Immunotherapies generate tremendous excitement for Merkel cell carcinoma

Immunotherapies are changing the treatment landscape for Merkel cell carcinoma.

Approximately 1,600 new cases of Merkel cell carcinoma — a rare but aggressive skin cancer linked to UV light exposure — are reported each year in the United States.

Until this year, no FDA–approved treatments existed.

Pharmaceutical companies regarded Merkel cell carcinoma as “too small” of a disease on which to focus, according to Paul T. Nghiem, MD, PhD, professor of medicine in the division of dermatology at University of Washington School of Medicine and Seattle Cancer Care Alliance.

Paul T. Nghiem, MD, PhD
Paul T. Nghiem

Consequently, chemotherapy had been the only treatment option.

“Despite a high rate of initial response to chemotherapy, outcomes were deeply disappointing if the goal was to be alive in 1 year,” Nghiem told HemOnc Today.

In March, the FDA approved avelumab (Bavencio; EMD Serono, Pfizer) — an anti–PD-L1 monoclonal antibody — for first- or second-line treatment of patients aged 12 years and older with metastatic Merkel cell carcinoma.

This approval has coincided with positive preliminary data on other drugs in the pipeline.

“It’s clearly an exciting time ... for a cancer that has not gotten attention, and for patients who have felt alone,” Nghiem said.

The long-term survival rates observed with avelumab are a huge improvement from what had been observed with chemotherapy, Howard L. Kaufman, MD, FACS, surgical oncologist at Rutgers Cancer Institute of New Jersey, said in an interview.

Howard L. Kaufman, MD, FACS
Howard L. Kaufman

“We were previously seeing few patients surviving past 12 months with these agents, so now having avelumab as an agent that works is really important,” Kaufman, lead researcher on the study that led to the drug’s approval, told HemOnc Today. “We are seeing 72% of our patients still in response after 1 year of treatment. It’s a tremendous advance.”

Treatment evolution

Merkel cell carcinoma often is considered more aggressive than melanoma, as its historical 3-year mortality rate is more than twice as high (33% vs. 15%).

The prognosis for patients with Merkel cell carcinoma varies greatly based on extent of disease at presentation. Ninety percent of patients with local disease survive 3 years, compared with 52% of patients with nodal involvement and 10% of those with metastatic disease.

Incidence increased significantly from 1986 to 2011, from 0.22 cases per 100,000 people to 0.79 cases per 100,000 people, according to data from Fitzgerald and colleagues. Further, there has been a 333% increase in Merkel cell carcinoma mortality.

This trend could be due to an aging population — median age at diagnosis is 65 years — and increased aggregate sun exposure.

Prior to avelumab’s approval, chemotherapy had been the only option for patients.

In a study published last year in Cancer Medicine, Iyer and colleagues evaluated 62 patients with metastatic Merkel cell carcinoma treated with first-line and second-line chemotherapy.

In the first-line group, researchers reported a 55% overall response rate (median duration of response, 85 days), median PFS of 93 days and median OS of 9.5 months.

In the second-line group, researchers reported a 23% ORR (median duration of response, 101 days) and median PFS of 61 days.

The data indicate patients with Merkel cell carcinoma develop rapid chemotherapy resistance, researchers wrote.

Hence the excitement surrounding immunotherapy.

More than half of Merkel cell tumors express PD-L1, a protein shown to be an effective target for immunotherapy in other malignancies. Also, Merkel cell polyomavirus–specific T cells express PD-1 in about two-thirds of patients.

Nghiem and colleagues evaluated data from 24 patients with unresectable or metastatic disease treated with 2 mg/kg pembrolizumab (Keytruda, Merck) — an anti–PD-1 antibody — via IV every 3 weeks for up to 2 years.

Results — presented at last year’s American Association for Cancer Research (AACR) Annual Meeting and published simultaneously in The New England Journal of Medicine — revealed a 56% ORR. Most responses (86%; n = 12) were ongoing at the time of data cutoff, and regression of cutaneous tumors began within days of the first dose.

