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FDA Approves Nivolumab as Neoadjuvant Therapy for Resectable Non–Small Cell Lung Cancer

Lung cancer biopsy

 The FDA has approved nivolumab (Opdivo®, Bristol-Myers Squibb) in combination with platinum doublet chemotherapy for the treatment of adult patients with early-stage, resectable non–small cell lung cancer (NSCLC). Nivolumab is a fully human programmed cell death ligand 1 (PD-L1)–targeted antibody, and its use is approved without regard for PD-L1 expression level.

"In patients with nonmetastatic NSCLC, surgery has curative potential, but 30% to 80% who undergo resection experience recurrence. CheckMate 816 is the first positive phase 3 trial demonstrating a significant improvement in pathologic response with neoadjuvant immunotherapy plus [chemotherapy] in resectable NSCLC," wrote Patrick M. Forde, MBBCh, Director of Thoracic Oncology Clinical Research at Johns Hopkins Medicine, and colleagues, about the trial on which the approval was based (NCT02998528). Pathologic response results were presented at the 2021 American Association for Cancer Research Annual Meeting.

This phase 3 randomized clinical trial evaluated the efficacy of nivolumab with platinum doublet chemotherapy compared with platinum doublet chemotherapy alone. A total of 358 patients with stage IB to stage IIIA resectable NSCLC without known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations were randomized 1:1 to receive 360 mg nivolumab with platinum doublet chemotherapy or chemotherapy alone every three weeks for three cycles. Surgery was performed within six weeks of treatment. The primary end points were improved pathological complete response, which was defined as 0% viable tumor cells in the lung and lymph nodes, and event-free survival. Exploratory end points included objective response rate, predictive biomarkers such as PD-L1 expression, feasibility of surgery, and adverse events related to surgery.

The addition of nivolumab to platinum doublet chemotherapy produced a 24.0% pathological complete response rate compared with 2.2% with chemotherapy alone in the intent-to-treat population. This result was consistent across disease stages, tumor mutational burden, and PD-L1 expression levels. The addition of nivolumab also improved event-free survival as assessed by blinded independent reviewers. Median event-free survival was 31.6 months in the nivolumab plus chemotherapy group and 20.8 months in the chemotherapy alone arm.

Surgical results of the trial were presented at the 2021 American Society of Clinical Oncology (ASCO) annual meeting. Definitive surgery occurred for 83% of patients receiving nivolumab compared with 75% of patients receiving chemotherapy only. Median residual viable tumor cells in the primary tumor bed remaining after surgery were 10% with nivolumab compared with 74% with chemotherapy only. It was found that adding nivolumab to chemotherapy did not significantly increase surgical complications, alter the timing of surgery, or extend hospital stay.

Adverse events associated with nivolumab and chemotherapy in this trial were consistent with previous studies of this regimen. Surgery was canceled due to adverse events for two patients in each arm of the trial. Treatment-related grade 3 and 4 adverse events were reported in 33.5% of patients treated with nivolumab plus chemotherapy compared with 36.9% of patients treated with chemotherapy alone. Grade 3 and 4 surgery-related adverse events were reported in 11.4% and 14.8% of patients in the nivolumab plus chemotherapy and chemotherapy arms, respectively. Serious adverse reactions and severe laboratory abnormalities with this combination included pneumonia, vomiting, cytopenias, hyperglycemia, increased amylase, and hypernatremia. The most common adverse events (≥20%) were nausea, constipation, fatigue, decreased appetite, and rash.

"In CheckMate 816, neoadjuvant nivolumab plus chemotherapy did not impede the feasibility and timing of surgery, nor the extent or completeness of resection versus chemo alone; treatment was tolerable and did not increase surgical complications," concluded Jonathan Spicer, MD, a Dr. Ray Chiu Distinguished Scientist in Surgical Research at Montreal General Hospital, and colleagues. "The surgical outcome data from CheckMate 816 along with significant improvement in pathologic complete response support nivolumab plus chemotherapy as a potential neoadjuvant option for patients with stage IB to IIIA resectable NSCLC."

The recommended neoadjuvant dose of nivolumab is 360 mg with platinum doublet chemotherapy every three weeks for three cycles.

For More Information

Spicer J, Wang C, Tanaka F, et al (2021). Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol (ASCO Annual Meeting Abstracts), 39(suppl_15). Abstract 8503. DOI:10.1200/JCO.2021.39.15_suppl.8503

Forde PM, Spicer J, Lu S, et al (2021). Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (1B-IIIA) non-small cell lung cancer NSCLC in the phase 3 CheckMate 816 trial. American Association for Cancer Research Annual Meeting 2021. Abstract CT003.

Clinicaltrials.gov (2016). A neoadjuvant study of nivolumab plus ipilimumab or nivolumab plus chemotherapy versus chemotherapy alone in early stage non-small cell lung cancer (NSCLC) CheckMate 816. NLM identifier: NCT02998528.

Opdivo® (nivolumab) prescribing information (2022). Bristol-Myers Squibb Company. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/225554s112lbl.pdf

US Food & Drug Administration (2021). FDA approves neoadjuvant nivolumab and platinum-doublet chemotherapy for early-stage non-small cell lung cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-nivolumab-and-platinum-doublet-chemotherapy-early-stage-non-small-cell-lung

Image credit: Hellerhoff. Licensed under CC-BY-SA 3.0


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