Roy S. Herbst, MD, PhD
Treatment with pembrolizumab (Keytruda) reduced the risk of death by 29% versus docetaxel in patients with >1% PD-L1 expressing non–small cell lung cancer (NSCLC), according to findings from the phase II/III KEYNOTE-010 study presented at the 2015 ESMO Asia Congress and published in The Lancet.
In the open-label study, median overall survival (OS) was 10.4 months with the FDA-approved dose of 2 mg/kg of pembrolizumab compared with 8.5 months with docetaxel in those with >1% PD-L1 expressing NSCLC (HR, 0.71; 95% CI, 0.58-0.88; P
= .0008). With a larger dose of pembrolizumab (10 mg/kg), median OS was 12.7 months, representing a 39% reduction in the risk of death versus docetaxel (HR, 0.61; 95% CI, 0.49-0.75; P
“This is an exciting time, and studies such as KEYNOTE-010 with Keytruda are paving the way to a better understanding of how to identify the right medicine for each patient,” senior author Roy S. Herbst, MD, the Ensign Professor of Medicine and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, said in a statement. “These study findings show Keytruda provided superior overall survival in patients with advanced lung cancer who had positive PD-L1 expression, and support its potential in the treatment of this disease.”
The FDA granted an accelerated approval to pembrolizumab for previously treated patients with NSCLC that had ≥50% PD-L1 expression on October 2, 2015. Findings from the KEYNOTE-010 study will be submitted to the FDA and European Medicines Agency within the coming months to potentially expand this approval, according to the developer of the drug, Merck.
In the KEYNOTE-010 study, 1034 patients with PD-L1 expression on at least 1% of tumor cells were randomized in a 1:1:1 ratio to receive docetaxel at 75 mg/m2
(n = 343) or pembrolizumab at 2 mg/kg (n = 345) or a larger experimental dose of 10 mg/kg (n = 346). All treatments were administered every 3 weeks.
All patients enrolled in the study had progression on at least 2 cycles of a prior platinum-containing chemotherapy, and had an ECOG PS between 0 and 1. The primary endpoints of the study were OS and progression-free survival (PFS) in the full population and those with PD-L1 expression on greater than 50% of tumor cells. PD-L1 was confirmed by immunohistochemistry using the companion diagnostic test PD-L1 IHC 22C3 PharmDx.
After a median follow-up of 13.1 months, the estimated 1-year OS rates were 43.2% and 52.3% for the 2 mg/kg and 10 mg/kg doses, respectively. The 1-year OS rate with docetaxel was 34.6%.
In those with ≥50% PD-L1 expression, the median OS with the 2 mg/kg dose of pembrolizumab was 14.9 months versus 8.2 months with docetaxel (HR, 0.54; 95% CI, 0.38-0.77; P
= .0002). In the 10 mg/kg arm, the median OS was 17.3 months, representing a 50% improvement over docetaxel (HR, 0.50; 95% CI, 0.36-0.70; P
Median PFS was not significantly improved with pembrolizumab in those with >1% PD-L1 expression, possibly due to pseudoprogression. In this group, median PFS was 3.9 months with the 2 mg/kg dose of pembrolizumab versus 4.0 months with docetaxel (HR, 0.88; 95% CI, 0.74-1.05; P
= .07). For the 10 mg/kg dose of pembrolizumab, median PFS was 4.0 months (HR vs docetaxel, 0.79; 95% CI, 0.66-0.94; P
= .004). The P
value for significance was set as <.001.
In those with ≥50% PD-L1 expression, media PFS was 5.0 and 5.2 months, with the 2 mg/kg and 10 mg/kg doses of pembrolizumab, respectively. With docetaxel, median PFS was 4.1 months. Overall, there was a statistically significant 41% reduction in the risk of progression or death for both doses of pembrolizumab over chemotherapy (P
Grade 3 to 5 treatment-related adverse events (AEs) were less frequently observed with pembrolizumab compared with docetaxel. In the 2 mg/kg arm, 13% of patients experienced a grade 3 to 5 AE versus 35% in the docetaxel arm. In the 10 mg/kg arm, 16% of patients had a grade 3/5 AE.
“This treatment provides real hope of long-lasting responses while avoiding the toxicities of typical chemotherapy in a broad population of lung cancer patients,” study coauthor Edward Garon, the study's senior author and a researcher at the UCLA Jonsson Comprehensive Cancer Center, said in a statement. “For most patients, this now offers data showing that immunotherapy leads to superior clinical outcomes with a side effect profile that is generally favorable to our traditional therapies.”
The most frequently observed grade 3 to 5 AEs with pembrolizumab were decreased appetite, fatigue, nausea, rash, diarrhea, asthenia, stomatitis, and anemia. Three treatment-related deaths occurred within each pembrolizumab arm. The most common immune-mediate AEs with pembrolizumab in the 2 mg/kg and 10 mg/kg arms, respectively, were hypothyroidism (8% and 8%), hyperthyroidism (4% and 6%), and pneumonitis (5% and 4%).
“Because lung cancer remains one of the most common and most challenging cancers to treat, understanding the role that Keytruda can play in helping patients was essential to our development program,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement. “In this study in patients with PD-L1 expression of 1% or greater, Keytruda demonstrably improved overall survival compared to chemotherapy in previously-treated patients with non–small cell lung cancer, including both squamous and non-squamous histologies.”
The accelerated approval for pembrolizumab in lung cancer was based on the phase I KEYNOTE-001 trial, in which the objective response rate with the drug was 41% among a subgroup of 61 patients with pretreated ≥50% PD-L1–expressing advanced NSCLC as determined by the 22C3 pharmDx diagnostic test. Response duration ranged from 2.1 to 9.1 months.
“I believe we should treat patients with the best available drugs as soon as possible. Now that we have learned which patients are most likely to benefit from the anti–PD-L1 strategy, we could begin moving this drug to the earlier setting stages,” said Herbst. “In this direction, I am eager to see the results of ongoing studies testing pembrolizumab in the first-line setting and as an adjuvant after surgery to hopefully reduce high rates of lung cancer recurrence.”
In addition to the NSCLC approval, pembrolizumab is also approved at a recommended dose of 2 mg/kg every 3 weeks for patients with unresectable or metastatic melanoma. The agent continues to be assessed across a variety of settings and various tumor types.
Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial [Published Online December 19, 2015]. Lancet. DOI:10.1016/S0140-6736(15)01281-7.