The early-stage NSCLC comes with challenges and limited treatment options. OPDIVO + chemotherapy is approved in the US and several other countries as a neoadjuvant therapy for adult patients with resectable NSCLC (tumors > 4 cm or node-positive) and in the EU as a neoadjuvant therapy for patients with resectable NSCLC at high risk of recurrence and with tumor PD-L1 expression > 1%. 

CheckMate-816 is a Phase III randomized, open-label, multicenter trial evaluating nivolumab with chemotherapy compared to chemotherapy alone as neoadjuvant treatment in patients with resectable stage IB to IIIA non-small cell lung cancer, regardless of PD-L1 expression. For the primary analysis, 358 patients were randomized to receive either nivolumab 360 mg plus histology-based platinum doublet chemotherapy every three weeks for three cycles, or platinum doublet chemotherapy every three weeks for three cycles, followed by surgery. The CheckMate 816 trial met both of its primary endpoints, with neoadjuvant nivolumab + chemotherapy demonstrating statistically significant and clinically meaningful improvements in EFS and PCR vs chemo in patients with resectable NSCLC.

In the concurrently randomized nivolumab + ipilimumab and chemotherapy arms, baseline characteristics were generally balanced between treatment arms. According to the data presented at the ESMO 2023 conference, at a median follow-up of 49.2 months as of data cut off October 2022, both EFS and OS appeared to favor nivolumab + ipilimumab vs. chemotherapy.  Median EFS was 54.8 months vs. 20.9 months with nivolumab + ipilimumab vs. chemotherapy. Median OS was not reached in either treatment arm. Definitive surgery occurred for 74% and 76% of patients in the nivolumab + ipilimumab and chemotherapy arms, respectively. A high versus low baseline 4-gene inflammatory score was associated with improved EFS and pCR with nivolumab + ipilimumab. Grade 3–4 treatment-related adverse events (AEs) and grade 3–4 surgery-related AEs were reported in 14% vs. 36% and 15% vs. 14% of patients in the nivolumab + ipilimumab and chemotherapy arms, respectively.

KOL insights

“Neoadjuvant Opdivo (nivolumab) with Chemotherapy Provides Benefits for Patients with Resectable Non-Small Cell Lung Cancer Across PD-L1 Expression Levels with Three-Year Follow Up in CheckMate -816 Trial” -Medical Oncology Chair, University Hospital, Universidad Autónoma de Madrid, Spain

Conclusion

The exploratory analysis of CheckMate 816 suggests that neoadjuvant treatment with nivolumab + ipilimumab holds potential clinical benefits for patients with resectable NSCLC. Notably, it yielded higher rates of pathologic complete response (PCR) and major pathologic response (MPR) compared to chemotherapy, along with favorable trends in event-free survival (EFS) and overall survival (OS) after one year. 

Furthermore, the study indicates that a high baseline tumor inflammation, as assessed by a 4-gene inflammatory signature, may enhance the EFS and PCR outcomes with neoadjuvant nivolumab + ipilimumab. Importantly, nivolumab + ipilimumab maintained a manageable safety profile and a comparable rate of definitive surgery as chemotherapy. However, it is worth noting that nivolumab + chemotherapy remains the established standard neoadjuvant treatment for eligible patients with resectable NSCLC.

While OPDIVO made significant strides by gaining approval in March 2022 as the sole neoadjuvant player for early-stage NSCLC, its dominance was short-lived. In October 2023, KEYTRUDA emerged as the first PD-1 inhibitor to secure approval for both pre-and post-surgical treatment in resectable NSCLC, raising questions about OPDIVO's market impact. AstraZeneca's positive EFS results with IMFINZI in the perioperative context from the AEGEAN trial, while promising, are too early for regulatory support. Meanwhile, Roche's TECENTRIQ has encountered delays in its IMpower-030 trial, with results anticipated in 2024.

NSCLC accounts for up to 85% of lung cancer. DelveInsight estimates that the total NSCLC incident population in the 7MM will reach nearly 600,000 in 2032. Estimates show that the highest incident population of NSCLC is in the United States followed by Japan, Germany, and the UK. PD-L1 expression accounted for up to 50% of the NSCLC cases in the United States.

Note: The therapeutics segment is experiencing significant NSCLC clinical trial activity, which is further expected to drive Non-Small Cell Lung Caner market growth in the coming years.