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FDA Approves Pembrolizumab for Frontline PD-L1+ NSCLC

Jason M. Broderick @jasoncology
Published: Monday, Oct 24, 2016

“Keytruda improved survival, compared to traditional chemotherapy, in patients with non–small cell lung cancer whose tumors express high levels of PD-L1,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, the manufacturer of pembrolizumab, said in a statement. “The approval of Keytruda for the first-line treatment of metastatic non-small cell lung cancer has the potential to change the treatment landscape for these patients.”

Fewer treatment-related adverse events (AEs) were seen with the PD-1 inhibitor versus chemotherapy (73.4% vs 90%). Grade 3 to 5 AEs were significantly less common with pembrolizumab (26.6%) compared with chemotherapy (53.3%). Serious AEs were similar between the 2 arms for pembrolizumab and chemotherapy, respectively (21.4% vs 20.7%). AEs led to treatment discontinuation for 7.1% of patients in the pembrolizumab arm versus 10.7% of those receiving chemotherapy.

The most common treatment-related AEs of any severity for pembrolizumab were diarrhea (14.3%), fatigue (10.4%), and pyrexia (10.4%). With chemotherapy, the most common AEs of any-grade were anemia (44%), nausea (43.3%), and fatigue (28.7%). Immune-mediated AEs occurred in 29.2% of those treated with pembrolizumab versus 4.7% of those in the chemotherapy arm.

“It is exciting to have an expanded group of patients who are now eligible for this drug," Edward B. Garon, MD, director, Thoracic Oncology, Jonsson Comprehensive Cancer Center, UCLA, said in a statement. "What is particularly encouraging is that we are now able to select, based on features in the tumor, approximately a quarter of advanced lung cancer patients who can receive immunotherapy as their initial treatment. This will allow them to live longer while delaying, and in some cases potentially avoiding, the side effects of traditional chemotherapy.”

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 either 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 performance status between 0 and 1. The primary endpoints of the study were OS and 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.

The median OS was 10.4 months with the 2-mg/kg dose 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 = .001). With the 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 <.001).

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 = .001). 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 <.001).

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, 0.73-1.04; 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 5.2 months with both the 2-mg/kg and 10-mg/kg doses of pembrolizumab, and 4.1 months with docetaxel. Overall, there was a statistically significant 42% reduction in the risk of progression or death for both doses of pembrolizumab over chemotherapy (HR, 0.58; 95% CI, 0.43-0.77; P = .001).

Grade 3 to 5 treatment-related 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.

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%).

References:
  1. Reck M, Rodriguez-Abreu D, Robinson AG, et al. KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA8.
  2. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for  PD-L1–Positive Non–Small-Cell Lung Cancer [published online October 9, 2016]. N Engl J Med. DOI: 10.1056/NEJMoa1606774.
  3. 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. Lancet. 2016;387(10027):1540-1550.



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