Immunotherapy Advances Are Explored in Merkel Cell Carcinoma

Early-stage skin cancers that remain localized are often successfully treated through a variety of surgical techniques as well as radiation therapy, photodynamic therapy, and topical chemotherapy, but advanced cases that are beyond surgery may respond to immunotherapies. This setting will be discussed during the Society for Immunotherapy of Cancer’s 34th Annual Meeting (SITC 2019).

For example, Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer known to grow quickly and metastasize early.¹Although uncommon (about 2488 cases per year are diagnosed in the United States), its incidence is rising.^2,3MCC occurs more often in those who have weakened immune systems and is considered an immunogenic cancer.⁴Suspecting that MCC had an infectious origin because of its propensity for elderly and immunosuppressed individuals, Huichen Feng, PhD, and colleagues conducted studies that led to the detection of the Merkel cell polyomavirus (MCPyV) in MCC tumors.⁵This virus has been identified in 40% to 100% of MCC tumors.^6-9In MCPyV-negative tumors, the mutational burden is very high. Sun exposure is a probable major risk factor,¹⁰and in the United States, most patients with MCC are white and elderly.¹¹

Nonmelanoma skin cancer (NMSC), including MCC, is on the rise. To estimate the number of new NMSC diagnoses and the number of individuals affected by an NMSC diagnosis in the United States in 2012, Howard W. Rogers, MD, PhD, and his colleagues analyzed Medicare beneficiary data as well as information from the National Ambulatory Medical Care Survey. They found that the number of new NMSC diagnoses and the number of individuals with NMSC were increasing. From 2006 to 2012, there was a 14% increase in NMSC procedures among Medicare beneficiaries and a 14% increase in the number of people undergoing at least 1 procedure for NMSC. According to their calculations, approximately 5.4 million cases of NMSC were diagnosed and 3.3 million individuals were treated for NMSC in the United Statesowing to lack of national reporting and previously nonspecific diagnosis classification, accurate measurement of the US incidence of nonmelanoma skin cancer (NMSC in 2012).¹²

In their study published in 2018, Kelly G. Paulson, MD, PhD, and her team focused on MCC and confirmed that the incidence rates for MCC were increasing and were “strongly age-associated.” Using Surveillance, Epidemiology, and End Results 18 data, they found that from 2000 to 2013, the number of reported MCC cases increased 95%, whereas they noted a 57% increase of reported melanoma and a 15% increase in solid cancer reports during the same period. Age was associated with a substantial increase in incidence. Individuals aged 40 to 44 years had an incidence of 0.1 per 100,000 person-years versus 9.8 per 100,000 person-years for those at least 85 years old. By 2025, MCC incidence is expected to reach approximately 3300 cases per year.²

To better understand the genetics behind MCC, Gerald Goh, PhD, et al completed exome sequencing on 49 MCCs. They found that the number of somatic single-nucleotide variants (SSNVs) per exome is quite different between MCPyV-negative MCCs and MCPyV-positive MCCs. In their study, the median number of SSNVs per exome was 1121.0 for MCPyV-negative MCCs versus a median of 12.5 SSNVs per tumor for MCPyV-positive MCCs. For MCPyV-negative MCCs, frequent mutations were seen in RB1 and TP53 and the DNA-damage, JNK, and chromatin modification pathways. In this study, MCPyV-positive MCCs did not have SSNVs in any of these genes. That said, the investigators found infrequent cancer-promoting mutations in both groups, including those expected to inactivate the Notch pathway and those likely to activate the PI3K pathway. Thirty-seven percent of the virus-negative MCCs had a TP53 gain-of-function mutation. In addition, 5-year survival was very different in early MCC depending on whether the MCC was wild-type or TP53 mutant. For the wild-type, the 5-year survival was 92% versus 20% for TP53 mutant (P= .0036).¹⁰

