Background

DESTINY-Breast04 (NCT03734029) demonstrated significantly improved overall and progression-free survival (PFS) with T‑DXd vs TPC in pts with HER2‑low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-negative) mBC, with manageable safety. Here, we report additional safety data.

Methods

Pts with centrally confirmed HER2‑low mBC, treated with 1-2 prior lines of chemotherapy, were randomly assigned 2:1 to receive T‑DXd or TPC. An analysis of selected treatment-emergent adverse events (TEAEs) and age (<65 vs ≥65 years [y]) was done; endpoints included time to first onset (TTO), duration of first event (DUR), and resolution.

Results

At data cutoff (January 11, 2022), median (m) treatment duration was 8.2 months (mo; range [r], 0.2-33.3) for T‑DXd vs 3.5 mo (r, 0.3-17.6) for TPC. Exposure-adjusted incidence rates (EAIRs; per pt-y) for any-grade TEAEs were lower for T‑DXd vs TPC (1.30 vs 2.66). mTTO and mDUR of any-grade interstitial lung disease (ILD) in pts treated with T‑DXd were 129 days (d; r, 26-710 d) and 47 d (r, 13-365 d). 13 pts had adjudicated drug-related grade 1 ILD; of those pts, 6 were rechallenged with T‑DXd after resolution (details to be presented). Incidence of any‑grade drug-related neutropenia (NP) and febrile NP was lower for T‑DXd vs TPC; subsequent granulocyte colony-stimulating factor use was 6.7% vs 19.8%. Nausea/vomiting (N/V) events in T‑DXd vs TPC were 79.5% vs 35.5%. T‑DXd-treated pts received more antiemetic prophylaxis (AP; 50.9%) vs TPC‑treated pts (37.2%); 92.3% of T‑DXd and 68.8% of TPC N/V events in AP‑treated pts resolved. Incidence of any-grade drug-related TEAE was consistent between pts aged <65 y and ≥65 y. For T‑DXd, incidence of grade ≥3 TEAEs and TEAEs associated with drug discontinuations (DD) was higher in pts aged ≥65 y compared to those aged <65 y; the most common TEAE associated with DD was ILD/pneumonitis. However, mPFS favored T‑DXd over TPC in all patients, regardless of age. EAIR, TTO, and DUR data for selected TEAEs will be presented.

Conclusions

T‑DXd demonstrated a manageable safety profile to support its use as the new standard of care in pts with HER2-low mBC.

Clinical trial identification

NCT03734029

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Elize Wolmarans, PhD, and Soniya Patel, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Background

In DESTINY-Breast02 (NCT03523585), T-DXd improved progression-free and overall survival vs TPC in pts with HER2+ mBC who were resistant/refractory to trastuzumab emtansine (T-DM1) (Krop et al. SABCS 2022). Here, we report data on PROs and health-related quality of life (QoL).

Methods

Pts with HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization amplified) T-DM1–resistant/refractory mBC were assigned 2:1 to T-DXd or TPC (trastuzumab + capecitabine or lapatinib + capecitabine). PROs were collected and measured at prespecified timepoints using the European Organization for Research and Treatment of Cancer QoL questionnaires (EORTC QLQ)-C30, the breast-cancer–specific EORTC QLQ-BR45 (scored as EORTC QLQ-BR23), and the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analog scale. Change from baseline (CFB) and time to definitive deterioration (TDD) were assessed. QLQ-C30 global health status (GHS)/QoL score was the primary variable of interest.

Results

In the T-DXd (n = 406) and TPC (n = 202) arms (median treatment duration of the safety analysis set: 11.3 vs ~4.5 mo), questionnaire compliance was >92% at baseline and >76% at cycles 3-29. Mean CFB of GHS/QoL remained stable (within ±10 points) up to cycle 39 for T-DXd and cycle 21 for TPC, after which the number of pts on treatment was not informative (n < 10%). Median TDD was longer with T-DXd vs TPC for GHS/QoL (14.1 vs 5.9 mo; HR, 0.56 [95% CI, 0.44-0.71]) and for all measured QLQ-C30 subscales, including physical functioning (18.7 vs 6.8 mo; HR, 0.46 [95% CI, 0.36-0.60]) and pain (18.7 vs 5.8 mo; HR, 0.38 [95% CI, 0.29-0.49]), with the exception of nausea/vomiting (5.7 vs 6.1 mo; HR, 1.09 [95% CI, 0.86-1.39]). With T-DXd vs TPC, pts experienced prolonged TDD on the QLQ-BR23 arm symptom subscale (18.3 vs 8.8 mo; HR, 0.57 [95% CI, 0.44-0.75]).

