Efficacy assessments
death, tumor, Tumor, toxicity, ocular and dermatologic, Cancer
DISEASE PROGRESSION, ADVERSE EVENT, TUMOR, TUMOR, DISEASE, SECONDARY, CANCER
Patients received study therapy until disease progression, unacceptable toxicity, death or discontinuation for any other reason. Safety was monitored throughout the study for all patients across cohorts via physical examinations, laboratory evaluations, vital sign and weight measurements, performance status evaluations, ocular and dermatologic examinations, concomitant medication monitoring, electrocardiograms, echocardiograms and AE monitoring (characterized and graded per Common Terminology Criteria for Adverse Events v.4.0). AEs were recorded using the standard Medical Dictionary for Regulatory Activities coding. Dose interruptions, reductions and discontinuations for all of the study drugs were monitored.The primary end point was ORR; secondary end points were PFS, disease control rate, duration of response and OS, and the exploratory end point was scRNAseq analysis. Antitumor efficacy was assessed by CT or MRI at baseline and then, every 8 weeks until progression or death. Response determination was based on RECIST v.1.1 by the Dana-Farber/Harvard Cancer Center Tumor Metrics Core. For the subset of patients who showed a confirmed CR or PR, duration of response was defined as the time in weeks from the first documented evidence of CR or PR (the first response prior to confirmation) until the time of documented disease progression or death due to any cause, whichever was first. PFS was defined as the time in weeks between the first dose and the date of disease progression or death due to any cause. Finally, OS was defined as the time in weeks from the first dose of study drug until death due to any cause. PFS and time on treatment were summarized with Kaplan–Meier methodology using medians and 95% CIs (estimated using the Brookmeyer–Crowley method). Time on treatment was defined as the time until final treatment discontinuation. Fresh tumor biopsies were collected before dose (day 1) for scRNAseq analysis and patient-derived organoids generation as well as after dose (day 15) for scRNAseq analysis. The same tumor lesion was biopsied at baseline and at day 15. Formalin-fixed paraffin-embedded (FFPE) and flash-frozen tumor samples were collected at day 1 for genomic and molecular analyses.