Immunotherapy before targeted therapy extends OS in metastatic melanoma
Click Here to Manage Email Alerts
Patients with BRAF V600 mutation-positive metastatic melanoma who received an immune checkpoint inhibitor combination followed by targeted therapy survived longer than those who received the reverse sequence, according to study findings.
Results of the randomized phase 3 DREAMseq trial — presented during the inaugural ASCO Plenary Series — challenge existing treatment standards.
“Our findings establish definitively that, even for this oncogene-driven tumor, the sequence beginning with immunotherapy — rather than targeted therapy — produces better overall survival for the vast majority of patients,” researcher Michael B. Atkins, MD, deputy director of Georgetown Lombardi Comprehensive Cancer Center, said in an ASCO-issued press release. “This is practice-changing because many patients, especially in the community oncology setting, receive targeted therapy as their initial treatment.”
The combination of immune checkpoint inhibitors that block PD-1 and CTLA-4, as well as combinations of BRAF/MEK inhibitors, have demonstrated the potential to extend OS for patients with BRAF V600-mutant metastatic melanoma.
Despite broad regulatory approval of both approaches, prospective data that can guide decisions about treatment sequencing are limited, according to study background.
The DREAMseq trial compared the efficacy and toxicity of an immune checkpoint inhibitor combination followed by a targeted therapy combination vs. the reverse sequence.
The trial included 265 patients (median age, 61 years; range, 25-85; 63% men) with treatment-naive BRAF V600-mutant metastatic melanoma, all of whom had ECOG performance status of 0 or 1.
Researchers randomly assigned 133 patients to initial treatment with the anti-PD-1 antibody nivolumab (Opdivo, Bristol Myers Squibb) plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb). Patients received 1 mg/kg nivolumab plus 3 mg/kg ipilimumab every 3 weeks for four doses, followed by 240 mg nivolumab via IV every 2 weeks for up to 72 weeks.
Upon disease progression, patients received the BRAF inhibitor dabrafenib (Tafinlar, Novartis) dosed at 150 mg orally twice daily, plus the MEK1/2 inhibitor trametinib (Mekinist, Novartis) dosed at 2 mg orally daily.
The other 132 patients received initial treatment with dabrafenib and trametinib. Upon disease progression, they received nivolumab plus ipilimumab.
Two-year OS served as the primary endpoint.
At a fourth interim analysis, more than half (59%) of patients had been on study for at least 2 years. At that time, the data safety monitoring committee and NCI Cancer Therapy Evaluation Program representatives recommended investigators stop accrual — short of the planned 300-patient enrollment — and release trial data.
Median follow-up was 27.7 months.
Researchers reported a statistically significant improvement in 2-year OS among patients who received the immunotherapy combination first (72% vs. 52%; P = .0095).
Results showed 115 patients developed progression on their initial regimen (nivolumab-ipilimumab, n = 44; dabrafenib-trametinib, n = 71).
Patients who received the immunotherapy combination first achieved longer median duration of response (not reached vs. 12.7 months; P < .001).
A higher percentage of patients initially assigned the immunotherapy combination experienced grade 3 or higher toxicity (60% vs. 52%).
Researchers reported two grade 5 treatment-related adverse events among patients on initial therapy with nivolumab-ipilimumab, and one grade 5 treatment-related adverse event among a patient who switched from the immunotherapy combination to dabrafenib-trametinib.
“The drug combinations tested in this trial all improve survival compared to prior standards of care, but we now know which combination should be administered first to achieve maximum benefit for the vast majority of our patients,” Atkins said in a Georgetown-issued press release. “This trial should provide clearer guidance to clinicians on when to administer particular treatments.”
Collapse
Atkins MB, et al. Abstract 356154. Presented at: ASCO Plenary Series (virtual); Nov. 16, 2021.
Read more about
Click Here to Manage Email Alerts