A greater proportion of patients with Merkel cell polyomavirus–positive tumors responded to treatment, but this difference did not reach statistical significance (62% vs. 44%).

Overall, median PFS was 9 months, and 67% (95% CI, 49-86) of patients achieved 6-month PFS.

“At the time, there had not been a trial ... that showed benefit in this cancer, and there actually was a lot of doubt in the pharmaceutical industry that a trial could be positive,” Nghiem said.

The National Comprehensive Cancer Network now lists pembrolizumab as an option for disseminated disease.

“The hint in all of this is that early exposure to the immunostimulating drug may be better than getting it later, after chemotherapy,” Kaufman said. “The FDA approval [of avelumab] surprised us a little bit — pleasantly, though, because the approval was for both first- and second-line to really ensure that these patients can get rapid access to the drug.”

Kaufman presented updated efficacy data at this year’s AACR Annual Meeting on 88 previously treated patients with metastatic Merkel cell carcinoma who received avelumab. These data, based on more than 1 year of follow-up, led to the agent’s approval (see related meeting news and FDA news).

Results showed that response persisted for 6 months in 92% of patients, and for 1 year in 74% of patients.

“This is important because it suggests the patients are behaving like we’d expect with immunotherapy, which is to have long-term durable responses,” Kaufman said. “We initially reported a 32% response rate. It appears that our response rate has now actually gone up a little to 33%, based on a few additional complete responders occurring between 6 and 12 months.”

Other agents

Because not all patients with Merkel cell carcinoma respond to avelumab or pembrolizumab, investigations into the efficacy of other immunotherapies continue.

At this year’s AACR Annual Meeting, Topalian and colleagues presented data from the CheckMate 358 study. The analysis included 25 patients with Merkel cell carcinoma treated with nivolumab (Opdivo, Bristol-Myers Squibb) — an anti–PD-1 antibody — with median follow-up of 26 weeks (range, 5-35).

Researchers reported a 68% ORR among 22 patients evaluable for response, with ongoing responses in 13 of 15 (87%) patients.

Topalian and colleagues observed responses in treatment-naive patients (71%), patients with one or two prior systemic therapies (63%), and patients with virus-positive and virus-negative tumors. Two-thirds (67%) of responses occurred at less than 8 weeks.

At 3 months, 92% of patients remained alive and 82% were progression free.

“We now have public data on three immune checkpoint–based therapies that suggest remarkable efficacy compared with chemotherapy,” Nghiem said. “That is a big deal, considering that just 1 year ago, medical oncologists routinely used a platinum and etoposide regimen for managing Merkel cell carcinoma.”

Clinical trials investigating other regimens for Merkel cell carcinoma are underway, including a trial that will combine a patient’s own anti-Merkel polyomavirus–specific T cells with avelumab, as well as a trial of activated natural killer cells (NantKwest) in patients who previously failed checkpoint inhibition therapy.

“I anticipate there will be a lot of other trials, as well,” Nghiem added.

Kaufman will serve as a researcher on a trial conducted with the NCI that will combine talimogene laherparepvec (Imlygic, Amgen), an oncolytic virus, with nivolumab.

“I do think in the future there will be a combination treatment available,” Kaufman said. “There are a few already in progress and if we can, in fact, rescue some of the nonresponders, we can increase the response rate.”

There are other opportunities to “reinvigorate” immune response despite checkpoint failure, Nghiem said.

“The list of opportunities is long and includes innate immune stimulation and potentially therapeutic vaccination, either to UV–induced neoantigens or viral antigens in combination with immune stimulation,” Nghiem said.

Because Merkel cell carcinoma antigens are shared across many patients — with the Merkel cell polyomavirus accounting for 80% of cases — there are many different directions to look at for therapy, Nghiem added.

Challenges ahead

Despite the advances in treatment, risk for recurrence or nonresponse represents a challenge for this already complicated disease.

“It is still possible some patients will recur at some point, and we really need to understand why that happens,” Kaufman said.

