Neoadjuvant nivolumab plus chemo: New SoC in resectable NSCLC

In patients with resectable non-small-cell lung cancer (NSCLC), neoadjuvant nivolumab in combination with platinum-based chemotherapy significantly improves event-free survival (EFS) and shows a trend towards better overall survival (OS) vs chemotherapy alone, without impeding the feasibility of surgery or increasing adverse events (AEs), according to results of the phase III CheckMate 816 trial.

On the basis of these results, the US FDA has approved nivolumab in combination with platinum doublet chemotherapy Q3W for three cycles for treatment of adult patients with resectable NSCLC (tumours ≥4 cm or node-positive) in the neoadjuvant setting.

“Results of CheckMate 816 support neoadjuvant nivolumab in combination with chemotherapy as a new standard of care [SoC] for patients with resectable NSCLC,” said investigator Professor Nicolas Girard of Institut du Thorax Curie-Montsouris, Paris, France, who presented the results at the American Association for Cancer Research (AACR) Annual Meeting 2022.

Describing the results as “another quantum leap in lung cancer therapy”, invited discussant Professor David Carbone of Ohio State University Comprehensive Cancer Center, Columbus, Ohio, US, said combining immuno-oncology (IO) therapy with surgery represents a new SoC that will likely improve survival in early-stage NSCLC.

 

EFS benefit with nivolumab plus chemo

The open-label CheckMate 816 trial included 358 patients with newly diagnosed, resectable, stage IB (≥4 cm) to stage IIIA NSCLC with no known sensitizing EGFR mutations or ALK alterations. The patients were randomized 1:1 to receive nivolumab 360 mg plus platinum doublet chemotherapy (n=179; median age, 64 years; male, 71.5 percent; from Asia, 47.5 percent; stage IIIA disease, 63.1 percent; PD-L1–positive; 49.7 percent; PD-L1 ≥50 percent, 21.2 percent), or platinum doublet chemotherapy alone (n=179; median age, 65 years; male, 70.9 percent; from Asia, 51.4 percent; stage IIIA disease, 64.2 percent; PD-L1–positive; 49.7 percent; PD-L1 ≥50 percent, 23.5 percent), Q3W for three cycles, followed by surgery within 6 weeks after treatment. [Girard N, et al, AACR 2022, abstract CT012; N Engl J Med 2022;doi:10.1056/NEJMoa2202170]

Previously reported results showed significantly improved pathological complete response (pCR; one of the primary endpoints) with nivolumab plus chemotherapy vs chemotherapy alone (24.0 percent vs 2.2 percent; odds ratio [OR], 13.94; p<0.001). [Forde PM, et al, AACR 2021, abstract 5218] Results of the first prespecified interim analysis of EFS (another primary endpoint) and OS (a key secondary endpoint) were presented at AACR 2022.

“After a median follow-up of 29.5 months, EFS was significantly improved – by nearly 1 year – with nivolumab. Median EFS was 31.6 months in the nivolumab plus chemotherapy group vs 20.8 months in the chemotherapy alone group [hazard ratio (HR), 0.63; 97.38 percent confidence interval (CI), 0.43 to 0.91; p=0.005],” reported Girard. “EFS rates were 76.1 percent vs 63.4 percent at 1 year, and 63.8 percent vs 45.3 percent at 2 years, respectively.”

“Consistent improvement in EFS was observed with nivolumab across most subgroups,” he added.

Notably, the magnitude of EFS benefit with nivolumab was greater in patients with stage IIIA disease (HR, 0.54; 95 percent CI, 0.37 to 0.80) than those with stage IB–II disease (HR, 0.87; 95 percent CI, 0.48 to 1.56), and in patients with nonsquamous (HR, 0.50; 95 percent CI, 0.32 to 0.79) compared with squamous (HR, 0.77; 95 percent CI, 0.49 to 1.22) histology.

The EFS benefit with nivolumab was also greater in patients with PD-L1 expression ≥1 percent (HR, 0.41; 95 percent CI, 0.24 to 0.70) compared with <1 percent (HR, 0.85; 95 percent CI, 0.54 to 1.32), and in patients with PD-L1 ≥50 percent (HR, 0.24; 95 percent CI, 0.10 to 0.61) compared with 1–49 percent (HR, 0.58; 95 percent CI, 0.30 to 1.12).

 

pCR as early indicator of therapeutic benefit

In an exploratory analysis, EFS was longer in patients who achieved pCR than in those without pCR.

In the nivolumab plus chemotherapy group, median EFS was not reached in patients who achieved pCR compared with 26.6 months in patients without pCR (HR, 0.13; 95 percent CI, 0.05 to 0.37). In the chemotherapy group, corresponding median EFS was not reached vs 18.4 months (HR not computed).

Among patients without pCR, a numerical improvement in EFS was observed with nivolumab plus chemotherapy vs chemotherapy alone (HR, 0.84; 95 percent CI, 0.61 to 1.17).

“These findings suggest pCR as a surrogate for long-term outcomes and an early indicator of therapeutic benefit with nivolumab plus chemotherapy,” said Girard.

 

Trend for OS improvement

At the time of analysis, median OS was not reached in both treatment groups, while 2-year OS rate was 82.7 percent in the nivolumab plus chemotherapy group vs 70.6 percent in the chemotherapy alone group (HR, 0.57; 99.67 percent CI, 0.30 to 1.07; p=0.008). “The difference in 2-year OS rate is clinically meaningful,” commented Girard.

“An OS benefit is likely, given the convincing separation of curves seen in the trial,” suggested Carbone. 

 

Safety profile and surgery

“The safety profile of neoadjuvant nivolumab plus chemotherapy was consistent with previous reports and did not impact the feasibility of surgery vs chemotherapy alone,” reported Girard.

Grade 3/4 treatment-related AEs (TRAEs) occurred in 33.5 percent vs 36.9 percent of patients in the nivolumab plus chemotherapy vs chemotherapy alone group, leading to treatment discontinuation in 5.7 percent vs 3.4 percent of patients.

Definitive surgery was performed in 83.2 percent of patients in the nivolumab plus chemotherapy group vs 75.4 percent of those in the chemotherapy alone group, while R0 resection was performed in 83.2 percent vs 77.8 percent of patients. Grade 3/4 surgery-related AEs occurred in 11.4 percent vs 14.8 percent of patients. Grade 5 surgery-related AEs were reported in two patients in the nivolumab plus chemotherapy group and were deemed to be unrelated to study drugs.

“About 20 percent of patients did not undergo definitive surgery or R0 resection, which is on the high side,” commented Carbone. “We need to be careful in selecting patients who are good surgical candidates in neoadjuvant therapy studies. Biomarkers are needed to select patients who need therapy and those who will benefit from IO or novel combinations.”

“Neoadjuvant IO has multiple theoretical advantages over adjuvant IO,” Carbone added. “While perioperative tyrosine kinase inhibitors may provide a transient improvement in disease-free survival [DFS] vs chemotherapy, no DFS or OS benefit was seen after 5–6 years of follow-up.” [Wu YL, et al, ASCO 2020, abstract 9005]