Novel combination therapy for advanced melanoma points to future directions

Oncology research at its best drives new treatment options with life-saving potential. And, according to Mohammed Milhem, MBBS, Melanoma Program Director at UI’s Holden Comprehensive Cancer Center, even one additional option can be the difference between survival and death for a patient.

A new treatment option can only be introduced, however, after researchers verify its safety. To this end, members of our Hematology and Oncology division and fellowship program evaluated the safety of a novel therapeutic combination—cabozantinib and pembrolizumab—for the treatment of advanced cutaneous melanoma.

The primary objective for the first portion of this trial was achieved when researchers verified the combination’s safety and determined its maximum tolerated dose. Although the team terminated the phase 2 portion early, lead manuscript author Dong Hyun Kim, MD, PhD, said the study met its intended goals as an early-phase trial. Overall, their findings concluded that this combination is safe and can therefore yield responses in some patients.

Context
Survival odds for patients with metastatic melanoma transformed after the FDA approved the first immune checkpoint inhibitor (ICI) in 2011. Since the advent of checkpoint inhibitors such as pembrolizumab—an anti-programmed cell death-1 (PD-1)—5-year survival rates for patients with metastatic melanoma have jumped from 5% to more than 50%.

Unfortunately, treatment options remain limited for patients who are unresponsive to ICI. The Iowa researchers sought to determine whether a receptor tyrosine kinase inhibitor (TKI), cabozantinib, could augment the anti-PD-1 activity of pembrolizumab. Multitarget TKIs blocking vascular endothelial growth factor receptor (VEGFR) 1-3 have exhibited two primary functions: 1) stifling the development of blood vessels used to promote tumor spread and 2) blocking hypoxic signaling—a cellular survival mechanism in rapidly growing tumors.

Results and ongoing discussion
Efficacy measures from the study’s available data found that combined pembrolizumab-cabozantinib treatment yielded an overall response rate of 45%. Numerically, this measure compares favorably with single-agent anti-PD-1 therapy, which has an estimated response rate of 31-33%.

Kim, a third-year fellow in our Hematology and Medical Oncology fellowship program working toward a career as a clinical trialist, shared more of his thoughts on the trial results and broader trends in this class of treatment.

He noted that multiple prospective trials evaluating similar combinations of ICIs and TKIs in treatment-naïve advanced melanoma have not demonstrated a survival benefit or met predefined efficacy targets.

Kim also pointed out the ethical and clinical considerations that researchers balance in the field. “Patients enrolled in oncology clinical trials often have limited treatment options and limited time, making it essential to continuously reassess whether ongoing trials remain in their best interest.”

Nonetheless, Kim recognizes the importance of this work in relation to other malignancies and the investigation of newer therapies of the same class.

“The concept remains relevant in other malignancies, and newer multi-targeted TKIs are being actively investigated in combination with ICIs,” he said. “I believe the safety data generated from our study will serve as a valuable reference for future trials exploring similar combinations.”

Options as miracles
In a field of aggressive disease and rapidly changing research paradigms, oncology trials set different benchmarks for translational success. A therapy with broad-sweeping efficacy in a particularly aggressive late-stage cancer is unlikely to emerge from one trial alone. What these trials can do, however, is verify that a treatment is safe, and therefore a possibility for a patient running out of options. This perspective is what Milhem returns to often—that just one more option can re-route a patient’s life and even future research.

“Providing trials in different spaces gives patients opportunities that might not exist otherwise,” he said. “This study’s findings point to potential effectiveness in combining an anti-PD-1 with a VEGF inhibitor, reinforcing its viability for future research. Our work lays the foundation for others to launch improved studies targeting these two pathways, offering hope for better outcomes.”