FDA Approves Perioperative Nivolumab for Resectable NSCLC

FDA

The FDA has approved nivolumab (Opdivo) with platinum-doublet chemotherapy as neoadjuvant treatment, followed by single-agent nivolumab after surgery as adjuvant treatment, for adults with resectable (tumors ≥ 4 cm and/or node positive) non–small cell lung cancer (NSCLC) and no known EGFR mutations or ALK rearrangements.¹

“Given the rates of disease recurrence in patients with resectable NSCLC, there is a clear need for options that can be administered before and after surgery that may target micrometastasis, help reduce the risk of cancer returning and improve the chance of successful surgical treatment,” Tina Cascone, MD, PhD, associate professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, said in a news release.² “This approval is a step forward for patients with resectable disease, as the perioperative nivolumab plus neoadjuvant chemotherapy regimen can offer an improved event-free survival [EFS] compared with neoadjuvant chemotherapy alone and has the potential for achieving a pathologic response [pCR] in one in four patients.”

Efficacy of the regimen was evaluated in the randomized, phase 3 CheckMate-77T trial (NCT04025879) in 461 patients with treatment-naive, resectable stage IIA to select stage IIIB NSCLC. Eligible patients were randomly assigned 1:1 to neoadjuvant treatment with nivolumab or placebo, both in combination with platinum-based chemotherapy, every 3 weeks for up to 4 cycles, followed by adjuvant treatment with either continued single-agent nivolumab or placebo every 4 weeks for up to 13 cycles.¹

The major efficacy outcome measure was EFS by blinded independent central review. The median EFS was not reached (95% CI, 28.9-not estimable [NE]) in the nivolumab arm vs 18.4 months (95% CI, 13.6-28.1) in the chemotherapy arm (HR, 0.58; 95% CI, 0.43-0.78; P = 0.00025). At the prespecified interim analysis, overall survival (OS) was not formally tested for statistical significance; however, a descriptive analysis revealed no detriment.

Regarding safety, adverse effects (AEs) were comparable to those previously described in other clinical trials with nivolumab plus chemotherapy. Among patients who received neoadjuvant nivolumab, 5.3% were unable to undergo surgery because of AEs compared with 3.5% in the placebo arm. Additionally, 4.5% of patients who received neoadjuvant treatment and surgery in the nivolumab arm had delays in surgery because of AEs compared with 3.9% in the placebo arm.

Secondary end points of the study included pCR and major pathologic response rates by blinded independent pathologic review, as well as OS and safety. Outcomes by pCR status and circulating tumor DNA (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.³

Updated data from the trial were presented during the 2024 ESMO Congress. With 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.⁴

Moreover, patients who experienced a 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.

“This milestone expands the role of [nivolumab]-based treatments and builds upon the foundation set by the FDA approval of neoadjuvant-only [nivolumab] plus chemotherapy in resectable NSCLC based on the CheckMate-816 trial [NCT02998528],” Wendy Short Bartie, senior vice president of US Oncology and Hematology at Bristol Myers Squibb, stated.² “With this new [nivolumab]-based regimen, we are reinforcing our commitment to helping improve patient outcomes and expanding our thoracic portfolio in early-stage disease.”

References

1. FDA approves neoadjuvant/adjuvant nivolumab for resectable non-small cell lung cancer. FDA. October 3, 2024. Accessed October 3, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-nivolumab-resectable-non-small-cell-lung-cancer
2. U.S. Food and Drug Administration approves perioperative treatment of neoadjuvant Opdivo (nivolumab) and chemotherapy followed by surgery and adjuvant single-agent Opdivo for resectable non-small cell lung cancer (NSCLC). News release. Bristol Myers Squibb. October 3, 2024. Accessed October 3, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Approves-Perioperative-Treatment-of-Neoadjuvant-Opdivo-nivolumab-and-Chemotherapy-Followed-by-Surgery-and-Adjuvant-Single-Agent-Opdivo-for-Resectable-Non-Small-Cell-Lung-Cancer-NSCLC/default.aspx
3. 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
4. Pulla MP, Awad MM, Cascone T, et al. Perioperative nivolumab (NIVO) v placebo (PBO) in patients (pts) with resectable NSCLC: Clinical update from the phase III CheckMate 77T study. Ann Oncol. 2024;35(suppl 2):S1239-S1240. doi:10.1016/j.annonc.2024.08.2291