M. Alexander Otto

There were no local recurrences when Mohs surgery was used to treat early stage Merkel cell carcinomas in 53 patients at the Zitelli and Brodland Skin Cancer Center, Pittsburgh.

The results compare favorably with the standard treatment approach, wide local excision with or without radiation, which has a local recurrence rate of 4.2%-31.7% because of incomplete excision or false negative margins, said Vitaly Terushkin, MD, a Mohs surgeon who presented the findings of the study, a retrospective chart review, at the annual meeting of the American College of Mohs Surgery.

Mohs surgery as monotherapy offered “survival at least as good as historical controls treated with wide local excision plus radiation therapy, and because of the superior local control, Mohs surgery may obviate the need for adjuvant radiation and decrease the chance for additional surgery for the treatment of local recurrence,” said Dr. Terushkin, now in practice in the New York City area.

“We hope this data fuel additional studies with larger cohorts to continue to explore the value of Mohs for Merkel cell carcinoma,” he said.

The findings add to a growing body of literature supporting Mohs for many types of rare tumors. “Micrographic surgery or complete circumferential peripheral and deep margin analysis has been shown to be superior to wide local excision in a variety of tumors and clinical scenarios,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington.

“When the entire margin is able to be evaluated over random bread-loafed sections, there is growing evidence that this leads to superior outcomes and disease specific mortality,” he said when asked for comment on the study results.

In all, 56 primary Merkel cell carcinomas were treated in the 53 patients from 2001 to 2019; about two-thirds of the patients had stage 1 tumors and the rest stage 2a.

They were treated with Mohs alone, without radiation. Average follow up was 4.6 years, with about a third of patients followed for 5 or more years.

The average age of the patients was 78 years, and just over half were men. In more than half the cases, tumors were located on the head and neck (62.5%), and the mean tumor size was 1.7 cm. Patients were negative for lymphadenopathy and declined lymph node biopsy.

Although there was no local recurrence, defined as tumor reemerging within or adjacent to the surgery site, 7 patients (12.7%) developed in-transit metastases, 13 (23.6%) developed nodal metastases, and 3 developed distant metastases.

The 5-year disease-specific survival rate was 91.2% for stage 1 and 68.6% for stage 2a patients, which compared favorably with historical controls treated with wide local excision with or without radiation, with reported 5-year disease-specific survival rates of 81%-87% for stage 1 disease and 63%-67% for stage 2. Although radiation wasn’t used in the study, Dr. Patel noted that more investigation is needed about the role of adjuvant radiation therapy after Mohs surgery “given recent publications showing improved outcomes in patients with narrow margin excision and postoperative radiation therapy.”

No external funding of the study was reported. Dr. Terushkin had no disclosures. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.

[email protected]

There were no local recurrences when Mohs surgery was used to treat early stage Merkel cell carcinomas in 53 patients at the Zitelli and Brodland Skin Cancer Center, Pittsburgh.

The results compare favorably with the standard treatment approach, wide local excision with or without radiation, which has a local recurrence rate of 4.2%-31.7% because of incomplete excision or false negative margins, said Vitaly Terushkin, MD, a Mohs surgeon who presented the findings of the study, a retrospective chart review, at the annual meeting of the American College of Mohs Surgery.

Mohs surgery as monotherapy offered “survival at least as good as historical controls treated with wide local excision plus radiation therapy, and because of the superior local control, Mohs surgery may obviate the need for adjuvant radiation and decrease the chance for additional surgery for the treatment of local recurrence,” said Dr. Terushkin, now in practice in the New York City area.

“We hope this data fuel additional studies with larger cohorts to continue to explore the value of Mohs for Merkel cell carcinoma,” he said.

The findings add to a growing body of literature supporting Mohs for many types of rare tumors. “Micrographic surgery or complete circumferential peripheral and deep margin analysis has been shown to be superior to wide local excision in a variety of tumors and clinical scenarios,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington.

“When the entire margin is able to be evaluated over random bread-loafed sections, there is growing evidence that this leads to superior outcomes and disease specific mortality,” he said when asked for comment on the study results.

In all, 56 primary Merkel cell carcinomas were treated in the 53 patients from 2001 to 2019; about two-thirds of the patients had stage 1 tumors and the rest stage 2a.

They were treated with Mohs alone, without radiation. Average follow up was 4.6 years, with about a third of patients followed for 5 or more years.

The average age of the patients was 78 years, and just over half were men. In more than half the cases, tumors were located on the head and neck (62.5%), and the mean tumor size was 1.7 cm. Patients were negative for lymphadenopathy and declined lymph node biopsy.

Although there was no local recurrence, defined as tumor reemerging within or adjacent to the surgery site, 7 patients (12.7%) developed in-transit metastases, 13 (23.6%) developed nodal metastases, and 3 developed distant metastases.

The 5-year disease-specific survival rate was 91.2% for stage 1 and 68.6% for stage 2a patients, which compared favorably with historical controls treated with wide local excision with or without radiation, with reported 5-year disease-specific survival rates of 81%-87% for stage 1 disease and 63%-67% for stage 2. Although radiation wasn’t used in the study, Dr. Patel noted that more investigation is needed about the role of adjuvant radiation therapy after Mohs surgery “given recent publications showing improved outcomes in patients with narrow margin excision and postoperative radiation therapy.”

No external funding of the study was reported. Dr. Terushkin had no disclosures. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.

[email protected]

There were no local recurrences when Mohs surgery was used to treat early stage Merkel cell carcinomas in 53 patients at the Zitelli and Brodland Skin Cancer Center, Pittsburgh.

The results compare favorably with the standard treatment approach, wide local excision with or without radiation, which has a local recurrence rate of 4.2%-31.7% because of incomplete excision or false negative margins, said Vitaly Terushkin, MD, a Mohs surgeon who presented the findings of the study, a retrospective chart review, at the annual meeting of the American College of Mohs Surgery.

Mohs surgery as monotherapy offered “survival at least as good as historical controls treated with wide local excision plus radiation therapy, and because of the superior local control, Mohs surgery may obviate the need for adjuvant radiation and decrease the chance for additional surgery for the treatment of local recurrence,” said Dr. Terushkin, now in practice in the New York City area.

“We hope this data fuel additional studies with larger cohorts to continue to explore the value of Mohs for Merkel cell carcinoma,” he said.

The findings add to a growing body of literature supporting Mohs for many types of rare tumors. “Micrographic surgery or complete circumferential peripheral and deep margin analysis has been shown to be superior to wide local excision in a variety of tumors and clinical scenarios,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington.

“When the entire margin is able to be evaluated over random bread-loafed sections, there is growing evidence that this leads to superior outcomes and disease specific mortality,” he said when asked for comment on the study results.

In all, 56 primary Merkel cell carcinomas were treated in the 53 patients from 2001 to 2019; about two-thirds of the patients had stage 1 tumors and the rest stage 2a.

They were treated with Mohs alone, without radiation. Average follow up was 4.6 years, with about a third of patients followed for 5 or more years.

The average age of the patients was 78 years, and just over half were men. In more than half the cases, tumors were located on the head and neck (62.5%), and the mean tumor size was 1.7 cm. Patients were negative for lymphadenopathy and declined lymph node biopsy.

Although there was no local recurrence, defined as tumor reemerging within or adjacent to the surgery site, 7 patients (12.7%) developed in-transit metastases, 13 (23.6%) developed nodal metastases, and 3 developed distant metastases.

The 5-year disease-specific survival rate was 91.2% for stage 1 and 68.6% for stage 2a patients, which compared favorably with historical controls treated with wide local excision with or without radiation, with reported 5-year disease-specific survival rates of 81%-87% for stage 1 disease and 63%-67% for stage 2. Although radiation wasn’t used in the study, Dr. Patel noted that more investigation is needed about the role of adjuvant radiation therapy after Mohs surgery “given recent publications showing improved outcomes in patients with narrow margin excision and postoperative radiation therapy.”

