Updated CheckMate 816 Data Reinforce Neoadjuvant Nivolumab/Chemo as a SOC for Resectable NSCLC

Neoadjuvant nivolumab (Opdivo) paired with chemotherapy showcased durable event-free survival (EFS) benefit and a trend toward improved overall survival (OS) vs chemotherapy alone in patients with resectable non–small cell lung cancer (NSCLC), according to data from the 4-year update of the phase 3 CheckMate 816 study (NCT02998528).¹

The findings, which were presented during the 2024 ASCO Annual Meeting, showed that the median EFS with nivolumab plus chemotherapy (n = 179) was 43.8 months (95% CI, 30.6-not reached [NR]) vs 18.4 months (95% CI, 14.0-26.7) with chemotherapy alone (n = 179), with a hazard ratio of 0.66 (95% CI, 0.49-0.90). The 48-month respective Kaplan Meier–estimated EFS rates were 49% (95% CI, 41%-57%) and 38% (95% CI, 30%-46%), respectively.

The median OS was NR in both arms with a hazard ratio of 0.71 (98.36% CI, 0.47-1.07; unstratified HR, 0.69; 95% CI, 0.49-0.97). The significance boundary for OS, which was a P value of .0164, has not been met yet (P = .0451). The respective Kaplan Meier–estimated 48-month OS rates were 71% (95% CI, 63%-77%) and 58% (95% CI, 50%-65%). The median lung cancer–specific survival was also NR in both arms (unstratified HR, 0.62; 95% CI, 0.41-0.93), with respective Kaplan Meier–estimated 48-month rates of 79% (95% CI, 72%-84%) and 66% (95% CI, 58%-72%).

“The 4-year updated [showed] that nivolumab plus chemotherapy had durable benefit despite the short course of treatment. This is statistically significant, as we have previously reported for EFS, and I would argue, clinically important, in terms of OS as opposed to chemotherapy [alone], with improved lung cancer–specific survival,” lead study author Jonathan D. Spicer, MD, PhD, assistant professor of surgery at McGill University Health Centre, in Quebec, Canada, said in a presentation of the data. “These improvements are occurring regardless of the type of platinum backbone utilized or the extent of surgical resection, sort of pointing to the fact that the surgeons need to extirpate all the disease by all means necessary in well-selected patients.”

The international, open-label, phase 3 CheckMate 816 study enrolled adults with resectable stage IB to IIIA NSCLC who had an ECOG performance status of 0 or 1 and had not previously received anticancer therapy.² To enroll, patients were required to have measurable disease by RECIST 1.1 criteria. Those whose tumors harbored known ALK translocations or EGFR mutations were excluded.

Study participants were randomly assigned 1:1 to receive 360 mg of nivolumab plus platinum-doublet chemotherapy or platinum-doublet chemotherapy alone every 3 weeks for 3 cycles prior to undergoing definitive surgery. A third group of patients was given 3 mg/kg of nivolumab every 2 weeks for 3 cycles plus 1 mg/kg of ipilimumab (Yervoy) for cycle 1 only; this cohort closed enrollment early. Surgery was planned to happen within 6 weeks of the completion of the neoadjuvant treatment. After the procedure, patients in both groups were permitted to receive up to 4 cycles of adjuvant chemotherapy, radiotherapy, or both.

The primary end points of the study were EFS by blinded independent central review and pathologic complete response (pCR). Secondary end points comprised major pathologic response, time to death or distant metastases. Safety was assessed in all patients.

Prior data from the prespecified interim analysis 1 of EFS and OS published in the New England Journal of Medicine, which had a median follow-up of 29.5 months, showed that the median EFS with nivolumab plus chemotherapy was 31.6 months (95% CI, 95% CI, 30.2-NR) vs 20.8 months (95% CI, 14.0-26.7) with chemotherapy alone (HR, 0.63; 97.38% CI, 0.43-0.91; P = .005). The respective pCRs were 24.0% (95% CI, 18.0%-31.0%) and 2.2% (95% CI, 0.6%-5.6%; OR, 13.94; 99% CI, 3.49%-55.75%; P < .001).

