsone maintenance therapy.

The immunotherapy treatment for cancer was interrupted in four of nine patients due to the bullous disorders, and was permanently discontinued in another four, Dr. Leventhal said.

It’s not clear why patients receiving cancer immunotherapy treatment develop bullous pemphigoid. However, the 180-kd bullous pemphigoid antigen (BP180) is expressed in melanoma and non-small cell lung cancer, which may lead to production of antibodies against tumor cell antigens that also impact the skin, according to Dr. Leventhal.

Further studies are needed to evaluate whether immune-related bullous disorders have any prognostic significance in cancer patients, he added.

Dr. Leventhal reported that he had no relevant disclosures.

MILAN – DC-HIL is a novel immune checkpoint with “great promise” as a treatment target for melanoma and other cancers, Ponciano D. Cruz Jr., MD, said at the World Congress of Dermatology.

Andrew D. Bowser/MDedge News

Dr. Cruz, who along with colleagues discovered the immune checkpoint, have generated an anti–DC-HIL monoclonal antibody, which he said dramatically reduces melanoma growth and metastasis in animal models.

That antibody has also been shown to block the T-cell suppressor function of myeloid-derived suppressor cells (MDSCs), according to Dr. Cruz, who is with the department of dermatology at the University of Texas Southwestern Medical Center, Dallas.

“To date, we haven’t subjected our antibodies to clinical trials, but that will happen soon,” he said in an oral presentation at the meeting.

Also referred to as GPNMB, DC-HIL exists as a cell-bound receptor, and as a soluble factor secreted into circulation, according to Dr. Cruz.

In healthy subjects, DC-HIL is expressed in low levels by certain immune cells but is highly expressed by MDSCs in patients with melanoma, as well as other cancers including breast, colorectal, kidney, lung, and prostate cancers, he said. Those MDSCs expand exponentially as malignancies progress, he noted.

Soluble DC-HIL can be detected in the blood of many patients, and at increasing levels with metastasis, he added. DC-HIL–positive MDSC, and soluble DC-HIL, are blood markers that “may prognosticate the course and response to treatment of these cancers,” he said.

The researchers have demonstrated that DC-HIL inhibits T-cell activation by binding to its ligand, syndecan-4, on effector T cells, Dr. Cruz told attendees. “Thus, DC-HIL/syndecan-4 is a coinhibitory pathway akin to immune checkpoints CTLA4 [cytotoxic T-lymphocyte antigen 4] and PD-1 [programmed death-1],” he said.

In DC-HIL knockout mice, melanoma growth is suppressed in comparison to melanoma growth in wild-type mice, Dr. Cruz and colleagues have found in previous experiments. They subsequently found that their anti–DC-HIL monoclonal antibody reduced melanoma growth and metastasis in mice.

The antibody reversed the T-cell suppressor effect of MDSC in patients with metastatic melanoma and other cancers, he said.

Dr. Cruz has reported a disclosure (patents, royalties, other intellectual property) related to the use of anti–DC-HIL antibodies for cancer diagnosis, prognosis, and therapy.

MILAN – DC-HIL is a novel immune checkpoint with “great promise” as a treatment target for melanoma and other cancers, Ponciano D. Cruz Jr., MD, said at the World Congress of Dermatology.

Andrew D. Bowser/MDedge News

Dr. Cruz, who along with colleagues discovered the immune checkpoint, have generated an anti–DC-HIL monoclonal antibody, which he said dramatically reduces melanoma growth and metastasis in animal models.

That antibody has also been shown to block the T-cell suppressor function of myeloid-derived suppressor cells (MDSCs), according to Dr. Cruz, who is with the department of dermatology at the University of Texas Southwestern Medical Center, Dallas.

“To date, we haven’t subjected our antibodies to clinical trials, but that will happen soon,” he said in an oral presentation at the meeting.

Also referred to as GPNMB, DC-HIL exists as a cell-bound receptor, and as a soluble factor secreted into circulation, according to Dr. Cruz.

In healthy subjects, DC-HIL is expressed in low levels by certain immune cells but is highly expressed by MDSCs in patients with melanoma, as well as other cancers including breast, colorectal, kidney, lung, and prostate cancers, he said. Those MDSCs expand exponentially as malignancies progress, he noted.

Soluble DC-HIL can be detected in the blood of many patients, and at increasing levels with metastasis, he added. DC-HIL–positive MDSC, and soluble DC-HIL, are blood markers that “may prognosticate the course and response to treatment of these cancers,” he said.

The researchers have demonstrated that DC-HIL inhibits T-cell activation by binding to its ligand, syndecan-4, on effector T cells, Dr. Cruz told attendees. “Thus, DC-HIL/syndecan-4 is a coinhibitory pathway akin to immune checkpoints CTLA4 [cytotoxic T-lymphocyte antigen 4] and PD-1 [programmed death-1],” he said.

In DC-HIL knockout mice, melanoma growth is suppressed in comparison to melanoma growth in wild-type mice, Dr. Cruz and colleagues have found in previous experiments. They subsequently found that their anti–DC-HIL monoclonal antibody reduced melanoma growth and metastasis in mice.

The antibody reversed the T-cell suppressor effect of MDSC in patients with metastatic melanoma and other cancers, he said.

Dr. Cruz has reported a disclosure (patents, royalties, other intellectual property) related to the use of anti–DC-HIL antibodies for cancer diagnosis, prognosis, and therapy.

MILAN – DC-HIL is a novel immune checkpoint with “great promise” as a treatment target for melanoma and other cancers, Ponciano D. Cruz Jr., MD, said at the World Congress of Dermatology.

Andrew D. Bowser/MDedge News

Dr. Cruz, who along with colleagues discovered the immune checkpoint, have generated an anti–DC-HIL monoclonal antibody, which he said dramatically reduces melanoma growth and metastasis in animal models.

That antibody has also been shown to block the T-cell suppressor function of myeloid-derived suppressor cells (MDSCs), according to Dr. Cruz, who is with the department of dermatology at the University of Texas Southwestern Medical Center, Dallas.

“To date, we haven’t subjected our antibodies to clinical trials, but that will happen soon,” he said in an oral presentation at the meeting.

Also referred to as GPNMB, DC-HIL exists as a cell-bound receptor, and as a soluble factor secreted into circulation, according to Dr. Cruz.

