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Immunotherapy in Merkel Cell Carcinoma: ‘Field Has Been Thrown on Its Head’


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At the 2018 ASCO Annual Meeting, investigators presented long-term follow-up data for immunotherapy in patients with Merkel cell carcinoma and new data for its use in the neoadjuvant setting. The results drew high interest from attendees and a number of questions were raised following the presentation.

Merkel cell carcinoma is a rare, aggressive, and often fatal skin cancer that is associated with the Merkel cell polyomavirus in ~80% of patients. The other 20% of patients harbor a heavy ultraviolet-induced mutation load. Until recently, chemotherapy was the only treatment option for unresectable disease.

Paul Nghiem, MD, PhD

Paul Nghiem, MD, PhD

As pointed out by an expert in the area, Paul Nghiem, MD, PhD, “Merkel cell typically responds to cytotoxic chemotherapy, but responses are frustratingly nondurable…. This cancer will be fatal in 33% to 46% of patients within the first 5 years of diagnosis—at least it was so, in the era before we had more effective therapies.” The effective therapies are antibodies targeting the inhibitory programmed cell death protein 1 (PD-1) receptor or its ligand (PD-L1). A prognosis that was once dire has become more hopeful, at least for patients who respond to immunotherapy.

These are truly striking data indicating that immunotherapy is a preferred way to treat this cancer, compared with chemotherapy.
— Paul Nghiem, MD, PhD

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“In 2018, happily the field has been thrown on its head in terms of early management of advanced disease,” said Dr. Nghiem, George F. Odland Endowed Chair in Dermatology at the University of Washington, Seattle. The National Comprehensive Cancer Network (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) still list clinical trials as the preferred first treatment option, but now avelumab (Bavencio), pembrolizumab (Keytruda), and nivolumab (Opdivo) are listed ahead of chemotherapy.

In 2017, avelumab became the first drug ever approved by the U.S. Food and Drug Administration for Merkel cell carcinoma. Pembrolizumab and nivolumab have shown similar efficacy in metastatic disease, and their approval in this setting is pending. Updates of these studies were presented at the ASCO meeting, as were new data for neoadjuvant nivolumab in resectable disease.

Neoadjuvant Nivolumab

“Neoadjuvant nivolumab resulted in high response rates after just two doses. Median progression-free and overall survival have not been reached,” reported Suzanne Topalian, MD, Director of the Melanoma Program, at Johns Hopkins Medicine, and Associate Director of the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore.1 “Nivolumab induced radiographic responses in 40% and major pathologic responses in 65% of evaluable patients. In some patients, this avoided the need for more extensive surgery,” she added.

Suzanne Topalian, MD

Suzanne Topalian, MD

The results came from the international phase I/II CheckMate 358 trial that included a cohort of patients with resectable stages IIA to IV Merkel cell carcinoma. Patients with stage IIA Merkel cell cancer have a ~50% risk of mortality within 5 years, according to Dr. Topalian.

Patients received nivolumab every 2 weeks (on days 1 and 15) for 2 doses and underwent surgery about 2 weeks later. Nine patients also received postoperative radiation therapy. Patients could resume nivolumab if they developed progressive disease within 1 year, as one of the patients did.

The analysis was based on 29 patients who received at least 1 dose of nivolumab; 27 went on to surgery about 4 weeks later. The median follow-up was 67 weeks, with some patients followed for about 2 years. No new safety signals were seen with the drug in the neoadjuvant setting, and only 2 patients had a grade 3 or 4 adverse event.

Now the question is whether these changes will translate into prolonged survival.
— Suzanne Topalian, MD

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Radiographic regression by computed tomography was noted for 40% of 25 evaluable patients, in whom target lesions were reduced by more than 30%, she reported. Dr. Topalian added that radiographic response underestimated the impact of nivolumab in this short treatment interval; a better reflection was pathologic tumor response.

