Ben Creelan, MD
Following the recent FDA approval of nivolumab (Opdivo) for non-squamous non–small cell lung cancer (NSCLC), the PD-1 inhibitor is now approved across all NSCLC histologies and is poised to make a significant impact in the treatment of lung cancer.
The nonsquamous approval was based on data from the phase III CheckMate-057 trial, in which second-line nivolumab reduced the risk of death by 27% versus docetaxel. This included a 60% risk reduction among patients with the highest levels of PD-L1 expression.
A diagnostic for PD-L1, the IHC 28-8 pharmDx test, was approved along with the expanded indication, to help guide treatment decisions for patients with both histologies of NSCLC. However, the test is a "complementary," not a "companion," diagnostic, meaning its use is not mandated prior to administering nivolumab.
Nivolumab was previously approved in March 2015 for patients with squamous cell NSCLC who have progressed on or after platinum-based chemotherapy. This initial approval was based on the phase III Check-Mate-017 trial, in which nivolumab improved overall survival (OS) by 3.2 months versus docetaxel in previously treated patients with advanced or metastatic squamous cell NSCLC. The estimated 1-year survival rate was 41% and the median OS was 8.2 months.
The PD-1 inhibitor pembrolizumab (Keytruda) was also recently approved by the FDA for patients with pretreated advanced non–small cell lung cancer (NSCLC) across all histologies. Unlike nivolumab, pembrolizumab was only approved for patients with PD-L1–positive tumors, as determined by the PD-L1 IHC 22C3 pharmDx companion diagnostic, which was simultaneously approved with the drug.
For additional insight on the impact of the expanded approval of nivolumab in NSCLC and how the drug compares with pembrolizumab, OncLive
spoke with the Ben Creelan, MD, a clinical investigator on both the Check-Mate-057 and -017 trials, and a medical oncologist at the Moffitt Cancer Center.
OncLive: What impact will the expanded approval of nivolumab have on clinical practice?
: I think it will have a broad and sustained impact in community practice nationwide. It is the first trial to show an OS benefit of immunotherapy compared to chemotherapy for this nonsquamous NSCLC population.
Can you discuss the trial that lead to the approval of nivolumab in nonsquamous NSCLC? What questions still remain regarding the use of the drug in this patient population?
The CheckMate-057 design was quite simple, almost identical to the CheckMate-017 trial for squamous NSCLC. It randomized almost 600 patients to our gold standard of docetaxel versus nivolumab. Patients were required to have progressive or refractory measurable cancer after prior platinum-doublet chemotherapy. All patients were required to have tumor tissue for PD-L1 determination by immunohistochemistry using Dako’s antibody, 28-8 epitope, with automated scoring, but this was a secondary endpoint. Since docetaxel was adopted as our standard in 1999, no monotherapy has beat docetaxel for OS benefit. Therefore, this trial was not simply an incremental addition to our arsenal of drugs, but a big leap forward. All our trials should aim for these kind of gains.
Like the 017 trial, this trial hit it out of the park. At a planned interim analysis after 86% of events, it crossed the boundary for superiority and the trial was reported early. The HR was 0.73 with P
= .0015, which equates to almost a 30% higher probability of surviving with nivolumab during the course of the study. The response rate was 19% compared to 12% for docetaxel, with an odds ratio of 1.7, P
= .02, which equates to a 1.7 times higher odds of achieving a partial or complete response with nivolumab compared with docetaxel. Also, the median duration of response was roughly 17 months, which was over twice as long as the chemotherapy, which was 5.6 months. Over half of these nivolumab responses were ongoing at the time of analysis.
It is true the survival difference was greatest in the higher PD-L1 expressing tumors. However, even in the <1% PD-L1 expression subgroup, the survival curve was essentially identical compared to docetaxel. So nivolumab, may still offer less toxicity than docetaxel for these patients. Most patients who have progressed after platinum chemotherapy want to try something new. Also, the <1% PD-L1 expression subgroup had a 10% overall response rate, which is still better than docetaxel.