No external funding of the study was reported. Dr. Terushkin had no disclosures. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.

[email protected]

In new small cell lung cancer guidelines, the European Society of Medical Oncology calls for upfront atezolizumab or durvalumab in combination with four to six cycles of etoposide and a platinum for stage 4 disease.

The strong recommendation is based on two phase 3 trials that showed improved overall survival when the checkpoint inhibitors were added to standard chemotherapy. “With very similar results, and in the context of a severe unmet need, both trials justify the need for immunotherapy in the frontline setting” and established “new standards of care” for stage 4 disease, the group said. “Atezolizumab or durvalumab in combination with a platinum plus etoposide should be offered to all eligible chemotherapy-naive patients” with a performance status of 0-1, said the group led by Anne-Marie Dingemans, MD, PhD, a pulmonology professor at Maastricht (the Netherlands) University Medical Center.

Alessio Cortellini, MD, a consulting oncologist and visiting researcher at Imperial College London, said he strongly endorses the recommendation when asked for comment.

“The addition of a PD-L1 inhibitor to a platinum/etoposide backbone is the first strategy that has led to a significant benefit in terms of overall survival. After decades of disappointing results, the bar has” been raised, said Dr. Cortellini.
 

New inhibitor

EMSO also incorporated the new RNA polymerase II inhibitor lurbinectedin into their guidelines as an option for patients progressing on or after first-line platinum-based chemotherapy.

The agent was approved by the U.S. Food and Drug Administration in June 2020 for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

The recommendations – more than 50 in all – are based on a literature review and expert opinion, and cover SCLC diagnosis, staging, treatment, and follow-up, with flowcharts outlining treatment pathways.

Atezolizumab earned the endorsement following the IMpower133 trial, which showed a median overall survival of 12.3 months for atezolizumab in combination with carboplatin and etoposide, versus 10.3 months on chemotherapy alone; 34% of the atezolizumab group was alive at 18 months versus 21% in the placebo arm.

The durvalumab recommendation is based on the CASPIAN trial, in which the addition of durvalumab to platinum plus etoposide improved median overall survival from 10.5 to 12.9 months; 32% of durvalumab patients were alive at 18 months versus 24.8% in the chemotherapy-alone arm.

ESMO said “it is important to stress that, in both trials,” patients were in good clinical condition with a median age in the early 60s, so relatively young for SCLC. Also, the modest benefits “clearly emphasize the need for” biomarkers that predict response in order to better select patients.

Immunotherapy has improved cancer treatment across many malignancies and continues to be actively investigated in SCLC, but so far only atezolizumab and durvalumab have phase 3 evidence of benefit.

Makers of the blockbuster checkpoint inhibitors nivolumab and pembrolizumab recently withdrew their FDA approval for stage 4 SCLC that’s progressed after platinum-based chemotherapy and at least one other line of therapy; phase 3 trials failed to confirm the modest survival benefit found in early studies.

Lurbinectedin earned its place in the guidelines based on a single-arm study with 105 relapsed patients that showed an overall response rate of 22.2% in platinum-resistant and 45% in platinum-sensitive patients, with a median overall survival of 9.3 months.

The jury is still out, however. A phase 3 trial of lurbinectedin plus doxorubicin versus topotecan or CAV [cyclophosphamide, adriamycin, and vincristine] for advanced recurrent disease failed to meet its endpoint of superior overall survival, according to a recent press release from the its maker.

“It might be a bit early to discuss” routine use of lurbinectedin, although having it available is good “since literally nothing works in the second line setting,” Dr. Cortellini said.

There was no external funding for the work. The authors had numerous ties to pharmaceutical companies, including Dr. Dingemans who reported adviser and speakers fees and/or research funding from Roche, Lilly, Bristol-Myers Squib, and others. Dr. Costellini reported speakers fees from Novartis, Astrazeneca, and Astellas and consultant payments from Bristol-Myers Squibb, Roche, MSD, and AstraZeneca.

[email protected]

In new small cell lung cancer guidelines, the European Society of Medical Oncology calls for upfront atezolizumab or durvalumab in combination with four to six cycles of etoposide and a platinum for stage 4 disease.

The strong recommendation is based on two phase 3 trials that showed improved overall survival when the checkpoint inhibitors were added to standard chemotherapy. “With very similar results, and in the context of a severe unmet need, both trials justify the need for immunotherapy in the frontline setting” and established “new standards of care” for stage 4 disease, the group said. “Atezolizumab or durvalumab in combination with a platinum plus etoposide should be offered to all eligible chemotherapy-naive patients” with a performance status of 0-1, said the group led by Anne-Marie Dingemans, MD, PhD, a pulmonology professor at Maastricht (the Netherlands) University Medical Center.

Alessio Cortellini, MD, a consulting oncologist and visiting researcher at Imperial College London, said he strongly endorses the recommendation when asked for comment.

“The addition of a PD-L1 inhibitor to a platinum/etoposide backbone is the first strategy that has led to a significant benefit in terms of overall survival. After decades of disappointing results, the bar has” been raised, said Dr. Cortellini.
 

New inhibitor

EMSO also incorporated the new RNA polymerase II inhibitor lurbinectedin into their guidelines as an option for patients progressing on or after first-line platinum-based chemotherapy.

The agent was approved by the U.S. Food and Drug Administration in June 2020 for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

The recommendations – more than 50 in all – are based on a literature review and expert opinion, and cover SCLC diagnosis, staging, treatment, and follow-up, with flowcharts outlining treatment pathways.

Atezolizumab earned the endorsement following the IMpower133 trial, which showed a median overall survival of 12.3 months for atezolizumab in combination with carboplatin and etoposide, versus 10.3 months on chemotherapy alone; 34% of the atezolizumab group was alive at 18 months versus 21% in the placebo arm.

The durvalumab recommendation is based on the CASPIAN trial, in which the addition of durvalumab to platinum plus etoposide improved median overall survival from 10.5 to 12.9 months; 32% of durvalumab patients were alive at 18 months versus 24.8% in the chemotherapy-alone arm.

ESMO said “it is important to stress that, in both trials,” patients were in good clinical condition with a median age in the early 60s, so relatively young for SCLC. Also, the modest benefits “clearly emphasize the need for” biomarkers that predict response in order to better select patients.

Immunotherapy has improved cancer treatment across many malignancies and continues to be actively investigated in SCLC, but so far only atezolizumab and durvalumab have phase 3 evidence of benefit.

Makers of the blockbuster checkpoint inhibitors nivolumab and pembrolizumab recently withdrew their FDA approval for stage 4 SCLC that’s progressed after platinum-based chemotherapy and at least one other line of therapy; phase 3 trials failed to confirm the modest survival benefit found in early studies.

Lurbinectedin earned its place in the guidelines based on a single-arm study with 105 relapsed patients that showed an overall response rate of 22.2% in platinum-resistant and 45% in platinum-sensitive patients, with a median overall survival of 9.3 months.

The jury is still out, however. A phase 3 trial of lurbinectedin plus doxorubicin versus topotecan or CAV [cyclophosphamide, adriamycin, and vincristine] for advanced recurrent disease failed to meet its endpoint of superior overall survival, according to a recent press release from the its maker.

“It might be a bit early to discuss” routine use of lurbinectedin, although having it available is good “since literally nothing works in the second line setting,” Dr. Cortellini said.

