Search

LBA3 Background: About 55% of mBC typically categorized as HER2 negative, express low levels of HER2 (IHC 1+ or IHC 2+/ISH− by ASCO/CAP 2018 guidelines) with poor outcomes in later lines (Tarantino 2020). T-DXd has shown promising efficacy in HER2-low mBC in a phase 1 study (NCT02564900; Modi 2020). This is the primary report from DESTINY-Breast04 (NCT03734029), the first randomized, multicenter, open-label, phase 3 study comparing efficacy and safety of T-DXd vs TPC in pts with HER2-low mBC treated with 1-2 prior lines of chemotherapy in the metastatic setting. Methods: 557 pts with centrally confirmed HER2-low mBC were randomly assigned 2:1 to T-DXd 5.4 mg/kg or TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR) in pts with hormone receptor–positive (HR+) mBC. Key secondary endpoints (hierarchically tested after the primary endpoint) include PFS by BICR in the full analysis set (FAS; HR+/−) and overall survival (OS) in pts with HR+ mBC and in FAS. Other endpoints were objective response rate, duration of response, safety, and an exploratory analysis of pts with HR− mBC. Results: As of Jan 11, 2022, 373 and 184 pts (88.7% and 88.6% HR+ mBC) were assigned to T-DXd and TPC, respectively. Median follow-up was 18.4 months (mo; 95% CI, 17.9-19.1). Median treatment duration was 8.2 mo (range, 0.2-33.3) with T-DXd and 3.5 mo (range, 0.3-17.6) with TPC. Efficacy results are in the Table. 52.6% of pts with T-DXd vs. 67.4% of pts with TPC had grade (G) ≥ 3 treatment-emergent adverse events (TEAEs). With T-DXd, 45 pts (12.1%; 10.0% G1/2, 1.3% G3/4, 0.8% G5) had independently adjudicated drug-related interstitial lung disease [ILD]/pneumonitis vs. 1 pt (0.6% G1) with TPC. Conclusions: DESTINY-Breast04 is the first phase 3 trial of a HER2-directed therapy in pts with HER2-low mBC to show a statistically significant and clinically meaningful benefit in PFS and OS compared to standard-of-care treatment, regardless of HR status, with a generally manageable safety profile. Funding: Daiichi Sankyo, Inc., and AstraZeneca. Clinical trial information: NCT03734029. [Table: see text]

1000 Background: In the DESTINY-Breast03 (NCT03529110) primary analysis (data cutoff [DCO], May 21, 2021), T-DXd showed superiority over T-DM1 in pts with HER2+ mBC, with a significant improvement of progression-free survival by blinded independent central review (HR, 0.284; 95% CI, 0.217-0.373; P < 0.001), and a safety profile consistent with prior studies. This analysis provides updated safety data with longer follow-up. Methods: Pts were randomized 1:1 to T-DXd or T-DM1. Prespecified safety analysis of treatment-emergent adverse events (TEAEs) was conducted; endpoints included time to event, duration of event, and resolution. Results: At DCO (September 7, 2021), 116 (45.1%) pts vs 39 (14.9%) pts remained on treatment in the T-DXd vs T-DM1 arms; median treatment duration was 16.1 mo (range, 0.7-33.0) for T-DXd vs 6.9 mo (range, 0.7-28.5) for T-DM1. Any-grade (G), G≥3, and serious AE (SAE) rates were similar for T-DXd vs T-DM1 (99.6% vs 95.4%; 53.3% vs 49.8%; and 21.0% vs 19.2%), while exposure-adjusted incidence rates (EAIRs; per pt-year) for G≥3 and SAEs were lower for T-DXd vs T-DM1 (0.42 vs 0.70 and 0.17 vs 0.27). Median time to TEAE associated with drug discontinuation or dose reduction was longer with T-DXd vs T-DM1 (224.0 vs 147.0 d and 96.0 v 19.0 d, respectively). Most TEAEs in ≥20% of pts were hematologic or gastrointestinal. Median time to first onset of select any-G TEAEs was 70.0 vs 42.0 d for anemia, 196.0 vs 168.0 d for lymphopenia, 132.0 vs 8.0 d for thrombocytopenia, 22.0 vs 24.0 d for fatigue, 74.5 vs 92.0 d for leukopenia, and 64.0 vs 105.0 d for neutropenia, with T-DXd vs T-DM1, respectively. In both arms, most nausea and vomiting events were G1/2; while G≥3 events with T-DXd vs T-DM1 were 6.6% vs 0.4% for nausea and 1.6% vs 0.8% for vomiting, respectively. Rates of nausea, vomiting, and alopecia were highest in cycle 1 and lower in subsequent cycles for T-DXd. Rates of hematologic events were generally lower in earlier cycles vs cycle ≥8 in both arms. Rates of adjudicated, drug-related ILD/pneumonitis were 10.9% (1 G2 event since previous DCO) with T-DXd vs 1.9% with T-DM1, with no G4/5 events. Median time to first adjudicated, drug-related ILD/pneumonitis event was 5.9 vs 9.5 mo for T-DXd vs T-DM1, respectively; at DCO, most events resolved (57.1% vs 80.0%), and follow-up is ongoing. Conclusions: In this updated safety analysis, T-DXd demonstrated a tolerable safety profile consistent with prior studies. Despite longer treatment duration with T-DXd, EAIRs of G≥3 and SAEs were lower for T-DXd vs T-DM1. Rates of ILD/pneumonitis for T-DXd were similar to those in the previous DCO. Nausea, vomiting, and alopecia rates decreased over time. This longer safety update reinforces the consistent safety profile of T-DXd, supporting the clinical benefit of T-DXd over T-DM1 in patients with HER2+ mBC. Clinical trial information: NCT03529110.

