Sustained Survival Shown in Updated Nivolumab Results in NSCLC

Hossein Borghaei, DO

Updated findings from the phase III CheckMate-057 and -017 trials showed sustained improvements in overall survival (OS) data of nivolumab (Opdivo) treatment in pretreated patients with nonsquamous or squamous non—small cell lung cancer (NSCLC). Two-year follow-up data was presented at the 2016 ASCO Annual Meeting.

In the CheckMate-057 trial, the 2-year OS rate in patients with nonsquamous NSCLC was 29% with nivolumab versus 16% with docetaxel. In the CheckMate-017 study, patients with squamous NSCLC who received nivolumab had a 2-year OS rate of 23% (29/135) compared with 8% in the docetaxel group. In both trials, nivolumab continued to have a more favorable safety profile than docetaxel.

“These results give us confirmation that the drug is active and that patients do truly benefit from immunotherapy,” lead study author Hossein Borghaei, DO, chief of Thoracic Oncology at Fox Chase Cancer Center, said in an interview withTargeted Oncology. “As far as 2-year survival data goes with a single agent in the second-line setting for a very difficult patient population and disease, the data are very exciting and very much confirmatory in favor of nivolumab.”

In the 2-year follow-up, PD-L1 status was still not linked to survival in CheckMate-017; however, in CheckMate-057, stronger OS outcomes were again observed in PD-L1—positive patients, including a 57% reduction in the risk of death at 2 years for those with the highest PD-L1 levels.

Based on the initial data from the CheckMate-057 and -017 studies, nivolumab was previously approved by the FDA for use in the treatment of patients with nonsquamous or squamous NSCLC who have progressed on platinum-based chemotherapy.

CheckMate-057

The open-label CheckMate-057 trial randomized 582 patients with advanced nonsquamous NSCLC after the failure of platinum-based doublet chemotherapy to nivolumab at 3 mg/kg IV every 2 weeks (n = 292) or docetaxel at 75 mg/m²intravenously every 3 weeks (n = 290). The treatments were administered until disease progression or unacceptable toxicity. Patients received a median of 6 and 4 doses in the nivolumab and docetaxel arms, respectively.  

Patients had an ECOG performance status of 0 or 1. The median patient age was 61 years in the nivolumab arm and 64 years in the docetaxel cohort. Prior maintenance with bevacizumab, pemetrexed, or erlotinib was allowed, as was TKI therapy for knownEGFRmutations or ALKtranslocation. Forty-percent and 38% of patients in the nivolumab and docetaxel arms, respectively, had received prior maintenance therapy. In the nivolumab arm, 15% of patients were EGFR-positive and 4% wereALK-positive, with comparable rates of 13% and 3%, respectively, in the docetaxel group.

OS was the primary endpoint, with secondary objectives focused on progression-free survival (PFS), objective response rate (ORR) per RECIST v1.1, efficacy by PD-L1 expression, and safety.

The study was stopped early after an independent monitoring panel determined the primary endpoint of improved OS had been reached. Eligible patients were allowed to continue treatment or cross over to the nivolumab arm in an open-label extension of the study.

Six percent (n = 16) of patients in the docetaxel arm crossed over to receive nivolumab.

Fifty-five percent (25/45) of the patients initially randomized to docetaxel who were alive at 2 years received an anti­—PD-L1 or anti­–CTLA-4 agent through crossover or a subsequent line of treatment.

The previously reported 1-year OS rates were 50.5% versus 39.0%, with nivolumab versus docetaxel, respectively. The median OS at 2 years was 12.2 months (95% CI, 9.7-15.1) with nivolumab versus 9.5 months (95% CI, 8.1-10.7) with docetaxel (HR, 0.75; 95% CI, 0.63-0.91).

The 2-year PFS rate was 12% with nivolumab versus 1% with docetaxel. The median PFS was 2.3 months (95% CI; 2.2-3.4) versus 4.3 months (95% CI, 3.4-4.9), respectively (HR, 0.89; 0.75-1.07).

The CheckMate-57 researchers measured PD-L1 levels in pretreatment tumor biopsies with the Dako automated IHC assay. At the 2-year analysis, higher PD-L1 expression continued to be associated with improved survival outcomes among the 78% (n = 455) of patients for whom PD-L1 status was detectable.

