Opdivo continues to demonstrate improved overall survival in lung cancer.
Pretreated patients with either nonsquamous or squamous non-small cell lung cancer showed overall survival improvements with Opdivo in the phase 3 CheckMate trials.
In the CheckMate-057 trial, the two-year OS rate in patients with nonsquamous NSCLC was 29 percent with Opdivo versus 16 percent with docetaxel. In the CheckMate-017 study, patients with squamous NSCLC who received Opdivo had a two-year OS rate of 23 percent (29/135) compared with 8 percent in the docetaxel group. In both trials, Opdivo 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, chief of Thoracic Oncology at Fox Chase Cancer Center, said in an interview with CURE. “As far as two-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 Opdivo.”
In the two-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 percent reduction in the risk of death at two years for those with the highest PD-L1 levels.
Based on the initial data from the CheckMate-057 and -017 studies, Opdivo 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.
The open-label CheckMate-057 trial randomized 582 patients with advanced nonsquamous NSCLC after the failure of platinum-based doublet chemotherapy to Opdivo at three mg/kg IV every two weeks (292 patients) or docetaxel at 75 mg/m2 intravenously every three weeks (290 patients). The treatments were administered until disease progression or unacceptable toxicity. Patients received a median of six and four doses in the Opdivo and docetaxel arms, respectively.
Patients had an ECOG performance status of zero or one. The median patient age was 61 years in the Opdivo arm and 64 years in the docetaxel cohort. Prior maintenance with Avastin (bevacizumab), Alimta (pemetrexed), or Tarceva (erlotinib) was allowed, as was TKI therapy for known EGFR mutations or ALK translocation. Forty-percent and 38 percent of patients in the Opdivo and docetaxel arms, respectively, had received prior maintenance therapy. In the Opdivo arm, 15 percent of patients were EGFR-positive and 4 percent were ALK-positive, with comparable rates of 13 percent and 3 percent, 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 Opdivo arm in an open-label extension of the study.
Six percent (16 patients) of patients in the docetaxel arm crossed over to receive Opdivo.
Fifty-five percent (25/45) of the patients initially randomized to docetaxel who were alive at two years received an anti—PD-L1 or anti–CTLA-4 agent through crossover or a subsequent line of treatment.
The previously reported one-year OS rates were 50.5 percent versus 39.0 percent, with Opdivo versus docetaxel, respectively. The median OS at two years was 12.2 months with Opdivo versus 9.5 months with docetaxel.
The two-year PFS rate was 12 percent with Opdivo versus 1 percent with docetaxel. The median PFS was 2.3 months versus 4.3 months, respectively.
The CheckMate-57 researchers measured PD-L1 levels in pretreatment tumor biopsies with the Dako automated IHC assay. At the two-year analysis, higher PD-L1 expression continued to be associated with improved survival outcomes among the 78 percent (455 patients) of patients for whom PD-L1 status was detectable.
Among patients with PD-L1 expression on 1 or more percent of tumor cells, the two-year OS rate was 37 percent versus 17 percent with Opdivo versus docetaxel. At PD-L1 levels at least 5 percent, the two-year OS rates were 44 percent versus 14 percent, respectively, and at PD-L1 levels greater than or equal to 10 percent, the rates were 45 percent versus 13 percent, respectively. Two-year OS rates were similar between the Opdivo and docetaxel arms among patients who did not express PD-L1: 25 percent versus 18 percent.
Consistent with the one-year follow-up, the incidence of all-grade and grade 3/4 adverse events (AEs) was lower with Opdivo compared with docetaxel. The specific overall AE rates were also similar at two years compared with the one-year analysis.
The all-grade AE rate at two years was 71 percent with Opdivo versus 88 percent with docetaxel, with grade 3/4 AE rates of 11 percent versus 54 percent, respectively. The most common all-grade AEs with docetaxel versus Opdivo were neutropenia (31 vs less than 1 percent), fatigue (29 percent vs 17 percent), alopecia (25 percent vs less than 1 percent), diarrhea (23 percent vs 9 percent) and anemia (20 percent vs 2 percent).
Six patients in the Opdivo arm and 15 patients in the chemotherapy arm discontinued treatment due to AEs. There was one treatment-related death with Opdivo (encephalitis) and one with docetaxel (grade 4 febrile neutropenia).
The open-label CheckMate-017 trial randomized 272 previously treated patients with advanced or metastatic squamous cell NSCLC to Opdivo at three mg/kg IV every two weeks (135 patients) or docetaxel at 75 mg/m2 IV (137 patients) every three weeks. In the docetaxel arm, 4 percent (six patients) of patients crossed over to receive Opdivo.
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 (16 patients) of patients in the docetaxel arm crossed over to receive Opdivo.
The previously reported one-year OS rates were 42 percent and 24 percent, with Opdivo and docetaxel, respectively. The median OS at two years was 9.2 months with Opdivo versus six months with docetaxel. Unlike CheckMate-057, PD-L1 status was not linked with efficacy outcomes in CheckMate-017. Regardless of tumor PD-L1 levels, OS HRs favored Opdivo.
The two-year PFS rate was 16 percent with Opdivo and was not calculable for the docetaxel arm. The median PFS was 3.5 months and 2.8 months, respectively.
The incidence of all-grade and grade 3/4 AEs at two years was similar to the one-year rates, and was once again lower with Opdivo versus docetaxel.
The all-grade AE rate at two years was 61 percent with Opdivo versus 87 percent with docetaxel, with grade 3/4 AE rates of 8 percent versus 56 percent, respectively. The most common all-grade AEs with docetaxel versus Opdivo were neutropenia (33 vs 1 percent), fatigue (33 percent vs 16 percent), alopecia (22 percent vs 0), anemia (22 percent vs 2 percent) and diarrhea (20 percent vs 8 percent).
Six patients in the Opdivo arm and 10 patients in the chemotherapy arm discontinued treatment due to AEs. There were no treatment-related deaths with Opdivo and three 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 with CURE. “The cytokine data does not necessarily indicate which patients are going to benefit from Opdivo; 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’t have as much of the cytokine expression. This requires further research and we’re hoping we can test it in a more prospective manner.”