Results from the Phase 3 CheckMate-816 trial showed that neoadjuvant treatment with three cycles of nivolumab (Opdivo®; Bristol Myers Squibb), a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response, in combination with chemotherapy significantly improved event-free survival (EFS), a primary endpoint, compared to chemotherapy alone in patients with resectable non-small cell lung cancer (NSCLC).[1]

Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer, representing up to 84% of diagnoses. Non-metastatic cases account for the majority of NSCLC diagnoses (approximately 60%, with up to half of these being resectable), and the proportion is expected to grow over time with enhanced screening programs. While many non-metastatic NSCLC patients are cured by surgery, 30% to 55% develop recurrence and die of their disease despite resection, contributing to a need for treatment options administered before surgery (neoadjuvant) and/or after surgery (adjuvant) to improve long-term outcomes.

“The standard treatment for resectable lung cancer is surgery to remove the tumor. Despite this, many patients experience recurrence of their lung cancer and when this happens, it is usually incurable,” explained Patrick Forde, MBBCh, associate professor at Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University.

“Platinum-based chemotherapy given either before (neoadjuvant) or after (adjuvant) surgery improves survival of patients by only 5% at five years.

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CheckMate-816 is is a Phase 3 randomized, open-label, multi-center clinical study designed to evaluate nivolumab in combination with chemotherapy compared to chemotherapy alone as neoadjuvant treatment in patients with resectable stage IB to IIIA non-small cell lung cancer (per the 7th edition American Joint Committee on Cancer/Union for International Cancer Control staging criteria), regardless of PD-L1 expression.

In the study adults with stage 1b-3a resectable NSCLC and no known activating alterations in the EGFR or ALK genes were randomly assigned to receive either nivolumab 360 mg with histology-based platinum doublet chemotherapy every three weeks for three cycles (179 patients), or platinum doublet chemotherapy every three weeks for three cycles (179 patients), followed by surgery.

pCR was defined as no residual viable tumor when the resected lung specimen and the sampled lymph nodes were examined after surgery. The primary endpoints of the trial are event-free survival and pathologic complete response. Secondary endpoints include overall survival, major pathologic response, and time to death or distant metastases.

Study results
With a minimum follow-up of 21.0 months, nivolumab with chemotherapy reduced the risk of disease recurrence, progression, or death by 37% (Hazard Ratio [HR] 0.63; 97.38% Confidence Interval [CI]: 0.43 to 0.91; p=0.0052) across randomized patients when administered before surgery.

In patients receiving the combination, median EFS was 31.6 months, compared to 20.8 months for patients treated with chemotherapy alone.

Additionally, while the data are still immature and the analysis did not reach statistical significance, favorable early overall survival (OS) results were observed with nivolumab in combination with chemotherapy (HR 0.57; 99.67% CI: 0.30 to 1.07). At two years, 83% of patients treated with neoadjuvant nivolumab and chemotherapy were alive, compared to 71% with chemotherapy alone. OS will continue to be followed for upcoming analyses.

CheckMate-816 represents the first Phase 3 study with an immunotherapy-based combination to show a significant improvement in EFS, as well as in the other primary endpoint of pathologic complete response (pCR), in the neoadjuvant setting of NSCLC. The EFS data were being presented for the first time during the Neoadjuvant and Perioperative Immunotherapy Clinical Trials Plenary Session (Abstract #CT012) at the American Association for Cancer Research (AACR) Annual Meeting 2022 on Monday, April 11, 2022, from 10:15 a.m. to 12:15 p.m. CT. The data was simultaneously published in The New England Journal of Medicine.[1]

“pCR was assessed in both lung and lymph nodes by pathology central review and the pathologist was blinded as to which arm of the study the specimen came from. Therefore, this provides a unique and more stringent assessment of pCR, as compared to other early trials evaluating immunotherapy in the neoadjuvant setting,” Forde noted.

“For the first time in a phase 3 trial, we see the potential for an anti-PD-1 immunotherapy to improve outcomes in earlier-stage NSCLC. We are highly encouraged by the marked improvement in pCR, the overall good tolerability, and the absence of impact on surgery feasibility when nivolumab is added to neoadjuvant chemotherapy,” Forde said.

