Frontline Nivolumab Combo Succeeds in Squamous NSCLC, But Misses OS Endpoint in Nonsquamous Histology

Luis Paz-Ares, MD, PhD

The first-line combination of nivolumab (Opdivo) and platinum-based chemotherapy improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared with chemotherapy in patients with squamous non—small cell lung cancer (NSCLC), but did not improve survival in those with nonsquamous disease, according to findings from part 2 of the final analysis of the phase III CheckMate-227 trial that was reported at the 2019 ESMO Immuno-Oncology Congress.

In the cohort of patients with squamous NSCLC who received nivolumab and chemotherapy, the median OS was 18.3 months compared with 12.0 months in those who received chemotherapy alone (HR, 0.69; 95% CI, 0.50-0.97). The 12-month OS rates were 66% versus 48% and the 18-month OS rates were 50% versus 35%, respectively.

However, with a minimum follow-up of 19.5 months, the OS improvement with the combination did not reach statistical significance compared with chemotherapy alone in those with nonsquamous NSCLC; the median OS in this subgroup was 18.8 months versus 15.6 months with the respective treatments (HR, 0.86; 95% CI, 0.69-1.08; P = .1859). The 12- and 18-month OS rates were 67% versus 59% and 51% versus 45%, respectively.

“Although CheckMate-227 part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy compared with chemotherapy alone in the cohort of patients with nonsquamous NSCLC, numerical improvements were seen in PFS,” said lead study author Luiz Paz-Ares, MD, PhD, chair of the Medical Oncology Department at Hospital Doce de Octubre, and associate professor at the Universidad Complutense in Madrid, Spain. “In addition, OS was significantly improved with nivolumab plus chemotherapy in patients with squamous NSCLC and in all randomized patients.”

The multipart, open-label, phase III CheckMate-227 study (NCT02477826) enrolled 755 patients with chemotherapy-naïve stage IV or recurrent NSCLC who had an ECOG performance status of 0 or 1. Patients also had no sensitizing EGFR/ALK alterations.

Following 1:1 randomization, patients received nivolumab at 360 mg for up to 2 years plus histology-based chemotherapy for up to 4 cycles (n = 377) or the same chemotherapy regimen alone (n = 378). Patients were stratified by histology (squamous vs nonsquamous), sex, and PD-L1 expression status (<1% vs ≥1%). Pemetrexed maintenance was available to patients with nonsquamous disease.

The primary endpoint was OS with nivolumab plus chemotherapy compared with chemotherapy in patients with nonsquamous NSCLC, and a secondary hierarchical endpoint was OS in all randomized patients.

Regarding the entire study population, the median OS was 18.3 months in the nivolumab/chemotherapy arm and 14.7 months with chemotherapy alone (HR, 0.81; 95% CI, 0.67-0.97). The 12-month OS rates were 67% versus 56%, and the 18-month OS rates were 51% versus 42%, respectively.

The combination improved objective response rates (ORR) over chemotherapy alone in patients with nonsquamous NSCLC. In the nonsquamous subgroup, the ORRs were 48.1% versus 29.3% with nivolumab/chemotherapy and chemotherapy alone, respectively. Complete responses (CRs) were achieved in 3.7% of patients and partial responses (PRs) in 44.4% of patients receiving the combination. With chemotherapy, the CR rate was 1.8% and the PR rate was 27.5%. The median duration of response (DOR) by blinded independent central review (BICR) was 11.1 months with the combination compared with 8.6 months in the chemotherapy arm.

“Both PFS and the ORR favored nivolumab plus chemotherapy over chemotherapy across all three cohorts, including patients with nonsquamous NSCLC,” Paz-Ares noted.

The median PFS by BICR in patients with nonsquamous NSCLC was 8.7 months versus 5.8 months (HR, 0.67; 95% CI, 0.55-0.82), and the 12-month PFS rates were 40% versus 26% with nivolumab/chemotherapy versus chemotherapy, respectively. The 18-month PFS rates were 26% versus 13%, respectively.

Patients with squamous histology had a median PFS of 7.1 months with nivolumab plus chemotherapy versus 4.4 months with chemotherapy alone (HR, 0.51; 95% CI, 0.37-0.70), and the 12-month PFS rates were 32% versus 9%. The 18-month PFS rates were 22% versus 8%, respectively.

In all randomized patients, the median PFS was 8.4 months with nivolumab plus chemotherapy versus 5.5 months with chemotherapy (HR, 0.62; 95% CI, 0.52-0.73), and the 12-month PFS rates were 37% versus 21%. abstract. The 18-month PFS rates were 25% versus 11%, respectively. Also overall, the ORR was 51.5% with nivolumab/chemotherapy versus 30.2% with chemotherapy.

Regarding safety, grade 3/4 treatment-related adverse events (TRAEs) occurred in 45% and 35% of all nivolumab/chemotherapy— and chemotherapy alone–treated patients, respectively.

TRAEs specific to patients receiving nivolumab plus chemotherapy were mostly grade 1/2 and included skin (20%), hepatic (14%), gastrointestinal (11%), renal (10%), endocrine (10%), pulmonary (5%), and hypersensitivity/infusion reaction (4%). Grade 3/4 skin and hepatic TRAEs each occurred in 2% of patients; 1% each had grade 3/4 renal, gastrointestinal, and pulmonary TRAEs, and 0.5% of patients experienced grade 3/4 endocrine and hypersensitivity/infusion reaction TRAEs.

In the nonsquamous NSCLC cohort, 12% of patients remain on combination treatment versus 6% in the chemotherapy arm; in the respective arms, 52% versus 63% of patients experienced disease progression. Treatment was discontinued due to toxicity by 14% of patients receiving the combination versus 9% on chemotherapy. Subsequent treatment may have influenced the OS outcome in the nonsquamous cohort; Paz-Ares pointed out that subsequent therapy was administered to 36% versus 48% of patients on nivolumab/chemotherapy versus chemotherapy, respectively. Of these, 4% versus 34% of patients received subsequent systemic immunotherapy, respectively.

Solange Peters, MD, PhD, a professor at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, questioned choosing OS in the nonsquamous NSCLC cohort as the primary endpoint of part 2 of this trial.

“In part 1 of the trial, we saw the opposite results and the nonsquamous NSCLC cohort was larger, so we thought it would provide more robust data,” Paz-Ares replied.

Paz-Ares L, Ciuleanu TE, Yu X et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (aNSCLC): CheckMate 227 - part 2 final analysis. Presented at: 2019 ESMO Immuno-Oncology Congress; December 10-14, 2019; Geneva; Switzerland. Abstract LBA3.