Pembrolizumab-ATRA combination shows benefit in metastatic melanoma
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The addition of all-trans retinoic acid to pembrolizumab conferred benefit to patients with metastatic melanoma, according to results of a phase 1b/phase 2 trial published in Clinical Cancer Research.
The combination extended PFS and duration of response, and also increased complete response rate, compared with prior clinical trials of pembrolizumab (Keytruda, Merck) monotherapy for similar patient populations.
“We would like to believe it is the effect on the MDSCs that is enhancing the efficacy of pembrolizumab in these patients,” researcher Martin D. McCarter, MD, professor of surgical oncology at University of Colorado School of Medicine, told Healio. “We demonstrate some supporting data to suggest this relationship but cannot prove for sure that was the mechanism. For example, it could have been patient selection in a relatively small study.”
Background and methodology
Immune checkpoint inhibitors have improved outcomes in melanoma. However, many patients develop resistance to these therapies, including through expansion of myeloid-derived suppressor cells (MDSCs).
MDSCs are potent suppressors of antitumor immunity and represent a substantial challenge for immune checkpoint therapy in several cancer types.
McCarter and colleagues sought to use ATRA (Vesanoid, Merck), a vitamin A derivative, to decrease the frequency and function of MDSCs to increase the effectiveness of pembrolizumab.
The open-label trial included 24 adults (median age, 66 years; range, 42-94; 87% men) with stage IV melanoma who had not received prior anti-PD-1 therapy. Seventy-five percent had received no prior treatment. All patients had ECOG performance status of 0 or 1.
Study participants received 200 mg pembrolizumab every 3 weeks plus 150 mg/m2 ATRA orally on the day before, day of and day after the first four infusions of pembrolizumab.
Results
Researchers reported a 71% overall response rate and 50% complete response rate, with median PFS of 20.3 months.
The majority (80%) remained alive at 1 year.
The most common adverse events of any grade likely related to ATRA included headache (92%), fatigue (46%), nausea (29%), vomiting (21%), dry mouth (17%) and dry skin (17%).
The most common adverse events of any grade likely related to pembrolizumab included fatigue (67%), diarrhea (21%), rash maculo-papular (21%) and dry mouth (17%).
Next steps
Researchers noted study limitations, including the small sample size, single-institution design and lack of a pembrolizumab monotherapy control arm.
In addition, the fact most study participants had a low disease burden and had received few prior therapies may have contributed to the high response rates, investigators noted.
“We would like to see if this combination and strategy for targeting MDSCs can be reproduced by other investigators or in other patient populations,” McCarter told Healio. “Merck has enrolled patients into their umbrella platform testing this combination in patients who have previously progressed on PD-1 inhibitors. We’ll be looking to expand this strategy into other tumors for which MDSCs may be playing a role to prevent an effective immune response to move forward.”
For more information:
Martin D. McCarter, MD, can be reached at University of Colorado Anschutz Medical Center, 12800 East 19th Ave., Aurora, CO 80045; email: martin.mccarter@cuanschutz.edu.
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Tobin RP, et al. Clin Cancer Res. 2023;doi:10.1158/1078-0432.CCR-22-2495.
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