There was no external funding for the work. The authors had numerous ties to pharmaceutical companies, including Dr. Dingemans who reported adviser and speakers fees and/or research funding from Roche, Lilly, Bristol-Myers Squib, and others. Dr. Costellini reported speakers fees from Novartis, Astrazeneca, and Astellas and consultant payments from Bristol-Myers Squibb, Roche, MSD, and AstraZeneca.

[email protected]

In new small cell lung cancer guidelines, the European Society of Medical Oncology calls for upfront atezolizumab or durvalumab in combination with four to six cycles of etoposide and a platinum for stage 4 disease.

The strong recommendation is based on two phase 3 trials that showed improved overall survival when the checkpoint inhibitors were added to standard chemotherapy. “With very similar results, and in the context of a severe unmet need, both trials justify the need for immunotherapy in the frontline setting” and established “new standards of care” for stage 4 disease, the group said. “Atezolizumab or durvalumab in combination with a platinum plus etoposide should be offered to all eligible chemotherapy-naive patients” with a performance status of 0-1, said the group led by Anne-Marie Dingemans, MD, PhD, a pulmonology professor at Maastricht (the Netherlands) University Medical Center.

Alessio Cortellini, MD, a consulting oncologist and visiting researcher at Imperial College London, said he strongly endorses the recommendation when asked for comment.

“The addition of a PD-L1 inhibitor to a platinum/etoposide backbone is the first strategy that has led to a significant benefit in terms of overall survival. After decades of disappointing results, the bar has” been raised, said Dr. Cortellini.
 

New inhibitor

EMSO also incorporated the new RNA polymerase II inhibitor lurbinectedin into their guidelines as an option for patients progressing on or after first-line platinum-based chemotherapy.

The agent was approved by the U.S. Food and Drug Administration in June 2020 for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

The recommendations – more than 50 in all – are based on a literature review and expert opinion, and cover SCLC diagnosis, staging, treatment, and follow-up, with flowcharts outlining treatment pathways.

Atezolizumab earned the endorsement following the IMpower133 trial, which showed a median overall survival of 12.3 months for atezolizumab in combination with carboplatin and etoposide, versus 10.3 months on chemotherapy alone; 34% of the atezolizumab group was alive at 18 months versus 21% in the placebo arm.

The durvalumab recommendation is based on the CASPIAN trial, in which the addition of durvalumab to platinum plus etoposide improved median overall survival from 10.5 to 12.9 months; 32% of durvalumab patients were alive at 18 months versus 24.8% in the chemotherapy-alone arm.

ESMO said “it is important to stress that, in both trials,” patients were in good clinical condition with a median age in the early 60s, so relatively young for SCLC. Also, the modest benefits “clearly emphasize the need for” biomarkers that predict response in order to better select patients.

Immunotherapy has improved cancer treatment across many malignancies and continues to be actively investigated in SCLC, but so far only atezolizumab and durvalumab have phase 3 evidence of benefit.

Makers of the blockbuster checkpoint inhibitors nivolumab and pembrolizumab recently withdrew their FDA approval for stage 4 SCLC that’s progressed after platinum-based chemotherapy and at least one other line of therapy; phase 3 trials failed to confirm the modest survival benefit found in early studies.

Lurbinectedin earned its place in the guidelines based on a single-arm study with 105 relapsed patients that showed an overall response rate of 22.2% in platinum-resistant and 45% in platinum-sensitive patients, with a median overall survival of 9.3 months.

The jury is still out, however. A phase 3 trial of lurbinectedin plus doxorubicin versus topotecan or CAV [cyclophosphamide, adriamycin, and vincristine] for advanced recurrent disease failed to meet its endpoint of superior overall survival, according to a recent press release from the its maker.

“It might be a bit early to discuss” routine use of lurbinectedin, although having it available is good “since literally nothing works in the second line setting,” Dr. Cortellini said.

There was no external funding for the work. The authors had numerous ties to pharmaceutical companies, including Dr. Dingemans who reported adviser and speakers fees and/or research funding from Roche, Lilly, Bristol-Myers Squib, and others. Dr. Costellini reported speakers fees from Novartis, Astrazeneca, and Astellas and consultant payments from Bristol-Myers Squibb, Roche, MSD, and AstraZeneca.

[email protected]

Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) proved to be the most effective treatment for locally advanced squamous cell head and neck cancer in a network meta-analysis of nearly 30,000 patients.

Of the 16 treatment options compared and ranked, HFCRT topped the list for overall survival, event-free survival, locoregional control, and cancer-specific death.

The results also suggested that taxane-based induction chemotherapy followed by locoregional therapy, especially with concomitant chemotherapy, “is another good option in selected patients with a good performance status and minor comorbidities,” according to investigator Claire Petit, MD, PhD, of Centre hospitalier de l’Université de Montréal in Canada, and colleagues.

The investigators concluded that further intensifying chemoradiotherapy with these approaches “could improve outcomes over chemoradiotherapy.”

The findings, published in The Lancet Oncology, “could help to guide clinical decision-making in locally advanced head and neck cancer with a high risk of locoregional failure, especially human papillomavirus–negative tumours,” the authors wrote.

However, Jared Weiss, MD, of the University of North Carolina, Chapel Hill, cautioned that this “study is an individual patient data network meta-analysis, not a randomized controlled trial. As the authors note, it can help frame existing data but cannot define standard of care.”

Still, “it does support the efficacy of two commonly considered intensification strategies for high-risk patients – hyperfractionation of the radiation and the addition of preceding induction chemotherapy. Both of these intensifications substantially increase the time commitment from the patient, and many patients find this unacceptable. But, for select patients, hyperfractionation and induction chemotherapy have a role and may be considered for patients at high risk of treatment failure,” Dr. Weiss said.
 

Study details

The goal of this study was to find the best option among many chemoradiation approaches for head and neck cancer. The investigators pulled together and reanalyzed individual patient data from recently updated meta-analyses.

The current analysis included 115 randomized trials that enrolled patients between Jan. 1, 1980, and April 30, 2012. This encompassed 28,978 patients with 20,579 progression events and 19,253 deaths over a median follow-up of 6.6 years.

Treatments were ranked by P score, with higher scores indicating more effective therapies.

For overall survival, HFCRT had a P score of 97%. The hazard ratio (HR) was 0.63 for the comparison with locoregional therapy alone (surgery, radiotherapy, or both). The absolute benefit at 5 years, compared with locoregional therapy alone, was 16.7% with HFCRT.

The P score for the second most effective treatment option – induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC_TaxPF-LRT) – was 89%, with a hazard ratio of 0.69 and an absolute benefit at 5 years of 13.4%, versus locoregional therapy.

The HR of HFCRT versus the accepted standard of care worldwide – locoregional therapy with concomitant platinum-based chemotherapy and radiotherapy (CLRT_P) – was 0.82 in favor of HFCRT for overall survival and 0.80 for event-free survival.

For overall survival, the P score for CLRT_P was 78%. Three other treatment options had a better P score than CLRT_P but not a better HR (0.77). These included IC_TaxPF-LRT (P score, 89%; HR, 0.69), accelerated radiotherapy with concomitant chemotherapy (P score, 82%; HR, 0.75), and IC_TaxPF-LRT followed by CLRTP (P score, 80%; HR, 0.75).

In the end, the investigators found “superiority of HFCRT over other treatments,” but noted it can be difficult to implement HFCRT in the era of intensity-modulated radiotherapy for head and neck cancer. Even so, HFCRT “could be considered as an option for tertiary centres with a high throughput of patients,” the investigators wrote.

The team noted that one of the limitations of this study is that cancer care has improved substantially since the very earliest trials that were included in the analysis. This introduces potential confounders, including that patients in older trials might have been understaged so that even an experimental local therapy would have been less effective.

