Abstract OT2-07-03: Trastuzumab deruxtecan (DS-8201a) vs ado-trastuzumab emtansine (T-DM1) for subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: A phase 3, randomized study

Background: There is no uniform standard of care for HER2-positive breast cancer (BC) after disease progression on ado-trastuzumab emtansine (T-DM1). DS-8201a is a novel HER2-targeted antibody-drug conjugate (ADC) with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a drug-to-antibody ratio of 7 to 8. It is designed with the goal of improving critical attributes of an ADC. In an ongoing phase 1 trial, DS-8201a showed promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed objective response rate [ORR] of 54.5%; April 2018 data cutoff; Iwata et al, ASCO 2018). Based on preliminary results from the phase 1 trial, DS-8201a received FDA breakthrough therapy and fast track designations for metastatic BC that progressed after prior treatment with T-DM1. The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC whose disease progressed on or after T-DM1 (NCT03523585, DESTINY-BREAST02). Approximately 600 subjects will be randomized (2:1) to DS-8201a or investigator's choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine). Randomization is stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. DS-8201a (5.4 mg/kg) will be administered IV once every 3 weeks. Progression free survival (PFS) based on blinded, independent central review using RECIST v1.1 criteria is primary efficacy endpoint; overall survival (OS) is the key secondary endpoint. Other secondary efficacy endpoints are ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health-related quality of life will also be measured. The primary analysis for PFS will occur when approximately 372 PFS events have been observed; providing 90% power to detect a hazard ratio of 0.70 in PFS (a 43% improvement in median PFS from 3.3 months with investigator's choice to 4.7 months with DS-8201a) with a 1-sided alpha of 0.025. An interim OS analysis is planned at the time of the PFS analysis. Final OS analysis will occur when approximately 428 OS events have been observed. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 160 sites including in North and South America, Europe, and Asia. For further information on this trial, contact Fabrice André at FABRICE.ANDRE@gustaveroussy.fr or visit clinicaltrials.gov. Citation Format: André F, Shahidi J, Lee C, Wang K, Krop IE. Trastuzumab deruxtecan (DS-8201a) vs investigator's choice of treatment in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received T-DM1: A randomized, phase 3 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-02.

Tucatinib approval by EMA expands options for HER2-positive locally advanced or metastatic breast cancer

Background: Ado-trastuzumab emtansine (T-DM1), a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC), is approved for subjects with HER2-positive metastatic breast cancer (BC) after disease progression on a trastuzumab-based regimen. Approval of T-DM1 was based on the EMILIA trial, in which T-DM1 demonstrated an objective response rate (ORR) of 43.6%, a median progression-free survival (PFS) of 9.6 months, and an overall survival (OS) of 30.9 months (Verma et al, N Engl J Med, 2012). [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is a novel HER2-targeted ADC with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker and a high drug-to-antibody ratio of 7 to 8. In an ongoing, phase 1 study, T-DXd showed promising antitumor activity in subjects with HER2-positive BC previously treated with T-DM1, with a confirmed ORR of 59.5% (Tamura et al, Lancet Oncol, 2019). Results from the pivotal, phase 2 study of subjects with HER2-positive BC previously treated with T-DM1 (DESTINY-Breast01) confirmed the activity observed in the phase 1 trial and will be presented at the meeting (Krop, et al). Here, we describe the phase 3 trial evaluating T-DXd in subjects with HER2-positive, unresectable and/or metastatic BC who previously received trastuzumab and a taxane. Study Description: DESTINY-Breast03 is a multicenter, open-label, phase 3 trial that will assess the efficacy and safety of T-DXd vs T-DM1 in subjects with centrally confirmed HER2-positive (immunohistochemistry [IHC] 3+ or in situ hybridization [ISH]+), unresectable and/or metastatic BC previously treated with trastuzumab and a taxane. The trial started in July 2018 and is recruiting subjects from ≈ 160 sites in North and South America, Europe, and Asia. Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive T-DXd (5.4 mg/kg) or T-DM1 (3.6 mg/kg) intravenously once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, the treatment will be in accordance with the approved label. The primary efficacy endpoint is PFS based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include OS, ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health-related quality of life will also be measured. Long-term follow-up will continue every 3 months until death, withdrawal of consent, loss to follow-up, or trial closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥ 1 dose of trial treatment. For further information on this trial, visit ClinicalTrials.gov (NCT03529110). Citation Format: Javier Cortés, Javad Shahidi, Caleb Lee, Yufen Zhang, Sunil Verma. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) vs ado-trastuzumab emtansine (T-DM1) in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: A phase 3, randomized trial (DESTINY-Breast03) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-07-01.

