Regulatory Filings Accepted for Perioperative Nivolumab Plus Chemotherapy in NSCLC

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The FDA and EMA have accepted applications seeking the approval of neoadjuvant nivolumab/chemotherapy followed by surgery and adjuvant nivolumab in NSCLC.

FDA

FDA

The FDA has accepted a supplemental biologics license application (sBLA) seeking the approval of neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by surgery and adjuvant nivolumab in the perioperative treatment of patients with resectable stage IIA to IIIB non–small cell lung cancer (NSCLC).1 In late January, the European Medicines Agency also validated the type II variation application for the regimen in this indication.

The applications are based on findings from the phase 3 CheckMate -77T study (NCT04025879), in which neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab significantly improved event-free survival (EFS) vs placebo plus chemotherapy in this population.2 At a median follow-up of 25.4 months (range, 15.7-44.2), the median EFS per blinded independent central review (BICR) with nivolumab (n = 229) was not yet reached (NR; 95% CI, 28.9-NR) vs 18.4 months (95% CI, 13.6-28.1) with placebo (n = 232; HR, 0.58; 95% CI, 0.42-0.81; P = .00025). The 18-month EFS rates were 70% vs 50%, respectively.

The pathologic complete response rate (pCR) achieved with nivolumab plus chemotherapy followed by adjuvant nivolumab was 25.3% vs 4.7% with chemotherapy plus placebo, translating to 20.5% difference (OR, 6.64; 95% CI, 3.40-12.97). The major pathologic response (MPR) rate achieved in the nivolumab arm was 35.4% vs 12.1% in the placebo arm, translating to a difference of 23.2% (OR, 4.01; 95% CI, 2.48-6.49).

The FDA assigned a goal date of October 8, 2024, under the Prescription Drug User Fee Act.

“With CheckMate -77T, we have evaluated the potential for neoadjuvant immunotherapy to induce pathological complete response and the role of perioperative Opdivo treatment in reducing the likelihood that the cancer will return and help make extended survival possible for patients,” Abderrahim Oukessou, MD, vice president of thoracic cancers and global program lead at Bristol Myers Squibb, stated in a press release.1 “The acceptance of these applications underscores our impactful progress in addressing unmet needs across several non-small cell lung cancer treatment settings and brings us one step closer to offering a new perioperative Opdivo-based regimen to patients who may benefit.”

The double-blind, randomized, phase 3 study enrolled patients with resectable stage IIA to IIIB NSCLC who had not previously received systemic treatment and who had an ECOG performance status ranging from 0 to 1. Patients could not have tumors harboring EGFR mutations or known ALK alterations.

Participants (n = 461) were randomly assigned 1:1 to the nivolumab or placebo arm. Patients received placebo or 360 mg of nivolumab every 3 weeks plus chemotherapy every 3 weeks for 4 cycles, underwent radiologic restaging, went on to receive surgery within 6 weeks after neoadjuvant treatment, and then received adjuvant placebo or nivolumab at 480 mg every 4 weeks for 1 year. Chemotherapy was administered based on histology. Those with nonsquamous disease were given cisplatin plus pemetrexed, carboplatin plus pemetrexed, or carboplatin plus paclitaxel. Those with squamous disease received cisplatin plus docetaxel or carboplatin plus paclitaxel.

The primary end point of the trial was EFS by BICR and secondary end points included pCR and MPR by blinded independent pathological review, as well as overall survival (OS) and safety. Exploratory analyses include EFS by pCR/MPR and EFS by adjuvant treatment.

The median patient age across the nivolumab and placebo arms was 66 years (range, 35-86) and most patients were male (73% vs 69%). In the nivolumab arm, 54% of patients were from Europe, 28% were from Asia, 10% were from North America, and 8% were from the rest of the world; in the placebo arm, these respective rates were 55%, 22%, 9%, and 15%, respectively. Most patients had an ECOG performance status of 0 (64% vs 61%), had stage IIIA to B disease (64% vs 64%), were current or former smokers (93% vs 88%), and received carboplatin (73% vs 78%).

With regard to histology, 51% of those in both arms had squamous disease and the remainder had nonsquamous disease. With regard to PD-L1 expression in the nivolumab arm, 41% had expression under 1%, 56% had 1% or higher, 36% had 1% to 49%, 20% had 50% or higher, and 4% were not evaluable; in the placebo arm, these respective rates were 40%, 55%, 33%, 22%, and 5%, respectively.

