Perioperative Nivolumab Plus Chemo Improves pCR, Survival in Stage III NSCLC

Neoadjuvant treatment with nivolumab (Opdivo) plus platinum-based chemotherapy followed by adjuvant nivolumab increased pathological complete response (pCR) rates and prolonged survival compared with neoadjuvant chemotherapy alone in patients with resectable stage IIIA/B non–small cell lung cancer (NSCLC), according to data from the phase 2 NADIM II trial (NCT03838159) published in The New England Journal of Medicine.

Data from the open-label, randomized, trial demonstrated that 37% (95% CI, 24%-51%) of patients in the neoadjuvant nivolumab plus chemotherapy arm (n = 57) experienced a pCR vs 7% (95% CI, 1%-23%) in the chemotherapy alone arm (n = 29; relative risk, 5.34; 95% CI, 1.34-21.23; P = .02), with benefit seen across all subgroups. The major pathological response rates were 53% (95% CI, 39%-66%) vs 14% (95% CI, 4%-32%), respectively (relative risk, 3.82; 95% CI, 1.49-9.79).

In the doublet arm, 93% of patients underwent surgery compared with 69% in the paclitaxel/carboplatin group (relative risk, 1.35; 95% CI, 1.05-1.74) and both arms experienced a median time from the end of neoadjuvant treatment to surgery of 7 weeks (range, 2-9).

Additionally, a benefit with the addition of nivolumab was seen regarding overall response rate (ORR), with 75% (95% CI, 62%-86%) of patients in combination arm experiencing a response compared with 48% (95% CI, 29%-67%) in the chemotherapy group (relative risk, 1.56; 95% CI, 1.04-2.34).

Further, at a median follow-up of 26.1 months (interquartile range [IQR], 17.4-30.9), 17 patients in each arm experienced disease progression. There were 12 deaths in the doublet arm, with 1 due to surgical complications, and 11 deaths in the chemotherapy arm at data cutoff.

“Distant recurrence occurred as the first event in 10 patients [18%] in the experimental group and in 8 patients [28%] in the control group. Locoregional recurrence occurred in 7 patients [12%] and 9 patients [31%], respectively. Relapses at the central nervous system occurred in 3 patients [5%] in the experimental group and in 4 patients [14%] in the control group,” lead study author Mariano Provencio, MD, PhD, the head of the Medical Oncology Department at Puerta de Hierro University Hospital and professor of the School of Medicine at Autonomous University of Madrid in Spain, and colleagues, wrote.

NADIM II was conducted at 21 hospitals in Spain and enrolled adult patients with histologically documented, previously untreated, surgically resectable stage IIIA/B NSCLC from June 2019 through February 2021. Patients also needed to have measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Those with nodal stage N3 disease or EGFR/ALK mutations were excluded.

Patients were randomly assigned in a 2:1 fashion. Prior to surgery, patients in the investigative arm received nivolumab at 360 mg, paclitaxel at 200 mg/m2, and carboplatin at an area under the curve 5 every 21 days for 3 cycles. Those with R0 resections were given adjuvant nivolumab at 480 mg once every 4 weeks for 6 months. In the control arm, Paclitaxel and carboplatin were given at the same doses prior to surgery, and there were 3 observation visits following surgery.

Within 3 to 4 weeks after day 21 of the third cycle of neoadjuvant treatment, investigators planned for surgery to be performed. Those who did not undergo surgery were considered to not have a response when assessing the primary end point of pCR or the secondary end point of major pathological response. Other secondary end points included progression-free survival (PFS) and overall survival (OS).

In the nivolumab plus chemotherapy arm and the chemotherapy alone arm, the median age was 65 years (IQR, 58-70) vs 63 years (IQR, 57-66), respectively, and a median tumor size of 50 mm (range, 15-155) vs 52 mm (15–166), respectively. Patients were mostly male (63% vs 55%), current smokers (53% vs 72%), and had a body mass index of greater than 25 (74% vs 66%). Adenocarcinomas (44% vs 38%) and squamous-cell carcinomas (37% vs 48%) were the most common histologies.

Patients receiving the nivolumab regimen compared with chemotherapy alone had TNM classifications of T1N2M0 (21% vs 14%), T2N2M0 (28% vs 24%), T3N1M0 (4% vs 3%), T3N2M0 (23% vs 17%), T4N0M0 (11% vs 31%), and T4N1M0 (14% vs 10%). Further, node stages included N0 (11% vs 31%), N1 (18% vs 14%), N2 (72% vs 55%), and N2 with multiple stations (39% vs 38%).

Additional data showed that at 24 months, PFS rates were 67.2% (95% CI, 55.8%-81.0%) in the nivolumab group vs 40.9% (95% CI, 26.2%-63.6%) in the chemotherapy group (HR, 0.47; 95% CI, 0.25-0.88). The estimated 24-month OS rates were 85.0% (95% CI, 75.9%-95.2%) vs 63.6% (95% CI, 47.8%-84.6%), respectively (HR, 0.43; 95% CI, 0.19-0.98).

Furthermore, study authors noted that nodal status was not associated with differences in survival outcomes, with nodal downstaging being reported in 72% vs 40% of patients in the experimental and control arms, respectively (relative risk, 1.79; 95% CI, 1.02-3.15). Patients achieved R0 resection at rates of 94% and 85%, respectively, with 66% of patients who were treated in the nivolumab arm (n = 50) receiving full adjuvant treatment with nivolumab; these patients had better survival outcomes than those who did not complete adjuvant treatment.

Safety findings showed that grade 3 or 4 adverse effects (AEs) occurred during neoadjuvant treatment in 19% of patients treated with nivolumab plus chemotherapy and 10% given chemotherapy alone, with febrile neutropenia (5%) and diarrhea (4%) being the most common grade 3/4 AEs in the investigational arm. Discontinuation of neoadjuvant treatment due to treatment-related AEs occurred in 4 patients and 1 patient in the experimental and control arms, respectively, and there were no delays in surgery due to AEs. Five percent of patients treated with adjuvant nivolumab experienced grade 3/4 AEs.

Reference

Provencio M, Nadal E, González-Larriba JL, et al. Perioperative nivolumab and chemotherapy in stage III non–small-cell lung cancer. N Engl J Med. Published online June 23, 2023. doi:10.1056/NEJMoa2215530