In 17 tumors evaluated by central pathologic review, the researchers documented a 47% rate of pathologic complete response by traditional criteria and an 18% major pathologic response rate, defined as up to 10% viable tumor cells remaining. These preliminary data yielded a total major pathologic response rate of 65% by central review, she reported.

Some of the responses were “striking,” added Dr. Topalian. One patient had a distended cheek and underlying 9-cm tumor. After a pathologic complete response and postoperative radiotherapy, she has no evidence of disease at 19 months. Another patient with a major pathologic response in bulky axillary lymph node metastases had 47 axillary nodes resected, only 2 of which contained microscopic tumor. Without any postoperative therapy, the patient appears to be disease-free at 18 months.

“Median progression-free survival for the 27 patients undergoing surgery has not been reached. Among 15 patients who had either a pathologic complete response or a major pathologic response by central or site investigator review, none has relapsed after surgery with a median follow-up of 12 months,” she said. “Now the question is whether these changes will translate into prolonged survival.”

Update on JAVELIN Merkel 200: ‘Striking Survival’

Dr. Nghiem presented an update on the international phase II JAVELIN Merkel 200 registration trial of avelumab in metastatic disease, calling the survival rates “striking,” as more than one-third of chemotherapy--refractory patients were still alive at 2 years.2

Patients who had previously been treated with at least one line of chemotherapy for metastatic disease received avelumab at 10 mg/kg once every 2 weeks. In the updated analysis, 88 patients were followed for a median of 29.2 months.

The confirmed overall response rate in the second-line setting or beyond was 33%, with 11.4% being complete responses. For the 29 responders, the median duration of response has not been reached. Of the 10 patients achieving complete responses, 7 are ongoing, and 67% of responders are expected to still be responding at 2 years.

Studies of anti–PD-1/PD-L1 agents in the first-line setting have demonstrated even higher response rates, essentially double those achieved with chemotherapy. This indicates Merkel cell carcinoma is a highly immunosensitive malignancy, he said.

Durable responses led to stable rates of progression-free survival: 29% at 12 months and 26% at 24 months. Median progression-free survival, however, was 3 months, due to early disease progression (< 3 months) in many patients.

When disease progression occurs, it is usually within 12 months, he added. “The duration of response and overall survival are perhaps the most important messages here…. If a responder makes it more than a year after beginning therapy, the chance of staying in response is very high,” he said.

Dr. Nghiem called the overall survival results “even more striking,” since in two historical cohorts, none of the patients with chemotherapy-refractory disease survived 1 year from starting second-line chemotherapy. For chemotherapy-refractory patients treated with avelumab, the median overall survival was 12.6 months, and 36% of patients were alive at 2 years.

This means a randomized trial comparing immunotherapy to chemotherapy is unlikely. “These are truly striking data indicating that immunotherapy is a preferred way to treat this cancer, compared with chemotherapy,” Dr. Nghiem commented.

Durability of First-Line Pembrolizumab

Dr. Nghiem also presented the results of a single-arm open-label multicenter phase II trial of pembrolizumab in treatment-naive patients with metastatic or inoperable recurrent locally advanced disease.3 Pembrolizumab was given at 2 mg/kg every 3 weeks for up to 2 years.

Early results were published in TheNewEnglandJournal of Medicine 2 years ago on the first 26 patients, after a median follow-up of 33 weeks.4 Dr. Nghiem reported on the complete cohort of 50 patients (most with distant metastatic disease) with an additional 2 years of follow-up, yielding a median follow-up time of 14.9 months.

IMMUNOTHERAPY FOR MERKEL CELL CARCINOMA

  • In an update of the JAVELIN study of avelumab for previously treated patients with advanced Merkel cell carcinoma, the response rate was 33%, and the median duration of response was not reached for the 29 responders. Of 10 complete responses, 7 are ongoing. Progression-free survival rates were 29% at 12 months and 26% at 24 months.
  • In a phase II study of first-line pembrolizumab in advanced disease, the response rate was 56%, and responses were durable. The median progression-free survival was 16.3 months.
  • In CheckMate 358, neoadjuvant nivolumab produced responses after two doses. The major pathologic response rate was 65%, and none of these patients had relapsed after 12 months.