In healthy subjects, DC-HIL is expressed in low levels by certain immune cells but is highly expressed by MDSCs in patients with melanoma, as well as other cancers including breast, colorectal, kidney, lung, and prostate cancers, he said. Those MDSCs expand exponentially as malignancies progress, he noted.

Soluble DC-HIL can be detected in the blood of many patients, and at increasing levels with metastasis, he added. DC-HIL–positive MDSC, and soluble DC-HIL, are blood markers that “may prognosticate the course and response to treatment of these cancers,” he said.

The researchers have demonstrated that DC-HIL inhibits T-cell activation by binding to its ligand, syndecan-4, on effector T cells, Dr. Cruz told attendees. “Thus, DC-HIL/syndecan-4 is a coinhibitory pathway akin to immune checkpoints CTLA4 [cytotoxic T-lymphocyte antigen 4] and PD-1 [programmed death-1],” he said.

In DC-HIL knockout mice, melanoma growth is suppressed in comparison to melanoma growth in wild-type mice, Dr. Cruz and colleagues have found in previous experiments. They subsequently found that their anti–DC-HIL monoclonal antibody reduced melanoma growth and metastasis in mice.

The antibody reversed the T-cell suppressor effect of MDSC in patients with metastatic melanoma and other cancers, he said.

Dr. Cruz has reported a disclosure (patents, royalties, other intellectual property) related to the use of anti–DC-HIL antibodies for cancer diagnosis, prognosis, and therapy.

MILAN – Hydroxychloroquine sulfate may be an effective and relatively safe treatment option for moderate to severe oral lichen planus, an investigator reported at the World Congress of Dermatology.

Andrew Bowser/MDedge News

In a small retrospective study, 85% of patients treated with the oral antimalarial agent had marked improvement or full remission, according to Ziyad Khamaysi, MD, a dermatologist at Rambam Health Care Campus, Haifa, Israel. Adverse effects leading to discontinuation occurred in a minority of patients and included elevated kidney function tests, hyperpigmentation, and an abnormal eye exam, he said.

“It may be a useful and convenient alternative treatment either as a monotherapy or where a rapid symptomatic relief during periods of exacerbations is needed,” he said in an oral presentation at the meeting.

A variety of medications have been used for palliation of oral lichen planus, including corticosteroids, cyclosporine, calcineurin inhibitors, retinoids, and biologics, but few have been evaluated in larger series of patients, he pointed out.

In the retrospective, nonrandomized study, 15 women and 6 men with erosive, recalcitrant oral lichen planus were treated with hydroxychloroquine (Plaquenil) at a dose of 200 mg/day, which was increased to 400 mg/day at one month. The mean age of the patients was 55 years.

In one patient, treatment was stopped after a month because of side effects, Dr. Khamaysi said. Among the remaining patients, 5 (25%) had a complete remission, while 12 (60%) had moderate to marked improvement, and 3 (15%) had no improvement, he said. In the patients who did respond, improvement was noted within 2-4 months of treatment initiation, he added. “Hydroxychloroquine kept the disease under control, with either full remission or marked improvement as long as the patients took it.”

Treatment appeared to be more effective in male patients and those under age 65 years, the investigator commented.

These data corroborate the findings of a smaller study evaluating hydroxychloroquine for oral lichen planus, published in 1993, according to Dr. Khamaysi. In that report, 9 of 10 patients had an “excellent” response to treatment, according to the investigator (J Am Acad Dermatol. 1993 Apr;28[4]:609-12).

Of the 10 patients in that study, 6 had erosions at the start of treatment, and 3 of these patients had complete healing with 3-6 months of therapy, and the other 3 had reepithelialization and at least a 50% reduction in lesion size, according to the report.

Dr. Khamaysi had no disclosures relevant to his presentation.

MILAN – Hydroxychloroquine sulfate may be an effective and relatively safe treatment option for moderate to severe oral lichen planus, an investigator reported at the World Congress of Dermatology.

Andrew Bowser/MDedge News

In a small retrospective study, 85% of patients treated with the oral antimalarial agent had marked improvement or full remission, according to Ziyad Khamaysi, MD, a dermatologist at Rambam Health Care Campus, Haifa, Israel. Adverse effects leading to discontinuation occurred in a minority of patients and included elevated kidney function tests, hyperpigmentation, and an abnormal eye exam, he said.

“It may be a useful and convenient alternative treatment either as a monotherapy or where a rapid symptomatic relief during periods of exacerbations is needed,” he said in an oral presentation at the meeting.

A variety of medications have been used for palliation of oral lichen planus, including corticosteroids, cyclosporine, calcineurin inhibitors, retinoids, and biologics, but few have been evaluated in larger series of patients, he pointed out.

In the retrospective, nonrandomized study, 15 women and 6 men with erosive, recalcitrant oral lichen planus were treated with hydroxychloroquine (Plaquenil) at a dose of 200 mg/day, which was increased to 400 mg/day at one month. The mean age of the patients was 55 years.

In one patient, treatment was stopped after a month because of side effects, Dr. Khamaysi said. Among the remaining patients, 5 (25%) had a complete remission, while 12 (60%) had moderate to marked improvement, and 3 (15%) had no improvement, he said. In the patients who did respond, improvement was noted within 2-4 months of treatment initiation, he added. “Hydroxychloroquine kept the disease under control, with either full remission or marked improvement as long as the patients took it.”

Treatment appeared to be more effective in male patients and those under age 65 years, the investigator commented.

These data corroborate the findings of a smaller study evaluating hydroxychloroquine for oral lichen planus, published in 1993, according to Dr. Khamaysi. In that report, 9 of 10 patients had an “excellent” response to treatment, according to the investigator (J Am Acad Dermatol. 1993 Apr;28[4]:609-12).

Of the 10 patients in that study, 6 had erosions at the start of treatment, and 3 of these patients had complete healing with 3-6 months of therapy, and the other 3 had reepithelialization and at least a 50% reduction in lesion size, according to the report.

Dr. Khamaysi had no disclosures relevant to his presentation.

MILAN – Hydroxychloroquine sulfate may be an effective and relatively safe treatment option for moderate to severe oral lichen planus, an investigator reported at the World Congress of Dermatology.

Andrew Bowser/MDedge News

In a small retrospective study, 85% of patients treated with the oral antimalarial agent had marked improvement or full remission, according to Ziyad Khamaysi, MD, a dermatologist at Rambam Health Care Campus, Haifa, Israel. Adverse effects leading to discontinuation occurred in a minority of patients and included elevated kidney function tests, hyperpigmentation, and an abnormal eye exam, he said.

