Nivolumab Plus Chemotherapy Shows Significant Improvements in Resectable NSCLC

Neoadjuvant nivolumab in combination with platinum-doublet chemotherapy significantly improved pathological complete response (pCR) rates and had a greater depth of pathological response compared with chemotherapy alone in patients with resectable non–small cell lung cancer (NSCLC), according to data presented during the 2021 virtual ASCO Annual Meeting.¹

Results from the phase 3 CheckMate 816 study (NCT02998528) showed that nivolumab plus chemotherapy elicited a pCR of 23% in patients with stage IIIA disease (n = 113), compared with 1% in the chemotherapy arm (n = 115). Patients with stage 1B NSCLC who received nivolumab plus chemotherapy (n = 10) had a pCR of 40% vs 0% in the chemotherapy group (n = 8). Patients with stage IIA disease registered pCRs of 23% and 3% in the nivolumab plus chemotherapy (n = 30) and chemotherapy (n = 32) arms, respectively. Patients with stage IIB NSCLC experienced a pCR of 24% in the nivolumab plus chemotherapy cohort (n = 25) vs 9% for those treated with chemotherapy (n = 23).

“In CheckMate 816, the primary endpoint of pCR was met,” said Jonathan Spicer, MD, PhD lead study author and assistant professor of surgery at McGill University Health Center in Montreal, Canada. “Patients had improved response rates and greater depth of pathological response, regardless of disease stage.”

Additionally, patients with stage IB or IIB disease treated with nivolumab plus chemotherapy (n = 52) had a median residual viable tumor of 28% vs 79% in those treated with chemotherapy alone (n = 49); median residual viable tumor was reported for patients with stage IIIA NSCLC at 8% in the nivolumab plus chemotherapy arm (n = 89) and 70% in chemotherapy treated patients (n = 77).

Investigators randomized a total of 358 patients in a 1:1 ratio to receive either nivolumab plus chemotherapy (n = 179) or chemotherapy alone (n = 179). Patients had newly diagnosed, resectable stage IB-IIIA NSCLC, an ECOG performance status of 0 to 1, and no known sensitizing EGFR mutations or ALK alterations. Patients were stratified by disease stage, PD-L1 expression, and sex.

Three cycles of therapy were planned in the neoadjuvant window. Nivolumab was administered at a dose of 360 mg. Surgery was performed within 6 weeks following the last dose of neoadjuvant treatment. After surgery, patients had the option to receive adjuvant chemotherapy or radiotherapy per local standard of care and no adjuvant immunotherapy was permitted.

The primary end points of the study were pCR by blinded independent committee review (BICR) and event free survival (EFS) by BICR. Secondary end points included major pathological response (MPR) by BICR, overall survival (OS), and time to death or distant metastases. The trial also examined exploratory endpoints including objective response rate (ORR) by BICR, the feasibility of surgery, and surgery-related adverse effects (AE).

Baseline characteristics were well balanced between the 2 arms. The median age in the nivolumab plus chemotherapy arm was 64 (range, 41-82) vs 65 (range, 34-84) in the chemotherapy arm. Patients in the nivolumab plus chemotherapy group were 28% female compared with 29% of patients in the chemotherapy cohort. The majority of patients in both groups had stage IIIA disease; 63% and 64%, respectively.

Neoadjuvant treatment was administered to 98% of patients in both arms; 94% of patients in the nivolumab plus chemotherapy arm completed the prescribed 3 cycles compared with 85% in the chemotherapy arm. Surgery was cancelled for 16% of patients in the nivolumab plus chemotherapy group vs 21% in the chemotherapy group. Reasons for cancellation included patients declining surgery, unresectable disease, and poor lung function. Cancellation of surgery due to neoadjuvant therapy toxicity occurred in 1% of patients in both arms.

Patients treated with nivolumab plus chemotherapy proceeded to surgery 83% of the time compared with 75% of those treated with chemotherapy alone. The median duration of operation was 184 minutes in the nivolumab plus chemotherapy group vs 217 minutes in the chemotherapy arm. Of note, 8% more surgical cancellations were reported for patients with stage IIIA disease in the chemotherapy arm than in the nivolumab combination arm (25% vs 17%, respectively).

No clinically meaningful differences were observed in time to surgery; median time to definitive surgery was 5.3 weeks (range, 4.6-6.0) in the nivolumab plus chemotherapy arm and 5.0 weeks (range, 4.6-5.9) in the chemotherapy cohort. Surgical procedures were delayed or occurred beyond the 6-week protocol window for 21% of patients in the nivolumab plus chemotherapy arm vs 18% for those in the chemotherapy group.

Thoracotomy was the most frequent surgical approach in both arms. Minimally invasive procedures were favored more frequently for patients with stage IIIA disease treated with nivolumab plus chemotherapy (30%; N = 94) vs chemotherapy alone (19%; N = 83). Lobectomy was the most common type of surgery across all stage subgroups and was more frequent in the nivolumab plus chemotherapy arm (n = 149) than in the chemotherapy arm (n = 135) at 77% vs 61%, respectively. Spicer noted that patients with stage IIIA disease treated with chemotherapy alone went on to pneumonectomy at a higher rate than those who received the nivolumab combination (30% vs 17%, respectively).

Regarding safety, nivolumab was tolerable and the addition to chemotherapy did not increase postsurgical complications. The median length of hospital stay was 10 days (range, 7.0-14.0) in both arms. Finally, the addition of nivolumab did not increase surgery-related AEs. Any grade surgery–related AEs occurred at a rate of 41% in the nivolumab plus chemotherapy arm vs 42% in the chemotherapy arm. Grade 3/4 AEs occurred in 11% of patients treated with nivolumab plus chemotherapy and 15% of those treated with chemotherapy alone.

The most common any-grade AEs 90-days after surgery for nivolumab plus chemotherapy and chemotherapy alone were anemia (12% and 12%, respectively), pain (8% and 16%), and wound complications (8% and 6%). Grade 3/4 postsurgical anemia occurred in 2% of each arm.

“The safety and surgical outcome data reported thus far from CheckMate 816, along with significant improvement in pCR, support nivolumab in combination with chemotherapy as an attractive neoadjuvant option for patients with resectable NSCLC,” Spicer concluded.

_Reference

_{Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8503. doi:10.1200/JCO.2021.39.15_suppl.8503}