Pembrolizumab With or Without Chemo Has Increased Efficacy With Increasing PD-L1 Expression in HNSCC

Pembrolizumab (Keytruda) with or without chemotherapy resulted in a numerically longer overall survival (OS) benefit vs cetuximab (Erbitux) plus chemotherapy in patients with head and neck squamous cell carcinoma (HNSCC) and a PD-L1 combined positive score (CPS) between 1 and 19, but did not improve survival in the subset with a PD-L1 CPS of less than 1, according to data from a subgroup analysis of the phase 3 KEYNOTE-048 trial (NCT02358031).¹

Results, which were published in the Journal of Clinical Oncology, showed that in the PD-L1 CPS 1-19 subset, pembrolizumab monotherapy (n = 124) resulted in a median OS of 10.8 months (95% CI, 9.0-12.6) compared with 10.1 months (95% CI, 8.7-12.1) with cetuximab plus chemotherapy (n = 133; HR, 0.86; 95% CI, 0.66-1.12; P = .12827). The addition of pembrolizumab to chemotherapy (n = 116) produced a median OS of 12.7 months (95% CI, 9.4-15.3) vs 9.9 months (95% CI, 8.6-11.5) with cetuximab plus chemotherapy (n = 125) in this subgroup (HR, 0.71; 95% CI, 0.54-0.94; P = .00726).

Conversely, in patients with a PD-L1 CPS of less than 1, pembrolizumab monotherapy (n = 44) resulted in a median OS of 7.9 months (95% CI, 4.7-13.6) vs 11.3 months (95% CI, 9.1-15.9) with cetuximab plus chemotherapy (n = 45; HR, 1.51; 95% CI, 0.96-2.37; P = .96241). In this subgroup, pembrolizumab plus chemotherapy (n = 39) resulted in a median OS of 11.3 months vs 10.7 months with cetuximab/chemotherapy (n = 43; HR, 1.21; 95% CI, 0.76-1.94; P = .78932).

“Although these results should be interpreted cautiously given the post-hoc nature of the analysis and the small PD-L1 CPS <1 subgroup, they remain consistent with the FDA approval of pembrolizumab as monotherapy for first-line treatment of patients with relapsed or metastatic HNSCC with PD-L1 CPS ≥ 1 and of pembrolizumab plus chemotherapy for first-line treatment irrespective of PD-L1 status,” lead study Barbara Burtness, MD, professor of medicine (Medical Oncology) at Yale School of Medicine, and colleagues, wrote. “These results suggest that PD-L1 expression may be useful in informing treatment decisions for some subgroups; however, additional biomarkers are needed to further select patients who will benefit from PD-1 inhibition.”

PD-L1 is commonly expressed in HNSCC, although some tumors have low or undetectable levels. Results from the phase 1b KEYNOTE-012 trial (NCT01848834) demonstrated that pembrolizumab alone produced a higher overall response rate (21% vs 6%; P = .023) and a longer median OS (10 months vs 5 months; P = .008) in those with as PD-L1 CPS of 1 or higher vs a CPS of less than 1.²

Prior data from KEYNOTE-048 showed that pembrolizumab alone significantly improved OS compared with cetuximab plus chemotherapy in the subsets of patients with a PD-L1 CPS of 20 or higher and a CPS of 1 or higher, and noninferior OS in the total population. Pembrolizumab plus chemotherapy also improved OS vs the control arm in patients with a PD-L1 CPS of 1 or higher, 20 or higher, and all patients.

Based on these results, in June 2019, the FDA approved pembrolizumab alone or pembrolizumab plus chemotherapy for the frontline treatment of patients with HNSCC.³

Patients enrolled to KEYNOTE-048 had recurrent and/or metastatic squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx who had a good ECOG performance status with tissue available for PD-L1 testing, and who had not received prior chemotherapy or systemic therapy for their recurrent or metastatic disease. Patients were stratified by PD-L1 expression, p16 status, and performance status.

Patients were randomized 1:1:1 to receive 200 mg of pembrolizumab alone every 3 weeks for 2 years (n = 301), pembrolizumab plus platinum-based chemotherapy and 5-fluorouracil (5-FU; n = 281), or the EXTREME regimen comprised of cetuximab at a loading dose of 400 mg/m² followed by a weekly dose of 250 mg/m², plus cisplatin at 100 mg/m² or carboplatin at area under the curve 5 given every 3 weeks, plus 5-FU at a daily dose of 1000 mg/m² on days 1 through 4 of each 3-week cycle for a maximum of 6 cycles (n = 300).

Of the 128 participants with a PD-L1 CPS of less than 1, 44 were randomly assigned to receive single-agent pembrolizumab, 39 to the pembrolizumab/chemotherapy arm, and 45 to the cetuximab/chemotherapy arm. Of the 373 participants with a PD-L1 CPS between 1 and 19, 124 received pembrolizumab monotherapy, 116 were given pembrolizumab/chemotherapy, and 133 received cetuximab/chemotherapy.

This post-hoc analysis of KEYNOTE-048 aimed to further characterize the effect of PD-L1 expression in patients with a PD-L1 CPS between 1 and 19 and a PD-L1 CPS of less than 1.