“Data accumulated to date from several retrospective studies show a clear trend that patients who achieve a pCR with neoadjuvant chemotherapy live longer than those who do not,” he noted.

“While resectable non-small cell lung cancer may be curable in some cases, patients face a high probability of recurrence after surgery, so we need effective systemic treatment options to interrupt this trajectory,” Nicolas Girard, M.D., Ph.D., CheckMate -816 investigator and professor and head of the Thorax Institute Curie-Montsouris added.

“The results from CheckMate -816 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. As we work toward the ultimate goal of curing these patients, these data suggest the potential for better long-term outcomes with nivolumab in combination with chemotherapy,” Girard added.

In the study, the safety profile of the neoadjuvant nivolumab-chemotherapy combination was consistent with previous reports, and no new safety signals were observed at the time of the EFS analysis. Rates of Grade 3-4 treatment-related adverse events were similar with the nivolumab-chemotherapy combination versus chemotherapy alone (34% vs. 37%), as were all causality surgery-related Grade 3-4 adverse events (11% with the combination vs. 15% with chemotherapy). With nivolumab in combination with chemotherapy, 83% of patients went on to receive surgery, compared to 75% with chemotherapy.

“Surgery is still the cornerstone of a cure for patients with non-small cell lung cancer,” noted Jonathan Spicer M.D., Ph.D., CheckMate -816 investigator and associate professor of surgery at McGill University and an attending surgeon in the division of thoracic and upper gastrointestinal surgery, Montreal General Hospital, McGill University Health Centre.

“The fact that neoadjuvant nivolumab with chemotherapy enabled shorter, less invasive, and less extensive operations without increasing complications or adverse events is of tremendous importance to thoracic surgeons and their patients,” Spicer said.

These findings, combined with the improved survival outcomes, have the potential to completely change the way surgeons and oncologists collaborate in treating patients with resectable non-small cell lung cancer,” he concluded.

Ushering a new era of treatment
“Immunotherapy has ushered in a new era of treatment in metastatic cancers, changing survival expectations for patients with lung cancer and many other tumor types. More recently, our understanding of the biology of the immune system and cancer has led us to explore the role of immunotherapy in the neoadjuvant, adjuvant, and peri-operative settings,” noted Abderrahim Oukessou, M.D., vice president, thoracic cancers development lead, Bristol Myers Squibb.

“The data from CheckMate-816, including the positive early overall survival results, reinforce the importance of researching immunotherapy in earlier stages of the disease, and we look forward to continuing to see this science translate into tangible benefits for patients and their families,” Oukessou said.

Based on the EFS and pCR results from CheckMate-816, the U.S. Food and Drug Administration approved nivolumab in combination with platinum-doublet chemotherapy every three weeks for three cycles for adult patients with resectable (tumors ≥4 cm or node-positive) NSCLC in the neoadjuvant setting in March 2022, and further applications are under review with health authorities globally.

In non-metastatic NSCLC, Bristol Myers Squibb and collaborators are exploring the use of immunotherapy in the neoadjuvant, adjuvant, and peri-operative settings, as well as in association with chemoradiation. The scientific rationale for using immunotherapy in the neoadjuvant setting is twofold: the presence of a tumor during immunotherapy treatment may enable a stronger immune response, potentially making the treatment more effective against a primary tumor, while offering an early opportunity to target covert micro-metastasis.

To date, nivolumabbased treatments have shown improved efficacy in the neoadjuvant or adjuvant treatment of four tumor types: lung cancer, bladder cancer, esophageal/gastroesophageal junction cancer, and melanoma.

Clinical trials
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) – NCT02998528

Highlights of prescription information
Nivolumab (Opdivo®; Bristol Myers Squibb)[Prescribing Information]

[1] Girard N, Spicer J, Provencio M, Lu S, Broderick S, Awad MM, Mitsudomi T, Kerr K, et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment for resectable (IB-IIIA) non-small cell lung cancer (NSCLC): Event-free survival (EFS) results from the phase 3 CheckMate 816 trial. In: Proceedings of the 113th Annual Meeting of the American Association for Cancer Research; 2021 April 8-13; New Orleans LA. Philadelphia (PA): AACR; 2022. Abstract CT012

Featured image: AACR 2016 Annual Meeting. Photo courtesy: ® 2016 – 2022 AACR. Used with permission.

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