“It may be a useful and convenient alternative treatment either as a monotherapy or where a rapid symptomatic relief during periods of exacerbations is needed,” he said in an oral presentation at the meeting.

A variety of medications have been used for palliation of oral lichen planus, including corticosteroids, cyclosporine, calcineurin inhibitors, retinoids, and biologics, but few have been evaluated in larger series of patients, he pointed out.

In the retrospective, nonrandomized study, 15 women and 6 men with erosive, recalcitrant oral lichen planus were treated with hydroxychloroquine (Plaquenil) at a dose of 200 mg/day, which was increased to 400 mg/day at one month. The mean age of the patients was 55 years.

In one patient, treatment was stopped after a month because of side effects, Dr. Khamaysi said. Among the remaining patients, 5 (25%) had a complete remission, while 12 (60%) had moderate to marked improvement, and 3 (15%) had no improvement, he said. In the patients who did respond, improvement was noted within 2-4 months of treatment initiation, he added. “Hydroxychloroquine kept the disease under control, with either full remission or marked improvement as long as the patients took it.”

Treatment appeared to be more effective in male patients and those under age 65 years, the investigator commented.

These data corroborate the findings of a smaller study evaluating hydroxychloroquine for oral lichen planus, published in 1993, according to Dr. Khamaysi. In that report, 9 of 10 patients had an “excellent” response to treatment, according to the investigator (J Am Acad Dermatol. 1993 Apr;28[4]:609-12).

Of the 10 patients in that study, 6 had erosions at the start of treatment, and 3 of these patients had complete healing with 3-6 months of therapy, and the other 3 had reepithelialization and at least a 50% reduction in lesion size, according to the report.

Dr. Khamaysi had no disclosures relevant to his presentation.

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.

Andrew Bowser/MDedge News

The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.

Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.

“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.

The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.

The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.

The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.

In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.

This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.

Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”

While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.

“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.

Mr. Molina reported no conflicts of interest.

MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.

Andrew Bowser/MDedge News

The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.

Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.

“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.

The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.

The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.

The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.

In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.

This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.

Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”

While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.

“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.

Mr. Molina reported no conflicts of interest.

MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.

Andrew Bowser/MDedge News

The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.

Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.

“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.

The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.

The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.

The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.

In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.

This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.

Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”

While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.

“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.

Mr. Molina reported no conflicts of interest.

MILAN – A checkpoint inhibitor given with or without targeted therapy resulted in robust response rates in patients with advanced basal cell carcinoma, according to an investigator in a recent proof-of-concept study.

The side effect profile for the progressive death 1 (PD-1) inhibitor pembrolizumab (Keytruda), plus or minus the hedgehog pathway inhibitor vismodegib (Erivedge), was “not out of range” with what’s been observed in other cancer types, said Anne Lynn S. Chang, MD, a medical dermatologist at Stanford (Calif.) University.

Taken together, these safety and efficacy results suggest pembrolizumab could prove useful for patients with advanced basal cell carcinomas, Dr. Chang said in an oral presentation at the World Congress of Dermatology.

Unexpectedly, dual therapy with pembrolizumab and vismodegib was not clearly superior to pembrolizumab alone, though the two arms are not directly comparable in this nonrandomized, investigator-initiated study, according to Dr. Chang.

“That was a surprise for us, but this is a subjective and a small study,” she told attendees at the conference.

There is currently a multi-institutional clinical trial underway to evaluate another PD-1 inhibitor, cemiplimab, in patients with advanced basal cell carcinoma previously treated with a hedgehog pathway inhibitor, she said.

While a large fraction of basal cell carcinomas are cured by resection, those that are locally advanced or metastatic to lymph nodes or distant organs are challenging to manage. Hedgehog pathway inhibitors, which include vismodegib and sonidegib, are the only Food and Drug Administration–approved drug class in this setting, but more than half of patients do not have a response to treatment, and another 20% or so will initially respond but develop resistance, Dr. Chang said.

Other treatments that have been tried in advanced basal cell carcinomas include taxanes, platinum-based agents, 5-fluorouracil, and everolimus, but their efficacy is unclear, according to Dr. Chang, because of a lack of systematic studies.

Investigators thought PD-1 inhibitors might be promising in basal cell carcinoma for a few reasons, Dr. Chang said. In particular, PD-1 inhibitor treatment response has been linked to mutational burden and PD–ligand 1 expression, and advanced basal cell carcinomas have the largest mutational burden of all human cancers, a large proportion of which express PD-L1.

There are multiple case reports in the literature suggesting that advanced basal cell carcinoma is responsive to PD-1 inhibitors, she added.

In the study, nine patients received 200 mg infusion of pembrolizumab every 3 weeks, and seven received the pembrolizumab infusions plus oral vismodegib 150 mg per day.

The pembrolizumab monotherapy group included patients who had tumor progression on vismodegib, did not tolerate vismodegib, or had contraindications to vismodegib. The pembrolizumab-vismodegib regimen was used in patients who had prior stable or partial responses to hedgehog pathway inhibitors.

The overall response rate was 38%, or 6 of 16 patients, with a 70% probability of 1-year progression-free survival and 94% probability of 1-year overall survival, Dr. Chang reported.

The results did not make the case that pembrolizumab and vismodegib was superior to pembrolizumab alone, though as Dr. Chang noted, the numbers of patients were small. Response rates were 29% (two of seven patients) in the combination arm and 44% (four of nine patients) in the monotherapy arm.

There were 24 immune-related adverse events in the trial; the most serious was hyponatremia, which was reversible, according to Dr. Chang. The overall rates of grade 3-4 adverse events were 22% for pembrolizumab monotherapy and 17% for dual therapy.

A report on the study has also been published in the Journal of the American Academy of Dermatology.

Funding for the study was provided by Merck. Dr. Chang reported serving as a clinical investigator and advisory board member for studies sponsored by Genentech-Roche, Merck, Novartis, and Regeneron.
 

MILAN – A checkpoint inhibitor given with or without targeted therapy resulted in robust response rates in patients with advanced basal cell carcinoma, according to an investigator in a recent proof-of-concept study.