More education is needed on available tools — such as certain blood tests — that can detect cancer recurrence sooner, Nghiem said.

“We routinely use a blood test to find the cancer when it is coming back, which is earlier than waiting for clinical evidence or even a scan,” he said. “Although it is broadly available, most people are not familiar with it, so some degree of education is needed.”

Detecting cancer recurrence early and managing patients at risk for recurrence will be key considerations to continue improving outcomes, Nghiem said.

“Nearly half of patients will not respond to a checkpoint inhibitor or will not remain in response,” he said. “The list of opportunities for how to understand who is not responding and how to reverse it is truly long, exciting, interesting and hopeful, but I’m sure it will be very challenging.” – by Melinda Stevens

References:

Fitzgerald TL, et al. Am Surg. 2015;81:802-806.

Hodgson NC. J Surg Oncol. 2005;89:1-4.

Iyer JG, et al. Cancer Med. 2016;doi:10.1002/cam4.815.

Kaufman HL, et al. Abstract CT079. Presented at: AACR Annual Meeting; April 1-5, 2017; Washington, D.C.

Nghiem P, et al. Abstract CT-096. Presented at: AACR Annual Meeting; April 16-20, 2016; New Orleans.

Topalian S, et al. Abstract CT074. Presented at: AACR Annual Meeting; April 1-5, 2017; Washington, D.C.

For more information:

Howard L. Kaufman, MD, FACS, can be reached at Rutgers Cancer Institute of New Jersey, 195 Little Albany St., New Brunswick, NJ 08903; email: hk553@cinj.rutgers.edu.

Paul T. Nghiem, MD, PhD, can be reached at Division of Dermatology, University of Washington School of Medicine, 1959 NE Pacific St., Seattle, WA 98195.

Disclosure: Kaufman reports advisory roles with Amgen, Celldex, Compass Therapeutics, EMD Serono, Merck, Prometheus and Turnstone Biologics. Nghiem reports a consultant role with EMD Serono, as well as funding from Bristol-Myers Squibb to perform biomarker studies in clinical trials.

Immunotherapies are changing the treatment landscape for Merkel cell carcinoma.

Approximately 1,600 new cases of Merkel cell carcinoma — a rare but aggressive skin cancer linked to UV light exposure — are reported each year in the United States.

Until this year, no FDA–approved treatments existed.

Pharmaceutical companies regarded Merkel cell carcinoma as “too small” of a disease on which to focus, according to Paul T. Nghiem, MD, PhD, professor of medicine in the division of dermatology at University of Washington School of Medicine and Seattle Cancer Care Alliance.

Paul T. Nghiem, MD, PhD
Paul T. Nghiem

Consequently, chemotherapy had been the only treatment option.

“Despite a high rate of initial response to chemotherapy, outcomes were deeply disappointing if the goal was to be alive in 1 year,” Nghiem told HemOnc Today.

In March, the FDA approved avelumab (Bavencio; EMD Serono, Pfizer) — an anti–PD-L1 monoclonal antibody — for first- or second-line treatment of patients aged 12 years and older with metastatic Merkel cell carcinoma.

This approval has coincided with positive preliminary data on other drugs in the pipeline.

“It’s clearly an exciting time ... for a cancer that has not gotten attention, and for patients who have felt alone,” Nghiem said.

The long-term survival rates observed with avelumab are a huge improvement from what had been observed with chemotherapy, Howard L. Kaufman, MD, FACS, surgical oncologist at Rutgers Cancer Institute of New Jersey, said in an interview.

Howard L. Kaufman, MD, FACS
Howard L. Kaufman

“We were previously seeing few patients surviving past 12 months with these agents, so now having avelumab as an agent that works is really important,” Kaufman, lead researcher on the study that led to the drug’s approval, told HemOnc Today. “We are seeing 72% of our patients still in response after 1 year of treatment. It’s a tremendous advance.”

Treatment evolution

Merkel cell carcinoma often is considered more aggressive than melanoma, as its historical 3-year mortality rate is more than twice as high (33% vs. 15%).

