Perioperative Nivolumab Shows EFS Benefit vs Placebo in Resectable NSCLC

Perioperative nivolumab (Opdivo) continued to display an event-free survival (EFS) benefit compared with placebo in patients with resectable non–small cell lung cancer (NSCLC), according to findings from an updated analysis of the phase 3 CheckMate 77T study (NCT04025879).¹

Data presented during the 2024 ESMO Congress demonstrated that, at a median follow-up of 33.3 months (range, 23.6-52.1), patients who received perioperative nivolumab (n = 229) achieved a median EFS of 40.1 months (95% CI, 33.7-not reached) compared with 17.0 months (95% CI, 13.6-28.1) among patients who received placebo (n = 232; HR, 0.59; 95% CI, 0.45-0.79). The 12-month EFS rates were 73% (95% CI, 67%-79%) vs 59% (95% CI, 52%-65%), and the 24-month rates were 65% (95% CI, 58%-71%) vs 44% (95% CI, 38%-51%), respectively.

Moreover, patients who experienced a pathologic complete response (pCR) who received nivolumab (n = 58) experienced a significant EFS benefit vs those who received placebo (n = 11; HR, 0.59; 95% CI, 0.12-2.91). Similarly, patients without a pCR in the nivolumab arm (n = 98) also experienced an EFS benefit compared with those who received placebo and did not achieve a pCR (n = 148; HR, 0.75; 95% CI, 0.51-1.09).

During the neoadjuvant period, evaluable patients in the nivolumab arm (n = 76) and the placebo arm (n = 64) achieved ctDNA clearance at respective rates of 66% vs 38%. The EFS HR among these patients was 0.38 (95% CI, 0.16-0.88) in favor of nivolumab and the 2-year EFS rates were 81% vs 58%, respectively. The EFS HR was 0.74 (95% CI, 0.39-1.42) in favor of nivolumab in patients without ctDNA clearance; the 2-year EFS rates among these patients were 50% vs 31%, respectively.

Among evaluable patients with ctDNA clearance in the nivolumab (n = 50) and placebo (n = 24) arms during the neoadjuvant period, the pCR rates were 50% vs 12%. Evaluable patients without ctDNA clearance in the nivolumab (n = 26) and placebo (n = 40) arms experienced pCR rates of 0% vs 2%, respectively.

During the post-operative period, evaluable patients in the nivolumab arm (n = 48) and the placebo arm (n = 44) experienced ctDNA recurrence at rates of 8% vs 20%, respectively. Evaluable patients with a pCR in the nivolumab (n = 26) and placebo arms (n = 5) experienced ctDNA recurrence at rates of 4% vs 20%, respectively. Evaluable patients without a pCR in the nivolumab (n = 22) and placebo arms (n = 39) experienced ctDNA recurrence at rates of 14% vs 21%, respectively.

“[The EFS data] show an improvement that is both statistically and clinically significant with the addition of perioperative nivolumab, with an increase in median EFS from 17.0 months to 40.1 months with the addition of perioperative nivolumab,” Jonathan D. Spicer, MD, PhD, FRCS, said during the presentation. “The addition of perioperative nivolumab provided some benefit, both in the pCR and the non-pCR patients with HRs that are commensurate to the degree of pathological response….These data support the use of perioperative nivolumab as an efficacious regimen for patients with resectable NSCLC.”

Spicer is the Dr. Ray Chiu Distinguished Scientist in Surgical Research, the Advanced Thoracic and Upper GI Surgical Oncology Fellowship program director, the Rossy Cancer Network Lung Cancer Disease Site Lead​, and an attending surgeon in then Division of Thoracic and Upper Gastrointestinal Surgery at McGill University Health Centre in Montreal, Canada.

CheckMate 77T Study Design

CheckMate 77T was a double-blind study that enrolled patients with resectable stage IIA to IIIB NSCLC per AJCC 8th Edition staging criteria who received no prior systemic anti-cancer therapy, had an ECOG performance status of 1 or less, and did not have EGFR mutations or known ALK translocations. Patients were stratified by histology (nonsquamous vs squamous), disease stage (II vs III), and tumor PD-L1 expression (≥1% vs <1% vs not evaluable/indeterminate).^1,2

Eligible patients were randomly assigned 1:1 to receive nivolumab at a dose of 360 mg or placebo every 3 weeks, both in combination with chemotherapy every 3 weeks for up to 4 cycles. Both groups then underwent surgery followed by adjuvant nivolumab at a dose of 480 mg every 4 weeks or placebo at the same dosing schedule, both for up to 13 cycles.¹

The primary end point was EFS by blinded independent central review. Secondary end points included pCR and major pathologic response rates by blinded independent pathologic review, as well as overall survival and safety. Outcomes by pCR status and ctDNA clearance and recurrence were also evaluated in exploratory analyses.