The side effect profile for the progressive death 1 (PD-1) inhibitor pembrolizumab (Keytruda), plus or minus the hedgehog pathway inhibitor vismodegib (Erivedge), was “not out of range” with what’s been observed in other cancer types, said Anne Lynn S. Chang, MD, a medical dermatologist at Stanford (Calif.) University.

Taken together, these safety and efficacy results suggest pembrolizumab could prove useful for patients with advanced basal cell carcinomas, Dr. Chang said in an oral presentation at the World Congress of Dermatology.

Unexpectedly, dual therapy with pembrolizumab and vismodegib was not clearly superior to pembrolizumab alone, though the two arms are not directly comparable in this nonrandomized, investigator-initiated study, according to Dr. Chang.

“That was a surprise for us, but this is a subjective and a small study,” she told attendees at the conference.

There is currently a multi-institutional clinical trial underway to evaluate another PD-1 inhibitor, cemiplimab, in patients with advanced basal cell carcinoma previously treated with a hedgehog pathway inhibitor, she said.

While a large fraction of basal cell carcinomas are cured by resection, those that are locally advanced or metastatic to lymph nodes or distant organs are challenging to manage. Hedgehog pathway inhibitors, which include vismodegib and sonidegib, are the only Food and Drug Administration–approved drug class in this setting, but more than half of patients do not have a response to treatment, and another 20% or so will initially respond but develop resistance, Dr. Chang said.

Other treatments that have been tried in advanced basal cell carcinomas include taxanes, platinum-based agents, 5-fluorouracil, and everolimus, but their efficacy is unclear, according to Dr. Chang, because of a lack of systematic studies.

Investigators thought PD-1 inhibitors might be promising in basal cell carcinoma for a few reasons, Dr. Chang said. In particular, PD-1 inhibitor treatment response has been linked to mutational burden and PD–ligand 1 expression, and advanced basal cell carcinomas have the largest mutational burden of all human cancers, a large proportion of which express PD-L1.

There are multiple case reports in the literature suggesting that advanced basal cell carcinoma is responsive to PD-1 inhibitors, she added.

In the study, nine patients received 200 mg infusion of pembrolizumab every 3 weeks, and seven received the pembrolizumab infusions plus oral vismodegib 150 mg per day.

The pembrolizumab monotherapy group included patients who had tumor progression on vismodegib, did not tolerate vismodegib, or had contraindications to vismodegib. The pembrolizumab-vismodegib regimen was used in patients who had prior stable or partial responses to hedgehog pathway inhibitors.

The overall response rate was 38%, or 6 of 16 patients, with a 70% probability of 1-year progression-free survival and 94% probability of 1-year overall survival, Dr. Chang reported.

The results did not make the case that pembrolizumab and vismodegib was superior to pembrolizumab alone, though as Dr. Chang noted, the numbers of patients were small. Response rates were 29% (two of seven patients) in the combination arm and 44% (four of nine patients) in the monotherapy arm.

There were 24 immune-related adverse events in the trial; the most serious was hyponatremia, which was reversible, according to Dr. Chang. The overall rates of grade 3-4 adverse events were 22% for pembrolizumab monotherapy and 17% for dual therapy.

A report on the study has also been published in the Journal of the American Academy of Dermatology.

Funding for the study was provided by Merck. Dr. Chang reported serving as a clinical investigator and advisory board member for studies sponsored by Genentech-Roche, Merck, Novartis, and Regeneron.
 

MILAN – A checkpoint inhibitor given with or without targeted therapy resulted in robust response rates in patients with advanced basal cell carcinoma, according to an investigator in a recent proof-of-concept study.

The side effect profile for the progressive death 1 (PD-1) inhibitor pembrolizumab (Keytruda), plus or minus the hedgehog pathway inhibitor vismodegib (Erivedge), was “not out of range” with what’s been observed in other cancer types, said Anne Lynn S. Chang, MD, a medical dermatologist at Stanford (Calif.) University.

Taken together, these safety and efficacy results suggest pembrolizumab could prove useful for patients with advanced basal cell carcinomas, Dr. Chang said in an oral presentation at the World Congress of Dermatology.

Unexpectedly, dual therapy with pembrolizumab and vismodegib was not clearly superior to pembrolizumab alone, though the two arms are not directly comparable in this nonrandomized, investigator-initiated study, according to Dr. Chang.

“That was a surprise for us, but this is a subjective and a small study,” she told attendees at the conference.

There is currently a multi-institutional clinical trial underway to evaluate another PD-1 inhibitor, cemiplimab, in patients with advanced basal cell carcinoma previously treated with a hedgehog pathway inhibitor, she said.

While a large fraction of basal cell carcinomas are cured by resection, those that are locally advanced or metastatic to lymph nodes or distant organs are challenging to manage. Hedgehog pathway inhibitors, which include vismodegib and sonidegib, are the only Food and Drug Administration–approved drug class in this setting, but more than half of patients do not have a response to treatment, and another 20% or so will initially respond but develop resistance, Dr. Chang said.

Other treatments that have been tried in advanced basal cell carcinomas include taxanes, platinum-based agents, 5-fluorouracil, and everolimus, but their efficacy is unclear, according to Dr. Chang, because of a lack of systematic studies.

Investigators thought PD-1 inhibitors might be promising in basal cell carcinoma for a few reasons, Dr. Chang said. In particular, PD-1 inhibitor treatment response has been linked to mutational burden and PD–ligand 1 expression, and advanced basal cell carcinomas have the largest mutational burden of all human cancers, a large proportion of which express PD-L1.

There are multiple case reports in the literature suggesting that advanced basal cell carcinoma is responsive to PD-1 inhibitors, she added.

In the study, nine patients received 200 mg infusion of pembrolizumab every 3 weeks, and seven received the pembrolizumab infusions plus oral vismodegib 150 mg per day.

The pembrolizumab monotherapy group included patients who had tumor progression on vismodegib, did not tolerate vismodegib, or had contraindications to vismodegib. The pembrolizumab-vismodegib regimen was used in patients who had prior stable or partial responses to hedgehog pathway inhibitors.

The overall response rate was 38%, or 6 of 16 patients, with a 70% probability of 1-year progression-free survival and 94% probability of 1-year overall survival, Dr. Chang reported.

The results did not make the case that pembrolizumab and vismodegib was superior to pembrolizumab alone, though as Dr. Chang noted, the numbers of patients were small. Response rates were 29% (two of seven patients) in the combination arm and 44% (four of nine patients) in the monotherapy arm.