At the data cutoff date of September 6, 2023, 228 of the 229 patients in the nivolumab arm received neoadjuvant treatment and 194 completed treatment; 178 went on to receive definitive surgery and 142 received adjuvant treatment. A total of 85 patients completed treatment and 8 were still receiving treatment at cutoff. In the placebo arm, 230 of the 232 patients received neoadjuvant treatment and 205 completed it. A total of 178 went on to undergo surgery and 152 of them received adjuvant treatment. Ninety-two patients completed treatment and 8 patients were still receiving treatment at cutoff.

In the nivolumab arm, 80% had lobectomy and 9% had pneumonectomy; these respective rates were 72% and 14% in the placebo arm. In the nivolumab arm, 89% achieved R0 and 11% had R1 or R2; in the placebo arm, these rates were 90% and 10%, respectively.

Additional data presented during the 2023 ESMO Congress showed that those with stage II disease who received nivolumab plus chemotherapy followed by nivolumab (n = 81) experienced a median EFS that was NR (95% CI, 22.6-NR) vs NR (95% CI, 24.2-NR) in those who received chemotherapy plus placebo (n = 81; HR, 0.81; 95% CI, 0.46-1.43). In the subset of patients with stage III disease who received nivolumab (n = 148) or placebo (n = 149), the median EFS was 30.2 months (95% CI, 26.9-NR) and 13.4 months (95% CI, 9.8-17.7), respectively (HR, 0.51; 95% CI, 0.36-0.72).

Within the subset of patients who had PD-L1 expression less than 1% and received nivolumab (n = 93) or placebo (n = 93), the median EFS was 29.0 months (95% CI, 21.4-NR) and 19.8 months (95% CI, 13.9-NR), respectively (HR, 0.73; 95% CI, 0.47-1.15). In the subset of patients with a PD-L1 expression of 1% or higher who received nivolumab (n = 128) or placebo (n = 128), the median EFS was NR (95% CI, 28.9-NR) and 15.8 months (95% CI, 9.3-35.1), respectively (HR, 0.52; 95% CI, 0.35-0.78).

Exploratory analyses findings indicated that in those who achieved a pCR the HR for EFS was 0.33 (95% CI, 0.08-1.37); in those who did not achieve a pCR, the HR for EFS was 0.79 (95% CI, 0.58-1.06). In those who achieved an MPR, the HR for EFS was 0.40 (95% CI, 0.16-0.99); in those who did not, the HR for EFS was 0.85 (95% CI, 0.62-1.15).

Moreover, nivolumab plus chemotherapy followed by adjuvant nivolumab improved EFS compared with chemotherapy plus placebo, with a numerically higher benefit in those who received adjuvant treatment (HR, 0.45; 95% CI, 0.29-0.69) compared with those who did not (HR, 0.55; 95% CI, 0.37-0.83). In those who received adjuvant treatment and achieved a pCR, the HR for EFS was 0.22 (95% CI, 0.04-1.08); in those who received adjuvant treatment but did not achieve a pCR, the HR for EFS was 0.63 (95% CI, 0.40-0.99).

The perioperative nivolumab-based regimen did not showcase any new safety signals. Overall, adverse effects (AEs) occurred in 97% of those in the nivolumab arm vs 98% of those in the placebo arm; these effects were grade 3 or higher for 47% and 43% of patients, respectively.

Treatment-related AEs (TRAEs) occurred in 89% of those on the nivolumab arm vs 87% of those in the placebo arm; these effects were grade 3 or higher for 32% and 25% of patients, respectively. TRAEs led to discontinuation for 19% and 7% of patients, respectively. Serious AEs occurred in 42% and 31% of patients, respectively; these effects were treatment related in 19% vs 10% of patients, respectively.

References

  1. Bristol Myers Squibb announces acceptance of US and EU regulatory filings for neoadjuvant Opdivo (nivolumab) and chemotherapy followed by surgery and adjuvant Opdivo in resectable non-small cell lung cancer. News release. Bristol Myers Squibb. February 7, 2024. Accessed February 7, 2024. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Announces-Acceptance-of-U.S.-and-EU-Regulatory-Filings-for-Neoadjuvant-Opdivo-nivolumab-and-Chemotherapy-Followed-by-Surgery-and-Adjuvant-Opdivo-in-Resectable-Non-Small-Cell-Lung-Cancer/default.aspx
  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):S1295. doi:10.1016/j.annonc.2023.10.050
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