The prognosis for patients with Merkel cell carcinoma varies greatly based on extent of disease at presentation. Ninety percent of patients with local disease survive 3 years, compared with 52% of patients with nodal involvement and 10% of those with metastatic disease.

Incidence increased significantly from 1986 to 2011, from 0.22 cases per 100,000 people to 0.79 cases per 100,000 people, according to data from Fitzgerald and colleagues. Further, there has been a 333% increase in Merkel cell carcinoma mortality.

This trend could be due to an aging population — median age at diagnosis is 65 years — and increased aggregate sun exposure.

PAGE BREAK

Prior to avelumab’s approval, chemotherapy had been the only option for patients.

In a study published last year in Cancer Medicine, Iyer and colleagues evaluated 62 patients with metastatic Merkel cell carcinoma treated with first-line and second-line chemotherapy.

In the first-line group, researchers reported a 55% overall response rate (median duration of response, 85 days), median PFS of 93 days and median OS of 9.5 months.

In the second-line group, researchers reported a 23% ORR (median duration of response, 101 days) and median PFS of 61 days.

The data indicate patients with Merkel cell carcinoma develop rapid chemotherapy resistance, researchers wrote.

Hence the excitement surrounding immunotherapy.

More than half of Merkel cell tumors express PD-L1, a protein shown to be an effective target for immunotherapy in other malignancies. Also, Merkel cell polyomavirus–specific T cells express PD-1 in about two-thirds of patients.

Nghiem and colleagues evaluated data from 24 patients with unresectable or metastatic disease treated with 2 mg/kg pembrolizumab (Keytruda, Merck) — an anti–PD-1 antibody — via IV every 3 weeks for up to 2 years.

Results — presented at last year’s American Association for Cancer Research (AACR) Annual Meeting and published simultaneously in The New England Journal of Medicine — revealed a 56% ORR. Most responses (86%; n = 12) were ongoing at the time of data cutoff, and regression of cutaneous tumors began within days of the first dose.

A greater proportion of patients with Merkel cell polyomavirus–positive tumors responded to treatment, but this difference did not reach statistical significance (62% vs. 44%).

Overall, median PFS was 9 months, and 67% (95% CI, 49-86) of patients achieved 6-month PFS.

“At the time, there had not been a trial ... that showed benefit in this cancer, and there actually was a lot of doubt in the pharmaceutical industry that a trial could be positive,” Nghiem said.

The National Comprehensive Cancer Network now lists pembrolizumab as an option for disseminated disease.

“The hint in all of this is that early exposure to the immunostimulating drug may be better than getting it later, after chemotherapy,” Kaufman said. “The FDA approval [of avelumab] surprised us a little bit — pleasantly, though, because the approval was for both first- and second-line to really ensure that these patients can get rapid access to the drug.”

Kaufman presented updated efficacy data at this year’s AACR Annual Meeting on 88 previously treated patients with metastatic Merkel cell carcinoma who received avelumab. These data, based on more than 1 year of follow-up, led to the agent’s approval (see related meeting news and FDA news).

PAGE BREAK

Results showed that response persisted for 6 months in 92% of patients, and for 1 year in 74% of patients.

“This is important because it suggests the patients are behaving like we’d expect with immunotherapy, which is to have long-term durable responses,” Kaufman said. “We initially reported a 32% response rate. It appears that our response rate has now actually gone up a little to 33%, based on a few additional complete responders occurring between 6 and 12 months.”

Other agents

Because not all patients with Merkel cell carcinoma respond to avelumab or pembrolizumab, investigations into the efficacy of other immunotherapies continue.

At this year’s AACR Annual Meeting, Topalian and colleagues presented data from the CheckMate 358 study. The analysis included 25 patients with Merkel cell carcinoma treated with nivolumab (Opdivo, Bristol-Myers Squibb) — an anti–PD-1 antibody — with median follow-up of 26 weeks (range, 5-35).

Researchers reported a 68% ORR among 22 patients evaluable for response, with ongoing responses in 13 of 15 (87%) patients.

