Nivolumab Approved as Neoadjuvant, Adjuvant Therapy for NSCLC by FDA

The FDA has approved nivolumab (Opdivo; Bristol Myers Squibb) for adult patients who are node positive or have resectable non–small cell lung cancer (NSCLC) tumors that are at least 4 cm but who do not have EGFR mutations or ALK rearrangements. This approval is for neoadjuvant treatment with nivolumab plus platinum-doublet chemotherapy and for adjuvant treatment with nivolumab after surgery, making nivolumab the only PD-1 inhibitor approved in both settings with proven statistically significant and clinically meaningful benefits for this patient population.¹ The approval came days before the FDA’s expected Prescription Drug User Fee Act deadline of October 8.

Bristol Myers Squibb announced it had submitted the applications for these indications for regulatory acceptance in February to the FDA and the European Medicines Agency.² Data from the phase 3, randomized, double-blind, multicenter CheckMate-77T (NCT04025879) trial served as the basis of these applications.^1,2

“Given the rates of disease recurrence in patients with resectable NSCLC,” said Tina Cascone, MD, PhD, associate professor of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, in a statement, “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.”¹

This early approval for nivolumab marks a significant milestone for the PD-1 inhibitor, as it is now the only drug in that class to be approved for resectable NSCLC in the neoadjuvant and adjuvant settings. | Image Credit: © BHM-stock.adobe.com

Patients were randomized 1:1 to neoadjuvant nivolumab plus platinum-doublet chemotherapy—from among carboplatin, cisplatin, paclitaxel, pemetrexed, and docetaxel³—surgery, and adjuvant nivolumab, in that order (n= 229) or neoadjuvant platinum-doublet chemotherapy and placebo followed by surgery and adjuvant placebo (n = 232).

In the ongoing CheckMate-77T trial—the expected completion date is July 30, 2027—patients were enrolled who had resectable suspected or histologically confirmed stage IIA (> 4 cm) to IIIB (T3N2) NSCLC without brain metastasis, an ECOG performance status of 1 or below, and sufficient tumor tissue for biomarker analysis, and who were treatment naïve. The primary end point is event-free survival (EFS), and secondary outcomes are overall survival, pathologic complete response (pCR), major pathological response, adverse events (AEs), participants with serious AEs, and participants with select AEs.³

Overall, over the median 25.4-month follow-up, nivolumab reduced the risk of disease recurrence, progression, or death by 42% (EFS HR, 0.58; 95% CI, 0.43-0.78; P = .00025) in the treatment arm compared with the placebo arm. EFS rate at 18 months was also 20 percentage points higher among the patients who received nivolumab vs placebo (70% vs 50%), and more of the patients randomized to treatment with nivolumab plus chemotherapy achieved pCR (25% vs 4.7%).¹

With this newest approval, comes the recommended regimen of (1) administering 360-mg nivolumab and platinum-doublet chemotherapy on the same day for 3 weeks for up to 4 cycles or until disease progress or unacceptable toxicity and (2) following that with single-agent 480-mg nivolumab every 4 weeks for up to 13 cycles (1 year) or until disease recurrence or unacceptable toxicity.

The approval also marks the fifth FDA-approved indication for nivolumab in 3 settings (neoadjuvant, adjuvant or perioperative) and across 4 cancer types (lung cancer, melanoma, bladder cancer and esophageal/gastroesophageal junction cancer). In addition to this newest regulatory decision, nivolumab also has these indications:

• As adjuvant treatment in patients 12 years or older with completely resected stage IIB, IIC, III, or IV melanoma
• As neoadjuvant treatment with platinum-doublet chemotherapy in adult patients with resectable NSCLC
• As adjuvant monotherapy in adult patients with urothelial carcinoma at high risk of recurrence after undergoing radical resection
• As adjuvant treatment following neoadjuvant chemoradiotherapy in adult patients with resected esophageal or gastroesophageal junction cancer with residual pathologic disease

Common AEs with nivolumab plus chemotherapy, as reported in 20% or more of patients, are anemia (39.5%), constipation (32.0%), nausea (28.9%), fatigue (28.1%), alopecia (25.9%), and cough (21.9%). The most frequent serious AE was pneumonia (≥ 2%), and 0.4% of patients each died as a result of cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis. Potential immune-mediated AEs also include hepatitis and hepatotoxicity, endocrinopathies, and nephritis with renal dysfunction. Complications of allogeneic hematopoietic stem cell transplantation and embryo-fetal toxicity are also possible.

This early approval—the original Prescription Drug User Fee Act deadline was October 8—follows the recent announcement at the European Society for Medical Oncology Congress 2024 of nivolumab in NSCLC as perioperative therapy and an interim analysis from May showing increased survival.^4,5

References

1. 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 4, 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

2. 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. News release. BusinessWire; February 7, 2024. Accessed October 4, 2024. https://www.businesswire.com/news/home/20240206288537/en/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

3. A study of neoadjuvant chemotherapy plus nivolumab versus neoadjuvant chemotherapy plus placebo, followed by surgical removal and adjuvant treatment with nivolumab or placebo for participants with surgically removable early stage non-small cell lung cancer. ClinicalTrials.gov. Updated July 23, 2024. Accessed October 4, 2024. https://www.clinicaltrials.gov/study/NCT04025879

4. Hippensteele A. Advances in the treatment of resectable NSCLC: key insights from CheckMate 77T, NEOSTAR, and CA209-159 trials. AJMC^®. September 15, 2024. Accessed October 4, 2024. https://www.ajmc.com/view/advances-in-the-treatment-of-resectable-nsclc-key-insights-from-checkmate-77t-neostar-and-ca209-159-trials

5. Shaw ML. Perioperative nivolumab boosts NSCLC survival: CheckMate 77T trial. AJMC. May 16, 2024. Accessed October 4, 2024. https://www.ajmc.com/view/perioperative-nivolumab-boosts-nsclc-survival-checkmate-77t-trial