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Pembrolizumab regimens approved in EU for the frontline treatment of patients with PD-L1-positive metastatic or unresectable recurrent head and neck squamous cell carcinoma

The European Commission has approved Keytruda ( Pembrolizumab ) as a monotherapy or in combination with Platinum and 5-Fluorouracil ( 5-FU ) chemotherapy for the frontline treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma ( HNSCC ) and PD-L1 expression ( composite positive score [ CPS ] ≥1 ) on their tumors.

The approval is based on results from the phase III KEYNOTE-048 trial, in which single-agent Pembrolizumab, a PD-1 inhibitor, has demonstrated a statistically significant improvement in overall survival ( OS ) compared with the standard EXTREME regimen, which comprises Cetuximab with Carboplatin or Cisplatin plus 5-FU, in patients with PD-L1-positive tumors ( hazard ratio, HR=0.74; 95% CI, 0.61-0.90; P = 0.00133 ).

When used in combination with chemotherapy, the PD-1 inhibitor led to a 35% reduction in the risk of disease progression or death ( HR=0.65; 95% CI, 0.53-0.80; P = 0.00002 ).
Both OS improvements were observed in patients whose tumors have PD-L1 expression ( CPS ≥1 ).

In the open-label, randomized, phase III KEYNOTE-048 study, researchers have evaluated whether Pembrolizumab could prolong survival and slow disease progression versus the EXTREME regimen ( Platinum-based chemotherapy with Cisplatin or Carboplatin, 5-FU, and Cetuximab ) in the recurrent or metastatic setting.
A total 882 patients were randomized in a 1:1:1 ratio to either standard EXTREME treatment ( Cetuximab at 400 mg/m2 loading dose followed by 250 mg/m2 weekly, plus Cisplatin at 100 mg/m2 or Carboplatin AUC 5 every 3 weeks, plus 5-FU at 1000 mg/m2 daily on day 1 through 4 of each 3-week cycle for a maximum of 6 cycles; n = 300 ); single-agent Pembrolizumab at 200 mg every 3 weeks for 2 years ( n = 301 ); or a combination of Pembrolizumab and Platinum-based chemotherapy with 5-FU ( n = 281 ).
Treatment was administered until unacceptable toxicity or progressive disease.

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

The primary endpoints were progression-free survival ( PFS ) and overall survival in patients with a PD-L1 CPS ≥20, ≥1, and in all patients enrolled.

For single-agent Pembrolizumab, results in those with PD-L1 CPS ≥1 have shown that the median overall survival was 12.3 months for patients with who received Pembrolizumab ( n = 257 ) compared with 10.3 months for those who received standard therapy ( n = 255 ), leading to a 26% reduction in the risk of death.
However, the median progression-free survival was 3.2 months and 5.0 months, respectively ( HR=1.13; 95% CI, 0.94-1.36; P = 0.89580 ).

Also with the monotherapy regimen, the overall response rate ( ORR ) was lower with Pembrolizumab at 19.1% compared with 35% with the EXTREME regimen; the complete response ( CR ) and partial response ( PR ) rates were 5% and 14% with Pembrolizumab and 3% and 32% with standard therapy ( P = 1.0000 ).
The duration of response ( DOR ) with Pembrolizumab was 23.4 months and was 4.5 months with the EXTREME regimen; 81% of patients on Pembrolizumab had a DOR lasting 6 months or more compared with 36% of those on standard treatment.

The Pembrolizumab / chemotherapy combination has demonstrated a median overall survival of 13.6 months and 10.4 months with the Pembrolizumab regimen ( n = 242 ) and standard treatment ( n = 235 ), respectively, which led to a 35% reduction in the risk of death.
The median progression-free survival was similar, at 5.1 months with Pembrolizumab / chemotherapy and 5.0 months with EXTREME ( HR=0.84; 95% CI, 0.69-1.02; P = 0.03697 ).
The ORR was 36% in both arms; in the Pembrolizumab arm, there was a 7% CR rate and a 30% PR rate. The CR rate and PR rate with EXTREME was 3% and 33%.
Additionally, the median DOR was 6.7 months and 4.3 months with Pembrolizumab/chemotherapy and EXTREME, respectively. 54% of patients on Pembrolizumab had a DOR ≥6 months compared with 34% of those who received EXTREME regimen. ( Xagena )

Source: MSD / Merck, 2019