The ground-breaking NCI-MATCH precision medicine cancer trial continues to offer treatment opportunities for adult patients with relapsed, refractory cancers. Two treatment arms are open, while others are now closed to enrollment. In addition, multiple journals are expected to publish the results of individual treatment arms.

"The last two arms in NCI-MATCH are highly-focused. Both illustrate the ability of precision medicine trials to be nimble in response to positive findings, and to develop positive efficacy signals into studies that have the potential to change clinical practice," said Peter J. O'Dwyer, MD, group co-chair of the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), which is co-leading the trial with the National Cancer Institute (NCI).

Together, the two treatment arms seek to enroll 85 patients.

Treatment Opportunity for Patients with dMMR and LAG-3 Expression

A new treatment arm (Arm Z1M) is evaluating the two-drug immunotherapy combination, relatlimab plus nivolumab. It is for patients whose cancer has progressed after treatment with anti–PD-1/PD-L1 immunotherapy. To be eligible, patients must have DNA mismatch repair deficiency (dMMR) on genomic testing and tumors that express LAG-3.

"Multiple trials have shown exciting and compelling responses for patients who have DNA mismatch repair deficiency treated with PD-1 inhibitors, including pembrolizumab and nivolumab. But, unfortunately, half of the patients won't respond or will progress when they are on therapy," said lead investigator Nilofer Azad, MD (pictured) from Johns Hopkins University.

However, recent data suggest that LAG-3 inhibition may restore anti–PD-1 sensitivity.

Patients with melanoma are not eligible for Arm Z1M. The exclusion is based on the phase III trial, RELATIVITY-047, in patients with previously untreated metastatic or unresectable melanoma. This trial showed that inhibition of two immune checkpoints, LAG-3 and PD-1, provided a median progression-free survival (PFS) of 10.4 months compared to median PFS of 4.6 months with inhibition of PD-1 alone (Tawbi HA. N Engl J Med. January 2022). On March 18, 2022, the US FDA approved the relatlimab-nivolumab combination to treat patients with unresectable or metastatic melanoma.

Testing BRAF/MEK Combination in BRAF-Mutated Cancers

Arm H is investigating the combination of the selective BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients whose tumors harbor BRAF V600E or BRAF V600K mutations. Dabrafenib and trametinib are both targeted therapies. A promising efficacy signal in the first group of NCI-MATCH patients to receive this treatment led to the opening of an expansion cohort. The initial study met its primary endpoint with an overall objective response rate of 38% in a heavily pre-treated cohort of 17 distinct tumor types—several rare—with BRAF mutations (Salama AKS. J Clin Oncol. August 2020).

"NCI-MATCH's Arm H shows promising activity outside of currently approved FDA indications," said lead researcher April K.S. Salama, MD (pictured) from Duke University. "So far, the data show that BRAF/MEK combination therapy has widespread activity across multiple cancer types whose tumors harbor BRAF mutations. Therefore, we hope to identify 50 more patients for Arm H to define the broad applicability of these positive findings."

Read this companion article NCI-MATCH: The Blueprint for Future Precision Medicine Trials.

Learn more about NCI-MATCH at ecog-acrin.org.

Questions? Send an email to the trial team.

NCI-MATCH is sponsored by the NCI, part of the National Institutes of Health. ECOG-ACRIN is co-leading the trial with NCI. Other NCI-funded network groups are participating: Alliance for Clinical Trials in Oncology, Children's Oncology Group, NRG Oncology, and SWOG Cancer Research Network.

Bristol Myers Squibb and Novartis provided support to Arms Z1M and H through their respective agreements with the NCI.