FDA Grants Frontline Pembrolizumab Regimen Priority Review for Squamous NSCLC

Roy Baynes, MD, PhD

The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) for first-line pembrolizumab (Keytruda) for use in combination with carboplatin/paclitaxel or nab-paclitaxel (Abraxane) for the treatment of patients with metastatic squamous non—small cell lung cancer (NSCLC), regardless of PD-L1 expression.

The sBLA is based on results from the phase III KEYNOTE-407 trial, in which combining pembrolizumab with chemotherapy reduced the risk of death by 36% compared with chemotherapy alone in patients with metastatic squamous NSCLC. The median overall survival (OS) was 15.9 months (95% CI, 13.2 — not evaluable) with pembrolizumab versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0008). The OS benefit was observed regardless of PD-L1 expression level, choice of taxane, age, sex, and ECOG performance status.

Progression-free survival (PFS) was also improved with the addition of pembrolizumab. The median PFS was 6.4 months (95% CI, 6.2-8.3) with the PD-1 inhibitor compared with 4.8 months (95% CI, 4.3-5.7) with chemotherapy alone (HR, 0.56; 95% CI, 0.45-0.70; P <.0001). While the PFS benefit was also observed across all PD-L1 expression levels, there was a correlation between an increase in PD-L1 level and a greater magnitude of benefit.

The objective response rate (ORR) in the pembrolizumab arm was 57.9%, comprising a complete response (CR) rate of 1.4% and a partial response (PR) rate of 56.5%. In the control arm, the ORR was 38.4%, comprising a CR rate of 2.1% and a PR rate of 36.3%. The duration of response was 7.7 months (range, 1.1+ to 14.7+) versus 4.8 months (1.3+ to 15.8+) in the pembrolizumab versus placebo arms, respectively.

In the pembrolizumab cohort, 28.1% of patients had stable disease, 6.1% had progressive disease, and 2.2% of patients were not evaluable for response. The corresponding rates in the chemotherapy-alone group were 37.0%, 13.9%, and 2.5%, respectively.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make its final decision on the sBLA by October 30, 2018.

“Keytruda has already been established as an important treatment option for non-small cell lung cancer in the first-line setting, and with our broad development program in lung cancer, we are committed to improving survival for as many patients as we can,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, the developer of pembrolizumab, said in a statement.

“We are pleased that our application for squamous cell carcinoma — a historically challenging-to-treat disease—is under priority review with the FDA,” added Baynes.

After the initial 4 cycles, patients randomized to the placebo arm were allowed to cross over to receive pembrolizumab for the potential additional 31 cycles. The coprimary endpoints were OS and PFS. A key secondary endpoint for the study was ORR.

Two-hundred seventy-eight patients were treated in the pembrolizumab cohort and 281 patients received treatment in the chemotherapy-alone arm. In the pembrolizumab arm, 121 patients remained on treatment and 157 had discontinued. The primary reasons for discontinuing were progressive disease (n = 99) and adverse events (AEs; n = 48). In the chemotherapy-alone arm, 72 patients remained on treatment, with 208 having discontinued, primarily due to progression (n = 166) and AEs (n = 25).

Patient characteristics were well balanced at baseline between the 2 arms. In the pembrolizumab arm, the median age was 65.0 years (range, 29-87), 79.1% of patients were men, 73.7% had an ECOG performance status of 1, 7.2% had stable brain metastases, and 92.1% were current/former smokers. Additionally, 60.8% received paclitaxel as their taxane, 6.1% had prior thoracic radiation, and 1.8% had prior (neo)adjuvant therapy.

PD-L1 status was measured by tumor proportion score (TPS). In the pembrolizumab arm, 34.2%, 37.1% and 26.1% had a PD-L1 TPS status of <1%, 1%-49%, and ≥50%, respectively. The corresponding rates in the placebo arm were 35.2%, 37.0%, and 26.0%, respectively.

The HR for OS was 0.61, 0.57, and 0.64 favoring the pembrolizumab arm in the TPS <1%, <1%-49%, and ≥50% subgroups, respectively. Across the same 3 subgroups, the HR for PFS favoring the pembrolizumab arm was 0.68, 0.56, and 0.37, respectively.

The median treatment duration was 6.3 months in the pembrolizumab arm compared with 4.7 months in the placebo arm. Grade 3/5 all-causes AEs occurred in 69.8% versus 68.2% of the 2 arms, respectively. Treatment-related AEs (TRAEs) led to discontinuation in 23.4% of the experimental arm versus 11.8% of the control arm. Grade 3/5 immune-mediated AEs and infusion reactions occurred in 10.8% versus 3.2% of the 2 arms respectively. Overall, TRAEs led to death in 3.6% versus 2.1% of the 2 arms, respectively.

Pembrolizumab currently has 2 FDA approvals in the frontline NSCLC setting. In October 2016, the FDA approved single-agent pembrolizumab for the frontline treatment of patients with metastatic NSCLC whose tumors have ≥50% PD-L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations. In May 2017, the FDA granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous NSCLC, regardless of PD-L1 expression.

Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36 (suppl; abstr 105).

In the phase III KEYNOTE-407 trial (NCT02775435), 559 treatment-naive patients with metastatic squamous NSCLC received carboplatin (AUC 6) and paclitaxel (200 mg/m²) every 3 weeks or weekly nab-paclitaxel (100 mg/m²), plus pembrolizumab (200 mg every 3 weeks) or placebo for 4 cycles (each 3 weeks), followed by single-agent pembrolizumab (200 mg every 3 weeks) or placebo for up to 31 cycles, for a potential total of 35 cycles.