ABSTRACT
Background: Platinum agents induce DNA crosslinking and cause accumulation of genotoxic stress, which leads to immune activation via IFN-γ signaling, making the combination with nivolumab (PD-1 antibody) an attractive strategy to enhance the benefit of either agent alone in metastatic triple-negative breast cancer (mTNBC). Methods: In this phase II open-label, investigator-initiated, multicenter trial, patients with unresectable locally advanced or mTNBC treated with 0-1 prior lines of chemotherapy in the metastatic setting were randomized 1:1 to carboplatin (AUC 6) with or without nivolumab (360 mg) IV every 3 weeks. Stratification factors included: germline BRCA (gBRCA) status, prior neo/adjuvant platinum, and number of prior lines of metastatic therapy. After approval of PD-L1 inhibition for mTNBC, the study was amended to include first-line mTNBC only and PD-L1 status was added as a stratification factor. Patients randomized to carboplatin alone were allowed to crossover at progression to receive nivolumab (+ nab-paclitaxel post-amendment). The primary objective was to compare progression-free survival (PFS) per RECIST 1.1 criteria of carboplatin with or without nivolumab in first-line mTNBC in the S intent-to-treat (ITT) population. Key secondary objectives were objective response rate (ORR), overall survival (OS), clinical benefit rate, and duration and time to objective response. PD-L1 status was confirmed centrally using the SP142 Ventana assay (positive, ≥1% IC). Paired researchbiopsies at baseline, on-treatment and at progression were performed, if safely accessible. The trial closed to accrual prior to reaching target accrual due to approval of PD-1 inhibition in combination with platinum-based chemotherapy for PD-L1+ mTNBC. Results: Between 1/30/2018 and 12/9/2020, 78 patients enrolled. Three patients did not receive protocol treatment, and the safety analysis was conducted among the 75 that received any treatment;37 received carboplatin + nivolumab (Arm A), 38 received carboplatin alone (Arm B). Median age was 59.1 yrs (range: 25.4-75.8). Four patients (5.3%) had a known gBRCA1/2 mutation. Sixty-two (82.7%) patients received 0 prior lines (ITT population) and 13 (17.3%) 1 prior line of metastatic therapy. Sixty-seven patients (89.3%) experienced any grade ≥2 treatment-related adverse event (AE). The most frequent AE were platelet count decrease (n=40;53.3%), anemia (n=36;48.0%), neutrophil count decrease (n=33;44.0%) and fatigue (n=24;32.0%). Grade 3/4 AE were observed in 46 (61.3%) patients, and there was one grade 5 AE (COVID19 pneumonia). Any grade ≥2 immune-related AE (irAE) were observed in 25 of the 37 (67.6%) patients treated with carboplatin + nivolumab. Grade 3/4 irAE were observed in 11 (29.7%) patients. In the ITT population (32 on Arm A;30 on Arm B), median PFS was 4.2 months with carboplatin + nivolumab, and 5.5 months with carboplatin (stratified HR 0.98, 95% CI [0.51-1.88];p=0.95). ORR was 25% vs. 23.3%, respectively. At a median follow-up of 23.5 months, median OS was 17.5 months vs. 10.7 months (stratified HR 0.63, 95% CI [0.32-1.24];p=0.18). In patients with PD-L1+ mTNBC (13 on Arm A;11 on Arm B), median PFS was 8.3 months and 4.7 months, respectively (stratified HR 0.63, 95% CI [0.21-1.89];p=0.41). ORR was 23.1% vs. 27.3%, respectively. Median OS was 17.5 months vs. 9.6 months (stratified HR 0.59, 95% CI [0.20-1.75];p=0.34). Conclusions: Addition of nivolumab to carboplatin in patients with previously untreated mTNBC, unselected by PD-L1 status, did not significantly improve PFS. A trend toward improved PFS and OS was observed in patients with PD-L1+ mTNBC. Tissue, blood and intestinal microbiome biomarker analyses are planned;bulk tumor and single-cell sequencing, and TCR sequencing in peripheral blood are ongoing.
ABSTRACT
Cancer vaccines (CVs) represent a long-sought therapeutic and prophylactic immunotherapy strategy to obtain antigen (Ag)-specific T-cell responses and potentially achieve long-term clinical benefit. However, historically, most CV clinical trials have resulted in disappointing outcomes, despite promising signs of immunogenicity across most formulations. In the past decade, technological advances regarding vaccine delivery platforms, tools for immunogenomic profiling, and Ag/epitope selection have occurred. Consequently, the ability of CVs to induce tumor-specific and, in some cases, remarkable clinical responses have been observed in early-phase clinical trials. It is notable that the record-breaking speed of vaccine development in response to the coronavirus disease-2019 pandemic mainly relied on manufacturing infrastructures and technological platforms already developed for CVs. In turn, research, clinical data, and infrastructures put in place for the severe acute respiratory syndrome coronavirus 2 pandemic can further speed CV development processes. This review outlines the main technological advancements as well as major issues to tackle in the development of CVs. Possible applications for unmet clinical needs will be described, putting into perspective the future of cancer vaccinology.