FDA Grants Priority Review for Full Approval of Frontline Pembrolizumab Combo in NSCLC

Roger M. Perlmutter, MD, PhD

The FDA has granted a priority review to a supplemental biologics license application (sBLA) for frontline pembrolizumab (Keytruda) for use in combination with standard chemotherapy for patients with metastatic nonsquamous non—small cell lung cancer (NSCLC), according to Merck (MSD), the manufacturer of the PD-1 inhibitor.

UPDATE 8/20/2018: FDA Grants Full Approval to Pembrolizumab Plus Chemo for NSCLC >>>

The sBLA is based on the phase III KEYNOTE-189 trial, in which adding pembrolizumab to pemetrexed (Alimta) and either cisplatin or carboplatin in the first-line setting reduced the risk of death by over 50% in patients with NSCLC without EGFR or ALK mutations.^1,2

At a median follow-up of 10.5 months, the estimated 12-month overall survival (OS) rate was 69.2% (95% CI, 64.1-73.8) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1-56.2) in the control group (HR, 0.49; 95% CI, 0.38-0.64; P <.001).

The median OS was not reached in the pembrolizumab cohort, compared with 11.3 months (95% CI, 8.7-15.1) in the chemotherapy-alone arm. The OS benefit was observed, irrespective of PD-L1 status. The study also met the coprimary endpoint of progression-free survival (PFS), with a median PFS of 8.8 months (95% CI, 7.6-9.2) in the pembrolizumab group versus 4.9 months (95% CI, 4.7-5.5) in the control arm (HR, 0.52; 95% CI, 0.43 to 0.64; P <.001).

The study is a confirmatory trial to convert the accelerated approval of pembrolizumab in this setting to a full approval. The accelerated approval was based on cohort G in the KEYNOTE-021 trial, in which the 12-month PFS rate was 56% with pembrolizumab combined with pemetrexed and carboplatin compared with 34% with chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.84; P = .0038).³

“Keytruda is the first immunotherapy to significantly extend survival of patients with nonsquamous non—small cell lung cancer in combination with chemotherapy as a first-line treatment, including in patients whose tumors are either PD-L1 negative or are untested,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement. “With this sBLA acceptance by the FDA, we are pleased that data from KEYNOTE-189 is now under review by regulatory authorities in the United States, Europe, and Japan.”

In the experimental arm (n = 410), patients received pembrolizumab at a 200-mg fixed dose every 3 weeks plus 500 mg/m2 of pemetrexed plus either 75 mg/m² of cisplatin or carboplatin (AUC 5) on day 1 every 3 weeks for 4 cycles, followed by 200 mg of pembrolizumab plus 500 mg/m² of pemetrexed every 3 weeks. The regimen administered to the control group (n = 206) was identical, except that pembrolizumab was replaced with placebo.

Treatment was administered until disease progression, unacceptable toxicity, physician decision, or consent withdrawal. Patients in the control arm with disease progression were allowed to cross over to receive pembrolizumab. Beyond the primary OS and PFS endpoints, secondary endpoints included overall response rate (ORR) and duration of response.

Patient characteristics were well balanced between the 2 arms. The median age was 65.0 years in the pembrolizumab arm (range, 34.0-84.0), 62.0% of the patients were male, and all but 1 of the patients had an ECOG performance status of 0 or 1. Current/former smokers comprised 88.3% of the cohort and 96.1% of patients had adenocarcinoma.

Also in the pembrolizumab group, PD-L1 expression level as measured by tumor proportion score (% of tumor cells with membranous PD-L1 staining) was <1% in 31% of patients; ≥1% in 63.4%; 1% to 49% in 31.2% of patients; ≥50% in 32.2%; and not evaluable in 5.6%.

The pembrolizumab OS benefit was observed across PD-L1 subgroups, including the <1% expression group (12-month OS rate, 61.7% vs. 52.2%; HR, 0.59; 95% CI, 0.38-0.92); the 1% to 49% cohort (12-month OS rate, 71.5% vs. 50.9%; HR, 0.55; 95% CI, 0.34-0.90), and those with a score of 50% or greater (12-month OS rate, 73.0% vs. 48.1%; HR, 0.42; 95% CI, 0.26-0.68).

The ORR per blinded, independent central radiologic review was 47.6% (95% CI, 42.6-52.5) in the pembrolizumab arm and 18.9% (95% CI, 13.8-25.0) with chemotherapy alone (P <.001). The disease control rate was 84.6% versus 70.4%, and the median duration of response was 11.2 months versus 7.8 months in the pembrolizumab versus control arms, respectively.

The rate of discontinuation of all study drugs due to adverse events (AEs) was 13.8% in the pembrolizumab arm compared with 7.9% in the control arm. The discontinuation rate of pembrolizumab was 20.2% and placebo was 10.4%. Death related to AEs occurred in 6.7% versus 5.9% of the pembrolizumab versus control arms, respectively.

Diarrhea (30.9% vs 21.3%) and rash (20.2% vs 11.4%) were the only 2 AEs occurring in ≥10% of patients that occurred more commonly in the pembrolizumab versus the chemotherapy-alone arm. Grade ≥3 AEs occurring in at least 10% of patients in either arm were anemia (16.3% with pembrolizumab vs 15.3% in the control group) and neutropenia (15.8% vs 11.9%, respectively).

The rate of acute kidney injury was 5.2% in the pembrolizumab arm versus 0.5% in the chemotherapy-alone arm. Eight patients (2.0%) receiving the PD-1 inhibitor had grade ≥3 acute kidney injury.

Immune-mediated AEs occurred in 22.7% of the pembrolizumab group versus 11.9% of the control group, including grade ≥3 AEs in 8.9% versus 4.5%, respectively. Pneumonitis led to 3 deaths in the pembrolizumab cohort.

References

1. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. Presented at 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.
2. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer [published online April 16, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1801005.
3. Papadimitrakopoulou V, Gadgeel SM, Borghaei H, et al. First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G. J Clin Oncol. 2017;35 (suppl; abstr 9094).

The double-blind phase III KEYNOTE-189 study accrued 616 patients with advanced or metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Patients were not EGFR- or ALK-positive, and had not received systemic therapy for advanced disease. The trial randomization was 2:1 in favor of the pembrolizumab arm.