Clinical Activity Found With Triplet Combination and ADCs in HER2-Mutant MBC

The combination of neratinib (Nerlynx) and trastuzumab (Herceptin), with or without fulvestrant (Faslodex), demonstrated beneficial clinical activity in patients with heavily pretreated hormone receptor (HR)–positive, HER2-negative, HER2-mutant metastatic breast cancer (MBC). Komal Jhaveri, MD, FACP, presented these data along with the effectiveness of HER2-directed antibody-drug conjugates (ADCs) in patients with HER2-mutant breast cancer at the 21st Annual International Congress on the Future of Breast Cancer® East hosted by Physicians Education Resource, LLC (PER®) in New York, New York.¹

Results from the SUMMIT basket study (NCT01953926) revealed encouraging results with the triplet regimen in patients with HR-positive/HER2-negative MBC compared with other variations and monotherapies of the 3 drugs.² The study also assessed use of neratinib and trastuzumab alone among patients with triple-negative breast cancer (TNBC).

Patients with HR-positive MBC with prior CDK4/6 inhibition who received the triplet (n = 51) had an objective response rate (ORR) of 35.3% (n = 18), whereas patients who received fulvestrant plus trastuzumab or fulvestrant alone had no responses before crossing over to receive the triplet. Of the 18 responses with the triplet combination, 17 patients had partial response (PRs) and 1 patient had a complete response (CR). Best overall responses, whether confirmed or unconfirmed, to treatment with the triplet occurred in 25 patients (49.0%). The triplet regimen also had a median duration of response (DOR) of 14.3 months (95% CI, 6.4-not estimable [NE]) and a clinical benefit rate of 47.1%. The median progression-free survival (PFS) for patients receiving neratinib, trastuzumab, and fulvestrant was 8.2 months (95% CI, 4.7-12.7) compared with 3.9 months (95% CI, 1.9-4.1) with fulvestrant plus trastuzumab before crossover and with 4.1 months (95% CI, 1.6-4.1) with fulvestrant monotherapy before crossover.

The phase 2 SUMMIT trial had a Simon 2-stage design. The primary end point was ORR in patients with HR-positive tumors and ORR at first assessment for patients with TNBC. The secondary end point was confirmed ORR per investigator review.

The most common any-grade adverse events (AEs) among patients with HR-positive disease who received the triplet were diarrhea (90.2%), nausea (72.5%), vomiting (52.9%), and fatigue (43.1%). The most common grade 3 AEs in this group were diarrhea (51.0%), vomiting (7.8%), decreased appetite (7.8%), and fatigue (5.9%). Two grade 4 AEs were also reported: coma (n = 1) and muscle weakness (n = 1).

The neratinib/trastuzumab doublet also showed beneficial results among patients with TNBC (n = 18). The ORR was 33.3% (n = 6), with 1 CR (5.6%) and 5 PRs (27.8%). The best overall response rate was 38.9%. The median DOR was NE, and the clinical benefit rate was 38.9%. The median PFS was 6.2 months (95% CI, 2.1-8.2). The median duration of treatment was 4.4 months (range, 0.3-15.4).

The most common any-grade AEs in patients with TNBC who received the doublet regimen were diarrhea (88.9%), nausea (50.0%), vomiting (50.0%), and constipation (38.9%). The most common grade 3/4 AEs were diarrhea (16.7%) and fatigue (16.7%). Thirteen patients (72.2%) discontinued treatment because of disease progression.

ADC’s In HER2-Mutant Tumors

Jhaveri, an associate attending in the Breast Medicine and Early Drug Development Service, section head of the Endocrine Therapy Research Program, and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, explained the value of ADCs in HER2-mutant tumors, “What we're now beginning to learn with these novel antibody-drug conjugates, which have a higher drug to antibody ratio of cleavable linker and novel payloads, is that they exhibit bystander effect, which is not only causing apoptosis of the cancer cell, but it also causes killing of the neighboring cancer cells.”

The DESTINY-Breast04 (NCT03734029) trial is a phase 3 multicenter, randomized, open-label, active-controlled trial study of trastuzumab deruxtecan (T-DXd; Enhertu) vs treatment of physician’s choice in patients with unresectable or metastatic disease and low HER2 expression (IHC1+ or IHC2+/ISH–).3 Investigators randomized patients to receive T-DXd 5.4 mg/kg once every 3 weeks (n = 373) or physician’s choice of either capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane) (n = 184). The primary end point was PFS in the HR-positive population, and the secondary end points were PFS in all patients, overall survival (OS), ORR, and DOR.

The median PFS for the primary end point was 10.1 months with T-DXd vs 5.4 months with physician’s choice (HR, 0.51; 95% CI, 0.40-0.65; P < .001). The median PFS across the whole patient population was 9.9 months with T-DXd vs 5.1 months with physician’s choice (HR, 0.50; 95% CI, 0.40-0.63; P < .001). The median OS for patients with HR-positive tumors was 23.9 months with T-DXd vs 17.5 months with physician’s choice of therapy (HR, 0.64; 95% CI, 0.48-0.86; P = .003). The median OS among all patients was 23.4 months with T-DXd vs 16.8 months with physician’s choice (HR, 0.64; 95% CI, 0.49-0.84; P = .001). Patients with HR-negative and HER2-low tumors had a median PFS of 8.5 months with T-DXd vs 2.9 months (HR, 0.46; 95% CI, 0.24-0.89), and the median OS for this patient group was 18.2 months with T-DXd vs 8.3 months with physician’s choice (HR, 0.48; 95% CI, 0.24-0.95).

Any-grade AEs in patients treated with T-DXd were most commonly nausea (73%) and fatigue (48%), and alopecia (38%). The most common grade 3 AEs were neutropenia (14%), anemia (8%), and fatigue (8%). Jhaveri called special attention to drug-related interstitial lung disease (ILD)/pneumonitis and any-grade ILD/pneumonitis. This event occurred in 45 patients (12.1%) with 13 patients having grade 1, 24 as grade 2, 5 as grade 3, none as grade 4, and 3 as grade 5 events.

Activity with T-DXd was also reported in patients with HER2-low and HER2-negative MBC in the phase 2 DAISY trial (NCT04132960).⁴ Patients were stratified by HER2 status into 3 cohorts: HER2 overexpressing (cohort 1), HER2 low (cohort 2), and HER2 non-expressing (cohort 3). The best overall response rate was 71% in cohort 1, 38% in cohort 2, and 30% in cohort 3. The median DOR was 9.7 months in cohort 1, 7.6 in cohort 2, and 6.8 months in cohort 3. The median PFS 11.1 months in cohort 1, 6.7 months in cohort 2, and 4.2 months in cohort 3. However, there was no HER2 IHC scoring system optimized to distinguish a score of HER2 0 from HER2 1+.These results from the DAISY trial are promising but require validation.

_REFERENCES:

_{1. Jhaveri, Komal. What’s new for HER2-mutant and HER2-low metastatic breast cancers. Presented at the 21st Annual International Congress on the Future of Breast Cancer® East; July 15-16, 2022; New York, NY.}

_{2. Oaknin A, Friedman CF, Roman LD, et al. Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial. Gynecol Oncol. 2020;159(1):150-156. doi:10.1016/j.ygyno.2020.07.025}

_{3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690}

_{4. Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Session GS3-01.}