Even though virus-positive MCC has a very low mutational burden compared with virus-negative MCC, both can respond to immune checkpoint inhibitors. In a multicenter, noncontrolled, phase II study of 26 adults with advanced MCC who had not yet received systemic therapy, pembrolizumab (Keytruda) 2 mg/kg was given every 3 weeks. The objective response rate (ORR) was the primary end point. Ten patients had a partial response, and 4 had a complete response, and the ORR (calculated from the 25 patients to complete at least 1 evaluation during treatment) was 56% (95% CI, 35%-76%). The responses lasted 2.2 to at least 9.7 months. At 6 months, progression-free survival (PFS) was 67%. Tumors were MCPyV positive in 65% of patients (17 of 26), and the response rate for those with MCPyV-positive tumors was 62% versus 44% for those with MCPyV-negative tumors. The investigators concluded that “responses were observed in patients with virus-positive tumors and those with virus-negative tumors.”¹³

In addition to clinical trial evidence that anti—PD-1 therapy can increase PFS in patients with advanced MCC, Paul Nghiem, MD, PhD, and colleagues wanted more insight into how this treatment affects overall survival (OS) and the durability of tumor control. In their phase II, multicenter trial (Cancer Immunotherapy Trials Network-09/KEYNOTE-017), pembrolizumab 2 mg/kg was given every 3 weeks for up to 2 years to 50 adults with advanced MCC and no history of systemic treatment for MCC. Sixty-four percent of patients had virus-positive tumors. The median time of follow-up was 14.9 months. The partial response rate was 32%, and the complete response rate was 24%, for an ORR of 56%. In virus-positive tumors, the ORR was 59%, and in virus-negative tumors, it was 53%. Among those who responded to the treatment, the median duration of response was not reached. PFS was 48.3% at 24 months, with a median PFS of 16.8 months. OS was 68.7% at 24 months, without attainment of median OS. Twenty-eight percent (14 of 50) patients had grade ≥3 treatment-related adverse events (AEs), and 14% stopped treatment because of them. One treatment-related death was reported. The authors concluded that “pembrolizumab demonstrated durable tumor control, a generally manageable safety profile and favorable OS compared with historical data from patients treated with first-line chemotherapy.”¹⁴

A study of nivolumab in patients with MCC supports that anti—PD-1 treatment can be rapidly effective and durable in patients with and without previous treatment. CheckMate 358, a phase I and II, open-label, multiple-cohort, noncomparative study, assessed nivolumab in patients with advanced MCC. The primary end points were safety and ORR. PFS, OS, and duration of response (DOR) were the secondary end points. Of the 18 tumors tested for the virus, 12 (67%) were virus positive. Of the 25 treated patients, 60% had not been previously treated for MCC. Approximately two-thirds (67%) of responses happened around week 8. In the 22 patients whose responses could be evaluated, the ORR was 68%, and 87% (13 of 15) had ongoing responses. Treatment-naïve patients had a 71% response rate, and those who had had 1 or 2 previous systemic treatments had a 63% response rate. At month 3, PFS was 82% and OS was 92%. Sixty-eight percent of patients experienced a treatment-related AE, with 20% experiencing a grade 3 or 4 AE. Treatment-related AEs caused 12% of patients to stop nivolumab treatment.¹⁵

To see how patients with stage IV MCC who have already been treated with chemotherapy respond to an anti—PD-L1 antibody (avelumab [Bavencio]), Howard L. Kaufman, MD, and his team undertook a phase II trial (NCT02155647). In this open-label, single-group, prospective, multi-center trial, adults with chemotherapy-refractory, stage IV MCC were treated intravenously with avelumab 10 mg/kg every 2 weeks. The independent review committee used RECIST 1.1 criteria to calculate the primary end point, con-firmed objective response (partial or complete). In the 88 patients receiving at least 1 avelumab dose, with a median follow-up of 10.4 months, 28 of the 88 (31.8% [95.9% CI, 21.9%-43.1%]) had an objective response. Twenty patients had a partial response, and 8 had a complete response. When the publication analysis was performed, 23 of the 28 patients (82%) were still responding.¹⁶

For avelumab, the reason the response rate is a little lower is [that] these patients are chemotherapy treated,” said Shailender Bhatia, MD, an associate professor in the Department of Medicine, Division of Medical Oncology, at the University of Washington School of Medicine in Seattle, one of the study’s authors “The disease is more aggressive, and chemotherapy probably suppresses the immune system, so [the tumors] are less likely to respond.” Bhatia served as cochair for the Immunotherapy Advances in Skin Cancer concurrent session during SITC 2019.

