Novel IO Approaches Are in Development for PD-1/PD-L1–Resistant Merkel Cell Carcinoma

Paul T. Nghiem, MD, PhD

Immunotherapy is a promising approach in Merkel cell carcinoma (MCC) to treat patients with this disease, and PD-1/PD-L1 immune checkpoint inhibitors have already had a significant impact on the treatment landscape. Newer immunotherapy approaches continue to be explored to treat patients with relapsed or refractory MCC after PD-1/ PD-L1 inhibition.

In a presentation during the 2021 World Congress of Melanoma, Paul T. Nghiem, MD, PhD, explained that immunotherapy is especially promising in MCC because these patients tend to be immunosuppressed but the cancer is immunogenic and mitotically active, especially for MCC associated with the Merkel cell polyomavirus (MCPyV). Yarchoan et al showed that although the tumor mutational burden tends to be low for MCC, the response rate to anti–PD-1/PD-L1 therapy has been higher compared with that of many other cancer types.²

However, PD-1/PD-L1 inhibitors have not demonstrated benefit for all patients with MCC. Nghiem, the George F. Odland Endowed Chair in Dermatology and professor and head of dermatology at the University of Washington School of Medicine; director of the Skin Oncology Clinical Program at Seattle Cancer Care Alliance; and affiliate investigator for the Clinical Research Division of the Fred Hutchinson Cancer Research Center, all in Seattle, Washington, estimated that less than half of all patients with MCC will have long-term benefit from anti–PD-1/PD-L1 therapy. In the phase 2 JAVELIN Merkel 200 trial (NCT02155647), the objective response rate on avelumab (Bavencio), an anti–PD-L1 antibody, in patients with metastatic MCC who had progressed on prior chemotherapy was 33% (95% CI, 23.3%-43.8%), but the median duration of response had not yet been reached (95% CI, 18.0 to not estimable).³

Historically, this did show a significant improvement over subsequent chemotherapy in terms of higher overall survival (OS) rates. In the JAVELIN trial, the OS rate at 24 months was 36.0% with avelumab compared with 24.5% with chemotherapy.^3,4

The FDA approved avelumab for the treatment of adults and pediatric patients 12 years and older with metastatic MCC, including those who have not received prior chemotherapy, and the approval was based on results of the JAVELIN Merkel 200 trial.⁵ Shortly after, the PD-1 inhibitor pembrolizumab (Keytruda) was also approved by the FDA for adult and pediatric patients with recurrent locally advanced or metastatic MCC, based on the results of the phase 2 KEYNOTE-017 trial (NCT02267603).⁶ Both immunotherapy agents received accelerated approvals.

Newer Approaches for Refractory Disease

For patients with refractory MCC, following a lack of response to a PD-1/PD-L1 therapy, the current research focus is to make a cold tumor hot to get a response by adding additional treatments such as radiation, CTLA-4 inhibition with ipilimumab (Yervoy), intralesional therapy, HDAC inhibition, MDM2 inhibition, transgenic T-cell receptor (TCR) therapy, and other options being considered and explored.

The newer approach of transgenic TCR therapy is being investigated in a clinical trial in combination with avelumab and class I upregulation in patients with HLA-A02–positive advanced MCC who are resistant to checkpoint inhibition in the ATTACk-MCC trial in Seattle, Washington. Nghiem explained the potential of this approach: “The concept of transgenic T cells addresses the issue that some patients clearly do not have a large enough number of high-affinity T cells targeting the tumor that are functional, and we now can transgenically reprogram the receptors of T cells to attack the tumor.”

In the trial, autologous T cells are collected and high-affinity anti-MCPyV T-cell receptors are placed into CD8/CD4 “young” T cells, which are then reprogrammed and expanded. Nghiem noted that of 4 patients treated with this regimen, 1 has achieved a major response with shrinking of deep visceral disease.

In a subset of patients with MCC, intratumoral administration of G100, a toll-like receptor 4 agonist, has shown activity in a small first-in-human trial. Pathologic complete responses were seen after only 2 doses of G100 monotherapy.⁷

An additional consideration for MCC is an adjuvant immunotherapy to prevent the disease from recurring altogether. This is being explored in high-risk patients in various trials, but for lower-risk patients a therapeutic vaccine after initial MCC treatment would be more beneficial, Nghiem suggested. He explained that after surgery when the immune response targeting the cancer falls, a vaccine would help maintain anti-MCC immunity and increase the number of T cells targeting the cancer and potentially prevent recurrence. One such vaccine in development will hopefully begin phase 1 clinical trial testing later in the year.

Another approach is DNA damage response (DDR) inhibition with an ATR inhibitor and low-dose radiation. Nghiem suggested that this approach could be immunogenic.8 He explained that MCC is aggressive in removing blocks to cell cycle checkpoints, leading to cell death, and a median of 68% of MCC tumor cells are positive for Ki-67, which is susceptible to DDR inhibition and radiation.

In a preclinical study, the ATR kinase inhibitor given following radiation lowered tumor volume in mice with various solid tumors, but the same was not seen in immunodeficient mice, suggesting immunogenicity. Nghiem hopes this combination will also move to human trials.

_References:

_{1. Nghiem P. Promising approaches and trials for advanced MCC. Presented at: 10th World Congress of Melanoma & 17th EADO Congress; April 15-17, 2021; virtual.}

_{2. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377(25):2500-2501. doi:10.1056/NEJMc1713444}

_{3. 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. J Clin Oncol. 2018;36(suppl 15):9507. doi:10.1200/JCO.2018.36.15_suppl.9507}

_{4. Cowey CL, Mahnke L, Espirito J, Helwig C, Oksen D, Bharmal M. Real-world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA. Future Oncol. 2017;13(19):1699-1710. doi:10.2217/fon-2017-0187}

_{5. FDA approves first treatment for rare form of skin cancer. News release. FDA. March 23, 2017. Updated March 28, 2018. Accessed May 14, 2021. https://bit.ly/2RsAmsv}

_{6. FDA approves pembrolizumab for Merkel cell carcinoma. FDA. December 19, 2018. Accessed May 14, 2021. https://bit.ly/3oqbyxi}

_{7. Bhatia S, Miller NJ, Lu H, et al. Intratumoral G100, a TLR4 agonist, induces antitumor immune responses and tumor regression in patients with Merkel cell carcinoma. Clin Cancer Res. 2019;25(4):1185-1195. doi:10.1158/1078-0432.CCR-18-0469}

_{8. Vendetti FP, Karukonda P, Clump DA, et al. ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation. J Clin Invest. 2018;128(9):3926-3940. doi:10.1172/JCI96519}