Neoadjuvant nivolumab plus chemotherapy extends EFS in non-small cell lung cancer
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Neoadjuvant nivolumab plus chemotherapy significantly improved EFS in stage IB to stage IIIA resectable non-small cell lung cancer, according to research presented at American Association for Cancer Research Annual Meeting.
Results of the randomized phase 3 CheckMate 816 trial, published simultaneously in The New England Journal of Medicine, also showed no new adverse events associated with the nivolumab (Opdivo, Bristol Myers Squibb) combination.
“Right now, this is the standard of care for all patients with resectable stage IB to stage IIIA NSCLC,” Nicolas Girard, MD, PhD, professor of respiratory medicine at Versailles Saint Quentin University and head of Curie-Montsouris Thorax Institute, told Healio. “This treatment led to a reduction of the risk of death by 37%. This is impressive. It is completely changing the field.”
Background and methodology
Girard noted that although resectable NSCLC may be curable in some cases, many patients face a high probability of recurrence after surgery. Thus, researchers have explored effective systemic treatment options to prevent that trajectory.
“Survival for patients after lung cancer surgery is poor — more than 50% of patients experience a relapse of their cancer and, in most cases, this is eventually fatal,” Patrick M. Forde, MBBCh, study co-author and co-director of the division of upper aerodigestive malignancies and director of Thoracic Oncology Research Program at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University, told Healio. “Chemotherapy given before or after surgery improves survival modestly, with about 5% more patients alive at 5 years. Given significant benefits of immunotherapy for metastatic lung cancer, where it is approved for multiple indications, and building on a small pilot study we did in 2018, we performed the current phase 3 CheckMate 816 trial.”
The trial included 358 patients with stage IB, stage II or stage IIIA NSCLC and an ECOG performance status of 0 or 1. Girard, Forde and colleagues randomly assigned patients to nivolumab (360 mg) plus chemotherapy every 3 weeks or chemotherapy alone every 3 weeks (n = 179 each).
Primary endpoints included EFS and pathologic complete response assessed by blinded independent review. Secondary endpoints included OS, major pathologic response and time to death or distant metastasis.
Key findings
After a minimum follow-up of 21 months, results showed median EFS of 31.6 months among patients assigned nivolumab plus chemotherapy compared with 20.8 months with chemotherapy alone (HR for disease progression, disease recurrence or death = 0.63; 97.38% CI, 0.43-0.91).
Moreover, patients who received the nivolumab regimen had pathologic complete response rates of 24% (95% CI, 18-31) vs. 2.2% (95% CI, 0.6-5.6) with chemotherapy alone (OR = 13.94; 99% CI, 3.49-55.75).
“Patients who experienced a pathologic complete response did very well, with a more than 80% reduction in the risk for relapse compared with those not experiencing a pathologic complete response,” Forde said.
Researchers additionally observed a trend toward improved OS with nivolumab plus chemotherapy (HR = 0.57; 99.67% CI, 0.3-1.07) in the first interim preliminary analysis of OS, although they noted data remain immature.
A slightly higher proportion of patients in the chemotherapy-alone group vs. the combination group experienced grade 3 or grade 4 treatment-related adverse events (36.9% vs. 33.5%). Among all randomly assigned patients, 83.2% in the nivolumab combination group and 75.4% of those in the chemotherapy-alone group went on to receive surgery.
“The addition of nivolumab to chemotherapy in the preoperative setting did not impair surgery, and there was no increase in toxicity from treatment,” Forde told Healio. “In fact, it appeared that patients who received the neoadjuvant combination had shorter surgeries, lower rates of pneumonectomy, less blood loss and more minimally invasive surgeries than those who received chemotherapy alone.”
Girard said the results “represent the first demonstration of clear and significant benefits with neoadjuvant immunotherapy-based treatment over chemotherapy alone for these patients, initially seen with increased pathologic complete response and now with improved event-free survival and a positive trend in overall survival.”
Implications
The use of novel therapies prior to surgery is an exciting area, with four other randomized phase 3 trials exploring neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy, Forde said.
“CheckMate 816 is currently the only phase 3 trial that looked at preoperative chemoimmunotherapy without requiring further adjuvant therapy,” he said. “There are several earlier phase trials exploring novel combinations of neoadjuvant therapies, notably the NeoCOAST trial. These novel studies have the potential to offer insights into development of new therapies for both early- and late-stage cancer. Similarly, the use of pathologic response as a surrogate for longer term efficacy outcomes, highlighted by the CheckMate 816 trial, has the potential to dramatically speed up the timeline for development of new therapies for surgical lung cancer.”
Results of CheckMate 816 are expected to be practice-changing, as evidenced by the FDA approval of neoadjuvant nivolumab plus chemotherapy in March, according Christine M. Lovly, MD, PhD, associate professor of medicine in the division of hematology-oncology and associate professor of cancer research at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center.
“Although challenges remain, broad implementation of neoadjuvant therapy is expected to herald a new era for lung cancer, coupling innovative treatments supported by a strong biologic rationale with timely assessment of antitumor responses in order to deliver on the promise of a decreased incidence of lung cancer-associated mortality among patients with early-stage disease,” Lovly wrote in an editorial accompanying the published study.
References:
Forde PM, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2202170.
Forde PM, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1716078.
Girard N, et al. Abstract CT012. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans.
Lovly CM. N Engl J Med. 2022;doi:10.1056/NEJMe2203330.
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Girard N, et al. Abstract CT012. Presented at American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans.
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