medwireNews: Dual checkpoint inhibition with nivolumab plus ipilimumab may be a promising treatment option for people with HER2-negative metastatic breast cancer (MBC) and high tumor mutational burden (TMB-H), phase 2 NIMBUS study data show.
However, Romualdo Barroso-Sousa, from Hospital Sírio-Libanês in Brasília, Brazil, reported at the 2021 San Antonio Breast Cancer Symposium that the optimal TMB cutoff for selecting suitable patients is currently unclear.
The NIMBUS study included 30 women (median age 63 years) with HER2-negative MBC and a TMB of at least 9 mutations/Mb (median 10.9 mutations/Mb) who were given nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.
Two-thirds of participants had hormone receptor-positive breast cancer and the remainder had triple-negative breast cancer. The median number of prior chemotherapy lines was 1.5 and the maximum was three.
During a median 9.7 months of follow-up, there were five (16.7%) confirmed objective responses, all of which were partial. Barroso-Sousa said that this objective response rate (ORR) met the primary study endpoint of at least four confirmed responses and suggests that “the regimen is worthy of further study.”
A further six (20%) participants had stable disease during follow-up.
The median time to response and median response durations were 1.2 and 12.1 months, respectively, while median progression-free survival (PFS) and overall survival (OS) were a respective 1.4 and 19.3 months.
Exploratory analyses revealed that increasing the TMB-H cutoff to 14 mutations/Mb had a substantial impact on response rates. Specifically, the ORR was 60% among the five participants with a TMB of 14 mutations/Mb or higher and was significantly lower, at 8%, among the 25 participants with a TMB of 9–13 mutations/Mb.
Median PFS was 9.5 months in the group with a TMB of at least 14 mutations/Mb compared with 1.4 months in the group with a lower TMB, while median OS was not reached and 8.8 months in the two groups, respectively.
Conversely, response rates did not differ by hormone receptor status, PD-L1 status, or stromal tumor infiltrating lymphocytes level.
Barroso-Sousa said that the toxicity profile of nivolumab plus ipilimumab was “similar to what has been previously seen with other tumor histology using this combination.”
There were no grade 4 or 5 adverse events (AEs), but three patients experienced a grade 3 immune-related AE (one developed grade 3 adrenal insufficiency and myocarditis, and two had hepatitis). Two participants discontinued treatment due to unacceptable toxicity (one myocarditis and one fatigue).
Barroso-Sousa concluded: “This study supports the use of checkpoint inhibition for patients with HER2-negative metastatic breast cancer and high TMB regardless of hormone receptor status but does not answer the question if dual checkpoint inhibition is better than pembrolizumab monotherapy.”
He added: “While patients with TMB of 14 mutations/Mb or higher were a minority in this study, they did achieve an objective response of 60% and further work is needed to investigate the optimal cutoff for selecting patients to receive checkpoint inhibition.”
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