526 Background: Patients (pts) with HER2+ metastatic breast cancer (mBC) are at high risk of developing brain metastases (BMs), and treatment options are limited once BMs occur. T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. On the basis of findings of the phase 2 DESTINY-Breast01 trial (NCT03248492), T-DXd was approved for the treatment of adult pts with HER2+ unresectable or mBC who have received ≥2 prior anti-HER2–based regimens (US and Europe) or had prior chemotherapy and are refractory to or intolerant of standard treatments (Japan). Here we describe a subgroup analysis from DESTINY-Breast01 in pts with a history of BMs. Methods: DESTINY-Breast01 is an ongoing, 2-part, multicenter, open-label, phase 2 trial of T-DXd in adult pts with HER2+ unresectable or mBC previously treated with trastuzumab emtansine. Pts with baseline BMs that were treated, asymptomatic, and did not require therapy to control symptoms were eligible for enrollment. All treatment to control symptoms had to be completed ≥60 days before randomization. An MRI of the brain every 6 wks was only required for pts with BMs at baseline. Brain lesions were considered non-target lesions, and thus collection of diameter measurements was not required. This analysis includes pts with a history of BMs at baseline who received T-DXd at the approved dose of 5.4 mg/kg every 3 wks. Results: Twenty-four pts with a history of BMs were included (data cutoff, August 1, 2019). In these pts, the objective response rate (ORR), median progression-free survival (mPFS), and median duration of response (mDoR) per independent central review with T-DXd 5.4 mg/kg were 58.3% (95% CI, 36.6%-77.9%), 18.1 mo (95% CI, 6.7-18.1 mo), and 16.9 mo (95% CI, 5.7-16.9 mo), respectively, and were comparable to those in the total pt population (N = 184) treated at 5.4 mg/kg in the DESTINY-Breast01 study (ORR, 60.9%; mPFS, 16.4 mo; mDoR, 14.8 mo; median follow-up, 11.1 mo). The pattern of disease progression was similar in pts with and without BMs with 8 of 24 pts having progressed (33%; 2 in the brain) in the BMs subgroup and 40 of 160 pts (25%; 2 in the brain) in the non-BMs subgroup, suggesting durable systemic disease control. Baseline diameters of BMs were available for 14 of 24 pts (radiotherapy prior to study enrollment was reported in 12 of 14). Among the pts with information available on baseline BM diameter, the central nervous system response rate per investigators was 50% (7 of 14 pts). Conclusions: T-DXd showed strong clinical activity in both the overall population of pts with HER2+ mBC and the subgroup of pts with BMs. The demonstrable response of BMs to treatment and durable clinical activity of T-DXd in pts with a history of BMs at baseline are promising and warrant further investigation. Clinical trial information: NCT03248492.

