Phase II Study Assessing Safety, Efficacy of Novel PD-1 Inhibitor in Merkel Cell Carcinoma

A phase II trial is currently recruiting patients with Merkel cell carcinoma (MCC) to participate in a single-arm study evaluating the safety and efficacy of INCMGA00012.¹The open-label, multicenter study seeks to enroll 90 patients, including at least 52 patients who are treatment-naïve. In addition, only 40 patients who are chemotherapy-refractory will be allowed to participate (NCT03599713).

INCMGA00012 is a humanized immunoglobulin G4 (IgG4) monoclonal antibody against human PD-1 that lacks antibody dependent cell-mediated cytotoxicity directed against effector lymphocytes.

To be included in the trial, patients should have a diagnosis of MCC with distant metastasis as a component of tumor burden, measurable disease per RECIST v1.1, and an ECOG performance status 0 to 1. Patients should have received no more than 3 prior chemotherapy regimens, including systemic adjuvant therapy. Patients who central nervous system metastasis or have received previous treatment with any anti—PD-1 or anti–PD-L1 therapy, radiation therapy within 2 weeks, or radiation therapy in the thoracic region that is greater than 30 Gy, are ineligible to participate.

Primary endpoints of the trial include overall response rate (ORR) in treatment-naïve patients with MCC and secondary endpoints include ORR in the full study population, duration of response (DOR), disease control rate (DCR, defined as the sum of the complete, partial and stable disease rates), progression-free survival (PFS), and overall survival (OS) in in treatment-naïve patients and the full study population.

Enrollees in the trial will receive INCMGA00012 at a flat dose of 500 mg every 4 weeks on day 1 of each 28-day cycle for up to 2 years. Disease assessments will be conducted every 8 weeks and involve tumor imaging determined by computed tomography or contrast-enhanced magnetic resonance imaging. Tumor tissues will be collected during screening for evaluation of expression levels of PD-L1 protein and Merkel cell polyomavirus large T-antigen for tumor cells, and other translational assessments. Additionally, patients’ quality of life will be assessed using 2 questionnaires: the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) and EuroQol 5 dimensions (EQ-5D).

In an ongoing phase I study, INCMGA00012 has demonstrated acceptable tolerability with no dose-limiting toxicity at doses up to 10 mg/kg administered every 2 weeks.²Investigators have reported clinical activity across multiple tumor types. In this study, full and sustained receptor occupancy of INCMGA00012 on both CD4+ and CD8+ T cells, along with complete loss of competing fluorescently labeled anti—PD-1 staining (eJBio105 clone), were seen at all dose levels.

Prior phase I and II clinical trials involving PD-1/PD-L1 inhibitors have demonstrated promising antitumor activity and acceptable tolerability in patients with metastatic MCC. Paul Nghiem, MD, PhD, et al, and others reported an overall response rate (ORR) that ranged from 56% to 73%.^3-5Median PFS ranged from 9.1 months to 16.8 months in chemotherapy-naïve patients treated with pembrolizumab (Keytruda), avelumab (Bavencio), or nivolumab (Opdivo). For chemotherapy-refractory patients treated with avelumab or nivolumab, the ORR was 33% and 50%, respectively.^{5,6  }Howard Kaufman, MD, et al demonstrated a 1-year PFS rate of 30% and a median overall survival of 12.9 months in patients treated with avelumab.⁶

MCC is a rare, aggressive, and often fatal skin cancer that is associated with the Merkel cell polyomavirus in about 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.⁷Platinum-based chemotherapy regimens can result in a short DOR and pose toxicity challenges in older patients.⁸

The FDA approved the PD-L1 inhibitor avelumab in March 2017 for the treatment of adults and pediatric patients 12 years and older with metastatic MCC, including those who have not received prior chemotherapy. Recently, a supplemental biologics license application (sBLA) for pembrolizumab has been granted a priority review by the FDA for the treatment of pediatric and adult patients with recurrent locally advanced or metastatic MCC.

References:

1. Gibney GT, Mehmi I, Shankar S, Tian C, Puzanov I. INCMGA 0012-201: A phase 2 study of INCMGA00012 in patients with metastatic Merkel cell carcinoma. In: Proceedings from the 2018 SITC Annual Meeting; November 7-11, 2018; Washington, D.C. Abstract P313.
2. A phase 1 study of INCMGA00012 in patients with advanced solid tumors. ClinicalTrials.gov Identifier: NCT03059823. Available atclinicaltrials.gov/ct2/show/NCT03059823.
3. Nghiem PT, et al. Durable tumor regression and overall survival (OS) in patients with advanced Merkel cell carcinoma (aMCC) receiving pembrolizumab as first line therapy. Presented at: 2018 ASCO Annual Meeting; June 1—5, 2018; Chicago, IL.
4. D'Angelo SP, Russell J, Lebbé C, et al. Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma: a preplanned interim analysis of a clinical trial.JAMA Oncol. 2018;4(9):e180077. doi: 10.1001/jamaoncol.2018.0077.
5. Topalian SL, et al. CT074: non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC). Presented at: Annual Meeting of American Association for Cancer Research; April 1—5, 2017; Washington, DC.
6. Kaufman HL, Hunger M, Hennessy M, Schlichting M, Bharmal M. Nonprogression with avelumab treatment associated with gains in quality of life in metastatic Merkel cell carcinoma.Future Oncol. 2018;14(3):255-266. doi: 10.2217/fon-2017-0470.
7. Banks PD, Sandhu S, Gyorki DE, Johnston ML, Rischin D. Recent insights and advances in the management of Merkel cell carcinoma.J Oncol Pract. 2016;12(7):637-46. doi: 10.1200/JOP.2016.013367.
8. Colunga A, Pulliam T, Nghiem P. Merkel cell carcinoma in the age of immunotherapy: facts and hopes.Clin Cancer Res. 2018;24(9):2035-2043. doi: 10.1158/1078-0432.CCR-17-0439.