California's Melanoma Trials Are Testing Bold New Combinations—Here's What Could Change Treatment

California's top medical centers are running a massive wave of melanoma clinical trials—83 studies across UCSF and UCSD alone—testing combinations of immunotherapy drugs, personalized vaccines, and targeted treatments that could fundamentally change how advanced skin cancer is treated. These aren't incremental tweaks to existing therapies. Researchers are exploring whether pairing different immune-boosting drugs, combining immunotherapy with targeted genetic treatments, and even testing experimental approaches in transplant patients could help people with melanoma live longer and stay cancer-free.

What Makes These New Melanoma Combinations Different?

The traditional approach to advanced melanoma has relied on single immunotherapy drugs or chemotherapy. But the latest trials reflect a shift toward combination strategies—using two or more drugs together to attack cancer from multiple angles. One landmark study at UCSD is comparing pembrolizumab (an established immunotherapy) against the current standard of care, which includes high-dose interferon or ipilimumab, in patients whose melanoma has been surgically removed but is at high risk of returning. This trial, which began in 2015 and continues through early 2026, involves hundreds of patients and represents one of the largest efforts to determine whether newer immunotherapies outperform older treatments.

But the real innovation lies in the experimental combinations being tested. Researchers are investigating whether pairing different checkpoint inhibitors—drugs that release the brakes on the immune system—might work better together than alone. One UCSF trial is testing fianlimab combined with cemiplimab against the commercially available combination of relatlimab and nivolumab (sold as Opdualag) in patients with advanced melanoma. Another study is exploring whether a cancer vaccine called V940, combined with pembrolizumab, can prevent advanced melanoma from growing or spreading better than pembrolizumab alone.

Who Might Benefit Most From These New Approaches?

These trials are targeting specific patient populations that have historically been difficult to treat. Several studies focus on patients with rare melanoma subtypes or genetic mutations that don't respond well to standard therapies. For example, one UCSD trial is testing a combination of binimetinib and imatinib specifically for patients with KIT-mutant melanoma—a genetic variant that requires a different treatment strategy than common melanomas. Another UCSF study is investigating whether a drug called naporafenib, combined with trametinib, can improve survival in patients with NRAS-mutant melanoma, comparing it to physician's choice of chemotherapy or single-agent treatment.

Perhaps most notably, researchers are testing whether immunotherapy can work safely in transplant recipients—a population typically excluded from cancer trials because their immune systems are deliberately suppressed to prevent organ rejection. Multiple trials at both UCSF and UCSD are enrolling kidney, liver, heart, and lung transplant recipients with advanced skin cancer to see whether new immunotherapy approaches can kill cancer cells without triggering rejection of their transplanted organs.

What Types of Experimental Treatments Are Being Tested?

The breadth of approaches being investigated reflects how much the field has evolved. Beyond traditional checkpoint inhibitors, researchers are testing:

• CAR-T Cell Therapies: One UCSF trial is testing IMA203, an engineered immune cell therapy, combined with an mRNA vaccine called mRNA-4203 in patients with advanced melanoma or synovial sarcoma.
• Targeted Genetic Treatments: Multiple trials are pairing drugs that block specific cancer-driving mutations (like NRAS, KIT, or MAPK pathway mutations) with immunotherapy to hit tumors from two directions simultaneously.
• Intralesional Immunotherapy: One UCSD study is testing whether injecting cemiplimab directly into early-stage squamous cell carcinoma lesions might work as well as surgery, potentially avoiding the need for surgical removal.
• Combination Immunotherapy Plus Standard Care: A UCSD trial is testing whether combining nivolumab and ipilimumab with sirolimus and prednisone—drugs that suppress the immune system to protect transplanted kidneys—can safely treat skin cancer in kidney transplant recipients.

The diversity of these approaches reflects a fundamental shift in cancer treatment philosophy. Rather than assuming one drug works for everyone, researchers are increasingly asking: Which combination works best for which patient? Which genetic mutations predict who will respond? Can we personalize treatment based on tumor characteristics?

How Long Will It Take to Know If These Work?

Most of these trials are still enrolling patients or in active treatment phases. The UCSD pembrolizumab trial, one of the largest and longest-running studies, is expected to conclude in early 2026 after more than a decade of enrollment and follow-up. Patients in that study undergo computed tomography scans, positron emission tomography (PET) scans, and magnetic resonance imaging (MRI) throughout treatment, with follow-up visits continuing for up to five years after treatment ends to track whether cancer returns.

For newer trials still in early phases, results may take several more years. But the sheer number of trials running simultaneously—45 at UCSF and 38 at UCSD—suggests that researchers are confident enough in these approaches to invest heavily in testing them. If even a few of these combinations prove superior to current standards, they could become new treatment options within the next three to five years.

The stakes are high. Melanoma remains one of the most aggressive skin cancers, and while immunotherapy has dramatically improved outcomes for some patients, many still experience disease progression or severe side effects. These trials represent the next frontier in the effort to turn melanoma from a life-threatening diagnosis into a manageable condition.