The immunotherapy Opdivo (nivolumab) has been shown to convey an overall survival (OS) benefit superior to that offered by the chemotherapy docetaxel in both nonsquamous and squamous nonâ€“small cell lung cancer (NSCLC).
The immunotherapy Opdivo (nivolumab) has been shown to convey an overall survival (OS) benefit superior to that offered by the chemotherapy docetaxel in both nonsquamous and squamous non—small cell lung cancer (NSCLC), according to results from two phase 3 trials. Opdivo, which inhibits the protein PD-1 — thus freeing up the immune system to fight cancer — was also shown to be less toxic than docetaxel.
The results were announced May 29 during the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering that brought nearly 30,000 health care experts to Chicago to learn about the latest advances in oncology.
In the phase 3 CheckMate-017 trial,1 patients experienced a 41 percent improvement in OS with Opdivo versus docetaxel in the squamous setting, and in the phase 3 CheckMate-057 trial,2 the OS benefit with Opdivo was 27 percent in patients with nonsquamous NSCLC. Both studies enrolled patients whose disease had progressed following platinum-based doublet chemotherapy.
Having a cancer that expressed the protein PD-L1 was not linked to survival in CheckMate-017; however, in CheckMate-057, stronger OS outcomes were observed in PD-L1—positive patients, including a 60 percent reduction in the risk of death for those with the highest PD-L1 levels.
Opdivo was approved in March by the U.S. Food and Drug Administration for the treatment of squamous NSCLC based on data from CheckMate-017. Bristol-Myers Squibb (BMS), the manufacturer of Opdivo, has applied for an additional indication in the nonsquamous setting based on the results of Checkmate-057.
The drug was approved in 2014 for the treatment of melanoma.
The open-label CheckMate-057 trial randomized 582 patients with advanced nonsquamous NSCLC, after disease progression on platinum-based doublet chemotherapy, to intravenous Opdivo at 3 mg/kg every two weeks (292 patients) or intravenous docetaxel at 75 mg/m2 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 0 or 1. The median patient age was 61 years in the Opdivo arm and 64 years in the docetaxel cohort. Prior maintenance with Avastin (bevacizumab), pemetrexed, or Tarceva (erlotinib) was allowed, as was tyrosine kinase inhibitor (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) based on RECIST version 1.1 response evaluation criteria, efficacy stratified 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.
The median OS was 12.2 months with Opdivo versus 9.4 months with docetaxel (hazard ratio (HR) = 0.73; 96% confidence interval (CI), 0.59-0.89; P = .00155), with a one-year OS of 50.5 percent versus 39.0 percent, respectively.
“Nivolumab is the first PD-1 inhibitor to significantly improve OS as compared to docetaxel in [NSCLC] patients with prior treatment and nonsquamous histology,” said lead author Luis Paz-Ares, of the Hospital Universitario Doce de Octubre in Madrid, Spain, in a press conference at the ASCO meeting.
ORR was 19 percent with the PD-1 inhibitor compared with 12 percent with chemotherapy (Odds Ratio = 1.72; 95% CI, 1.1-2.6; P = .0246). Complete and partial response rates were 1 percent and 18 percent in the Opdivo arm and <1 percent and 12 percent in the docetaxel group, respectively. The stable disease rate was 25 percent and 42 percent with PD-1 inhibition and chemotherapy, respectively.
Median time to response was 2.1 months with Opdivo versus 2.6 months with docetaxel. Median duration of response was 17.2 months versus 5.6 months in the Opdivo and control arms, respectively. Fifty-two percent of the Opdivo responses are still ongoing compared with 14 percent of the docetaxel responses.
Median PFS was comparable between the cohorts at 2.3 months in the Opdivo arm compared with 4.2 months in the docetaxel group (HR = 0.92; 95% CI, 0.77-1.11; P = .393). One-year PFS favored Opdivo at 18.5 percent versus 8.1 percent for the control arm.
The researchers measured PD-L1 levels in pretreatment tumor biopsies with the Dako automated immunohistochemistry assay. Higher PD-L1 expression was associated with improved survival outcomes among the 78 percent of patients for whom PD-L1 status was detectable. “PD-L1 emerged as a clear predictive factor for the benefit from nivolumab treatment,” said Paz-Ares.