Toxicity wasn’t part of this analysis but must be taken into account when making therapeutic decisions, “especially because HFCRT and induction chemotherapy based on taxane, cisplatin, and fluorouracil are known to be toxic,” the investigators wrote.

This research was funded by the French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC. The authors disclosed relationships with numerous companies, including AbbVie, Lilly, and Merck. Dr. Weiss did not report any relevant conflicts.

[email protected]

Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) proved to be the most effective treatment for locally advanced squamous cell head and neck cancer in a network meta-analysis of nearly 30,000 patients.

Of the 16 treatment options compared and ranked, HFCRT topped the list for overall survival, event-free survival, locoregional control, and cancer-specific death.

The results also suggested that taxane-based induction chemotherapy followed by locoregional therapy, especially with concomitant chemotherapy, “is another good option in selected patients with a good performance status and minor comorbidities,” according to investigator Claire Petit, MD, PhD, of Centre hospitalier de l’Université de Montréal in Canada, and colleagues.

The investigators concluded that further intensifying chemoradiotherapy with these approaches “could improve outcomes over chemoradiotherapy.”

The findings, published in The Lancet Oncology, “could help to guide clinical decision-making in locally advanced head and neck cancer with a high risk of locoregional failure, especially human papillomavirus–negative tumours,” the authors wrote.

However, Jared Weiss, MD, of the University of North Carolina, Chapel Hill, cautioned that this “study is an individual patient data network meta-analysis, not a randomized controlled trial. As the authors note, it can help frame existing data but cannot define standard of care.”

Still, “it does support the efficacy of two commonly considered intensification strategies for high-risk patients – hyperfractionation of the radiation and the addition of preceding induction chemotherapy. Both of these intensifications substantially increase the time commitment from the patient, and many patients find this unacceptable. But, for select patients, hyperfractionation and induction chemotherapy have a role and may be considered for patients at high risk of treatment failure,” Dr. Weiss said.
 

Study details

The goal of this study was to find the best option among many chemoradiation approaches for head and neck cancer. The investigators pulled together and reanalyzed individual patient data from recently updated meta-analyses.

The current analysis included 115 randomized trials that enrolled patients between Jan. 1, 1980, and April 30, 2012. This encompassed 28,978 patients with 20,579 progression events and 19,253 deaths over a median follow-up of 6.6 years.

Treatments were ranked by P score, with higher scores indicating more effective therapies.

For overall survival, HFCRT had a P score of 97%. The hazard ratio (HR) was 0.63 for the comparison with locoregional therapy alone (surgery, radiotherapy, or both). The absolute benefit at 5 years, compared with locoregional therapy alone, was 16.7% with HFCRT.

The P score for the second most effective treatment option – induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC_TaxPF-LRT) – was 89%, with a hazard ratio of 0.69 and an absolute benefit at 5 years of 13.4%, versus locoregional therapy.

The HR of HFCRT versus the accepted standard of care worldwide – locoregional therapy with concomitant platinum-based chemotherapy and radiotherapy (CLRT_P) – was 0.82 in favor of HFCRT for overall survival and 0.80 for event-free survival.

For overall survival, the P score for CLRT_P was 78%. Three other treatment options had a better P score than CLRT_P but not a better HR (0.77). These included IC_TaxPF-LRT (P score, 89%; HR, 0.69), accelerated radiotherapy with concomitant chemotherapy (P score, 82%; HR, 0.75), and IC_TaxPF-LRT followed by CLRTP (P score, 80%; HR, 0.75).

In the end, the investigators found “superiority of HFCRT over other treatments,” but noted it can be difficult to implement HFCRT in the era of intensity-modulated radiotherapy for head and neck cancer. Even so, HFCRT “could be considered as an option for tertiary centres with a high throughput of patients,” the investigators wrote.

The team noted that one of the limitations of this study is that cancer care has improved substantially since the very earliest trials that were included in the analysis. This introduces potential confounders, including that patients in older trials might have been understaged so that even an experimental local therapy would have been less effective.

Toxicity wasn’t part of this analysis but must be taken into account when making therapeutic decisions, “especially because HFCRT and induction chemotherapy based on taxane, cisplatin, and fluorouracil are known to be toxic,” the investigators wrote.

This research was funded by the French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC. The authors disclosed relationships with numerous companies, including AbbVie, Lilly, and Merck. Dr. Weiss did not report any relevant conflicts.

[email protected]

Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) proved to be the most effective treatment for locally advanced squamous cell head and neck cancer in a network meta-analysis of nearly 30,000 patients.

Of the 16 treatment options compared and ranked, HFCRT topped the list for overall survival, event-free survival, locoregional control, and cancer-specific death.

The results also suggested that taxane-based induction chemotherapy followed by locoregional therapy, especially with concomitant chemotherapy, “is another good option in selected patients with a good performance status and minor comorbidities,” according to investigator Claire Petit, MD, PhD, of Centre hospitalier de l’Université de Montréal in Canada, and colleagues.

The investigators concluded that further intensifying chemoradiotherapy with these approaches “could improve outcomes over chemoradiotherapy.”

The findings, published in The Lancet Oncology, “could help to guide clinical decision-making in locally advanced head and neck cancer with a high risk of locoregional failure, especially human papillomavirus–negative tumours,” the authors wrote.

However, Jared Weiss, MD, of the University of North Carolina, Chapel Hill, cautioned that this “study is an individual patient data network meta-analysis, not a randomized controlled trial. As the authors note, it can help frame existing data but cannot define standard of care.”

Still, “it does support the efficacy of two commonly considered intensification strategies for high-risk patients – hyperfractionation of the radiation and the addition of preceding induction chemotherapy. Both of these intensifications substantially increase the time commitment from the patient, and many patients find this unacceptable. But, for select patients, hyperfractionation and induction chemotherapy have a role and may be considered for patients at high risk of treatment failure,” Dr. Weiss said.
 

Study details

The goal of this study was to find the best option among many chemoradiation approaches for head and neck cancer. The investigators pulled together and reanalyzed individual patient data from recently updated meta-analyses.

The current analysis included 115 randomized trials that enrolled patients between Jan. 1, 1980, and April 30, 2012. This encompassed 28,978 patients with 20,579 progression events and 19,253 deaths over a median follow-up of 6.6 years.

Treatments were ranked by P score, with higher scores indicating more effective therapies.

For overall survival, HFCRT had a P score of 97%. The hazard ratio (HR) was 0.63 for the comparison with locoregional therapy alone (surgery, radiotherapy, or both). The absolute benefit at 5 years, compared with locoregional therapy alone, was 16.7% with HFCRT.

The P score for the second most effective treatment option – induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC_TaxPF-LRT) – was 89%, with a hazard ratio of 0.69 and an absolute benefit at 5 years of 13.4%, versus locoregional therapy.

The HR of HFCRT versus the accepted standard of care worldwide – locoregional therapy with concomitant platinum-based chemotherapy and radiotherapy (CLRT_P) – was 0.82 in favor of HFCRT for overall survival and 0.80 for event-free survival.

For overall survival, the P score for CLRT_P was 78%. Three other treatment options had a better P score than CLRT_P but not a better HR (0.77). These included IC_TaxPF-LRT (P score, 89%; HR, 0.69), accelerated radiotherapy with concomitant chemotherapy (P score, 82%; HR, 0.75), and IC_TaxPF-LRT followed by CLRTP (P score, 80%; HR, 0.75).

In the end, the investigators found “superiority of HFCRT over other treatments,” but noted it can be difficult to implement HFCRT in the era of intensity-modulated radiotherapy for head and neck cancer. Even so, HFCRT “could be considered as an option for tertiary centres with a high throughput of patients,” the investigators wrote.