1036 Background: Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor. In the pivotal DESTINY-Breast01 trial, efficacy of T-DXd in HER2-positive metastatic breast cancer (mBC) was demonstrated, with an objective response rate (ORR) of 60.9% and median progression-free survival (mPFS) of 16.4 months. Methods: DESTINY-Breast01 was a single-group, open-label, multicenter, phase II trial of 184 patients with HER2-positive mBC previously treated with trastuzumab emtansine (T-DM1) who received T-DXd at 5.4 mg/kg. Multivariate analysis using logistic regression models (ORR) and Cox proportional hazards models (duration of response [DOR], mPFS) explored 15 relevant clinical predictor variables. Circulating tumor DNA (ctDNA) was collected prior to the first dose, every 3 cycles of treatment, and at the end of treatment. Sequencing was done via GuardantOMNI (Guardant Health) for single-nucleotide variation/insertion and deletion, amplification, and fusion of ≈ 500 genes. Results: Efficacy in all evaluated clinical subgroups was similar to the overall ORR 60.9% and mPFS 16.4 months with ranges from ORR 46.4%-74.5% and mPFS 12.3-18.1 months. Variables associated with improved ORR, DOR, or mPFS included hormone receptor positive status, fewer prior treatment regimens (continuous variable), pertuzumab given in the first or second line, and normal renal and hepatic function. Variables that did not impact efficacy outcomes compared to the overall population include age, race, region, ECOG PS, HER2 IHC 3+ status, progesterone receptor status, best response to T-DM1, time since diagnosis, and history of brain metastases. In 48 subjects with progression as of data cut date, metastases were most commonly observed in the liver, lung, and lymph nodes. Only 8% (4 of 48) had progression involvement in the brain upon disease progression. Decrease of ERBB2 copy number in ctDNA was seen on treatment and correlated with clinical response. Additional changes in molecular markers on treatment and following progression will be described. Conclusions: T-DXd demonstrated strong efficacy in all clinical subgroups analyzed. Further exploration of both clinical and molecular variables to determine biomarkers of efficacy may be warranted. Clinical trial information: NCT03248492 .

TPS1102Background: There is no standard of care for HER2-positive breast cancer refractory to T-DM1. DS-8201a is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attache...

148 Background: Aromatase inhibitor (AI) is a most commonly used as the endocrine therapy in postmenopausal hormone-dependent breast cancer. Paradoxically, estrogen additive therapy using ethinylestradiol can be useful after long-term estrogen deprivation therapies with AI. Furthermore, there is a possibility of the beneficial effect of AI or fulvestrant as a subsequent endocrine therapy after EE2 failure. Methods: Ethinylestradiol (EE2; 3mg/day, TID) therapy was performed in 20 patients with metastatic breast cancer (median; 62 years-old, the mean observation time: 13.6 months.), who were heavily treated by sequential endocrine therapies (3rd or more line) including cytotoxic chemotherapies. We examined the efficacy of a subsequent endocrine therapy of AI or fulvestrant after becoming resistance to the EE2 therapy in the patients who got the disease control by the prior EE2 therapy. The primary endpoint was clinical benefit rate (CBR) and the secondary endpoint was time to treatment failure (TTF). (Registration number; UMIN 000002831, additional analysis). Results: Median TTF of EE2 treatment was 46 weeks (23-62+, 2 cases were ongoing). The response rate was 41% (9/22), the clinical benefit rate was 50% (11/22). The stable disease (< 6 months) was 18% (4/22) and another 3 cases were judged as progressive disease. Four cases withdrew due to nausea, fatigue and muscle-skeletal pain. In 20 cases progressed after disease control (SD or more) of EE2, a subsequent endocrine therapy, fulvestrant for 10 cases and AI for 10 cases, was performed. Fulvestrant group showed 50% (3 in 6) of CBR and 15 weeks (5-55+) of TTF, and AI-treated group showed 43% (3 in 7) of CBR and 19 weeks (5-33+) of TTF. Two in three cases, who became resistance to anti-estrogen treatment, got long SD by further EE2 re-therapy. Conclusions: Some cases showed clinical benefits of a subsequent therapy by AI or fulvestrant after becoming to EE2 failure. Taken together, sequential use of estrogen and anti-estrogen therapy (vice versa) could be one of the options as a salvage endocrine therapy for the patients with end-stage breast cancer.