Three-year data from the trial shared during the 2023 European Lung Cancer Congress showed that at a median follow-up of 41.4 months, the median EFS with nivolumab plus chemotherapy was NR (95% CI, 31.6-NR) vs 21.1 months (95% CI, 14.8-42.1) with chemotherapy alone (HR, 0.68; 95% CI, 0.49-0.93).3 The median time between date of randomization and first date of distant metastases or date of death in the absence of distant metastases per BICR was NR (95% CI, 48.6-NR) in the nivolumab arm vs 34.3 months (95% CI, 23.6-NR) in the chemotherapy-alone arm (HR, 0.55; 95% CI, 0.39-0.78). OS data remained immature at the time of the analysis (HR, 0.62; 99.34% CI, 0.36-1.05).

At the 2024 ASCO Annual Meeting, Spicer shared findings from the 4-year update.¹

Spicer highlighted that, in concurrently randomized patients, the use of nivolumab plus chemotherapy was associated with a reduction in the need for any subsequent therapy vs chemotherapy alone (29% vs 50%), a reduction in the use of radiotherapy at any subsequent point for recurrent disease (13% vs 24%), and a reduction in the need for immunotherapy (10% vs 27%).

OS “is not yet statistically significant” as “the boundary of 0.0164 was not crossed, but we have a sustained improvement of approximately 13% in OS [rate] at 48 months,” Spicer said. “Just perhaps for reference for those of you who might not know, ADAURA [NCT02511106] had a 10% OS benefit, and here, we’re seeing a 13% increment, and I think that’s clinically important.”

He added, “With regard to lung cancer–specific survival, the median is, of course, NR, but we have corroborating evidence of improvements in disease control that is specific to lung cancer, with a 13% improvement at 40 months.” Moreover, those in the nivolumab/chemotherapy arm who had a pCR continued to have improved OS vs those who did not (HR, 0.08; 95% CI, 0.02-0.34), with respective 48-month OS rates of 95% and 63%.

Investigators also examined OS by the neoadjuvant platinum chemotherapy received. In those who received cisplatin who were in the nivolumab/chemotherapy arm (n = 124), the median OS was NR; those in the chemotherapy arm (n = 134) who received cisplatin also had a median OS that was NR (95% CI, 50.4-NR) with a hazard ratio of 0.79 (95% CI, 0.53-1.17). The respective 48-month OS rates were 69% (95% CI, 60%-76%) and 60% (95% CI, 51%-68%). In those given carboplatin, the median OS was NR in the nivolumab/chemotherapy arm (n = 39) vs 37.2 months (95% CI, 16.8-NR) in the chemotherapy-alone arm (n = 33), with a hazard ratio of 0.36 (95% CI, 0.16-0.81). The respective 48-month OS rates were 80% (95% CI, 63%-89%) and 50% (95% CI, 32%-66%).

“We see compelling data for carboplatin. Of course, this was perhaps enriched for squamous histology as this was the regimen that could be employed without having to reach out to medical monitor,” Spicer noted. “Otherwise, patients had to have comorbidities to justify the use of carboplatin. But an 80% OS [rate] at 48 months, it seems to be a perfectly reasonable regimen to employ.”

Spicer and colleagues also evaluated OS by extent of resection. In the lobectomy cohort, those who received nivolumab plus chemotherapy (n = 115) experienced a median OS that was NR vs NR in those given chemotherapy alone (n = 82), with a hazard ratio of 0.71 (95% CI, 0.41-1.21). The respective 48-month OS rates were 79% (95% CI, 70%-86%) and 69% (95% CI, 58%-78%). In the pneumonectomy cohort, those who received nivolumab/chemotherapy (n = 25) experienced a median OS that was NR vs 61.8 months (95% CI, 31.2-NR) with chemotherapy alone (n = 34), with a hazard ratio that was not calculable. The respective 48-month OS rates were 80% (95% CI, 58%-91%) and 56% (95% CI, 37%-70%).