The team noted that one of the limitations of this study is that cancer care has improved substantially since the very earliest trials that were included in the analysis. This introduces potential confounders, including that patients in older trials might have been understaged so that even an experimental local therapy would have been less effective.

Toxicity wasn’t part of this analysis but must be taken into account when making therapeutic decisions, “especially because HFCRT and induction chemotherapy based on taxane, cisplatin, and fluorouracil are known to be toxic,” the investigators wrote.

This research was funded by the French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC. The authors disclosed relationships with numerous companies, including AbbVie, Lilly, and Merck. Dr. Weiss did not report any relevant conflicts.

[email protected]

Debulking large exophytic basal cell carcinomas prior to hedgehog inhibitor therapy might improve outcomes, according to Allison Vidimos, MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.

She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.

Dr. Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.

An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.

An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.

Dr. Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.

After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Dr. Vidimos said.

The hedgehog inhibitors vismodegib (Erivedge) and sonidegib Odomzo are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.

But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Dr. Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.

Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Dr. Vidimos said.

Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.

“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.

Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Dr. Vidimos said.

Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.

Dr. Vidimos shared another case to illustrate the point.

A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.

She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Dr. Vidimos for Mohs reading.

Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.

The approach “was very successful for a very aggressive and worrisome tumor,” Dr. Vidimos said.

Dr. Vidimos did not have any relevant disclosures. Dr. Patel had no relevant disclosures.

[email protected]

Debulking large exophytic basal cell carcinomas prior to hedgehog inhibitor therapy might improve outcomes, according to Allison Vidimos, MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.

She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.

Dr. Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.

An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.

An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.

Dr. Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.

After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Dr. Vidimos said.

The hedgehog inhibitors vismodegib (Erivedge) and sonidegib Odomzo are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.

But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Dr. Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.

Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Dr. Vidimos said.

Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.

“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.

Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Dr. Vidimos said.

Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.

Dr. Vidimos shared another case to illustrate the point.

A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.

She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Dr. Vidimos for Mohs reading.

Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.

The approach “was very successful for a very aggressive and worrisome tumor,” Dr. Vidimos said.

Dr. Vidimos did not have any relevant disclosures. Dr. Patel had no relevant disclosures.

[email protected]

Debulking large exophytic basal cell carcinomas prior to hedgehog inhibitor therapy might improve outcomes, according to Allison Vidimos, MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.

She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.

Dr. Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.

An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.

An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.

Dr. Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.

After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Dr. Vidimos said.

The hedgehog inhibitors vismodegib (Erivedge) and sonidegib Odomzo are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.

But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Dr. Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.

Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Dr. Vidimos said.

Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.

“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.

Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Dr. Vidimos said.

Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.

Dr. Vidimos shared another case to illustrate the point.

A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.

She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Dr. Vidimos for Mohs reading.

Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.

The approach “was very successful for a very aggressive and worrisome tumor,” Dr. Vidimos said.

Dr. Vidimos did not have any relevant disclosures. Dr. Patel had no relevant disclosures.

[email protected]

Women had about a twofold higher risk than that of men of developing dermatologic adverse events while taking immune checkpoint inhibitors for metastatic melanoma in a review of 235 patients at Dana Farber Cancer Center, Boston.
 

Overall, 62.4% of the 93 women in the review and 48.6% of the 142 men experienced confirmed skin reactions, for an odds ratio (OR) of 2.11 for women compared with men (P = .01).

“Clinicians should consider these results in counseling female patients regarding an elevated risk of dermatologic adverse events” when taking checkpoint inhibitors, said investigators led by Harvard University medical student Jordan Said, who presented the results at the American Academy of Dermatology Virtual Meeting Experience.

Autoimmune-like adverse events are common with checkpoint inhibitors. Dermatologic side effects occur in about half of people receiving monotherapy and more than that among patients receiving combination therapy.

Skin reactions can include psoriasiform dermatitis, lichenoid reactions, vitiligo, and bullous pemphigoid and may require hospitalization and prolonged steroid treatment.

Not much is known about risk factors for these reactions. A higher incidence among women has been previously reported. A 2019 study found a higher risk for pneumonitis and endocrinopathy, including hypophysitis, among women who underwent treatment for non–small cell lung cancer or metastatic melanoma.

The 2019 study found that the risk was higher among premenopausal women than postmenopausal women, which led some to suggest that estrogen may play a role.

The results of the Dana Farber review argue against that notion. In their review, the investigators found that the risk was similarly elevated among the 27 premenopausal women (OR, 1.97; P = .40) and the 66 postmenopausal women (OR, 2.17, P = .05). In the study, women who were aged 52 years or older at the start of treatment were considered to be postmenopausal.

“This suggests that factors beyond sex hormones are likely contributory” to the difference in risk between men and women. It’s known that women are at higher risk for autoimmune disease overall, which might be related to the increased odds of autoimmune-like reactions, and it may be that sex-related differences in innate and adoptive immunity are at work, Mr. Said noted.

When asked for comment, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn., said that although some studies have reported a greater risk for side effects among women, others have not. “Additional research is needed to determine the interactions between sex and effects of immune checkpoint inhibitors, as well as many other possible triggers of immune-related adverse events,” he said.

“Continued work in this area will be so important to help determine how to best counsel women and to ensure early recognition and intervention for dermatologic side effects,” said Bernice Kwong, MD, director of the Supportive Dermato-Oncology Program at Stanford (Calif.) University.

The patients in the review were treated from 2011 to 2016 and underwent at least monthly evaluations by their medical teams. They were taking either nivolumab, pembrolizumab, or ipilimumab or a nivolumab/ipilimumab combination.

The median age of the men in the study was 65 years; the median age of women was 60 years. Almost 98% of the participants were White. The majority received one to three infusions, most commonly with pembrolizumab monotherapy.

No funding for the study was reported. Mr. Said has disclosed no relevant financial relationships.

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

Women had about a twofold higher risk than that of men of developing dermatologic adverse events while taking immune checkpoint inhibitors for metastatic melanoma in a review of 235 patients at Dana Farber Cancer Center, Boston.
 

Overall, 62.4% of the 93 women in the review and 48.6% of the 142 men experienced confirmed skin reactions, for an odds ratio (OR) of 2.11 for women compared with men (P = .01).

“Clinicians should consider these results in counseling female patients regarding an elevated risk of dermatologic adverse events” when taking checkpoint inhibitors, said investigators led by Harvard University medical student Jordan Said, who presented the results at the American Academy of Dermatology Virtual Meeting Experience.

Autoimmune-like adverse events are common with checkpoint inhibitors. Dermatologic side effects occur in about half of people receiving monotherapy and more than that among patients receiving combination therapy.

Skin reactions can include psoriasiform dermatitis, lichenoid reactions, vitiligo, and bullous pemphigoid and may require hospitalization and prolonged steroid treatment.

Not much is known about risk factors for these reactions. A higher incidence among women has been previously reported. A 2019 study found a higher risk for pneumonitis and endocrinopathy, including hypophysitis, among women who underwent treatment for non–small cell lung cancer or metastatic melanoma.

The 2019 study found that the risk was higher among premenopausal women than postmenopausal women, which led some to suggest that estrogen may play a role.

The results of the Dana Farber review argue against that notion. In their review, the investigators found that the risk was similarly elevated among the 27 premenopausal women (OR, 1.97; P = .40) and the 66 postmenopausal women (OR, 2.17, P = .05). In the study, women who were aged 52 years or older at the start of treatment were considered to be postmenopausal.

“This suggests that factors beyond sex hormones are likely contributory” to the difference in risk between men and women. It’s known that women are at higher risk for autoimmune disease overall, which might be related to the increased odds of autoimmune-like reactions, and it may be that sex-related differences in innate and adoptive immunity are at work, Mr. Said noted.

