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FDA has approved Keytruda in combination with Platinum and Fluorouracil for first-line treatment of head and neck squamous cell carcinoma


The Food and Drug Administration ( FDA ) has approved Keytruda ( Pembrolizumab ) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma ( HNSCC ).

Pembrolizumab was approved for use in combination with Platinum and Fluorouracil ( FU ) for all patients and as a single agent for patients whose tumors express PD‑L1 ( Combined Positive Score [ CPS ] greater than or equal to 1 ) as determined by an FDA‑approved test.

The FDA has also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with Pembrolizumab as a single agent.

Approval was based on KEYNOTE-048, a randomized, multicenter, three-arm, open‑label, active‑controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies.

Patients were randomized ( 1:1:1 ) to receive one of the following treatments: Pembrolizumab as a single agent; Pembrolizumab, Carboplatin or Cisplatin, and FU; or Cetuximab, Carboplatin or Cisplatin, and FU.
Randomization was stratified by tumor PD-L1 expression ( Tumor Proportion Score [ TPS ] greater than or equal to 50% or less than 50% ), HPV status according to p16 IHC ( positive or negative ), and ECOG PS ( 0 vs 1 ).
PD-L1 expression ( TPS and CPS ) was determined using the PD-L1 IHC 22C3 pharmDx kit.

Overall survival ( OS ), sequentially tested in the subgroup of patients with CPS 20 or more HNSCC, the subgroup of patients with CPS ≥1 HNSCC and the overall population, was the major efficacy measure.

The trial has demonstrated a statistically significant improvement in overall survival in the overall population for patients randomized to Pembrolizumab plus chemotherapy compared with Cetuximab plus chemotherapy at a pre-specified interim analysis.
The median overall survival was 13.0 months for the Pembrolizumab plus chemotherapy arm and 10.7 months for the Cetuximab plus chemotherapy arm ( hazard ratio, HR 0.77; 95% CI: 0.63, 0.93; p=0.0067 ).
Results were similar in the CPS ≥20 subgroup ( HR 0.69; 95% CI: 0.51, 0.94 ) and CPS ≥1 subgroup ( HR 0.71; 95% CI: 0.57, 0.88 ).

The trial has also demonstrated statistically significant improvements in overall survival for the subgroups of patients with PD‑L1 CPS ≥1 HNSCC and PD-L1 CPS ≥20 HNSCC randomized to Pembrolizumab as a single agent compared with Cetuximab plus chemotherapy.
In the CPS ≥1 subgroup, the median overall survival was 12.3 months for the Pembrolizumab arm and 10.3 months for the Cetuximab plus chemotherapy arm ( HR 0.78; 95% CI: 0.64, 0.96; p=0.0171 ).
For the CPS ≥20 subgroup, the median overall survival was 14.9 months for the Pembrolizumab arm and 10.7 months for the Cetuximab plus chemotherapy arm ( HR 0.61; 95% CI: 0.45, 0.83; p=0.0015 ).

At the time of the interim analysis, there was no significant difference in overall survival between the Pembrolizumab as a single agent arm and the Cetuximab plus chemotherapy arm for the overall population.

There were no significant differences in progression-free survival ( PFS ) for either Pembrolizumab-containing arm compared to the Cetuximab plus chemotherapy arm in any population.

The most common adverse reactions reported in ≥20% of patients who received Pembrolizumab as a single agent in KEYNOTE-048 were fatigue, constipation, and rash.
The most common adverse reactions reported in ≥20% of patients who received Pembrolizumab in combination with chemotherapy in KEYNOTE-048 were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.

The recommended Pembrolizumab dose for HNSCC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. ( Xagena )

Source: FDA, 2019

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