The baseline characteristics were well balanced between the nivolumab and placebo arms; the median patient age was 66 years (range, 37-83) vs 66 years (range, 35-86), respectively. Most patients in both arms were from Europe (54% vs 55%), had an ECOG performance status of 0 (64% vs 61%), had stage IIIA-B disease (64% vs 64%), had squamous histology (51% vs 51%), were current or former smokers (93% vs 88%), and had tumor PD-1 expression levels of at least 1% (56% vs 55%). Patients in both arms underwent prior platinum-based therapy with carboplatin (73% vs 78%) or cisplatin (24% vs 18%), respectively.²

Safety Outcomes by pCR Status inCheckMate 77T

In terms of safety, all patients in the nivolumab (n = 58) and placebo (n = 11) arms who achieved a pCR experienced an any-grade adverse effect (AE). Patients in both arms also experienced grade 3 to 4 AEs (48% vs 46%), any-grade treatment-related AEs (TRAEs; 97% vs 82%), any-grade serious AEs (43% vs 36%), and grade 3 to 4 serious AEs (28% vs 36%). In the nivolumab arm, grade 3 to 4 TRAEs (31%), any-grade AEs leading to treatment discontinuation (34%), grade 3 to 4 AEs leading to treatment discontinuation (17%), any-grade TRAEs leading to discontinuation (29%), any-grade treatment-related serious AEs (AEs; 24%), and grade 3 to 4 treatment-related serious AEs (14%) were also reported; no patients in the placebo arm experienced these events.¹

Patients without a pCR in the nivolumab (n = 170) and placebo (n = 219) arms experienced any-grade AEs (96% vs 98%), grade 3 to 4 AEs (46% vs 42%), any-grade TRAEs (86% vs 87%), grade 3 to 4 TRAEs (32% vs 26%), any-grade AEs leading to treatment discontinuation (22% vs 11%), grade 3 to 4 AEs leading to treatment discontinuation (13% vs 6%), any-grade TRAEs leading to treatment discontinuation (16% vs 8%), and grade 3 to 4 TRAEs leading to treatment discontinuation (10% vs 5%). Additionally, any-grade serious AEs (42% vs 31%), grade 3 to 4 serious AEs (29% vs 19%), any-grade treatment-related serious AEs (17% vs 10%), and grade 3 to 4 treatment-related serious AEs (14% vs 6%) also occurred.

Overall, 2 treatment-related deaths were reported in the nivolumab arm, both due to pneumonitis.

“Low-grade AEs and TRAEs are a bit more common in the pCR group vs the non-pCR group,” Spicer noted. “In total, these data are consistent with prior reports showing a significant improvement in EFS in the nivolumab cohort vs placebo, with a HR 0.59. Exploratory ctDNA analyzes indicate that ctDNA clearance is indicative of a higher likelihood of pCR and, perhaps more importantly, the lack of clearance is associated with residual disease.”

Disclosures: Dr Spicer reported receiving institutional research support/funding from AstraZeneca, Bristol Myers Squibb, CLS Therapeutics, Merck, Pfizer, Protalix Biotherapeutics, Regeneron, and Roche. He has received advisory/consultancy fees from Amgen, AstraZeneca, Bristol Myers Squibb, ChemoCentryx, Eisai, Medscape, Merck, Novartis, OncLive, PeerView, Pfizer, Protalix Biotherapeutics, Regeneron, Roche, and Xenetic Biosciences. Dr Spicer noted he has clinical trial leadership roles with AstraZeneca, Bristol Myers Squibb, Merck, Novartis, and Roche. This study was supported by Bristol Myers Squibb.

References

1. Pulla MP, Awad MM, Cascone T, et al. Perioperative nivolumab vs placebo in patients with resectable NSCLC: clinical update from the phase 3 CheckMate 77T study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA50.
2. Cascone T, Awad MM, Spicer JD, et al. CheckMate 77T: phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. Ann Oncol. 2023;34(suppl 2):1295. doi:10.1016/j.annonc.2023.10.050