Trastuzumab Deruxtecan Plus Endocrine Therapy Demonstrates Antitumor Activity in HER2-Low/HR+ Metastatic Breast Cancer

Komal Jhaveri, MD, FACP

Combination therapy with anastrozole or fulvestrant plus fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated encouraging antitumor activity in patients with chemotherapy-naïve, HER2-low hormone receptor–positive metastatic breast cancer, according to data from the phase 1b DESTINY-Breast08 trial (NCT04556773) presented by Komal Jhaveri, MD, FACP, during the 2023 San Antonio Breast Cancer Symposium (SABCS).

Findings from the study showed that patients in the trastuzumab deruxtecan plus anastrozole arm (n = 21) achieved a confirmed objective response rate (ORR) of 71.4% (95% CI, 47.8%-88.7%) vs 40.0% (95% CI, 19.1%-64.0%) in the trastuzumab deruxtecan plus fulvestrant arm (n = 20); the median duration of response (DOR) was 9.8 months (95% CI, 6.7-not estimable [NE]) vs NE (95% CI, 4.1-NE), respectively. The median progression-free survival (PFS) was 13.4 months (95% CI, 8.5-19.4) in the anastrozole arm vs NE (95% CI, 5.6-NE) in the fulvestrant arm; 6-month PFS rates were 80.7% (95% CI, 56.3%-92.3%) vs 75.3% (95% CI, 46.4%-90.0%) and the 12-month PFS rates were 50.4% (95% CI, 27.5%-69.5%) compared with 52.7% (95% CI, 25.0%-74.4%), respectively.

Jhaveri noted that efficacy results should be interpreted with caution due to the small number of patients in each arm. Additionally, 15% of patients in the trastuzumab deruxtecan plus fulvestrant arm withdrew consent, discontinuing treatment prior to disease progression. The median follow-up was also slightly shorter in the in trastuzumab deruxtecan plus fulvestrant arm at 15.2 months (range, 2.2-22.6) compared with 20.2 months (range, 4.9-24.8) in the trastuzumab deruxtecan plus anastrozole arm.

The multicenter, open-label study enrolled patients with locally assessed HER-low hormone receptor–positive advanced or metastatic breast cancer. Patients could have received a maximum of 1 prior line of endocrine therapy with or without a targeted agent for metastatic disease, however, no prior chemotherapy in the metastatic setting was allowed. Additionally, needed to have 1 measurable lesion per RECIST 1.1 and an ECOG performance status of 0 or 1. The primary end point was safety and tolerability. Secondary end points included ORR, PFS, DOR, and overall survival.

Results from the part 2 dose-expansion phase were presented from the trastuzumab deruxtecan plus anastrozole arm and the trastuzumab deruxtecan plus fulvestrant arm. Trastuzumab deruxtecan 5.4 mg/kg was administered every 3 weeks, anastrozole 1 mg daily, and fulvestrant 500 mg every 4 weeks with a 500 mg loading dose on cycle 1 day 15. An additional 2 arms of the trial examined trastuzumab deruxtecan plus capecitabine or capivasertib (Truqap) in patients with hormone receptor–negative disease but were not presented at SABCS.

At baseline, patients in the trastuzumab deruxtecan plus anastrozole arm were a median age of 55.0 years old (range, 29-75) compared with 65.5 years old (range, 31-73) in the trastuzumab deruxtecan plus fulvestrant arm. Patients had a HER2 status of IHC 1+ (76.2% vs 65.0%) or IHC 2+/ISH- (23.8 vs 35.0%); endocrine receptor (ER)-positive and progesterone receptor (PR)-positive (66.7% vs 50.0%), ER-positive and PR-negative (33.3% vs 45.0%), or ER-positive and PR missing (0.0% vs 5.0%) disease; and an ECOG performance status of 0 (57.1% vs 85.0%), 1 (38.1% vs 15.0%), or 2 (4.8% vs 0.0%) in the trastuzumab deruxtecan plus anastrozole arm vs trastuzumab deruxtecan plus fulvestrant arm, respectively.

“Safety evaluations were comparable to the safety [profile] of the individual agents alone,” Jhaveri, a breast oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York, said during the presentation. “One patient [died] on study and this was attributed to disease progression and drug-induced pneumonitis by the investigator, but per the adjudication committee, the interstitial lung disease [ILD] was not [determined] to be drug induced. There were there were a total of 5 cases of drug-induced pneumonitis or ILD all of which were grade 2. At the data cutoff, 2 had resolved, 1 was resolving, and 2 were not resolved. Four of these 5 patients had at least 1 potential risk factor for developing ILD/pneumonitis.”

Regarding safety, common any-grade adverse effects (AEs) observed in the anastrozole vs fulvestrant arms included nausea (66.7% vs 95.0%), alopecia (42.9% vs 50.0%), fatigue (42.9% vs 15.0%), anemia (33.3% vs 25.0%), COVID-19 (33.3% vs 25.0%), and decreased appetite (33.3% vs 55.0%), among others. AEs led to dose interruption (57.1% vs 45.0%), reduction (28.6% vs 20.0%), and discontinuation (19.0% vs 30.0%) of trastuzumab deruxtecan, respectively. Further, AEs of grade 3 or higher severity occurred in 47.6% vs 55.0% of patients in the anastrozole vs fulvestrant arms, respectively.

The median actual treatment duration in the anastrozole arm was 10.4 months (range, 2.8-22.2) for trastuzumab deruxtecan and 11.0 months (range, 1.4-22.4) for anastrozole. In the fulvestrant arm, median actual treatment duration was 6.3 months (range, 1.4-21.9) for trastuzumab deruxtecan and 8.3 months (range, 1.8-22.5) for fulvestrant.

Additionally, 33.3% of patients in the anastrozole arm did not receive a prior line of treatment for metastatic disease compared with 30.0% of patients in the fulvestrant arm. Investigators noted that as of August 16, 2023, 6 patients were ongoing treatment in the anastrozole arm vs 7 patients in the fulvestrant arm; disease progression was the primary reason for treatment discontinuation.

“Trastuzumab deruxtecan in combination with anastrozole or fulvestrant was active in chemotherapy-naive patients with HER2-low hormone receptor–positive metastatic breast, cancer demonstrating encouraging antitumor activity,” Jhaveri concluded. “However, these are small data sets that limit the interpretation of the efficacy results and further research to evaluate trastuzumab deruxtecan in combination with endocrine therapies is warranted.”

Editor’s note: Dr Jhaveri cited receiving funding from AstraZeneca, BluePrint Medicines, Genentech/Roche, Gilead, Lilly Pharmaceuticals/Loxo Oncology, Merck & Co, Novartis, Pfizer, Scorpion Therapeutics, and Zymeworks. He also cited receiving consulting fees from AbbVie, AstraZeneca, Biotheranostics, BluePrint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Genentech/Roche, Gilead, Jounce Therapeutics, Lilly Pharmaceuticals/Loxo Oncology, Menarini/Stemline, Novartis, Olema Pharmaceuticals, Pfizer, Scorpion Therapeutics, Seagen, Sun Pharma Advanced Research Company, and Taiho Oncology.

Reference

Jhaveri K, André F, Hamilton E, et al. Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08). Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX; Abstract RF02-03