The European Medicines Agency has validated its type II variation application for nivolumab in combination with chemotherapy for use in the neoadjuvant treatment of patients with unresectable stage IB to IIIA non–small cell lung cancer.
The European Medicines Agency (EMA) has validated its type II variation application for nivolumab (Opdivo) in combination with chemotherapy for use in the neoadjuvant treatment of patients with unresectable stage IB to IIIA non–small cell lung cancer (NSCLC).1
The application is based on findings from the open-label, multicenter, phase 3 CheckMate-816 trial (NCT02998528), in which the nivolumab combination resulted in a significant improvement in event-free survival (EFS) and pathologic complete response (pCR) compared with chemotherapy alone, when given prior to surgery in this population.2
“The CheckMate-816 trial has shown the potential for [nivolumab] with chemotherapy to address the need for new options that can be given to patients before surgery to help prevent recurrence and improve long-term outcomes,” Abderrahim Oukessou, MD, vice president of thoracic cancers and development lead at Bristol Myers Squibb, stated in a press release. “We look forward to working with the EMA with the goal of achieving the first approval of a neoadjuvant immunotherapy-based combination for NSCLC patients in the European Union.”
CheckMate-816 enrolled a total of 358 patients with newly diagnosed, resectable, stage IB to IIIA NSCLC who had an ECOG performance status of 0 or 1. Patients could not have any known sensitizing EGFR mutations or ALK alterations.
Participants were randomized 1:1 to receive nivolumab at 360 mg every 3 weeks in combination with platinum-doublet chemotherapy every 3 weeks for 3 doses (n = 179) or chemotherapy alone (n = 179). Patients underwent radiologic restaging, and then surgery within 6 weeks post treatment. Subsequently, they received optional adjuvant chemotherapy with or without radiation, and then entered follow-up.
Patients were stratified based on disease stage (IB/II vs IIIA), PD-L1 expression (1% or higher vs less than 1%), and sex (male vs female).
The primary end points of the trial included blinded independent pathological review (BIPR)–assessed pCR and EFS per blinded independent central review (BICR). Secondary end points comprised major pathological response by BIPR, overall survival (OS), and time to death or distant metastases. Important exploratory end points comprised BICR-assessed objective response rate, and feasibility of surgery as well as peri- and post-operative surgery–related toxicities.
At a database lock of September 16, 2020, and a minimum follow-up of 7.6 months in both treatment arms, 98% of patients in both arms received neoadjuvant treatment. Ninety-four percent of those in the investigative arm completed 3 cycles of the neoadjuvant treatment vs 85% of those in the control arm.
Sixteen percent of patients in the nivolumab arm cancelled surgery due to disease progression (7%), adverse effects (1%), or another unspecified reason (8%). Twenty-one percent of those in the chemotherapy-alone arm cancelled surgery; 10% did so because of progressive disease, 1% due to toxicity, and 11% due to another reason. Moreover, 83% of patients in the nivolumab arm went on to undergo surgery compared with 75% of those in the chemotherapy-alone arm. The median duration of surgery in these arms were 184 minutes and 217 minutes, respectively.
The median age of those on the investigative arm was 64 years (range, 41-82) compared with 65 years (range, 34-84) among those on the control arm; 28% and 29% of patients, respectively, were female, and 69% and 65% of patients, respectively, had an ECOG performance status of 0. In the investigative and control arms, 49% and 53% of patients, respectively, had squamous disease, and 51% and 47% of patients, respectively, had nonsquamous disease. The majority of patients on both arms were either current or former smokers.
The nivolumab combination resulted in a median EFS of 31.6 months (95% CI, 30.2–not reached) compared with 20.8 months (95% CI, 14.0-26.7) with chemotherapy alone (hazard ratio [HR], 0.63;95% CI, 0.45-0.87; P = .0052). Neoadjuvant nivolumab plus chemotherapy also produced a pCR of 24% (95% CI, 18.0%-31.0%) compared with just 2.2% (95% CI, 0.6%-5.6%) with chemotherapy alone (estimated treatment difference, 21.6; 95% CI, 15.1-28.2; P < .0001).
Data from a prespecified interim analysis for OS resulted in a HR of 0.57 (95% CI, 0.38-0.87), which was not found to cross the boundary for statistical significance.
Earlier data indicated that when broken down by disease stage at baseline, the pCR achieved with neoadjuvant nivolumab/chemotherapy (n = 10) among those with stage IB disease was 40% vs 0% with chemotherapy alone (n = 8).3,4 In those with stage IIA disease at baseline, the pCR in the nivolumab arm (n = 30) was 23% vs 3% in the chemotherapy-alone arm (n = 32); within those with stage IIB disease, these rates were 24% (n = 25) and 9% (n = 23), respectively. In those with stage IIIA disease, the pCR achieved with nivolumab/chemotherapy (n = 113) was 23% vs 1% with chemotherapy alone (n = 115).
Notably, the pCR improvement observed with the nivolumab combination compared with chemotherapy alone was observed irrespective of radiologic downstaging.
In March 2022, the FDA approved nivolumab in combination with platinum-doublet chemotherapyfor the treatment of adult patients with resectable NSCLC in the neoadjuvant setting based on findings from CheckMate-816.2