“In the longest observation to date of patients with advanced Merkel cell carcinoma receiving first-line anti–PD-1 therapy, the overall response rate was 56% and was similar for virus-positive and virus-negative tumors,” Dr. Nghiem reported. Of these responses, 24% were complete responses. Responses were usually observed by the first evaluation interval at 3 months, and some partial responses later converted to complete responses. Responses were durable, and the median progression-free survival was 16.8 months.

“This is a cancer that tends to grow very quickly unless it is interrupted, and immune therapy is a quick and effective way to affect the growth,” he said. “By the time of the first scan, most patients were classified as responders or nonresponders…. Most responses are ongoing, and most are durable after 24 months, the end of therapy…. At 12, 24, and even 36 months, the vast majority of patients who did respond to pembrolizumab are staying in response. This striking durability is in stark contrast to responses to chemotherapy, which are not durable.”

“There is also a many-fold better chance of remaining progression-free,” he continued. The median progression-free survival was 16.8 months with first-line pembrolizumab, compared historically with 3 to 5 months with chemotherapy. Similarly, median overall survival has not been reached, whereas it is approximately 10 months with chemotherapy. More than 60% of patients were alive at 3 years in the study.

Treatment-related adverse events led to treatment discontinuation in 14% of patients. Grade ≥ 3 toxicities were observed in 28%. One treatment-related death occurred in a patient with rapidly progressing disease and pleural effusions.

Discussion

Audience interest was high following the session on Merkel cell carcinoma, and a number of questions were asked of the presenters. One attendee questioned the panel about whether one of the anti–PD-1/PD-L1 agents could result in curing patients with Merkel cell cancer.Dr. Nghiem cautioned against using the word “cure” but indicated that there were a significant number of patients in the trial with complete responses who had come off therapy about 1 to 2 years earlier and remained free of disease, calling this “pretty close to a cure in that subset.” Dr. Nghiem also commented on cases of virus-related and virus-unrelated Merkel cell carcinoma in the trials, and he noted that the viral status of patients did not have any implications on treatment options in the clinical trials.

Dr. Topalian discussed the role of surgery in patients who respond to neoadjuvant checkpoint inhibition in the trial, and she indicated that although she believed surgery was still necessaryfollowing neoadjuvant therapy it might not need be as extensive an operation as it could be without neoadjuvant therapy. She clarified this by noting, “we may see findings on computed tomography scans, but there’s no way to know what is going on pathologically…. Thus, using the neoadjuvant approach, I would say we do need surgery.” ■

DISCLOSURE: Dr. Nghiem disclosed financial relationships with EMD Serono, Merck Sharp & Dohme, and Pfizer. Dr. Topalian disclosed financial relationships with Aduro Biotech, Compugen, DNAtrix, Five Prime Therapeutics, FLX Bio, Jounce Therapeutics, NexImmune, Potenza Therapeutics, Tizona Therapeutics, WindMIL, AbbVie, Amgen, Avidity Biosciences, MedImmune, Merck, Pfizer, and Sanofi.

REFERENCES

1. Topalian SL, Bhatia S, Kudchadkar RR, et al: Nivolumab as neoadjuvant therapy in patients with resectable Merkel cell carcinoma in CheckMate 358. 2018 ASCO Annual Meeting. Abstract 9505. Presented June 4, 2018.

2. Nghiem P, Bhatia S, Brohl AS, et al: Two-year efficacy and safety update from JAVELIN Merkel 200 part A: A registrational study of avelumab in metastatic Merkel cell carcinoma progressed on chemotherapy. 2018 ASCO Annual Meeting. Abstract 9507. Presented June 4, 2018.

3. Nghiem P, Bhatia S, Lipson EJ, et al: Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy. 2018 ASCO Annual Meeting. Abstract 9506. Presented June 4, 2018.

4. Nghiem PT, Bhatia S, Lipson EJ, et al: PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 374:2542-2552, 2016.


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