Nivolumab plus ipilimumab shows benefit in metastatic HER2-negative breast cancer
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Nivolumab plus ipilimumab induced durable responses among a small cohort of women with high tumor mutational burden metastatic HER2-negative breast cancer, according to study results presented at San Antonio Breast Cancer Symposium.
Researchers involved with the phase 2 NIMBUS trial observed no new safety concerns with the combination.
Increasing evidence suggests patients with high tumor mutational burden are more likely to benefit from immune checkpoint inhibitors, Romualdo Barroso-Sousa, MD, PhD, advanced fellow in breast oncology at Dana-Farber Cancer Institute, said during a presentation.
“Based on data from KEYNOTE-158, pembrolizumab [Keytruda, Merck] received accelerated approval for the treatment of patients with metastatic solid tumors with high tumor mutational burden, defined as 10 or more mutations per megabase,” Barroso-Sousa said. “However, [although] the prevalence of high tumor mutational burden in metastatic breast cancer is approximately 10%, the real benefit of checkpoint inhibition in this population is not well-established. In the NIMBUS trial, we hypothesized that patients with hypermutated breast cancer are more likely to benefit from an approach of dual checkpoint inhibition with the combination of nivolumab [Opdivo, Bristol Myers Squibb] with low-dose ipilimumab [Yervoy, Bristol Myers Squibb].”
The NIMBUS trial included 30 women (median age, 63 years; 90% white) with metastatic HER2-negative breast cancer who had undergone up to three prior lines of chemotherapy but had no prior checkpoint inhibitor therapy.
The women received 3 mg/kg nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks. Treatment continued for up to 2 years or until disease progression or unacceptable toxicity.
The efficacy of the combination, defined by objective response rate according to RECIST 1.1, served as the primary objective. Secondary objectives included safety and tolerability, clinical benefit rate, PFS and ORR specifically for patients with tumor mutational burden of 14 or more mutations per megabase.
“At the time of designing this trial, there were preliminary data suggesting that at least 13 or 14 mutations per megabase among patients with breast cancer would be an appropriate cutoff,” Barroso-Sousa said. “Recently, the ongoing phase 2 MyPathway trial in the U.K. suggested that, even for agnostic indications, a cutoff of 16 mutations per megabase may be better than 10 mutations.”
At median follow-up of 9.7 months, five women achieved partial response, equating to an ORR of 16.7%. Six (20%) demonstrated stable disease, 16 (53.3%) demonstrated progressive disease and 10 were not evaluable for response.
Patients received a median one cycle of the combination treatment and disease progression was the most common reason for treatment discontinuation,
Two of the patients who achieved partial response discontinued treatment due to toxicities — one due to myocarditis and one due to fatigue — but both still experienced prolonged treatment response, Barroso-Sousa said.
Three of the five responders had hormone receptor-positive breast cancer and two had triple-negative disease. One responder had a PD-L1-positive tumor. Two had tumor mutational burden less than 14 mutations per megabase and three had a tumor mutational burden of 14 or more mutations per megabase.
Researchers reported median time to treatment response of 1.2 months, median duration of response of 12.1 months, median PFS of 1.4 months (95% CI, 1.3-4.6) and median OS of 19.3 months (95% CI, 5.2-not reached).
Results showed patients with tumor mutational burden of 14 mutations per megabase or higher achieved longer median PFS (9.5 months vs. 1.4 months) and OS (not reached vs. 8.8 months) than those with lower tumor mutational burden.
“Although the numbers are small, patients with a tumor mutational burden of 14 or higher had a response rate of 60% compared with 8% in the group of patients with tumor mutational burden lower than 14,” Barroso-Sousa said.
Investigators reported 1-year OS rates of 100% among patients who achieved partial response to treatment, 80% among those with stable disease and 45% among those with progressive disease.
Researchers observed no new safety concerns.
“Our primary endpoint was met, with no new toxicities and no grade 4 or grade 5 adverse events reported,” Barroso-Sousa said. “This study supports the use of checkpoint inhibitors among patients with HER2-negattive metastatic breast cancer and high tumor mutational burden, regardless of hormone receptor status. However, the study does not answer the question of whether dual checkpoint inhibition is better than pembrolizumab monotherapy.”
Further research is needed to identify the optimal tumor mutational burden cutoff to ensure selection of patients most likely to derive benefit from checkpoint inhibitor therapy, Barroso-Sousa said.
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Barroso-Sousa R, et al. Abstract GS2-10. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 7-10, 2021.
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