Patients with advanced HER2-negative metastatic breast cancer and high tumor mutational burden achieved responses—often durable—from treatment with the immunotherapy doublet of nivolumab and ipilimumab, according to results of the phase II NIMBUS trial reported at the 2021 San Antonio Breast Cancer Symposium.¹

Of 30 patients with high tumor mutational burden, defined as ≥ 9 mutations per megabase (mut/Mb), 5 patients, or 16.7%, responded, meeting the study’s primary endpoint. Furthermore, for the small group of highly mutated individuals with ≥ 14 mut/Mb, the response rate rose to 60.0%, reported Romualdo Barroso-Sousa, MD, PhD, of Hospital Sírio-Libanês in Brasília, Brazil, who noted that the results could apply to a subgroup of about 10% of patients with metastatic breast cancer.

Romualdo Barroso-Sousa, MD, PhD

“Breast cancer is common, and 10% of all metastatic patients is a lot of people. If about 20% of these patients can respond to this treatment, that’s a lot of people. This treatment could be a game-changer for some,” Dr. Barroso-Sousa told The ASCO Post.

Increasing evidence has suggested that patients with high tumor mutational burden are more likely to benefit from immune checkpoint inhibition, he said, “but although the prevalence of high tumor mutational burden in metastatic breast cancer is around 10%, the real benefit of checkpoint inhibition in this population is not established.”

He said the results of NIMBUS support the use of immune checkpoint inhibitors for patients with metastatic breast cancer and high tumor mutational burden, but they do not answer the question of whether dual checkpoint inhibition is better than single-agent pembrolizumab. There is currently U.S. Food and Drug Administration approval for pembrolizumab in patients with unresectable or metastatic solid tumors with ≥ 10 mut/Mb.

In the phase II TAPUR study, 21% of patients with ≥ 9 mut/Mb responded to pembrolizumab,² but as Dr. Barroso-Sousa pointed out, TAPUR and NIMBUS differ in many ways. “For one thing, the NIMBUS population was enriched for patients with hormone receptor–positive disease, whereas TAPUR was more mixed. Additionally, NIMBUS was enriched for PD-L1–negative patients, whereas we don’t have this information from TAPUR,” he said.

About the Study Patients

Building on previous studies, the hypothesis for NIMBUS was that patients with hypermutated breast cancer could benefit from dual checkpoint inhibition that combined nivolumab with low-dose ipilimumab.

NIMBUS enrolled 30 patients with HER2-negative breast cancer, either untreated or with up to three prior lines of therapy but no treatment with a checkpoint inhibitor. Approximately 27% of patients had received no prior treatment, and 23% had received three prior treatments. A total of 70% of patients had hormone receptor–positive disease, whereas 30% had triple-negative disease. Only 13% of patients included were PD-L1–positive. All patients had a tumor mutational burden ≥ 9 mut/Mb; 10% had ≥ 20 mut/Mb. The mean number of prior lines of chemotherapy in the advanced setting was 1.5.

Patients were treated with nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (cycles were 6 weeks), until disease progression or unacceptable toxicity by 24 months. Two mandatory biopsies were performed in patients with safely accessible disease: at baseline and on day 29 of cycle 1.

Durable Responses

Patients were followed for a median of 9.7 months. Of the five patients who responded, four had durable responses that lasted longer than a year. Two of these patients had discontinued treatment because of toxicities, but they still maintained objective responses for 16 and 25 months. The median duration of response was 12.1 months.

The ≥ 14 mut/Mb cutoff was one of the prespecified secondary endpoints in the study, although the main cutoff in the trial was ≥ 9 mut/Mb. Although five patients had tumor mutational burden ≥ 14 mut/Mb, three (60%) responded, showing the potential value of this treatment in highly mutated disease, he said.

Sara M. Tolaney, MD, MPH

“Further work is needed to investigate the optimal tumor mutation burden cutoff for selecting patients to receive checkpoint inhibition,” added Sara M. Tolaney, MD, MPH, senior author of this Dana-Farber investigator–initiated trial. Dr. Tolaney is Associate Professor of Medicine at Harvard Medical School and Chief, Division of Breast Oncology of the Susan F. Smith Center for Women’s Cancers at Dana-Farber/Brigham and Women’s Cancer Center, Boston.

An exploratory analysis showed no other ­significant differences in response based on cancer subtype (triple-negative vs hormone receptor–positive), by PD-L1 status (positive or negative), or by level of stromal tumor–infiltrating lymphocytes (< 10 or ≥ 10). 

In the intent-to-treat population, median progression-free survival was 1.4 months, and median overall survival was 19.3 months. By the stricter cutoff in the exploratory analysis, median progression-free survival was 9.5 months for patients with ≥ 14 mut/Mb vs 1.4 months for < 14 mut/Mb; median overall survival was not reached in the patients with tumor mutational burden > 14 mut/Mb and was 8.8 months in those with < 14 mut/Mb, he reported.

All partial responders were alive at 24 months, as were 80% of patients achieving stable disease, vs 45% of patients with disease progression as best response.

Adverse events were similar to what has been previously seen in other tumor types treated with the combination of nivolumab and ipilimumab. There were no grade 4 or 5 events, and the most common toxicities were fatigue, diarrhea, anemia, and anorexia. Fewer than 7% of patients withdrew from the study due to toxicity. 

DISCLOSURE: Dr. Barroso-Sousa has served as a consultant or advisor to AstraZeneca, ­Daiichi-Sankyo, Eli Lilly, Libbs, Pfizer, Roche, and MSD; has served on speakers’ bureaus for AstraZeneca, Bard Access, Bristol Myers Squibb, Daiichi-Sankyo, Eli Lilly, Libbs, Novartis, Pfizer, Roche, and MSD; has received support for attending medical conferences from Astrazeneca, Eli Lilly, Daichi-Sankyo, and Merck; and has received institutional research funding from Bristol Myers Squibb and Roche. Dr. Tolaney has served as a consultant or advisor to Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech, Eisai, Sanofi, Celldex, Bristol Myers Squibb, Paxman, Seattle Genetics, Odonate Therapeutics, AbbVie, Silverback Therapeutics, G1 Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Immunomedics/Gilead, Mersana, and Certara; and has received institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Immunomedics, Odonate Therapeutics, Sanofi, and Seattle Genetics.

REFERENCES

1. Barroso-Sousa R, Li T, Reddy S, et al: Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated HER2-negative metastatic breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-10. Presented December 8, 2021.

2. Alva AS, Mangat PK, Garrett-Mayer E, et al: Pembrolizumab in patients with metastatic breast cancer with high tumor mutational burden: Results from the targeted agent and profiling utilization registry (TAPUR) study. J Clin Oncol 39:2443-2451, 2021.