# A phase 1b/2 study of cabozantinib in combination with pembrolizumab in advanced cutaneous melanoma

## TL;DR

A clinical trial tested combining cabozantinib and pembrolizumab for advanced melanoma, finding a 45% response rate but notable side effects.

## Contribution

This study evaluates the safety and preliminary efficacy of a new combination therapy for advanced melanoma.

## Key findings

- The combination therapy achieved a 45% overall response rate in phase 2.
- Median progression-free survival was 6.6 months and median overall survival was 29.5 months.
- Common grade ≥3 toxicities included hypertension, hypokalemia, and hypophosphatemia.

## Abstract

Pembrolizumab is approved for advanced cutaneous melanoma (aCM). Cabozantinib, an oral multi‐tyrosine kinase inhibitor, has demonstrated antitumor activity as monotherapy or in combination with anti‐PD‐1 therapy in malignancies. The objective of this study was to determine the safety and efficacy of cabozantinib and pembrolizumab for patients with aCM.

This phase 1b/2 study enrolled 28 patients with unresectable aCM. In phase 1b, escalating dose levels of cabozantinib (20 mg, 40 mg, and 60 mg) were administered concurrently with pembrolizumab 200 mg intravenously every 3 weeks using a 3 + 3 design to determine recommended phase 2 dose (RP2D). In phase 2, patients received cabozantinib at RP2D in combination with pembrolizumab using a Simon 2 stage design. Primary end point of phase 2 was overall response rate (ORR). Secondary end points included disease control rate, progression‐free survival (PFS), and overall survival (OS).

Phase 1b enrolled eight patients, cabozantinib 40 mg daily dose level was selected as RP2D. Response rate in stage 1 exceeded predefined criteria for proceeding to expansion phase; however, phase 2 was terminated after 20 patients due to low accrual in the setting of evolving standard of care. Among all treated patients, the most common grade ≥3 toxicities were hypertension (n = 10, 36%), hypokalemia (n = 5, 18%), hypophosphatemia (n = 4, 14%), and ALT elevation (n = 4, 14%). Among 20 patients treated in phase 2, ORR was 45%, median PFS was 6.6 months, and median OS was 29.5 months.

Cabozantinib and pembrolizumab combination was explored in treatment‐naive aCM. Toxicity was consistent with known profiles, but discontinuation rates were notable.

This phase 1b/2 study explored the safety and preliminary efficacy of the cabozantinib 40 mg daily and standard dose pembrolizumab combination therapy in frontline setting for patients with advanced or metastatic cutaneous melanoma. Toxicity was consistent with known safety profiles and efficacy data suggested an overall response rate of 45%, median progression‐free survival of 6.6 months, and median overall survival of 29.5 months.