The NCCN guidelines have been amended to include trastuzumab deruxtecan for use in patients with HER2-low metastatic breast cancer and sacituzumab govitecan for use in patients with triple-negative breast cancer or hormone receptor–positive, HER2-negative disease.
Following the presentation of “compelling” evidence supporting the use of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-low metastatic breast cancer (MBC) and the use of sacituzumab govitecan-hziy (Trodelvy) for patients with triple-negative breast cancer (TNBC) or hormone receptor–positive, HER2-negative disease, the National Comprehensive Cancer Network (NCCN) has updated its breast cancer guidelines to include the 2 agents.1
NCCN breast cancer committee chair William J. Gradishar, MD, said the committee had fielded several requests for guidance on the antibody-drug conjugates following the presentation of results from the phase 3 TROPiCS-02 (NCT03901339) and DESTINY-Breast04 (NCT03734029) trials at the 2022 ASCO Annual Meeting. The strength of the data compelled the committee to update its recommendations.
“For certain drugs to be approved, or certain strategies to be approved, insurers want to see that they’re on the NCCN guidelines,” Gradishar, chief of Hematology and Oncology in the Department of Medicine and the Betsy Bramsen Professor of Breast Oncology at Northwestern University Feinberg School of Medicine, said in an interview with OncLive®. “We weren’t being pushed by anybody, but we felt it was a service to patients, as long as the data was good, that both of these [agents were] included.”
TROPiCS-02 enrolled 543 patients with hormone receptor–positive, HER2-negative MBC who were relapsed/refractory following at least 2 prior systemic chemotherapy regimens for metastatic disease, including at least 1 prior anticancer hormonal treatment and at least 1 CDK4/6 inhibitor administered in the metastatic setting. At a median follow-up of 10.2 months, the median progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.0) with sacituzumab govitecan vs 4.0 months (95% CI, 3.1-4.4) with investigator’s choice chemotherapy (HR, 0.66; 95% CI, 0.53-0.83; P < .0003).2
At 6 months, 46% of patients who received sacituzumab govitecan (n = 272) were alive without worsening disease compared with 30% who received chemotherapy (n = 271). At 12 months the PFS rates were 21% vs 7%, respectively.
“The changes were subtle, but they now include, particularly for HER2-low [disease], options,” Gradishar said. “For sacituzumab govitecan, it’s not only for somebody who is triple negative. [The patient] could be endocrine refractory.”
Findings from DESTINY-Breast04 (n = 557) were presented at the 2022 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.3,4 Investigators defined HER2-low status as an immunohistochemistry score of 1+ or 2+ with a negative in situ hybridization test, representing approximately 65% of breast cancer diagnoses. Overall, 88.7% of patients were hormone receptor positive and 11.3% were negative.
Trastuzumab deruxtecan induced a median PFS of 10.1 months (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) for chemotherapy in patients with hormone receptor–positive, HER2-low disease (HR, 0.51; 95% CI, 0.40-0.64; P < .0001). The median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) with trastuzumab deruxtecan compared with 17.5 months (95% CI, 15.2-22.4) for chemotherapy (HR, 0.64; 95% CI, 0.40-0.86; P = .003).
The median PFS was 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan across the entire study population compared with 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63). The median OS in this group was 23.4 months (95% CI, 20.0-24.8) with trastuzumab deruxtecan compared with 16.8 months (95% CI, 14.5-20.0) for chemotherapy, representing a 6.6-month improvement in survival with the ADC (HR, 0.64; 95% CI, 0.49-0.84; P = .001).
In patients with hormone receptor–negative disease, the median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan and 2.9 months (95% CI, 1.4-5.1) for chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). The median OS in the hormone receptor–negative cohort was 18.2 months (95% CI, 13.6-not estimable) with trastuzumab deruxtecan vs 8.3 months (95% CI, 5.6-20.6) with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).
“Particularly with DESTINY-Breast04, for a large, randomized trial, both PFS and overall survival were statistically significant. It affects a huge pool of patients that fall into that HER2-low group,” Gradishar said. “These are patients who would typically go on to single agent chemotherapy and they don't necessarily do so well. So, when you have a pretty big trial by anybody’s measure and it was well done and the results aren’t subtle, but pretty glaring with respect to the advantage of trastuzumab deruxtecan, we felt that agent should go on [the guidelines].
On June 22, 2022, the European Medicines Agency (EMA) validated a Type II Variation application for trastuzumab deruxtecan monotherapy for adults with unresectable or metastatic HER2-low breast cancer.5
Validation confirms that the application is complete and commences the scientific review process by the EMA’s Committee for Medicinal Products for Human Use (CHMP). A Type II variation represents a major change to a drugs marketing authorization that may have a significant impact on the quality, safety or efficacy of a medicine, but does not involve a change to the active substance, strength, or method of administration. Such a change requires a formal approval.6 The CHMP typically releases an opinion, or requests more information on a Type II application, 60 days after initiating the evaluation.7