(NEW Update) Nivolumab in NSCLC

See Original Spotlight posted March 20, 2017, for commentary from lung cancer experts about the clinical use of nivolumab in NSCLC.) 

The U.S. Food and Drug Administration (FDA) first approved nivolumab (Opdivo) to treat metastatic squamous non–small cell lung cancer (NSCLC) in 2015. Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody against PD-1. This made it the first immunotherapy to be approved for the treatment of any type of lung cancer, and it brought about a paradigm shift in the management of advanced NSCLC. It has not only significantly improved the prognosis of patients but has also become a cornerstone of NSCLC treatment, especially for those without oncogenic driver mutations.¹

On October 9, 2015, the FDA granted regular approval to nivolumab for the treatment of patients with metastatic NSCLC who have experienced disease progression on or after platinum-based chemotherapy. CheckMate 057 and 017 were the first phase III trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, showing a greater than fivefold increase in 5-year overall survival rates with nivolumab compared with docetaxel.

Since then, the landscape of approved first- and second-line immunotherapeutic approaches with nivolumab has expanded to encompass monotherapy, immunotherapy-exclusive protocols, and combinations with chemotherapy. The following nivolumab indications in NSCLC were granted FDA approval between 2020 and 2022.

On May 15, 2020, nivolumab plus ipilimumab was approved by the FDA for the first-line treatment of adults with metastatic NSCLC whose tumors express PD-L1 (≥ 1%), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.² This approval was based on Part 1a of the phase III CheckMate 227 trial, in which nivolumab plus ipilimumab demonstrated superior overall survival vs chemotherapy, regardless of tumor histology, with a minimum follow-up of 29.3 months. Additionally, no new safety concerns emerged with longer follow-up.

On May 26, 2020, based on the CheckMate 9LA trial, the regimen of nivolumab plus ipilimumab given with two cycles of platinum-doublet chemotherapy was approved by the FDA for the first-line treatment of adults with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.³ The therapy is approved for patients with squamous or nonsquamous disease and regardless of PD-L1 expression.

On March 4, 2022, the FDA approved nivolumab with platinum-doublet chemotherapy for adults with resectable (tumors ≥ 4 cm or node-positive) NSCLC, based on results from the phase III CheckMate 816 trial.⁴ This was the first FDA approval for neoadjuvant therapy for early-stage NSCLC. The trial found that pretreated patients with NSCLC could obtain a long-term benefit from 2 years of nivolumab treatment, with an estimated 5-year survival rate of 16%. In 2023, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) panel added a recommendation that all patients should be evaluated for neoadjuvant therapy, with strong consideration for those with node-positive disease or tumors ≥ 4 cm and no contraindications for immune checkpoint inhibitors. However, neoadjuvant therapy should not be used to attempt to induce resectability in patients who do not already meet criteria for resectability on initial evaluation.

According to the NCCN Guidelines for Non–Small Cell Lung Cancer version 3.2024, clinical trials for neoadjuvant nivolumab plus chemotherapy excluded patients harboring EGFR mutations and ALK rearrangements. Thus, exclusion of these biomarkers, at a minimum, is recommended prior to consideration for neoadjuvant nivolumab plus chemotherapy.⁵

If patients have not previously received a PD-1/PD-L1 inhibitor, the NCCN Guidelines Panel for NSCLC recommends single-agent nivolumab as a subsequent therapeutic option for patients with metastatic nonsquamous or squamous NSCLC and disease progression on or after first-line chemotherapy. Testing for PD-L1 is not required for prescribing nivolumab, but it may provide useful information.

Nivolumab Indications in NSCLC

Nivolumab, in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adults with resectable (tumors ≥ 4 cm or node-positive) NSCLC; in combination with ipilimumab for the first-line treatment of adults with metastatic NSCLC whose tumors express PD-L1 (≥ 1%), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations; in combination with ipilimumab and two cycles of platinum-doublet chemotherapy for adults with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations; and for treatment of adults with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab.⁶

Warnings and Precautions

Immune-related adverse events, such as pneumonitis, may occur with nivolumab. Intravenous high-dose corticosteroids may be required for patients with immune-mediated adverse events, based on the severity of the reaction (see the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities, available at www.NCCN.org). Nivolumab should be discontinued for patients with severe or life-threatening pneumonitis or myocarditis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). If patients are receiving nivolumab plus ipilimumab and have treatment-related adverse events, it may be reasonable to discontinue ipilimumab and continue nivolumab.

References

1. Roque K, Ruiz R, Mas L, et al. Update in immunotherapy for advanced non-small cell lung cancer: optimizing treatment sequencing and identifying the best choices. Cancers 2023;15: 4547.
2. Hellmann MD, Paz-Ares L, Caro RB, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med 2019;381:2020–2031.
3. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:198–211.
4. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 2022;386:1973–1985.
5. Riely GJ, Wood DE, Ettinger DS, et al: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non–Small Cell Lung Cancer, Version 3.2024—March 12, 2024. For the latest version, visit NCCN.org.
6. Bristol Myers Squibb. Nivolumab (Opdivo) prescribing information. Updated 2024. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125554s128lbl.pdf. Accessed March 28, 2024.