In PD-L1—positive patients (defined as PD-L1 expression on ≥1 percent of tumor cells), median OS was improved by 41 percent among 123 individuals treated with Opdivo versus 123 patients who received docetaxel (median OS = 17.2 months versus 9.0 months; HR = 0.59).
The OS benefit continued to rise as PD-L1 levels increased. The reduction in the risk of death was 57 percent (median OS = 18.2 months) and 60 percent (median OS = 19.4 months) for patients expressing PD-L1 on ≥5 percent and ≥10 percent of their tumor cells, respectively.
The researchers did not observe a similar OS benefit among patients with low or undetectable PD-L1 levels. Median OS was 10.4, 9.7 and 9.9 months among patients with PD-L1 expression levels of <1 percent, <5 percent and <10 percent, respectively.
Opdivo was well tolerated and had a better safety profile than docetaxel. Among patients evaluable for safety, all-grade side effect rates were 69 percent versus 88 percent in the Opdivo versus docetaxel arms, respectively. The most common all-grade side effects with Opdivo versus docetaxel were fatigue (16 percent vs 29 percent), nausea (12 percent vs 26 percent), decreased appetite (11 percent vs 16 percent), weakness (10 percent vs 18 percent), and diarrhea (8 percent vs 23 percent).
Grade 3-5, or severe, side effects were reported in 10.5 percent of the Opdivo arm compared with 53.7 percent of the docetaxel cohort. The most common grade 3/4 side effects with Opdivo were fatigue, nausea and diarrhea, at 1 percent each. Twenty-seven percent of patients in the docetaxel arm had grade 3/4 neutropenia versus 0 in the Opdivo arm.
Toxicity-related discontinuations occurred in 4.9 percent of patients receiving Opdivo compared with 14.9 percent of those treated with chemotherapy. Systemic therapy was administered to 42.1 percent and 49.7 percent of patients who discontinued Opdivo and docetaxel, respectively. No treatment-related deaths occurred in the Opdivo group compared with one in the docetaxel arm.
“The CheckMate-057 results represent progress toward establishing a new standard of care that may replace docetaxel in PD-L1 expressers,” said Paz-Ares in a press release issued May 29 by BMS.
The open-label CheckMate-017 trial randomized 272 previously treated patients with advanced or metastatic squamous cell NSCLC to Opdivo at 3 mg/kg intravenously every two weeks (135 patients) or docetaxel at 75 mg/m2 intravenously every three weeks (137 patients).
The primary outcome measure of the trial was OS. Secondary endpoints included ORR (as per RECIST version 1.1 criteria), PFS, outcomes stratified by PD-L1 expression, and safety.
Median OS was 9.2 months with Opdivo versus 6.0 months with chemotherapy (HR = 0.59; 95% CI, 0.44-0.79; P = .00025), with a one-year OS of 42 percent versus 24 percent, respectively. Opdivo also improved median PFS by 38 percent versus docetaxel (3.5 vs 2.8 months; HR = 0.62; 95% CI, 0.47-0.81; P = .0004). One-year PFS was 21 percent versus 6 percent in the Opdivo and control arms, respectively.
ORR with Opdivo was 20 percent (27 patients) compared with 9 percent (12 patients) for chemotherapy (P = .0083). The median duration of response was 8.4 months in the docetaxel arm and had not yet been reached in patients receiving Opdivo.
Unlike in CheckMate-057, PD-L1 status was not linked with efficacy outcomes in CheckMate-017. Regardless of tumor PD-L1 levels, OS hazard ratios favored Opdivo. In PD-L1—positive patients (≥1 percent of tumor cells express PD-L1), median OS was improved by 31 percent (HR = 0.69) with Opdivo, versus a 42 percent benefit with the PD-1 inhibitor (HR = 0.58) in the PD-L1–negative group.
As in the CheckMate-057 results, Opdivo was less toxic than docetaxel. Grade 3/4 side effects were reported in 7 percent (9/131) of evaluable patients in the Opdivo arm versus 55 percent (71/129) of evaluable patients who received chemotherapy. There were no treatment-related deaths in the Opdivo cohort compared with three deaths linked to docetaxel.
In the BMS press release, Michael Giordano, senior vice president and head of development for oncology at the company, expressed his optimism about the progress of the Opdivo NSCLC program.
“The survival results from [CheckMate-057], as well as from CheckMate-017,” he said, “validate the Bristol-Myers Squibb development strategy for Opdivo to improve survival expectations for patients with lung cancer.”