New IO Approaches Under Development for PD-1 / PD-L1 Resistant Merkel Cell Carcinoma

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

However, PD-1 / PD-L1 inhibitors have not been shown to benefit all patients with MCC. Nghiem, George F. Odland Chair in Dermatology and Professor and Head of Dermatology, Washington University School of Medicine; director of the clinical skin oncology program at Seattle Cancer Care Alliance; and Affiliate Researcher for the Clinical Research Division of the Fred Hutchinson Cancer Research Center, all in Seattle, Wash., has estimated that less than half of all patients with MCC will benefit long-term from anti-PD-1 therapy / PD-L1. In the phase 2 trial JAVELIN Merkel 200 (NCT02155647), the objective response rate to avelumab (Bavencio), an anti-PD-L1 antibody, in patients with metastatic CCD who had progressed on previous 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 has shown a significant improvement over subsequent chemotherapy in terms of higher overall survival (OS) rates. In the JAVELIN trial, the OS level at 24 months was 36.0% with avelumab versus 24.5% with chemotherapy.3.4

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

New approaches for refractory diseases

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

New approach to transgenic TCR therapy is investigated in a clinical trial in combination with avelumab and class I upregulation in patients with advanced HLA-A02-positive MCC 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 problem that some patients clearly do not have sufficient numbers of high affinity T cells targeting the tumor that are functional, and we can now transgenically reprogram them. receivers. T cells to attack the tumor.

In the assay, autologous T cells are collected and high affinity anti-MCPyV T cell receptors are placed into “young” CD8 / CD4 T cells, which are then reprogrammed and developed. Nghiem noted that out of 4 patients treated with this regimen, 1 achieved a major response with a decrease in 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, novel human trial. Complete pathological responses were observed after only 2 doses of G100 monotherapy.7

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

Another approach is the inhibition of the DNA damage response (DDR) 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 blockages at cell cycle checkpoints, resulting in cell death, and a median of 68% of MCC tumor cells are positive. for Ki-67, which is sensitive to DDR Inhibition and Radiation.

In a preclinical study, the ATR kinase inhibitor administered after irradiation reduced tumor volume in mice with various solid tumors, but the same was not observed in immunodeficient mice, suggesting immunogenicity. Nghiem hopes that this combination will also pass to human trials.

The references:

1. Nghiem P. Promising approaches and trials for advanced MCC. Presented at: 10th World Melanoma Congress and 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 English 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 of JAVELIN Merkel 200 part A: A registration 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 United States. Future Oncol. 2017; 13 (19): 1699-1710. doi: 10.2217 / fon-2017-0187

5. FDA approves first treatment for rare form of skin cancer. Press 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 anti-tumor 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. The ATR kinase inhibitor AZD6738 potentiates the antitumor activity dependent on CD8 + T cells after irradiation. J Clin Invest. 2018; 128 (9): 3926-3940. doi: 10.1172 / JCI96519


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