When asked for comment, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn., said that although some studies have reported a greater risk for side effects among women, others have not. “Additional research is needed to determine the interactions between sex and effects of immune checkpoint inhibitors, as well as many other possible triggers of immune-related adverse events,” he said.

“Continued work in this area will be so important to help determine how to best counsel women and to ensure early recognition and intervention for dermatologic side effects,” said Bernice Kwong, MD, director of the Supportive Dermato-Oncology Program at Stanford (Calif.) University.

The patients in the review were treated from 2011 to 2016 and underwent at least monthly evaluations by their medical teams. They were taking either nivolumab, pembrolizumab, or ipilimumab or a nivolumab/ipilimumab combination.

The median age of the men in the study was 65 years; the median age of women was 60 years. Almost 98% of the participants were White. The majority received one to three infusions, most commonly with pembrolizumab monotherapy.

No funding for the study was reported. Mr. Said has disclosed no relevant financial relationships.

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

Women had about a twofold higher risk than that of men of developing dermatologic adverse events while taking immune checkpoint inhibitors for metastatic melanoma in a review of 235 patients at Dana Farber Cancer Center, Boston.
 

Overall, 62.4% of the 93 women in the review and 48.6% of the 142 men experienced confirmed skin reactions, for an odds ratio (OR) of 2.11 for women compared with men (P = .01).

“Clinicians should consider these results in counseling female patients regarding an elevated risk of dermatologic adverse events” when taking checkpoint inhibitors, said investigators led by Harvard University medical student Jordan Said, who presented the results at the American Academy of Dermatology Virtual Meeting Experience.

Autoimmune-like adverse events are common with checkpoint inhibitors. Dermatologic side effects occur in about half of people receiving monotherapy and more than that among patients receiving combination therapy.

Skin reactions can include psoriasiform dermatitis, lichenoid reactions, vitiligo, and bullous pemphigoid and may require hospitalization and prolonged steroid treatment.

Not much is known about risk factors for these reactions. A higher incidence among women has been previously reported. A 2019 study found a higher risk for pneumonitis and endocrinopathy, including hypophysitis, among women who underwent treatment for non–small cell lung cancer or metastatic melanoma.

The 2019 study found that the risk was higher among premenopausal women than postmenopausal women, which led some to suggest that estrogen may play a role.

The results of the Dana Farber review argue against that notion. In their review, the investigators found that the risk was similarly elevated among the 27 premenopausal women (OR, 1.97; P = .40) and the 66 postmenopausal women (OR, 2.17, P = .05). In the study, women who were aged 52 years or older at the start of treatment were considered to be postmenopausal.

“This suggests that factors beyond sex hormones are likely contributory” to the difference in risk between men and women. It’s known that women are at higher risk for autoimmune disease overall, which might be related to the increased odds of autoimmune-like reactions, and it may be that sex-related differences in innate and adoptive immunity are at work, Mr. Said noted.

When asked for comment, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn., said that although some studies have reported a greater risk for side effects among women, others have not. “Additional research is needed to determine the interactions between sex and effects of immune checkpoint inhibitors, as well as many other possible triggers of immune-related adverse events,” he said.

“Continued work in this area will be so important to help determine how to best counsel women and to ensure early recognition and intervention for dermatologic side effects,” said Bernice Kwong, MD, director of the Supportive Dermato-Oncology Program at Stanford (Calif.) University.

The patients in the review were treated from 2011 to 2016 and underwent at least monthly evaluations by their medical teams. They were taking either nivolumab, pembrolizumab, or ipilimumab or a nivolumab/ipilimumab combination.

The median age of the men in the study was 65 years; the median age of women was 60 years. Almost 98% of the participants were White. The majority received one to three infusions, most commonly with pembrolizumab monotherapy.

No funding for the study was reported. Mr. Said has disclosed no relevant financial relationships.

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

Lobaplatin-based induction plus chemoradiation was as effective as, and safer than, a cisplatin-based regimen in a phase 3 trial of more than 500 patients with advanced nasopharyngeal carcinoma.

The lobaplatin regimen proved to be a “promising alternative regimen to cisplatin-based treatment,” Xing Lv, MD, of Sun Yat-sen University Cancer Centre in Guangzhou, China, and colleagues wrote in The Lancet Oncology.

A lobaplatin-based regimen might be particularly attractive when cisplatin is contraindicated, according to authors of a related editorial.

Given the encouraging results in this trial, lobaplatin might even “overtake carboplatin” in cisplatin-ineligible patients, wrote the editorialists, Stefano Cavalieri, MD, and Lisa Licitra, MD, both of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano in Italy.

“Furthermore, the optimal treatment compliance in patients receiving lobaplatin [in the trial] suggests that this agent might be a good candidate for research into escalation strategies,” the editorialists wrote.
 

Study rationale

Cisplatin-based induction followed by concurrent chemoradiotherapy is a standard treatment option in the United States, recommended by National Comprehensive Cancer Network guidelines for stage II-IVB nasopharyngeal carcinoma.

However, cisplatin is associated with poor treatment compliance due to significant hematologic and nonhematologic side effects. Cisplatin also requires increased hydration for renal protection, increasing the risk of fluid overload.

“Safer and more effective platinum drugs are needed for the treatment of nasopharyngeal carcinoma,” the investigators wrote.

Carboplatin is an alternative available in the United States, but “the evidence supporting equivalence between cisplatin with carboplatin is still controversial” for nasopharyngeal cancer, the editorialists wrote.
 

Study details

The phase 3 study enrolled 502 patients from five hospitals in China. The patients had previously untreated, non-keratinizing stage III–IVB nasopharyngeal carcinoma and a Karnofsky performance status score of at least 70. The study excluded patients older than 60 years of age, and adequate renal, hematologic, and hepatic function were required.

Half of patients (n = 252) were randomized to induction with lobaplatin and fluorouracil for two cycles followed by concurrent therapy with lobaplatin for two cycles plus intensity-modulated radiotherapy. The other half of patients (n = 250) were randomized to cisplatin-fluorouracil induction for two cycles, followed by intensity-modulated radiotherapy plus two cycles of cisplatin.

The investigators opted for two-cycle chemotherapy instead of three cycles after observing good activity and safety with two cycles in a phase 2 trial.

Treatment compliance was better in the lobaplatin arm, with 91% of those patients completing two cycles of concurrent chemotherapy, compared with 84% of patients in the cisplatin arm.

The 5-year progression-free survival rate was 75% in the lobaplatin arm and 75.5% in the cisplatin arm in the intention-to-treat population (P noninferiority = .007).

In the per-protocol population, the 5-year progression-free survival rates were 74.8% with lobaplatin and 76.4% with cisplatin (P noninferiority = .016).

The most common grade 3-4 adverse events were mucositis (41% in the lobaplatin arm and 40% in the cisplatin arm), leukopenia (16% and 23%, respectively), and neutropenia (10% and 24%, respectively).

Grade 1-2 nephrotoxicity, nausea, vomiting, and weight loss were significantly less common with lobaplatin (P < .0001 for all).

Questions about generalizability

The editorialists urged caution about generalizing the study results to a wider population.

Study subjects were younger and had no major comorbidities as well as good renal function, which is not always the case with nasopharyngeal carcinoma. In addition, although antiemesis prophylaxis was the standard of care for the study period (2013-2015), guidelines have since been updated to included more intense premedication, which likely would have reduced nausea, vomiting, weight loss, and possibly nephrotoxicity, especially in the cisplatin group.

Induction chemotherapy consisted of cisplatin and fluorouracil, whereas current standards for induction chemotherapy are cisplatin plus gemcitabine or docetaxel plus cisplatin and fluorouracil, the editorialists noted.

