K药继续前进！一线HNSCC获批

K药基于KN-048的结果获批一线治疗转移或不可手术的复发HNSCC：其中K药联合铂+氟尿嘧啶获批治疗不区分PD-L1表达的一线治疗；而K药单药用于CPS≥1的患者的一线治疗

为什么看起来很拗口，因为KN-048本身也很复杂

眼花缭乱的主要终点

统计假设

PFS全军覆没，OS汇总如下，先看K药单药，只在CPS≥1和≥20的群体中达到了优效，在整个群体中只达到非劣本次最终分析也没有证明优效；而ESMO18上就报道了联合化疗优于EXTREME，本次最终分析没有进一步确认，只是确认了K药联合化疗在CPS≥1和≥20的群体中同样也优于EXTREME

具体结果如下，汇总了ESMO18和ASCO19上更新的结果

FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma

On June 10, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck) 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] ≥1) as determined by an FDA‑approved test. The FDA 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 (NCT02358031), 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] ≥50% or <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 HNSCC, the subgroup of patients with CPS ≥1 HNSCC and the overall population, was the major efficacy measure.

The trial demonstrated a statistically significant improvement in OS in the overall population for patients randomized to pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy at a pre-specified interim analysis. The median OS was 13.0 months for the pembrolizumab plus chemotherapy arm and 10.7 months for the cetuximab plus chemotherapy arm (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 also demonstrated statistically significant improvements in OS 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 OS 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 OS 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 OS 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 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.