Conclusions

Mean CFB in GHS/QoL suggested that overall health and QoL were maintained in T-DXd-treated pts. TDD was longer on all measured QLQ-C30 subscales, except for nausea/vomiting, for pts receiving T-DXd vs TPC. These results continue to support the benefit of T-DXd in pts with T-DM1–resistant HER2+ mBC.

Clinical trial identification

NCT03523585

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Caylin Bosch, PhD, and Toinette Labuschagné, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Background

Capivasertib is a potent, selective pan-AKT inhibitor. In the Phase 3 CAPItello-291 trial in pts with AI-resistant, HR+/HER2– ABC, the addition of capivasertib to fulvestrant (fulv) significantly improved the dual primary endpoints of PFS in the overall (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.51–0.71; p<0.001) and AKT pathway-altered population (HR 0.50; 95% CI 0.38–0.65; p<0.001) compared with placebo plus fulv. Here we report PFS in key clinically relevant subgroups (data cut-off Aug 15, 2022).

Methods

Pts were randomised 1:1 to receive fulv (500 mg IM on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle) with either placebo or capivasertib (400 mg twice daily; 4 days on, 3 days off). Randomisation was stratified by the presence of liver metastases, prior use of CDK4/6 inhibitor (CDK4/6i) and region. Preplanned exploratory PFS analyses included prior use of CDK4/6i, prior chemotherapy (CT) for ABC, and presence of liver metastases.

Results

Overall, 708 pts were randomised to capivasertib-fulv (n=355) or placebo-fulv (n=353): 289 pts (40.8%) had AKT pathway-altered tumours; 496 pts (70.1%) had received prior CDK4/6i; 129 pts (18.2%) had received prior CT for ABC, and 306 pts (43.2%) had liver metastases. PFS benefit of capivasertib-fulv over placebo-fulv was broadly consistent across key clinical subgroups (Table). In cross-subgroup comparison, placebo-fulv efficacy was lower in pts with prior CDK4/6i exposure and pts with liver metastases. Findings in the AKT pathway-altered population were consistent with the overall population and will be presented.

Conclusions

Exploratory PFS analyses confirmed a consistent benefit of treatment with capivasertib-fulv vs fulv alone in clinically relevant subgroups, including pts with prior CDK4/6i exposure or liver metastases, subgroups with poor prognosis on fulv alone.

Clinical trial identification

https://clinicaltrials.gov/: NCT04305496

Actual Primary Completion Date: August 15, 2022

Estimated Study Completion Date: June 7, 2024

Editorial acknowledgement

AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc.

Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

Background

The phase 3 EMERALD trial (NCT03778931) reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with elacestrant vs SoC endocrine therapy (ET) in patients (N=478) with ER+/HER2− advanced or mBC following progression on prior CDK4/6i plus ET. PROs measuring quality of life (QoL) are reported here.

Methods

EMERALD patients (pts) completed 3 PRO tools at prespecified time points: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the EuroQoL 5 Dimension 5 Level (EQ-5D-5L).

Results

The ratio of PROs tools completed vs. PROs tools expected was 80-90% through cycle 4 and approximately 70% at cycle 6; likely due to clinical study period overlapping with COVID-19 period. Overall, the EORTC QLQ-C30 scores were similar for elacestrant and SoC, with no differences across all time points for both functional and symptom scales. However, PRO-CTCAE results showed that fewer pts who received elacestrant reported very severe nausea (4.0% vs 14.3% by cycle 6) or very severe vomiting (9.1% vs 50% by cycle 6) compared with SoC. There were no clinically meaningful differences across all time points in adverse events typically observed with pts with cancer on ET, such as fatigue, nausea, vomiting, joint and muscle pain and hot flashes. EQ-5D-5L scores were generally comparable throughout treatment for both study arms, with elacestrant showing numerically better outcomes vs SoC for mobility, self-care and usual activities. Similar trends were observed for the full intent-to-treat population and in pts with detectable estrogen receptor 1 mutations (ESR1m).

Conclusions

This analysis confirmed that QoL was maintained between treatment groups in the EMERALD trial. Together with the previously described statistically significant prolonged PFS and manageable safety profile, these PRO results provide additional evidence that oral elacestrant is clinically meaningful in this patient population with limited therapeutic options.

Clinical trial identification

ClinicalTrials.gov Identifier: NCT03778931

Editorial acknowledgement

Jeffrey Walter, IQVIA