Roy Baynes, MD, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for first-line treatment with pembrolizumab (Keytruda) in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) in patients with metastatic squamous non–small cell lung cancer (NSCLC).1
The decision is based on findings from the phase III KEYNOTE-407 trial, in which patients were enrolled regardless of PD-L1 expression status. Results showed that there was a significant improvement in progression-free and overall survival (OS) for those who received the combination versus chemotherapy alone.2,3
If approved by the European Commission, this would mark the first immunotherapy/chemotherapy combination approval for patients with metastatic squamous NSCLC. The CHMP’s recommendation will now be reviewed by the European Commission for marketing authorization in the European Union. The decision on the approval is expected in the first quarter of 2019.
“We are pleased by today’s positive opinion from the CHMP, which brings us one step closer to potentially expanding our lung cancer indications in Europe to include first-line combination therapy for patients with metastatic squamous non-small cell lung cancer, regardless of PD-L1 expression,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, the developer of pembrolizumab. “This is important as squamous cell carcinoma continues to be an area of unmet need, and there was a significant overall survival benefit observed in the phase III KEYNOTE-407 trial.”
The recommendation is based on findings from the phase III KEYNOTE-407 trial, in which the pembrolizumab combination led to a 36% reduction in the risk of death versus chemotherapy alone in patients with metastatic squamous NSCLC. Results showed that the median 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
= .0017). This survival benefit was observed regardless of stratification factors, including PD-L1 expression level, choice of taxane, age, sex, and ECOG performance status.
In the randomized KEYNOTE-407 study, 559 treatment-naive patients 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 pembrolizumab monotherapy (200 mg every 3 weeks) or placebo for up to 31 cycles, for potentially up to 35 cycles.
After the initial 4 cycles, patients randomized to the placebo arm were permitted to cross over to receive pembrolizumab for the potential additional 31 cycles. The co-primary endpoints were OS and progression-free survival (PFS); a key secondary endpoint for the study was overall response rate (ORR).
A total 278 patients were treated in the pembrolizumab cohort and 281 patients received chemotherapy alone. In the pembrolizumab arm, 121 patients remained on therapy while 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).
Additionally, 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 or former smokers. Additionally, 60.8% received paclitaxel as their taxane, 6.1% had prior thoracic radiation, and 1.8% had prior (neo)adjuvant therapy.
Additional findings showed that PFS was also improved with the pembrolizumab/chemotherapy regimen. The median PFS was 6.4 months (95% CI, 6.2-8.3) with the PD-1 inhibitor versus 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.
In the pembrolizumab arm, the ORR was 58% versus 35% in the control arm. The median duration of response was 7.2 months (range, 2.4-12.4+) versus 4.9 months (range, 2.0-12.4+) in the pembrolizumab and placebo arms, respectively.
Moreover, 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.
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.
Regarding safety, grade 3/5 all-cause 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.
The FDA approved first-line pembrolizumab for use in combination with carboplatin and either paclitaxel or nab-paclitaxel for the treatment of patients with metastatic squamous NSCLC in October 2018.
- European Medicines Agency Adopts Positive Opinion for Merck’s KEYTRUDA® (pembrolizumab) in Combination with Chemotherapy for First-Line Treatment of Adults with Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC). Merck. Published February 3, 2019. https://bit.ly/2WyEIvQ. Accessed February 3, 2019.
- 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).
- Paz-Ares LG, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Eng J Med. 2018;379(21):2040-2051. doi: 10.1056/NEJMoa1810865.