There were 24 immune-related adverse events in the trial; the most serious was hyponatremia, which was reversible, according to Dr. Chang. The overall rates of grade 3-4 adverse events were 22% for pembrolizumab monotherapy and 17% for dual therapy.

A report on the study has also been published in the Journal of the American Academy of Dermatology.

Funding for the study was provided by Merck. Dr. Chang reported serving as a clinical investigator and advisory board member for studies sponsored by Genentech-Roche, Merck, Novartis, and Regeneron.
 

CHICAGO – A novel antibody against CD47 – the “do not eat me” protein – is well tolerated and active in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), according to initial results of a phase 1b study.

Combined with azacitidine, the antibody Hu5F9-G4 (5F9) produced an overall response rate of 64% in untreated AML (9 of 14 patients) and 91% in untreated MDS (10 of 11 patients), according to investigator David A. Sallman, MD, of Moffitt Cancer Center, Tampa, Fla.

With a median follow-up of 3.8 months, none of those patients had yet progressed on the 5F9/azacitidine combination, Dr. Sallman reported during a poster presentation at the annual meeting of the American Society of Clinical Oncology.

A maximum tolerated dose of 5F9 plus the hypomethylating agent was not reached in the study, according to the investigators.

“This was a well-tolerated and safe combination, with encouraging efficacy data in this small cohort that hasn’t been followed for too, too long,” Tara L. Lin, MD, of the University of Kansas Cancer Center, Kansas City, said during a poster discussion session.

“Most interesting is the fact that the combination seems to eliminate the leukemia stem cell population in those patients who respond,” she added.

The fact that 5F9 plus azacitidine eradicated leukemia stem cells in responding patients provides a mechanism for potential long-term durability of response, according to Dr. Sallman and his colleagues.

This first-in-class antibody targets CD47, a “do not eat me” macrophage checkpoint that is overexpressed on tumors, enabling immune invasion, they reported.

However, since CD47 is also expressed on older red blood cells, 5F9 is associated with transient anemia in the first cycle of treatment, Dr. Sallman told attendees at the poster discussion session.

“We do mitigate that with a priming dose of 5F9 that saturates these old red blood cells,” he said. “Over time, going along with the response, the patients have marked hemoglobin improvement, and we do not see worsening of other infection-related complications or cytopenias outside of anemia.”

Based on these results, expansion cohorts have been initiated in both AML and MDS, according to the investigators’ report.

When asked if 5F9 could be tolerable as part of more intensive regimens for fit patients, Dr. Sallman said there are a “whole host of combinations” that may possibly make sense.

“How chemotherapies and other novel agents impact these ‘eat me’ signals – I think some of that needs to be further investigated to come up with the most rational combination,” he said during a question and answer session.

Research funding for the study came from Forty Seven and the California Institute for Regenerative Medicine. Dr. Salman reported having no relationships to disclose. Study coauthors reported relationships with Abbvie, Agios, Celgene, Incyte, and Novartis, among other companies.

SOURCE: Sallman DA et al. ASCO 2019, Abstract 7009.

CHICAGO – A novel antibody against CD47 – the “do not eat me” protein – is well tolerated and active in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), according to initial results of a phase 1b study.

Combined with azacitidine, the antibody Hu5F9-G4 (5F9) produced an overall response rate of 64% in untreated AML (9 of 14 patients) and 91% in untreated MDS (10 of 11 patients), according to investigator David A. Sallman, MD, of Moffitt Cancer Center, Tampa, Fla.

With a median follow-up of 3.8 months, none of those patients had yet progressed on the 5F9/azacitidine combination, Dr. Sallman reported during a poster presentation at the annual meeting of the American Society of Clinical Oncology.

A maximum tolerated dose of 5F9 plus the hypomethylating agent was not reached in the study, according to the investigators.

“This was a well-tolerated and safe combination, with encouraging efficacy data in this small cohort that hasn’t been followed for too, too long,” Tara L. Lin, MD, of the University of Kansas Cancer Center, Kansas City, said during a poster discussion session.

“Most interesting is the fact that the combination seems to eliminate the leukemia stem cell population in those patients who respond,” she added.

The fact that 5F9 plus azacitidine eradicated leukemia stem cells in responding patients provides a mechanism for potential long-term durability of response, according to Dr. Sallman and his colleagues.

This first-in-class antibody targets CD47, a “do not eat me” macrophage checkpoint that is overexpressed on tumors, enabling immune invasion, they reported.

However, since CD47 is also expressed on older red blood cells, 5F9 is associated with transient anemia in the first cycle of treatment, Dr. Sallman told attendees at the poster discussion session.

“We do mitigate that with a priming dose of 5F9 that saturates these old red blood cells,” he said. “Over time, going along with the response, the patients have marked hemoglobin improvement, and we do not see worsening of other infection-related complications or cytopenias outside of anemia.”

Based on these results, expansion cohorts have been initiated in both AML and MDS, according to the investigators’ report.

When asked if 5F9 could be tolerable as part of more intensive regimens for fit patients, Dr. Sallman said there are a “whole host of combinations” that may possibly make sense.

“How chemotherapies and other novel agents impact these ‘eat me’ signals – I think some of that needs to be further investigated to come up with the most rational combination,” he said during a question and answer session.

Research funding for the study came from Forty Seven and the California Institute for Regenerative Medicine. Dr. Salman reported having no relationships to disclose. Study coauthors reported relationships with Abbvie, Agios, Celgene, Incyte, and Novartis, among other companies.

SOURCE: Sallman DA et al. ASCO 2019, Abstract 7009.

CHICAGO – A novel antibody against CD47 – the “do not eat me” protein – is well tolerated and active in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), according to initial results of a phase 1b study.

Combined with azacitidine, the antibody Hu5F9-G4 (5F9) produced an overall response rate of 64% in untreated AML (9 of 14 patients) and 91% in untreated MDS (10 of 11 patients), according to investigator David A. Sallman, MD, of Moffitt Cancer Center, Tampa, Fla.

With a median follow-up of 3.8 months, none of those patients had yet progressed on the 5F9/azacitidine combination, Dr. Sallman reported during a poster presentation at the annual meeting of the American Society of Clinical Oncology.

A maximum tolerated dose of 5F9 plus the hypomethylating agent was not reached in the study, according to the investigators.