Specifically, the analysis examined OS, progression-free survival (PFS), and ORR.

Baseline characteristics for patients with a PD-L1 CPS less than 1 or a PD-L1 CPS between 1 and 19 were comparable between the pembrolizumab-monotherapy arm and the cetuximab/chemotherapy arm. There was a lower proportion of patients with locoregionally recurrent-only disease in the pembrolizumab arms within the subgroups of CPS less than 1 and CPS between 1 and 19 (36.4% vs 51.1%; 46.0% vs 57.9%). Additionally, there was a higher proportion of patients with a primary tumor location of the larynx in the pembrolizumab arms of the subgroup of patients with a PD-L1 CPS of less than 1 (38.6% vs 17.8%).

Characteristics were also comparable between the pembrolizumab/chemotherapy and cetuximab/chemotherapy arms, except that there was a higher proportion of participants with a primary tumor location of the hypopharynx (28.2% vs 14.0%) and a lower proportion with a primary tumor location of the oral cavity (12.8% v 25.6%) in the pembrolizumab/chemotherapy arm of the subgroup with a PD-L1 CPS of less than 1.

When comparing the subgroups of patients with a CPS between 1 and 19 and a CPS greater than or equal to 20, the only difference in baseline characteristics was a higher proportion of current or former smokers in the pembrolizumab-alone and cetuximab/chemotherapy arms of the subgroup with a PD-L1 CPS of less than 1.

In the subgroup with a PD-L1 CPS of less than 1, those in the pembrolizumab-alone arm experienced a 12-month OS rate of 39% vs 49% in the cetuximab/chemotherapy arm. Moreover, the median PFS was 2.1 months with pembrolizumab monotherapy vs 6.2 months with cetuximab plus chemotherapy (HR, 4.31; 95% CI, 2.63-7.08; P = 1.00000). Pembrolizumab alone elicited an ORR of 4.5% (95% CI, 0.6%-15.5%) compared with 42.2% (95% CI, 27.7%-57.8%) with cetuximab plus chemotherapy.

Among those with a PD-L1 CPS between 1 and 19, the 12-month OS rate was 44% with pembrolizumab monotherapy and 42% with cetuximab/chemotherapy. The median PFS with pembrolizumab alone was 2.2 months vs 4.9 months with cetuximab plus chemotherapy (HR, 1.25; 95% CI, 0.96-1.61; P = .95093). Pembrolizumab monotherapy induced an ORR of 14.5% (95% CI, 8.8%-22.0%) vs 33.8% (95% CI, 25.9%-42.5%) with cetuximab plus chemotherapy.

When comparing pembrolizumab plus chemotherapy vs cetuximab plus chemotherapy in the PD-L1 CPS less than 1 subgroup, the 12-month OS rates were 41% and 47%, respectively. The median PFS with single-agent pembrolizumab was 4.7 months vs 6.2 months with cetuximab plus chemotherapy (HR, 1.46; 95% CI, 0.93-2.30; P = .94898). Additionally, pembrolizumab plus chemotherapy produced an ORR of 30.8% (95% CI, 17.0%-47.6%) vs 39.5% (95% CI, 25.0%-55.6%) with cetuximab plus chemotherapy.

In the PD-L1 CPS between 1 and 19 subgroup, the 12-month OS rate was 53% with pembrolizumab plus chemotherapy and 41% with cetuximab plus chemotherapy. The median PFS with pembrolizumab plus chemotherapy was 4.9 months vs 4.9 months for cetuximab plus chemotherapy (HR, 0.93; 95% CI, 0.71-1.21; P = .29189). Pembrolizumab plus chemotherapy produced an ORR of 29.3% (95% CI, 21.2%-38.5%), compared with 33.6% (95% CI, 25.4%-42.6%) with cetuximab plus chemotherapy.

“First-line pembrolizumab monotherapy resulted in a statistically significant and clinically meaningful improvement in OS over cetuximab/chemotherapy in the PD-L1 CPS ≥ 20 and CPS ≥ 1 populations in the primary analysis of KEYNOTE-048, as did pembrolizumab/chemotherapy in the overall, CPS ≥ 20, and CPS ≥ 1 populations,” the study authors wrote. “Results from the PD-L1 CPS 1-19 subgroup in the current analysis were generally consistent with the previously reported results of KEYNOTE-048, with pembrolizumab monotherapy compared with cetuximab/chemotherapy associated with a HR for death of 0.86.”

References

1. Burtness B, Rischin D, Greil R, et al. Pembrolizumab alone or with chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048: subgroup analysis by programmed death ligand-1 combined positive score. J Clin Oncol. Published online March 25, 2022. doi:10.1200/JCO.21.02198
2. Mehra R, Seiwert TY, Gupta S, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer. 2018;119(2):153-159. doi:10.1038/s41416-018-0131-9
3. FDA approves two new indications for Merck's Keytruda (pembrolizumab). News release. Merck. June 11, 2019. Accessed April 29, 2022.https://bit.ly/2WwH4dw