Intercalated Avelumab plus platinum-based chemotherapy in patients with Extensive-Stage Small-Cell Lung cancer (PAVE): Final outcome, immunophenotypic and biomarker analysis of a multi-center phase II Hellenic Cooperative Oncology Group study

BACKGROUND: Extensive stage small cell lung cancer (ES-SCLC) has poor prognosis, and first-line chemo-immunotherapy is now the standard-of-care. We hypothesized that intercalated immunotherapy administration in-between chemotherapy cycles, at maximal neoantigen release, might enhance immune response and efficacy. METHODS: PAVE is a multicenter phase II study. Patients with untreated ES-SCLC received standard platinum-etoposide every three weeks for 4-6 cycles. Avelumab 10mg/kg was administered every two weeks from cycle 3 until chemotherapy completion, and as maintenance thereafter. The primary endpoint was one-year PFS. Genotyping of FFPE tumors via targeted NGS, assessment of tumor-infiltrating lymphocytes (TILs) and analysis of CD8 and PD-L1, was performed. RESULTS: Between September 2018-September 2020, 55 pts, median age 65.9 years, 67.3 % male, were enrolled. With median follow-up of 10.3 months, 1-year PFS was 12.7 %, median PFS 5.8 months, 1-year OS 38.2 %, median OS 10.3 months. ORR was 69.1 % (CR 5.5 %, PR 63.6 %), median DoR 5.6 months. AEs grade 3-4 occurred in 56 % of patients. QoL, global health status and disease-related symptoms were significantly improved from baseline. The presence of TILs/CD8 in tumour was not significantly associated with survival. All but one tumor carried genetic alterations, with TP53 (89.5 %), RB1 (57.9 %), NOTCH (31.6 %) and MYC (23.7 %) being the most frequently mutated genes. Liver metastases, RB1 or TP53/RB1 co-mutations, no PCI and age > 65 years were negative PFS/ OS prognosticators. There were 10 Long Term Survivors (LTS) identified, the majority < 65 years old and most with ≤ 3 metastatic sites (50 %). Median OS of the LTS was 34.2 months and median PFS 19.9 months. CONCLUSIONS: Intercalated avelumab administration with chemotherapy did not meet the primary endpoint of 1-year PFS. However, our results suggest that this approach demonstrates clinically relevant PFS, DoR, and improved QoL, with overall outcomes similar to those seen with standard frontline chemotherapy in historical controls.