“This was a well-tolerated and safe combination, with encouraging efficacy data in this small cohort that hasn’t been followed for too, too long,” Tara L. Lin, MD, of the University of Kansas Cancer Center, Kansas City, said during a poster discussion session.

“Most interesting is the fact that the combination seems to eliminate the leukemia stem cell population in those patients who respond,” she added.

The fact that 5F9 plus azacitidine eradicated leukemia stem cells in responding patients provides a mechanism for potential long-term durability of response, according to Dr. Sallman and his colleagues.

This first-in-class antibody targets CD47, a “do not eat me” macrophage checkpoint that is overexpressed on tumors, enabling immune invasion, they reported.

However, since CD47 is also expressed on older red blood cells, 5F9 is associated with transient anemia in the first cycle of treatment, Dr. Sallman told attendees at the poster discussion session.

“We do mitigate that with a priming dose of 5F9 that saturates these old red blood cells,” he said. “Over time, going along with the response, the patients have marked hemoglobin improvement, and we do not see worsening of other infection-related complications or cytopenias outside of anemia.”

Based on these results, expansion cohorts have been initiated in both AML and MDS, according to the investigators’ report.

When asked if 5F9 could be tolerable as part of more intensive regimens for fit patients, Dr. Sallman said there are a “whole host of combinations” that may possibly make sense.

“How chemotherapies and other novel agents impact these ‘eat me’ signals – I think some of that needs to be further investigated to come up with the most rational combination,” he said during a question and answer session.

Research funding for the study came from Forty Seven and the California Institute for Regenerative Medicine. Dr. Salman reported having no relationships to disclose. Study coauthors reported relationships with Abbvie, Agios, Celgene, Incyte, and Novartis, among other companies.

SOURCE: Sallman DA et al. ASCO 2019, Abstract 7009.

CHICAGO – A chemotherapy-free regimen has produced promising early response and survival outcomes in patients with a particularly poor-prognosis subtype of diffuse large B-cell lymphoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

The overall response rate was 86% after two cycles of combined rituximab, lenalidomide, and ibrutinib – or RLI – in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of the non–germinal center (non-GCB) subtype, said Jason Westin, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.

The response rate increased to 96% after subsequent cycles of RLI plus standard chemotherapy, said Dr.Westin, who added that the rates of progression-free and overall survival at 1 year were also 96% in the investigator initiated, single-arm, open-label, phase 2 study, called Smart Start.

That looks quite favorable, compared with what’s been achieved in previous studies in this poor-prognosis group of patients, Dr. Westin said during a podium presentation of Smart Start data, though he cautioned against direct comparison to historical studies and added that further follow-up is needed.

“Our survival outcomes appear excellent with about a year’s worth of follow-up,” he said during his presentation. “I’d say the novel/novel combinations, with and without chemotherapy, are feasible for large cell, and next step studies are warranted.”

Jasmine M. Zain, MD, of City of Hope Comprehensive Cancer Center, said these results so far raise the possibility of an effective chemotherapy-free treatment regimen for aggressive lymphomas.

“This regimen, particularly for non-GCB subtypes, is extremely promising,” Dr. Zain said during a podium discussion of the study. “I think we were all oohing and aahing over the results, and it could possibly even be practice changing.”

Moving to a nonchemotherapy regimen could raise new questions for treatment of non-GCB and possibly also GCB subtypes of DLBCL, such as when the treatments could be stopped, or whether a maintenance approach would be useful, she added.

The Smart Start study enrolled a total of 60 patients with non-GCB DLBCL. The patients received RLI for two 21-day cycles, followed by another six cycles of RLI plus chemotherapy, which was either EPOCH or CHOP, at the investigators’ discretion.

“With a median follow-up of 362 days, we’ve had three progression events,” Dr. Westin said in his discussion of the preliminary efficacy results.

Adverse events were similar to what would be expected for standard chemotherapy, according to Dr. Westin, except for rash, which was seen mainly in cycles one and two.

There were two deaths on study protocol, including one fatal fungal infection that investigators attributed to high dose corticosteroids and RLI. There were no subsequent fungal infections after a protocol amendment prohibiting corticosteroids during the RLI-only cycles, according to the investigators’ report.

The high response rates following the initial lead-in phase made investigators wonder what would happen without subsequent chemotherapy, Dr. Westin told attendees during his oral presentation. In one case, a 74-year-old man did complete the two lead-in cycles of RLI and declined further therapy.

“He’s now nearly 2 years out, without any additional therapy, and has not relapsed to date,” Dr. Westin said. “This is, again, with 6 weeks worth of RLI therapy.”

Final results and minimal residual disease data from the Smart Start study will be presented at a conference later in 2019, Dr. Westin said.

The study received research support and funding from the ASCO Conquer Cancer Foundation. The trial drug and support were provided by Celgene and Janssen. Dr. Westin reported disclosures related to Celgene, Genentech/Abbvie, Kite Pharma, Kite/Gilead, Novartis, ProNAi, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Karyopharm Therapeutics.

SOURCE: Westin J et al. ASCO 2019, Abstract 7508.

CHICAGO – A chemotherapy-free regimen has produced promising early response and survival outcomes in patients with a particularly poor-prognosis subtype of diffuse large B-cell lymphoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

The overall response rate was 86% after two cycles of combined rituximab, lenalidomide, and ibrutinib – or RLI – in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of the non–germinal center (non-GCB) subtype, said Jason Westin, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.

The response rate increased to 96% after subsequent cycles of RLI plus standard chemotherapy, said Dr.Westin, who added that the rates of progression-free and overall survival at 1 year were also 96% in the investigator initiated, single-arm, open-label, phase 2 study, called Smart Start.

That looks quite favorable, compared with what’s been achieved in previous studies in this poor-prognosis group of patients, Dr. Westin said during a podium presentation of Smart Start data, though he cautioned against direct comparison to historical studies and added that further follow-up is needed.

“Our survival outcomes appear excellent with about a year’s worth of follow-up,” he said during his presentation. “I’d say the novel/novel combinations, with and without chemotherapy, are feasible for large cell, and next step studies are warranted.”

Jasmine M. Zain, MD, of City of Hope Comprehensive Cancer Center, said these results so far raise the possibility of an effective chemotherapy-free treatment regimen for aggressive lymphomas.

“This regimen, particularly for non-GCB subtypes, is extremely promising,” Dr. Zain said during a podium discussion of the study. “I think we were all oohing and aahing over the results, and it could possibly even be practice changing.”

