Discussion
tumor, pembrolizumab, melanoma, myocarditis, viral infection, hypothyroidism
TUMOR, MELANOMA, INFILTRATE, MYOCARDITIS, VIRAL INFECTION, INFILTRATING, EVENTS, HYPOTHYROIDISM, STAGE III MELANOMA
In the phase 1b CAPRA study, we evaluated the combination of intratumoral V937 and pembrolizumab in patients with advanced melanoma and demonstrated a manageable safety profile and encouraging antitumor activity. No new safety signals were identified; the types of treatment-related AEs reported were as anticipated for each drug, given prior history with V937 and pembrolizumab, and were mostly of grade 1 or 2 severity. No myocarditis events occurred. The most common immune-mediated AE, regardless of relationship to treatment, was hypothyroidism both with combination therapy in CAPRA (11%) and with pembrolizumab monotherapy in a pooled analysis (9.1%) [Notwithstanding the limitations of cross-study comparisons, based on immune-related response criteria, median PFS with the combination of V937 and pembrolizumab in CAPRA (11.9 months) was numerically greater than with V937 monotherapy in CALM (5.7 months) [Biomarkers were explored in CAPRA to gain insight into the possible mechanism for the systemic clinical responses. Surprisingly, responses were not associated with an increased baseline expression of viral entry proteins (ICAM-1 and DAF), PD-L1, or viral signaling proteins (RIG-I, TLR7, and TLR8), nor were they associated with an inflamed baseline tumor microenvironment. In fact, levels of infiltrating CD3Given our findings above and the supportive data in the literature, we hypothesize that V937 viral infection leads interferon-gamma–mediated secretion of CXCL10 by multiple cell types in the tumor microenvironment, especially macrophages [In conclusion, the combination of intratumoral V937 plus pembrolizumab had favorable safety and efficacy in patients with advanced melanoma. The ORR was 47%, and there was a high rate of complete responses (22%) not typically seen with pembrolizumab monotherapy. Thus, the addition of V937 to pembrolizumab appeared to improve efficacy with limited impact on tolerability. Biomarker analysis showed that responses were not associated with an inflamed baseline tumor microenvironment, indicating that a pre-existing tumor immune infiltrate is not required for response to this combination. Markers of the intensity of the viral infection (CXCL10, CCL22) were associated with response, suggesting that the downstream effects of viral replication contributed to antitumor immunity and potentiated the activity of pembrolizumab. Further evaluation of the combination of V937 plus pembrolizumab for the neoadjuvant treatment of stage III melanoma is being assessed in an ongoing phase 1/2, randomized, open-label study (KEYMAKER-U02 substudy 02C; NCT04303169).