Among patients with PD-L1 expression on ≥1% of tumor cells, the 2-year OS rate was 37% versus 17% with nivolumab versus docetaxel, respectively (HR, 0.62; 95% CI, 0.47-0.83). At PD-L1 levels ≥5%, the 2-year OS rates were 44% versus 14%, respectively (HR, 0.48; 95% CI, 0.34-0.68), and at PD-L1 levels ≥10%, the rates were 45% versus 13%, respectively (HR, 0.43; 95% CI, 0.30-0.62). Two-year OS rates were similar between the nivolumab and docetaxel arms among patients who did not express PD-L1: 25% versus 18% (HR, 0.91; 95% CI, 0.67-1.22).

Consistent with the 1-year follow-up, the incidence of all-grade and grade 3/4 adverse events (AEs) was lower with nivolumab compared with docetaxel. The specific overall AE rates were also similar at 2 years compared with the 1-year analysis.

The all-grade AE rate at 2 years was 71% with nivolumab versus 88% with docetaxel, with grade 3/4 AE rates of 11% versus 54%, respectively. The most common all-grade AEs with docetaxel versus nivolumab were neutropenia (31 vs <1%), fatigue (29% vs 17%), alopecia (25% vs <1%), diarrhea (23% vs 9%), and anemia (20% vs 2%).

Six patients in the nivolumab arm and 15 patients in the chemotherapy arm discontinued treatment due to AEs. There was 1 treatment-related death with nivolumab (encephalitis) and 1 with docetaxel (grade 4 febrile neutropenia).

CheckMate-017

The open-label CheckMate-017 trial randomized 272 previously treated patients with advanced or metastatic squamous cell NSCLC to nivolumab at 3 mg/kg IV every 2 weeks (n = 135) or docetaxel at 75 mg/m²IV (n = 137) every 3 weeks. In the docetaxel arm, 4% (n = 6) of patients crossed over to receive nivolumab.

The primary outcome measure of the trial was OS. Secondary endpoints included ORR (RECIST v1.1), PFS, outcomes by PD-L1 expression, and safety. Six percent (n = 16) of patients in the docetaxel arm crossed over to receive nivolumab.

The previously reported 1-year OS rates were 42% and 24%, with nivolumab and docetaxel, respectively. The median OS at 2 years was 9.2 months (95% CI, 7.3-12.6) with nivolumab versus 6 months (95% CI, 5.1-7.3) with docetaxel (HR, 0.62; 95% CI, 0.47-0.80). Unlike CheckMate-057, PD-L1 status was not linked with efficacy outcomes in CheckMate-017. Regardless of tumor PD-L1 levels, OS HRs favored nivolumab.

The 2-year PFS rate was 16% with nivolumab and was not calculable for the docetaxel arm. The median PFS was 3.5 months (95% CI, 2.1-5.1) and 2.8 months (95% CI, 2.1-3.5), respectively (HR, 0.63; 95% CI, 0.48-0.83).

The incidence of all-grade and grade 3/4 AEs at 2 years was similar to the 1-year rates, and was once again lower with nivolumab versus docetaxel.

The all-grade AE rate at 2 years was 61% with nivolumab versus 87% with docetaxel, with grade 3/4 AE rates of 8% versus 56%, respectively. The most common all-grade AEs with docetaxel versus nivolumab were neutropenia (33 vs 1%), fatigue (33% vs 16%), alopecia (22% vs 0), anemia (22% vs 2%), and diarrhea (20% vs 8%).

Six patients in the nivolumab arm and 10 patients in the chemotherapy arm discontinued treatment due to AEs. There were no treatment-related deaths with nivolumab and 3 with docetaxel (interstitial lung disease, pulmonary hemorrhage, and sepsis).

In their poster at ASCO, Borghaei et al also reported findings from an exploratory analysis of SQ- and non-SQ-cytoscores derived from baseline serum cytokine levels of patients from both the CheckMate-057 and -017 studies.

Borghaei discussed the outcomes of the analysis in his interview withOncLive. &ldquo;The cytokine data does not necessarily indicate which patients are going to benefit from nivolumab; however, the data does point to a patient population that seemed to do better in general if they have a high expression of the cytokines versus the ones who don&rsquo;t have as much of the cytokine expression. This requires further research and we&rsquo;re hoping we can test it in a more prospective manner.&rdquo;

Borghaei H, Brahmer JR, Horn L, et al. Nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses.J Clin Oncol34, 2016 (suppl; abstr 9025).