Kaufman and his team later reported updated efficacy results, after at least a year of follow-up, for NCT02155647. Best overall response was the primary end point. PFS, OS, and DOR were the secondary end points. In the 88 patients who were tracked for at least 1 year, the complete response rate was 11.4% and the ORR was 33.0%. Responses lasted at least 1 year in about 74% of patients and were ongoing in 72.4% at the end of data collection. The median DOR had not been achieved, which indicated durable responses. At 1 year, PFS was 30% and OS was 52%, with median OS reaching 12.9 months. Baseline characteristics did not affect durable responses. However, Kaufman and investigators wrote that “subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden and with PD-L1—positive tumors.”¹⁷

Bhatia added, “We should prioritize the use of immunotherapy in [appropriate] patients because [in those patients] that is the best approach with the most desirable outcomes…,we need to use chemotherapies later if immunotherapies later if immunotherapy doesn’t work.

The MCC response to anti—PD-1 treatment is so remarkable that it was recognized by the Nobel Assembly at Karolinska Institutet in its scientific background publicationDiscovery of Cancer Therapyby Inhibition of Negative Immune Regulation. This report underscores the accomplishments of James P. Allison, PhD, and Tasuku Honjo, MD, PhD, leading up to their 2018 Nobel Prize in Physiology or Medicine and highlights MCC, including it with tumors “that show the highest frequency of responses (50% to 90%)” to anti—PD-1 treatment.^13,18

However, as Bhatia reminds, “these drugs are not working for everybody… There are patients who are doing well…but then there are patients who never respond to PD-1 blockade…. There are patients who initially respond, but the responses are not durable; and these are the patients who have so-called acquired resistance…. We need more therapies for these [groups]….This is where the unmet need is.”

To better understand resistance, Paulson and her team used immune checkpoint inhibitors and autologous MCPyV-specific CD8-positive T cells to treat 2 patients with metastatic MCC. Although initially the tumors regressed, the 2 patients experienced relapse. The investigators found “dynamic transcriptional suppression of the specific human leukocyte antigen genes presenting the targeted viral epitope” and suggested “transcriptional suppression of class I loci may underlie resistance to other immunotherapies.”¹⁹

To deepen the understanding of MCC and develop novel treatments, clinical trials are a priority. Two presentations on the topic of MCC are slated for SITC 2019—O19 and P362. Presentation O19 describes a phase II, open-label, nonrandomized study (QUILT-3.009 [NCT02465957]) in patients with metastatic MCC. This study evaluated the effects of activated natural killer (aNK) cells plus ALT-803.²⁰Infusions of aNK cells were given on the first 2 days of 2-week cycles. The infusions consisted of 2 × 109 aNK cells per square meter. ALT-803 10 μg/kg was given every 2 weeks just before aNK infusion.²⁰Presentation P362 is entitled “First-Line Avelumab Treatment in Patients With Metastatic MCC: Primary Analysis After ≥ 15 Months Follow-up from JAVELIN Merkel 200, a Registrational Phase II Trial.”

Adjuvant Avelumab in Merkel Cell Cancer (ADAM) is an ongoing, phase III, randomized, double-blind trial of adjuvant avelumab versus placebo in patients with MCC that has spread to the lymph nodes and who have undergone surgery with or without radiation therapy.²¹The study is estimated to enroll 100 patients, and the primary objective is relapse-free survival. The study began in December 2017 and is expected to be completed by September 2024. The secondary end points are OS, disease-specific survival, distant metastases— free survival, and adjuvant avelumab’s safety and tolerability.²¹

In conclusion, MCC is an aggressive neuroendocrine skin cancer that is rare, but its incidence is rising. The MCPyV has been found in approximately 40% to 100% of tumors, and those tumors