Alberto Suárez Zaizar

BACKGROUND: The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown. METHODS: In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization. RESULTS: Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing. CONCLUSIONS: Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).

Patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer (BC) have low pathological complete response (pCR) rates with neoadjuvant chemotherapy. A subset of ER+/HER2- BC contains dense lymphocytic infiltration. We hypothesized that addition of an anti-programmed death 1 agent may increase pCR rates in this BC subtype. We conducted a randomized, multicenter, double-blind phase 3 trial to investigate the benefit of adding nivolumab to neoadjuvant chemotherapy in patients with newly diagnosed, high-risk, grade 3 or 2 (ER 1 to ≤10%) ER+/HER2- primary BC. In total, 510 patients were randomized to receive anthracycline and taxane-based chemotherapy with either intravenous nivolumab or placebo. The primary endpoint of pCR was significantly higher in the nivolumab arm compared with placebo (24.5% versus 13.8%; P = 0.0021), with greater benefit observed in patients with programmed death ligand 1-positive tumors (VENTANA SP142 ≥1%: 44.3% versus 20.2% respectively). There were no new safety signals identified. Of the five deaths that occurred in the nivolumab arm, two were related to study drug toxicity; no deaths occurred in the placebo arm. Adding nivolumab to neoadjuvant chemotherapy significantly increased pCR rates in high-risk, early-stage ER+/HER2- BC, particularly among patients with higher stromal tumor-infiltrating lymphocyte levels or programmed death ligand 1 expression, suggesting a new treatment paradigm that emphasizes the role of immunotherapy and T cell immunosurveillance in luminal disease. Clinical trials.gov identifier: NCT04109066.

Abstract Background: CheckMate 7FL (CM 7FL; NCT04109066) is a prospective, phase 3, randomized, multicenter, double-blind trial investigating nivolumab (NIVO) in combination with neoadjuvant chemotherapy (NACT) and adjuvant endocrine therapy (ET) in patients (pts) with high-risk, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) primary breast cancer (BC). The primary endpoint (pathological complete response, pCR) was met, resulting in a statistically significant improvement with added NIVO to NACT; residual cancer burden (RCB) 0–1 rate was meaningfully improved. NIVO benefit was larger in pts with PD-L1+ tumors (SP142 assay, % immune cells ≥ 1%). This analysis focuses on additional biomarkers to explore associations with NIVO treatment effect. Methods: The study enrolled newly diagnosed pts, stages T1c–2 N1–2 or T3–4 N0–2, grade 2 (ER 1–‍10%) or 3 (ER ≥ 1%). Pts were randomized 1:1 to NACT + NIVO 360 mg Q3W/NIVO 240 mg Q2W (arm A) or NACT + placebo (PBO; arm B). Clinical efficacy data included pCR (ypT0/is ypN0) and RCB 0–1 rates in the modified ITT (mITT) population and the SP142 PD-L1+ subgroup. Baseline PD-L1 expression from core biopsies was evaluated with the Dako 28-8 assay using the combined positive score (CPS) algorithm. Various cutoffs (CPS ≥ 1, 10, and 20) were used for this exploration. Concordance between PD-L1 SP142 and 28-8 CPS was evaluated, with assays performed on different slides from the same tumor biopsy blocks. Results of efficacy by ER and/or progesterone receptor (PR) expression, as well as Ki67 index and stromal tumor-infiltrating lymphocytes, will be presented at the meeting. Results: Overall, 830 pts were screened, 521 randomized, and 517 treated, with the primary efficacy population (mITT; n = 510) including all randomized pts but excluding 11 pts from Russian sites with insufficient follow-up. A total of 510 and 349 pts (68.4% of mITT population) were evaluated by PD-L1 SP142 and 28-8 CPS assays, respectively. The prevalence of PD-L1+ by CPS was balanced in arms A and B (52% vs 50% had CPS ≥ 1; 19% vs 16% had CPS ≥ 10, and 11% vs 9% had CPS ≥ 20, respectively). NIVO effect was larger in pts with tumors with increasing PD-L1 expression, with a ∆pCR rate (unweighted rate difference between arms A and B) of 16.6% in CPS ≥ 1 (40.4% vs 23.8% in arms A/B; 95% CI, 2.8 to 29.4), 32.4% in CPS ≥ 10 (65.7% vs 33.3% in arms A/B; 95% CI, 7.3 to 52.3), and 52.3% in CPS ≥ 20 (78.9% vs 26.7% in arms A/B; 95% CI, 18.6 to 72.4). In comparison, the ∆pCR rate was 10.7% in the mITT population (24.5% vs 13.8% in arms A/B; 95% CI, 3.9 to 17.4) and 5.7% in pts with CPS < 1 (14.0% vs 8.2% in arms A/B; 95% CI, -4.0 to 15.5; refer to the Table for additional details). Unweighted rate differences between arms A and B for RCB 0–1 (∆RCB 0–1 rate) followed a similar trend and were observed to be 17.0% in CPS ≥ 1, 34.4% in CPS ≥ 10, and 52.3% in CPS ≥ 20. In comparison, the ∆RCB 0–1 rate was 9.4% in the mITT population and 3.3% in pts with CPS < 1 (refer to the Table for additional details). Further biomarker data and cutoffs will be presented at the meeting. Conclusions: Greater PD-L1 expression was associated with higher pCR and RCB 0–1 rates, suggesting that pts with PD-L1+, high-risk, ER+/HER2− primary BC can achieve substantial pCR rates with the addition of NIVO to NACT. Table. Summary pCR and RCB 0–1 rates by PD-L1 SP142 and 28-8 CPS at various cutoffs. Note: CPS data with the cutoff at 5 will be presented at the meeting. Citation Format: Sherene Loi, Giuseppe Curigliano, Roberto Salgado, Roberto Iván Romero Díaz, Suzette Delaloge, Carlos Ignacio Rojas García, Marleen Kok, Cristina Saura, Nadia Harbeck, Elizabeth Mittendorf, Denise Yardley, Lajos Pusztai, Alberto Suárez Zaizar, Andrei Ungureanu, Felipe Ades, Rajalakshmi Chandra, Raheel Nathani, Misena Pacius, Thomas Spires, Jenny Wu, Heather McArthur. Biomarker Results in High-risk Estrogen Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative Primary Breast Cancer Following Neoadjuvant Chemotherapy ± Nivolumab: an Exploratory Analysis of CheckMate 7FL [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-01.