Topalian and colleagues observed responses in treatment-naive patients (71%), patients with one or two prior systemic therapies (63%), and patients with virus-positive and virus-negative tumors. Two-thirds (67%) of responses occurred at less than 8 weeks.

At 3 months, 92% of patients remained alive and 82% were progression free.

“We now have public data on three immune checkpoint–based therapies that suggest remarkable efficacy compared with chemotherapy,” Nghiem said. “That is a big deal, considering that just 1 year ago, medical oncologists routinely used a platinum and etoposide regimen for managing Merkel cell carcinoma.”

Clinical trials investigating other regimens for Merkel cell carcinoma are underway, including a trial that will combine a patient’s own anti-Merkel polyomavirus–specific T cells with avelumab, as well as a trial of activated natural killer cells (NantKwest) in patients who previously failed checkpoint inhibition therapy.

“I anticipate there will be a lot of other trials, as well,” Nghiem added.

Kaufman will serve as a researcher on a trial conducted with the NCI that will combine talimogene laherparepvec (Imlygic, Amgen), an oncolytic virus, with nivolumab.

“I do think in the future there will be a combination treatment available,” Kaufman said. “There are a few already in progress and if we can, in fact, rescue some of the nonresponders, we can increase the response rate.”

There are other opportunities to “reinvigorate” immune response despite checkpoint failure, Nghiem said.

“The list of opportunities is long and includes innate immune stimulation and potentially therapeutic vaccination, either to UV–induced neoantigens or viral antigens in combination with immune stimulation,” Nghiem said.

PAGE BREAK

Because Merkel cell carcinoma antigens are shared across many patients — with the Merkel cell polyomavirus accounting for 80% of cases — there are many different directions to look at for therapy, Nghiem added.

Challenges ahead

Despite the advances in treatment, risk for recurrence or nonresponse represents a challenge for this already complicated disease.

“It is still possible some patients will recur at some point, and we really need to understand why that happens,” Kaufman said.

More education is needed on available tools — such as certain blood tests — that can detect cancer recurrence sooner, Nghiem said.

“We routinely use a blood test to find the cancer when it is coming back, which is earlier than waiting for clinical evidence or even a scan,” he said. “Although it is broadly available, most people are not familiar with it, so some degree of education is needed.”

Detecting cancer recurrence early and managing patients at risk for recurrence will be key considerations to continue improving outcomes, Nghiem said.

“Nearly half of patients will not respond to a checkpoint inhibitor or will not remain in response,” he said. “The list of opportunities for how to understand who is not responding and how to reverse it is truly long, exciting, interesting and hopeful, but I’m sure it will be very challenging.” – by Melinda Stevens

References:

Fitzgerald TL, et al. Am Surg. 2015;81:802-806.

Hodgson NC. J Surg Oncol. 2005;89:1-4.

Iyer JG, et al. Cancer Med. 2016;doi:10.1002/cam4.815.

Kaufman HL, et al. Abstract CT079. Presented at: AACR Annual Meeting; April 1-5, 2017; Washington, D.C.

Nghiem P, et al. Abstract CT-096. Presented at: AACR Annual Meeting; April 16-20, 2016; New Orleans.

Topalian S, et al. Abstract CT074. Presented at: AACR Annual Meeting; April 1-5, 2017; Washington, D.C.

For more information:

Howard L. Kaufman, MD, FACS, can be reached at Rutgers Cancer Institute of New Jersey, 195 Little Albany St., New Brunswick, NJ 08903; email: hk553@cinj.rutgers.edu.

Paul T. Nghiem, MD, PhD, can be reached at Division of Dermatology, University of Washington School of Medicine, 1959 NE Pacific St., Seattle, WA 98195.

Disclosure: Kaufman reports advisory roles with Amgen, Celldex, Compass Therapeutics, EMD Serono, Merck, Prometheus and Turnstone Biologics. Nghiem reports a consultant role with EMD Serono, as well as funding from Bristol-Myers Squibb to perform biomarker studies in clinical trials.