As for the two-cycle approach, it’s known that concomitant chemoradiotherapy with two cycles of cisplatin in head and neck cancer “provides similar outcomes to concomitant chemoradiotherapy with three cycles, but only in cases of accelerated intensity-modulated radiotherapy,” not with the standard fractionation used in the study (30-32 fractions, 5 days per week), the editorialists wrote.

The study was funded by the National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. The investigators and Dr. Cavalieri declared no competing interests. Dr. Licitra disclosed relationships AstraZeneca, Bristol Myers Squibb, and Hoffmann-La Roche.

[email protected]

Lobaplatin-based induction plus chemoradiation was as effective as, and safer than, a cisplatin-based regimen in a phase 3 trial of more than 500 patients with advanced nasopharyngeal carcinoma.

The lobaplatin regimen proved to be a “promising alternative regimen to cisplatin-based treatment,” Xing Lv, MD, of Sun Yat-sen University Cancer Centre in Guangzhou, China, and colleagues wrote in The Lancet Oncology.

A lobaplatin-based regimen might be particularly attractive when cisplatin is contraindicated, according to authors of a related editorial.

Given the encouraging results in this trial, lobaplatin might even “overtake carboplatin” in cisplatin-ineligible patients, wrote the editorialists, Stefano Cavalieri, MD, and Lisa Licitra, MD, both of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano in Italy.

“Furthermore, the optimal treatment compliance in patients receiving lobaplatin [in the trial] suggests that this agent might be a good candidate for research into escalation strategies,” the editorialists wrote.
 

Study rationale

Cisplatin-based induction followed by concurrent chemoradiotherapy is a standard treatment option in the United States, recommended by National Comprehensive Cancer Network guidelines for stage II-IVB nasopharyngeal carcinoma.

However, cisplatin is associated with poor treatment compliance due to significant hematologic and nonhematologic side effects. Cisplatin also requires increased hydration for renal protection, increasing the risk of fluid overload.

“Safer and more effective platinum drugs are needed for the treatment of nasopharyngeal carcinoma,” the investigators wrote.

Carboplatin is an alternative available in the United States, but “the evidence supporting equivalence between cisplatin with carboplatin is still controversial” for nasopharyngeal cancer, the editorialists wrote.
 

Study details

The phase 3 study enrolled 502 patients from five hospitals in China. The patients had previously untreated, non-keratinizing stage III–IVB nasopharyngeal carcinoma and a Karnofsky performance status score of at least 70. The study excluded patients older than 60 years of age, and adequate renal, hematologic, and hepatic function were required.

Half of patients (n = 252) were randomized to induction with lobaplatin and fluorouracil for two cycles followed by concurrent therapy with lobaplatin for two cycles plus intensity-modulated radiotherapy. The other half of patients (n = 250) were randomized to cisplatin-fluorouracil induction for two cycles, followed by intensity-modulated radiotherapy plus two cycles of cisplatin.

The investigators opted for two-cycle chemotherapy instead of three cycles after observing good activity and safety with two cycles in a phase 2 trial.

Treatment compliance was better in the lobaplatin arm, with 91% of those patients completing two cycles of concurrent chemotherapy, compared with 84% of patients in the cisplatin arm.

The 5-year progression-free survival rate was 75% in the lobaplatin arm and 75.5% in the cisplatin arm in the intention-to-treat population (P noninferiority = .007).

In the per-protocol population, the 5-year progression-free survival rates were 74.8% with lobaplatin and 76.4% with cisplatin (P noninferiority = .016).

The most common grade 3-4 adverse events were mucositis (41% in the lobaplatin arm and 40% in the cisplatin arm), leukopenia (16% and 23%, respectively), and neutropenia (10% and 24%, respectively).

Grade 1-2 nephrotoxicity, nausea, vomiting, and weight loss were significantly less common with lobaplatin (P < .0001 for all).

Questions about generalizability

The editorialists urged caution about generalizing the study results to a wider population.

Study subjects were younger and had no major comorbidities as well as good renal function, which is not always the case with nasopharyngeal carcinoma. In addition, although antiemesis prophylaxis was the standard of care for the study period (2013-2015), guidelines have since been updated to included more intense premedication, which likely would have reduced nausea, vomiting, weight loss, and possibly nephrotoxicity, especially in the cisplatin group.

Induction chemotherapy consisted of cisplatin and fluorouracil, whereas current standards for induction chemotherapy are cisplatin plus gemcitabine or docetaxel plus cisplatin and fluorouracil, the editorialists noted.

As for the two-cycle approach, it’s known that concomitant chemoradiotherapy with two cycles of cisplatin in head and neck cancer “provides similar outcomes to concomitant chemoradiotherapy with three cycles, but only in cases of accelerated intensity-modulated radiotherapy,” not with the standard fractionation used in the study (30-32 fractions, 5 days per week), the editorialists wrote.

The study was funded by the National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. The investigators and Dr. Cavalieri declared no competing interests. Dr. Licitra disclosed relationships AstraZeneca, Bristol Myers Squibb, and Hoffmann-La Roche.

[email protected]

Lobaplatin-based induction plus chemoradiation was as effective as, and safer than, a cisplatin-based regimen in a phase 3 trial of more than 500 patients with advanced nasopharyngeal carcinoma.

The lobaplatin regimen proved to be a “promising alternative regimen to cisplatin-based treatment,” Xing Lv, MD, of Sun Yat-sen University Cancer Centre in Guangzhou, China, and colleagues wrote in The Lancet Oncology.

A lobaplatin-based regimen might be particularly attractive when cisplatin is contraindicated, according to authors of a related editorial.

Given the encouraging results in this trial, lobaplatin might even “overtake carboplatin” in cisplatin-ineligible patients, wrote the editorialists, Stefano Cavalieri, MD, and Lisa Licitra, MD, both of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano in Italy.

“Furthermore, the optimal treatment compliance in patients receiving lobaplatin [in the trial] suggests that this agent might be a good candidate for research into escalation strategies,” the editorialists wrote.
 

Study rationale

Cisplatin-based induction followed by concurrent chemoradiotherapy is a standard treatment option in the United States, recommended by National Comprehensive Cancer Network guidelines for stage II-IVB nasopharyngeal carcinoma.

However, cisplatin is associated with poor treatment compliance due to significant hematologic and nonhematologic side effects. Cisplatin also requires increased hydration for renal protection, increasing the risk of fluid overload.

“Safer and more effective platinum drugs are needed for the treatment of nasopharyngeal carcinoma,” the investigators wrote.

Carboplatin is an alternative available in the United States, but “the evidence supporting equivalence between cisplatin with carboplatin is still controversial” for nasopharyngeal cancer, the editorialists wrote.
 

Study details

The phase 3 study enrolled 502 patients from five hospitals in China. The patients had previously untreated, non-keratinizing stage III–IVB nasopharyngeal carcinoma and a Karnofsky performance status score of at least 70. The study excluded patients older than 60 years of age, and adequate renal, hematologic, and hepatic function were required.

Half of patients (n = 252) were randomized to induction with lobaplatin and fluorouracil for two cycles followed by concurrent therapy with lobaplatin for two cycles plus intensity-modulated radiotherapy. The other half of patients (n = 250) were randomized to cisplatin-fluorouracil induction for two cycles, followed by intensity-modulated radiotherapy plus two cycles of cisplatin.

The investigators opted for two-cycle chemotherapy instead of three cycles after observing good activity and safety with two cycles in a phase 2 trial.

Treatment compliance was better in the lobaplatin arm, with 91% of those patients completing two cycles of concurrent chemotherapy, compared with 84% of patients in the cisplatin arm.