Moving to a nonchemotherapy regimen could raise new questions for treatment of non-GCB and possibly also GCB subtypes of DLBCL, such as when the treatments could be stopped, or whether a maintenance approach would be useful, she added.

The Smart Start study enrolled a total of 60 patients with non-GCB DLBCL. The patients received RLI for two 21-day cycles, followed by another six cycles of RLI plus chemotherapy, which was either EPOCH or CHOP, at the investigators’ discretion.

“With a median follow-up of 362 days, we’ve had three progression events,” Dr. Westin said in his discussion of the preliminary efficacy results.

Adverse events were similar to what would be expected for standard chemotherapy, according to Dr. Westin, except for rash, which was seen mainly in cycles one and two.

There were two deaths on study protocol, including one fatal fungal infection that investigators attributed to high dose corticosteroids and RLI. There were no subsequent fungal infections after a protocol amendment prohibiting corticosteroids during the RLI-only cycles, according to the investigators’ report.

The high response rates following the initial lead-in phase made investigators wonder what would happen without subsequent chemotherapy, Dr. Westin told attendees during his oral presentation. In one case, a 74-year-old man did complete the two lead-in cycles of RLI and declined further therapy.

“He’s now nearly 2 years out, without any additional therapy, and has not relapsed to date,” Dr. Westin said. “This is, again, with 6 weeks worth of RLI therapy.”

Final results and minimal residual disease data from the Smart Start study will be presented at a conference later in 2019, Dr. Westin said.

The study received research support and funding from the ASCO Conquer Cancer Foundation. The trial drug and support were provided by Celgene and Janssen. Dr. Westin reported disclosures related to Celgene, Genentech/Abbvie, Kite Pharma, Kite/Gilead, Novartis, ProNAi, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Karyopharm Therapeutics.

SOURCE: Westin J et al. ASCO 2019, Abstract 7508.

CHICAGO – A chemotherapy-free regimen has produced promising early response and survival outcomes in patients with a particularly poor-prognosis subtype of diffuse large B-cell lymphoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

The overall response rate was 86% after two cycles of combined rituximab, lenalidomide, and ibrutinib – or RLI – in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of the non–germinal center (non-GCB) subtype, said Jason Westin, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.

The response rate increased to 96% after subsequent cycles of RLI plus standard chemotherapy, said Dr.Westin, who added that the rates of progression-free and overall survival at 1 year were also 96% in the investigator initiated, single-arm, open-label, phase 2 study, called Smart Start.

That looks quite favorable, compared with what’s been achieved in previous studies in this poor-prognosis group of patients, Dr. Westin said during a podium presentation of Smart Start data, though he cautioned against direct comparison to historical studies and added that further follow-up is needed.

“Our survival outcomes appear excellent with about a year’s worth of follow-up,” he said during his presentation. “I’d say the novel/novel combinations, with and without chemotherapy, are feasible for large cell, and next step studies are warranted.”

Jasmine M. Zain, MD, of City of Hope Comprehensive Cancer Center, said these results so far raise the possibility of an effective chemotherapy-free treatment regimen for aggressive lymphomas.

“This regimen, particularly for non-GCB subtypes, is extremely promising,” Dr. Zain said during a podium discussion of the study. “I think we were all oohing and aahing over the results, and it could possibly even be practice changing.”

Moving to a nonchemotherapy regimen could raise new questions for treatment of non-GCB and possibly also GCB subtypes of DLBCL, such as when the treatments could be stopped, or whether a maintenance approach would be useful, she added.

The Smart Start study enrolled a total of 60 patients with non-GCB DLBCL. The patients received RLI for two 21-day cycles, followed by another six cycles of RLI plus chemotherapy, which was either EPOCH or CHOP, at the investigators’ discretion.

“With a median follow-up of 362 days, we’ve had three progression events,” Dr. Westin said in his discussion of the preliminary efficacy results.

Adverse events were similar to what would be expected for standard chemotherapy, according to Dr. Westin, except for rash, which was seen mainly in cycles one and two.

There were two deaths on study protocol, including one fatal fungal infection that investigators attributed to high dose corticosteroids and RLI. There were no subsequent fungal infections after a protocol amendment prohibiting corticosteroids during the RLI-only cycles, according to the investigators’ report.

The high response rates following the initial lead-in phase made investigators wonder what would happen without subsequent chemotherapy, Dr. Westin told attendees during his oral presentation. In one case, a 74-year-old man did complete the two lead-in cycles of RLI and declined further therapy.

“He’s now nearly 2 years out, without any additional therapy, and has not relapsed to date,” Dr. Westin said. “This is, again, with 6 weeks worth of RLI therapy.”

Final results and minimal residual disease data from the Smart Start study will be presented at a conference later in 2019, Dr. Westin said.

The study received research support and funding from the ASCO Conquer Cancer Foundation. The trial drug and support were provided by Celgene and Janssen. Dr. Westin reported disclosures related to Celgene, Genentech/Abbvie, Kite Pharma, Kite/Gilead, Novartis, ProNAi, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Karyopharm Therapeutics.

SOURCE: Westin J et al. ASCO 2019, Abstract 7508.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – The oral tyrosine kinase inhibitor (TKI) repotrectinib is safe and has demonstrated encouraging activity in patients with advanced ROS1 fusion-positive non-small cell lung cancer, early results of a phase 1/2 study show.

Objective response rates of 82% in 11 TKI-naive patients and 39% in 22 TKI-pretreated patients were seen after treatment with repotrectinib, a next-generation inhibitor of ROS1/TRK/ALK with a 90-fold greater potency for ROS1 versus crizotinib, according to an investigator in the study.

“The TRIDENT-1 study supports repotrectinib as a potential best-in-class ROS1 agent in advanced non–small cell lung cancer,” said investigator ByoungChul Cho, MD, PhD, of Yonsei Cancer Center in Seoul, South Korea, in a podium presentation at the annual meeting of the American Society of Clinical Oncology.

For the 11 TKI-naive patients, no median duration of response had yet been reached over a median follow-up duration of nearly 17 months, with individual response durations that ranged from 10.9 to 17.7 or more months in the 5 of 9 patients remaining in response, Dr. Cho reported.

“This is exciting, because this is the most promising data presented so far with ROS1 TKI in TKI-naive patient population,” Dr. Cho said.

