Melanoma research: targeted drug duo reactivates immune response

Researchers at Sutter’s California Pacific Medical Center (CPMC) have identified potential new therapeutic strategies for patients with advanced melanoma who no longer respond to immunotherapy. Addressing this resistance is one of the most pressing challenges in cancer care today.

The study, led by Dr Mohammed Kashani-Sabet, MD, medical director of CPMC’s Cancer Center builds on years of foundational work by CPMC’s Cancer Avatar Program. The findings were published in the Journal of Clinical Investigation and will form the basis of a forthcoming investigator-initiated clinical trial at Sutter Health.

“Immunotherapy has transformed how we treat melanoma, but when it fails, our treatment options are extremely limited,” says Dr Kashani-Sabet. “We often need to resort to ineffective therapies developed decades ago. This study offers a new path forward.”

Profiling resistance and testing new drug combinations

Using transcriptomic profiling and high-throughput drug screening through the Cancer Avatar Program, Dr Kashani and his team analysed tumours from 14 CPMC patients whose melanoma had progressed after PD-1-based immunotherapy, comparing them with tumours from 15 treatment-naïve patients.

The researchers located several druggable genes and pathways – including those linked to MAPK signalling, angiogenesis and apoptosis – and tested combinations of FDA-approved drugs in patient-derived xenograft (PDX) models.

A promising combination emerges

One drug pairing, cobimetinib + regorafenib (Cobi+Reg), demonstrated synergistic anti-tumour activity across multiple melanoma subtypes, including BRAF-, NRAS- and NF1-mutant tumours. The regimen appeared to reverse key resistance mechanisms by restoring antigen presentation and boosting infiltration of activated CD8+ T cells.

“Cobi+Reg not only shrank tumours in preclinical models – it reactivated the immune system,” says Dr Kashani-Sabet. “This opens the door to combining targeted therapy with immunotherapy for even greater benefit.”

Building on precision oncology

The research was conducted under the Cancer Avatar Program, CPMC’s precision oncology initiative that uses living tumour models to inform treatment decisions. The program, supported by the CPMC Foundation and philanthropic partners, has already driven multiple clinical trials.

A clinical trial led by CPMC to test the promising drug combinations in patients with immunotherapy-resistant melanoma is currently in development and expected to begin enrolling patients by late 2025.

“This is a prime example of how precision oncology at Sutter is helping transform care for patients who need new options beyond standard of care,” says Amanda Wheeler, MD, chair of Sutter’s cancer service line.