The 5-year progression-free survival rate was 75% in the lobaplatin arm and 75.5% in the cisplatin arm in the intention-to-treat population (P noninferiority = .007).

In the per-protocol population, the 5-year progression-free survival rates were 74.8% with lobaplatin and 76.4% with cisplatin (P noninferiority = .016).

The most common grade 3-4 adverse events were mucositis (41% in the lobaplatin arm and 40% in the cisplatin arm), leukopenia (16% and 23%, respectively), and neutropenia (10% and 24%, respectively).

Grade 1-2 nephrotoxicity, nausea, vomiting, and weight loss were significantly less common with lobaplatin (P < .0001 for all).

Questions about generalizability

The editorialists urged caution about generalizing the study results to a wider population.

Study subjects were younger and had no major comorbidities as well as good renal function, which is not always the case with nasopharyngeal carcinoma. In addition, although antiemesis prophylaxis was the standard of care for the study period (2013-2015), guidelines have since been updated to included more intense premedication, which likely would have reduced nausea, vomiting, weight loss, and possibly nephrotoxicity, especially in the cisplatin group.

Induction chemotherapy consisted of cisplatin and fluorouracil, whereas current standards for induction chemotherapy are cisplatin plus gemcitabine or docetaxel plus cisplatin and fluorouracil, the editorialists noted.

As for the two-cycle approach, it’s known that concomitant chemoradiotherapy with two cycles of cisplatin in head and neck cancer “provides similar outcomes to concomitant chemoradiotherapy with three cycles, but only in cases of accelerated intensity-modulated radiotherapy,” not with the standard fractionation used in the study (30-32 fractions, 5 days per week), the editorialists wrote.

The study was funded by the National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. The investigators and Dr. Cavalieri declared no competing interests. Dr. Licitra disclosed relationships AstraZeneca, Bristol Myers Squibb, and Hoffmann-La Roche.

[email protected]

Nivolumab continues to demonstrate a substantial survival benefit over docetaxel at 5 years in advanced non-small cell lung cancer (NSCLC) patients who progressed on platinum-based therapies, according to a pooled analysis of two phase 3 trials published in the Journal of Clinical Oncology.

Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.

At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.

The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.

There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.

According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”

“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.

Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”

No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.

The optimal duration of nivolumab treatment beyond 1 year is also uncertain.

The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.

The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.

They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.

Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.

This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.

[email protected]

Nivolumab continues to demonstrate a substantial survival benefit over docetaxel at 5 years in advanced non-small cell lung cancer (NSCLC) patients who progressed on platinum-based therapies, according to a pooled analysis of two phase 3 trials published in the Journal of Clinical Oncology.

Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.

At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.

The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.

There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.

According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”

“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.

Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”

No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.

The optimal duration of nivolumab treatment beyond 1 year is also uncertain.

The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.

The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.

They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.

Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.

This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.

[email protected]

Nivolumab continues to demonstrate a substantial survival benefit over docetaxel at 5 years in advanced non-small cell lung cancer (NSCLC) patients who progressed on platinum-based therapies, according to a pooled analysis of two phase 3 trials published in the Journal of Clinical Oncology.

Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.

At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.

The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.

There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.

According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”

“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.

Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”

No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.

The optimal duration of nivolumab treatment beyond 1 year is also uncertain.

The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.

The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.

They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.

Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.

This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.

[email protected]

Combining plasma cell-free DNA (cfDNA) assessment with MRI improves prediction of pathological complete response to neoadjuvant chemotherapy in locally advanced breast cancer, according to researchers.

When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.

“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.

Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).

Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.

Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.

He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.

When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.

The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.

A total of 11 patients had pathological complete responses to neoadjuvant therapy.

The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.

The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.

The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.

Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.

The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.

[email protected]

Combining plasma cell-free DNA (cfDNA) assessment with MRI improves prediction of pathological complete response to neoadjuvant chemotherapy in locally advanced breast cancer, according to researchers.

When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.

“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.

Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).

Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.

Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.

He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.

When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.

The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.

A total of 11 patients had pathological complete responses to neoadjuvant therapy.

The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.

The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.

The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.

Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.

The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.

[email protected]

Combining plasma cell-free DNA (cfDNA) assessment with MRI improves prediction of pathological complete response to neoadjuvant chemotherapy in locally advanced breast cancer, according to researchers.

When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.

“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.

Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).

Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.

Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.

He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.

When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.

The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.

A total of 11 patients had pathological complete responses to neoadjuvant therapy.

The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.

The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.

The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.

Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.

The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.

[email protected]

Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.

They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.

In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”

Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.

The findings were published online in Annals of Oncology.

“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.

“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.

Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
 

Largest series to document delayed reactions

Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.

Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.

An expert not involved in the study agrees.

“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.

“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.

Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
 

Median onset was 16 months

The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.

The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.

In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.

Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.

Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
 

An early warning system

The most common reactions were colitis, pneumonitis, and rash.

The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.

“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.

Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.

On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.

Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
 

Question on treatment duration

No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.

The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.

The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.

However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.

“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.

Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.

No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.

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

Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.

They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.

In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”

Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.

The findings were published online in Annals of Oncology.

“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.

“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.

Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
 

Largest series to document delayed reactions

Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.

Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.

An expert not involved in the study agrees.

“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.

“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.

Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
 

Median onset was 16 months

The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.

The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.

In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.

Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.

Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
 

An early warning system

The most common reactions were colitis, pneumonitis, and rash.

The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.

“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.

Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.

On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.

Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
 

Question on treatment duration

No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.

The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.

The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.

However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.

“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.

Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.

No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.

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

Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.

They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.

In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”

Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.

The findings were published online in Annals of Oncology.

“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.

“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.

Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
 

Largest series to document delayed reactions

Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.

Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.

An expert not involved in the study agrees.

“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.

“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.

Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
 

Median onset was 16 months

The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.

The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.

In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.

Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.

Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
 

An early warning system

The most common reactions were colitis, pneumonitis, and rash.

The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.

“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.

Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.

On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.

Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
 

Question on treatment duration

No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.

The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.

The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.

However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.

“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.

Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.

No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.

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

The combination of copanlisib plus rituximab led to a 48% reduction in the risk of disease progression or death, when compared with rituximab plus placebo in a phase 3 trial of patients with relapsed, indolent non-Hodgkin lymphoma (NHL).

The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.

Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.

Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
 

Patient and treatment details

The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).

All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.

The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.

Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m² on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
 

Progression-free survival benefit

At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).

The PFS advantage with copanlisib was seen across subtypes:

• Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
• Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
• Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
• Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)

The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.

He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.

The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
 

More than double the rate of serious AEs

The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.

There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.

Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.

More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.

Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.

In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.

Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.

The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.

[email protected]

The combination of copanlisib plus rituximab led to a 48% reduction in the risk of disease progression or death, when compared with rituximab plus placebo in a phase 3 trial of patients with relapsed, indolent non-Hodgkin lymphoma (NHL).

The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.

Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.

Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
 

Patient and treatment details

The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).

All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.

The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.

Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m² on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
 

Progression-free survival benefit

At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).

The PFS advantage with copanlisib was seen across subtypes:

• Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
• Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
• Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
• Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)

The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.

He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.

The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
 

More than double the rate of serious AEs

The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.

There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.

Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.

More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.

Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.

In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.

Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.

The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.

[email protected]

The combination of copanlisib plus rituximab led to a 48% reduction in the risk of disease progression or death, when compared with rituximab plus placebo in a phase 3 trial of patients with relapsed, indolent non-Hodgkin lymphoma (NHL).

The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.

Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.

Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
 

Patient and treatment details

The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).

All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.

The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.

Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m² on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
 

Progression-free survival benefit

At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).

The PFS advantage with copanlisib was seen across subtypes:

• Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
• Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
• Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
• Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)

The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.

He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.

The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
 

More than double the rate of serious AEs

The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.

There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.

Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.

More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.

Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.

In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.

Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.

The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.

[email protected]