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The addition of nivolumab to chemotherapy resulted in a statistically significant and clinically meaningful improvement in event-free survival vs chemotherapy alone, when administered prior to surgery in patients with resectable stage IB to IIIA non–small cell lung cancer.
The addition of nivolumab (Opdivo) to chemotherapy resulted in a statistically significant and clinically meaningful improvement in event-free survival (EFS) vs chemotherapy alone, when administered prior to surgery in patients with resectable stage IB to IIIA non–small cell lung cancer (NSCLC), according to findings from the phase 3 CheckMate-816 trial (NCT02998528).1
The toxicity profile of the combination proved to be consistent with what has previously been reported in other clinical trials done in this disease.
Bristol Myers Squibb plans to complete a full evaluation of available data from the trial and to share the findings at an upcoming medical meeting, as well as with health authorities.
“While the intent of surgery is curative in resectable NSCLC, between 30% to 55% of patients experience recurrence after surgery and ultimately succumb to the disease, presenting a strong need for additional options that can disrupt this cycle,” Nicolas Girard, MD, PhD, professor of respiratory medicine at Paris Saclay University and head of the Thorax Institute Curie Montsouris, Paris, France, stated in a press release. “The positive EFS data seen with neoadjuvant nivolumab plus chemotherapy is groundbreaking and can have important implications for how we treat resectable NSCLC.”
CheckMate-816 enrolled 358 patients with newly diagnosed, resectable, stage IB to IIIA NSCLC who had an ECOG performance status of 0 or 1 and no known sensitizing EGFR mutations or ALK alterations.2 Participants were stratified by disease stage (IB/II vs IIIA), PD-L1 expression (≥ 1% vs < 1%), and sex (male vs female).
Patients were randomized 1:1 to receive either nivolumab at 360 mg every 3 weeks plus chemotherapy (n = 179) or chemotherapy alone for 3 cycles (n = 179). Those in the investigative arm who had nonsquamous disease received pemetrexed plus cisplatin or paclitaxel and carboplatin, and those with squamous disease were given gemcitabine plus cisplatin or paclitaxel and carboplatin.
Those in the control arm received vinorelbine plus cisplatin, docetaxel plus cisplatin, gemcitabine plus cisplatin if they had squamous disease, pemetrexed plus cisplatin if they had nonsquamous disease, or paclitaxel plus carboplatin.
Patients then went onto undergo surgery within 6 weeks after treatment. Following the procedure, they were able to receive adjuvant chemotherapy with or without radiation. Then, they underwent follow-up.
The co-primary end points of the trial were pathologic complete response (pCR) and EFS per blinded independent pathological review (BIPR). Important secondary end points comprised major pathologic response by BIPR, overall survival, and time to death or metastases. Key exploratory end points comprised objective response rate per BIPR, as well as feasibility of surgery and peri- or postoperative surgery-related adverse effects (AEs).
The median age between the arms was 64.5 years, and most patients had an ECOG performance status of 0, were current or former smokers, and had stage IIIA disease. Forty-nine percent of patients on the investigative arm had squamous histology vs 53% of those on the control arm. Moreover, 51% and 47% of patients, respectively, had nonsquamous disease.
Forty-eight percent of patients on the nivolumab/chemotherapy arm were from Asia vs 51% of those on the chemotherapy-alone arm. Regarding PD-L1 expression, 44% of those who received nivolumab had an expression of less than 1% vs 43% of those who received chemotherapy alone, and half of patients on both arms had an expression of 1% or higher.
Of the 358 patients who underwent randomization, 98% received neoadjuvant treatment with nivolumab plus chemotherapy and 98% received neoadjuvant treatment with chemotherapy alone. Ninety-four percent of those on the investigative arm completed the neoadjuvant treatment vs 85% of those on the control arm.
In the nivolumab/chemotherapy arm, 16% had their definitive surgery cancelled because of disease progression (7%), toxicity (1%), or another reason (8%). In the chemotherapy-alone arm, 21% had their procedure cancelled; 10% did so because of progressive disease, 1% because of an AE, and 11% for another reason. In the investigative and control arms, 83% and 75% of patients, respectively, received surgery and the median duration of the procedure was 184 minutes and 217 minutes, respectively.
Data from the 2021 ASCO Annual Meeting showed that in patients of all stages of disease, 21% of those on the nivolumab arm had delayed surgery vs 18% of those on the chemotherapy-alone arm. The length of delay in surgery was 2.0 weeks (range, 0.6-3.0) in the investigative arm vs 2.4 weeks (range, 1.0-3.7) in the control arm.
Among those with stage IB disease, the pCR with nivolumab plus chemotherapy was 40% vs 0% with chemotherapy alone. In those with stage IIA disease, the pCR in the investigative and control arms were 23% vs 3%, respectively. In those with stage IIB disease, the pCRs were 24% vs 9%, respectively, and in those with stage IIIA disease, these rates were 23% vs 1%, respectively. Notably, an improvement in pCR was observed with the nivolumab combination, irrespective of radiologic downstaging.
Moreover, the median residual viable tumor percentage in patients with stage IB/II and IIIA disease was 28% and 8%, respectively, with nivolumab plus chemotherapy, vs 79% and 70%, respectively, with chemotherapy alone.
R0, R1, and R2 rates of resection were found to be comparable irrespective of baseline disease stage in both arms. The median number of lymph nodes dissected also proved to be similar between the arms, at 19.0 (IQR, 12-25) with nivolumab plus chemotherapy and 18.5 (IQR, 10-
26) with chemotherapy alone. The length of hospital stay was also comparable irrespective of disease stage at baseline in both arms.
Regarding safety, 41 any-grade AEs were reported in the nivolumab/chemotherapy arm vs 47 in the chemotherapy-alone arm; 11 and 15 grade 3 to 4 toxicities were experienced, respectively. Grade 5 surgery-associated toxicities were experienced by 2 patients in the nivolumab arm and were not determined to be related to the study drug per investigator assessment; these toxicities were pulmonary embolism and aortic rupture.
“CheckMate-816 is the first phase 3 trial with an immunotherapy-based combination to demonstrate a statistically significant and clinically meaningful benefit as a neoadjuvant treatment for patients with NSCLC,” Abderrahim Oukessou, MD, vice president and thoracic cancers development lead at Bristol Myers Squibb, stated in a press release. “The combination of [nivolumab] plus chemotherapy first showed a statistically significant improvement in pCR rate without impacting surgical outcomes and has now extended to time patients live free of disease progression, recurrence, or death. The EFS data from CheckMate-816 strengthen the evidence for the potential of [nivolumab]-based therapies to improve long-term clinical outcomes when used in the earlier stages of nonmetastatic cancers.”