Addition of nivolumab to neoadjuvant chemotherapy confers benefit in resectable NSCLC
The addition of nivolumab to neoadjuvant chemotherapy led to a significantly higher pathologic complete response rate among patients with resectable non-small cell lung cancer, according to results of a randomized phase 3 trial.
Researchers presented the findings during the virtual American Association for Cancer Research Annual Meeting.
“The difference here is significant in terms of pathologic complete response, 2.2% going up to 24%, a more than 10-fold increase,” Patrick M. Forde, MD, director of the thoracic oncology clinical research program and associate professor of oncology at Sidney Kimmel Comprehensive Cancer Center and Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University, said during a press conference.
Surgical tumor removal has been a standard treatment for resectable NSCLC, but as many as 80% of patients experience recurrence, and treatment with chemotherapy before or after surgery improves 5-year OS by only 5%, according to Forde.
“For the first time in a phase 3 trial, we see the potential for an anti-PD-1 immunotherapy to improve outcomes in earlier-stage NSCLC,” Forde said. “We are highly encouraged by the marked improvement in [pathologic complete response], the overall good tolerability and the absence of impact on surgery feasibility when nivolumab [Opdivo, Bristol Myers Squibb] is added to neoadjuvant chemotherapy.”
The CheckMate 816 trial included 358 patients (50.8% aged 65 years; 71.2% men) with clinical stage IB (at least 4 cm) to stage IIIA resectable NSCLC, an ECOG performance status of 0 to 1 and no known EGFR/ALK alterations.
Researchers randomly assigned patients to platinum-doublet chemotherapy every 3 weeks for three cycles with (n = 179) or without (n = 179) 360 mg nivolumab every 3 weeks, followed by surgery within 6 weeks after treatment. They stratified patients by sex, NSCLC stage (IB to II vs. IIIA) and PD-L1 status ( 1% vs. < 1%).
Pathologic complete response — defined as absence of viable tumor cells in resected lung and lymph nodes — by blinded independent pathologic review and EFS by blinded independent central review served as the study’s primary endpoints. Secondary endpoints included OS, major pathologic response — defined as 10% or less viable tumor cells in lung and lymph nodes — by blinded review, and time to death or distant metastases. Exploratory endpoints included objective response rate by blinded review and possible predictive biomarkers, such as PD-L1 and tumor mutational burden.
Results showed the nivolumab-chemotherapy combination conferred a significantly higher pathologic complete response rate than chemotherapy alone among the intent-to-treat population (24% vs. 2.2%; OR = 13.94; 99% CI, 3.49-55.75).
Researchers reported consistent improvement in pathologic complete response with the nivolumab combination across key subgroups, including those based on disease stage (stage IB/stage II, 26.2% vs. 4.8%; stage IIIA, 23% vs. 0.9%), PD-L1 status (< 1%, 16.7% vs. 2.6%; 1%, 32.6% vs. 2.2%) and tumor mutational burden (low, 22.4% vs. 1.9%; high, 30.8% vs. 2.7%).
The combination also significantly increased rates of major pathologic response (36.9% vs. 8.9%), ORR on imaging prior to surgery (53.6% vs. 37.4%) and radiographic downstaging (30.7% vs. 23.5%).
The addition of nivolumab to chemotherapy did not affect patients’ ability to undergo definitive surgery, which 149 patients (83.2%) in the combination group and 135 (75.4%) in the chemotherapy group received. Moreover, 115 patients (77%) in the combination group had a lobectomy vs. 82 (61%) in the chemotherapy group.
Grade 3 to grade 4 treatment-related adverse events occurred among 33.5% of the patients in the combination therapy group and 36.9% of patients in the chemotherapy group, and 11.4% of patients in the combination group experienced surgery-related adverse events vs. 14.8% of those in the chemotherapy group.
“The significant improvement in [pathologic complete response] and absence of any meaningful increase in toxicity or decrease in the feasibility for surgery suggest that neoadjuvant nivolumab plus chemotherapy is a viable option for patients with resectable NSCLC at high risk [for] recurrence,” Forde said. “[Although] neoadjuvant therapy has historically been less commonly used than adjuvant therapy for this patient population, I believe that CheckMate 816 has the potential to change that treatment paradigm.”
Forde added that researchers will continue to monitor study results for data on EFS.
“Personally, I’m hopeful,” Forde said. “And we know from retrospective data that [pathologic complete response] has been pretty strongly associated with long-term outcomes, with a hazard ratio for death of 0.49 for those patients who achieve [pathologic complete response] compared to those who don’t after neoadjuvant chemotherapy.”
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Forde PM, et al. Abstract CT003. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.