Repotrectinib also showed a potential to overcome TKI resistance mutations, notably G2032R, which is the most common ROS1 resistance mutation after crizotinib treatment.

All five patients with ROS1 G2032R mutation experienced tumor regression, with a confirmed response rate of 40%, Dr. Cho said.

The TKI was relatively well tolerated with four dose-limiting toxicity events including grade 2-3 dizziness in three cases and grade 3 dyspnea and hypoxia in one case.

Of four grade 5 treatment-emergent adverse events, only one case was possibly related to the treatment, Dr. Cho said.

Based on this tolerability and preliminary activity, the pivotal phase 2 portion of TRIDENT-1 is set to begin in the second half of 2019.

Benjamin Besse, MD, PhD, of Paris-Sud University, Orsay, and Institut Gustave Roussy said these preliminary results were very encouraging.

“If we look at the global picture, repotrectinib is probably today the most potent TKI against ROS1,” Dr. Besse said in a podium discussion of the results. “We don’t know yet if this will translate in an improved progression-free survival.”

Close follow-up of adverse events are warranted in further investigations because of the potency of the drug, he added.

Turning Point Therapeutics sponsored the study. Dr. Cho reported disclosures related to TheraCanVac, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, Janssen, Mogam Institute, MSD, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan.
 

SOURCE: Cho BC et al. ASCO 2019, Abstract 9011.

CHICAGO – The oral tyrosine kinase inhibitor (TKI) repotrectinib is safe and has demonstrated encouraging activity in patients with advanced ROS1 fusion-positive non-small cell lung cancer, early results of a phase 1/2 study show.

Objective response rates of 82% in 11 TKI-naive patients and 39% in 22 TKI-pretreated patients were seen after treatment with repotrectinib, a next-generation inhibitor of ROS1/TRK/ALK with a 90-fold greater potency for ROS1 versus crizotinib, according to an investigator in the study.

“The TRIDENT-1 study supports repotrectinib as a potential best-in-class ROS1 agent in advanced non–small cell lung cancer,” said investigator ByoungChul Cho, MD, PhD, of Yonsei Cancer Center in Seoul, South Korea, in a podium presentation at the annual meeting of the American Society of Clinical Oncology.

For the 11 TKI-naive patients, no median duration of response had yet been reached over a median follow-up duration of nearly 17 months, with individual response durations that ranged from 10.9 to 17.7 or more months in the 5 of 9 patients remaining in response, Dr. Cho reported.

“This is exciting, because this is the most promising data presented so far with ROS1 TKI in TKI-naive patient population,” Dr. Cho said.

Repotrectinib also showed a potential to overcome TKI resistance mutations, notably G2032R, which is the most common ROS1 resistance mutation after crizotinib treatment.

All five patients with ROS1 G2032R mutation experienced tumor regression, with a confirmed response rate of 40%, Dr. Cho said.

The TKI was relatively well tolerated with four dose-limiting toxicity events including grade 2-3 dizziness in three cases and grade 3 dyspnea and hypoxia in one case.

Of four grade 5 treatment-emergent adverse events, only one case was possibly related to the treatment, Dr. Cho said.

Based on this tolerability and preliminary activity, the pivotal phase 2 portion of TRIDENT-1 is set to begin in the second half of 2019.

Benjamin Besse, MD, PhD, of Paris-Sud University, Orsay, and Institut Gustave Roussy said these preliminary results were very encouraging.

“If we look at the global picture, repotrectinib is probably today the most potent TKI against ROS1,” Dr. Besse said in a podium discussion of the results. “We don’t know yet if this will translate in an improved progression-free survival.”

Close follow-up of adverse events are warranted in further investigations because of the potency of the drug, he added.

Turning Point Therapeutics sponsored the study. Dr. Cho reported disclosures related to TheraCanVac, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, Janssen, Mogam Institute, MSD, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan.
 

SOURCE: Cho BC et al. ASCO 2019, Abstract 9011.

CHICAGO – The oral tyrosine kinase inhibitor (TKI) repotrectinib is safe and has demonstrated encouraging activity in patients with advanced ROS1 fusion-positive non-small cell lung cancer, early results of a phase 1/2 study show.

Objective response rates of 82% in 11 TKI-naive patients and 39% in 22 TKI-pretreated patients were seen after treatment with repotrectinib, a next-generation inhibitor of ROS1/TRK/ALK with a 90-fold greater potency for ROS1 versus crizotinib, according to an investigator in the study.

“The TRIDENT-1 study supports repotrectinib as a potential best-in-class ROS1 agent in advanced non–small cell lung cancer,” said investigator ByoungChul Cho, MD, PhD, of Yonsei Cancer Center in Seoul, South Korea, in a podium presentation at the annual meeting of the American Society of Clinical Oncology.

For the 11 TKI-naive patients, no median duration of response had yet been reached over a median follow-up duration of nearly 17 months, with individual response durations that ranged from 10.9 to 17.7 or more months in the 5 of 9 patients remaining in response, Dr. Cho reported.

“This is exciting, because this is the most promising data presented so far with ROS1 TKI in TKI-naive patient population,” Dr. Cho said.

Repotrectinib also showed a potential to overcome TKI resistance mutations, notably G2032R, which is the most common ROS1 resistance mutation after crizotinib treatment.

All five patients with ROS1 G2032R mutation experienced tumor regression, with a confirmed response rate of 40%, Dr. Cho said.

The TKI was relatively well tolerated with four dose-limiting toxicity events including grade 2-3 dizziness in three cases and grade 3 dyspnea and hypoxia in one case.

Of four grade 5 treatment-emergent adverse events, only one case was possibly related to the treatment, Dr. Cho said.

Based on this tolerability and preliminary activity, the pivotal phase 2 portion of TRIDENT-1 is set to begin in the second half of 2019.

Benjamin Besse, MD, PhD, of Paris-Sud University, Orsay, and Institut Gustave Roussy said these preliminary results were very encouraging.

“If we look at the global picture, repotrectinib is probably today the most potent TKI against ROS1,” Dr. Besse said in a podium discussion of the results. “We don’t know yet if this will translate in an improved progression-free survival.”

Close follow-up of adverse events are warranted in further investigations because of the potency of the drug, he added.

Turning Point Therapeutics sponsored the study. Dr. Cho reported disclosures related to TheraCanVac, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, Janssen, Mogam Institute, MSD, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan.
 

SOURCE: Cho BC et al. ASCO 2019, Abstract 9011.