“These data from a surgical perspective are quite important and provocative,” Spicer said. “We see the benefit with the lobectomy cohort, but the pneumonectomy cohort has [OS rates of] 80% vs 56%. If you think back to what we know of the trial [led by Dr Kathy Albain and colleagues], where there was a clear toxicity for the application of pneumonectomy after chemoradiation, here, we’re seeing a scenario where in well-selected patients, we can offer really excellent survival metrics for [certain] patients.”

In concurrently randomized patients, 25% (n = 89) had evaluable circulating tumor DNA (ctDNA) levels and 24% (n = 86) had detectable ctDNA levels at baseline. The percentage of patients in the nivolumab/chemotherapy arm who achieved ctDNA clearance was 56% vs 35% of those in the chemotherapy-alone arm. The hazard ratio for ctDNA clearance vs no ctDNA clearance with nivolumab plus chemotherapy was 0.31 (95% CI, 0.10-0.90); with chemotherapy alone, the HR was 0.58 (95% CI, 0.20-1.64).

“We have a 56% ctDNA clearance rate in the patients who are biomarker evaluable [in the nivolumab group] vs 35% in the chemotherapy group,” Spicer said. “If you look at the Kaplan-Meier curves for OS by ctDNA clearance, they are somewhat reminiscent of what you might see for the pCR vs non-pCR patients. Clearly, ctDNA clearance is a very strong prognostic factor for predicting OS.”

The safety profile of neoadjuvant nivolumab plus chemotherapy was consistent with what has previously been reported with the regimen.

In the nivolumab/chemotherapy arm (n = 176), any-grade adverse effects (AEs) occurred in 94% of patients, with 43% of events being grade 3 or 4. Any-grade serious AEs occurred in 17% of patients, with 11% of effects grade 3 or 4 in severity.

Any-grade surgery-related AEs were reported in 45% of patients; 11% of these effects were grade 3 or 4. Grade 5 surgery-related AEs occurred in 2 patients on the nivolumab/chemotherapy arm, but both were not related to study treatment (pulmonary embolism, n = 1; aortic rupture, n = 1). All-grade treatment-related AEs led to discontinuation for 11% of patients who received the combination, and no treatment-related deaths were observed.

“These 4-year results from CheckMate 816 provide the first understanding of the long-term benefits of neoadjuvant immunotherapy and chemotherapy and reinforce nivolumab plus chemotherapy as a standard of care for patients with resectable NSCLC,” Spicer concluded.

Disclosures: Dr Spicer received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb/Medarex, Chemocentryx, Merck, Novartis, and Pfizer; he serves in a consulting or advisory role for AstraZeneca, Bristol Myers Squibb/Medarex, Merck, Protalix Biotherapeutics, Regeneron, and Xenetic Biosciences; research funding was provided by AstraZeneca (Inst), Bristol Myers Squibb/Medarex (Inst), CLS-Therapeutics (Inst), Merck (Inst), Protalix Biotherapeutics (Inst), and Roche (Inst); and travel expenses were covered by AstraZeneca, Bristol Myers Squibb/Medarex, and Merck.

References

1. Spicer J, Girard N, Provencio M, et al. Neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: 4-year update from CheckMate 816. J Clin Oncol. 2024;42(suppl 17):LBA8010. doi:10.1200/JCO.2024.42.17_suppl.LBA8010
2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170
3. Neoadjuvant Opdivo (nivolumab) with chemotherapy demonstrates long-term, durable clinical benefits for patients with resectable non-small cell lung caner at three years in the CheckMate -816 trial. News release. Bristol Myers Squibb. March 30, 2023. Accessed June 3, 2024. https://news.bms.com/news/details/2023/Neoadjuvant-Opdivo-nivolumab-with-Chemotherapy-Demonstrates-Long-Term-Durable-Clinical-Benefits-for-Patients-with-Resectable-Non-Small-Cell-Lung-Cancer-at-Three-Years-in-the-CheckMate--816-Trial/default.aspx