The KEYNOTE-630 Trial: A Phase 3 Study of Adjuvant Pembrolizumab in High-Risk Locally Advanced (LA) Cutaneous Squamous Cell Carcinoma (cSCC)

Purpose/Objective(s) In high-risk LA cSCC, approximately 20% of patients (pts) experience local disease recurrence within 5 years after surgical resection and adjuvant radiotherapy (RT). Therefore, improved treatment options are needed. The PD-1 inhibitors pembrolizumab (pembro) and cemiplimab have demonstrated durable antitumor activity in advanced metastatic cSCC. The randomized, double-blind, placebo-controlled, phase 3 KEYNOTE-630 (NCT03833167) trial will evaluate adjuvant pembro in pts with resectable, high-risk, LA cSCC. Materials/Methods Eligible pts have histologically confirmed LA cSCC as the primary site of malignancy and have undergone complete macroscopic resection of all disease with ≥1 high-risk feature: histologically involved nodal disease with extracapsular extension, with ≥1 lymph node >2 cm in diameter or ≥2 lymph nodes involved; any gross cortical bone, skull base, and/or skull base foramen invasion; any index tumor with ≥2 of the following: tumor ≥4 cm with >6-mm depth or invasion beyond subcutaneous fat, multifocal perineural invasion for nerves <0.1 mm in diameter (≥3 foci) or any involved nerve ≥0.1 mm in diameter, poor differentiation and/or sarcomatoid and/or spindle cell histology, recurrent disease (recurrence within 3 years in the previously treated area), or satellite lesions and/or in-transit metastases, lymphatic or vascular involvement. Pts must have received adequate postoperative dose of hypofractionated or conventional RT, including a BED EQD2 >48 Gy, have ECOG PS of 0 or 1, and completed adjuvant RT ≥4 and ≤16 weeks from randomization. Pts are required to provide tumor tissue for PD-L1 testing. Eligible pts will be randomly assigned 1:1 to receive pembro 400 mg IV Q6W or placebo for approximately 1 year (≤9 cycles) and will be followed up for as long as 5 years. Stratification factors are extracapsular extension, cortical bone invasion, and prior systemic therapy (all, yes vs no). Placebo pts may switch to pembro treatment (≤18 cycles) if they have a recurrence within 5 years. In the pembo arm, pts may also receive up to 18 cycles of pembro retreatment. Primary end point is RFS per investigator assessment with biopsy confirmation and secondary end points include OS, HRQoL, and safety. Computed tomography/magnetic resonance imaging will be performed at screening and every 12 weeks until end of year 2, then every 6 months until end of 5 years. Adverse events will be monitored throughout the study and for 30 days after treatment end and graded per NCI CTCAE v4.0. Results Approximately 570 pts will be enrolled at sites in Asia, Australia, Europe, and North and South America. Conclusion Results of KEYNOTE-630 will elucidate the role of adjuvant pembro among pts with high-risk, LA cSCC.