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial

Background Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of an HER2-directed antibody and a topoisomerase I inhibitor covalently linked via a tetrapeptide-based cleavable linker. In DESTINY-Breast01, tolerability and efficacy of T-DXd including overall response rate, progression-free survival, duration of response and overall survival have been demonstrated for HER2-positive metastatic and/or unresectable BC in patients (pts) relapsing after 2 or more anti-HER2-based regimens. In France, rapid and fair access to innovative drugs outside clinical trials, prior to their marketing authorization in a given indication, is granted by the French Health Agency, ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé), through cATU program. Here we report first real world evidence data from cATU program in HER2+ BC pts treated with T-DXd. Methods T-DXd 5.4mg/kg was given intravenously in monotherapy every 3 weeks in HER2-positive metastatic and/or unresectable BC pts who had previously received at least 2 lines of anti-HER2 regimens in the metastatic setting. Eligible pts needed to have normal neutrophil count and no left ventricular dysfunction. Pts with active or history of interstitial lung disease (ILD), pneumonitis, severe pulmonary disease were excluded. Clinical, biological and safety data were collected until the end of cATU, as well as treatment response according to RECIST 1.1., dose modification, treatment interruption and discontinuation. Analysis was performed on March 31th, 2021 on the basis of available collected data. Results From September 30th, 2020 to March 31th, 2021, 155 centers requested at least one ATU for a total of 539 adult pts; 468 requests were accepted and 71 were refused as they did not meet eligibility criteria. T-DXd was received by 459 pts with the following characteristics: 99.1% were women, median age was 58 years, 90.4% had a ECOG score of 0-1, 98.9% had initial HER2-positive BC (IHC 3+ or IHC 2+/ISH+), 67% were hormone receptor positive. The main sites of metastases were bones (57.3%), lymph nodes (51.6%), lungs (36.2%), liver (33.1%), brain (28.1%) and cutaneous/subcutaneous (13.9%). Median time between initial diagnosis of primary BC and inclusion was 6.6 years (range: 6.6 months - 33.9 years). 81.7% of pts had previously received radiotherapy and 76.5% underwent surgery. The median number of prior cancer regimens in the metastatic setting was 4 (range: 2-22). 21.1% received 2 prior lines of metastatic treatments, 19.6% received 3 lines and 59.3% received 4 lines or more. 94.8% pts received prior trastuzumab emtansine, and 79.3% had prior pertuzumab. During follow-up, data on tumor assessment were available for 160 pts. Of these, 56.7% had complete or partial response and 12.1% had progression. Of the 459 treated pts, 97 pts (21.1%) experienced ≥ 1 Adverse Drug Reaction (ADR) including 41 pts (8.9%) with ≥ 1 serious ADR. Most frequent ADRs were related to gastrointestinal toxicity (35.4%). During cATU, 17 cases (3.7%) with ILD or considered as ILD were reported but no cases had a fatal outcome (only grade 1 or 2 when reported by physicians). 13 fatal cases were reported (no drug-related deaths, attributed by physician). ADRs leading to T-DXd discontinuation were reported in 4 pts (0.9%). Dose reductions were reported in 17 pts (3.7%) and 21 pts (4.6%) had temporary interruptions. Conclusions We report here the first real world data from the French cATU in HER2-positive BC pts treated by T-DXd. The enrolment of 468 pts in 6 months illustrated the unmet medical need for this population. T-DXd had antitumor activity with a similar response rate to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed. Citation Format: Thierry Petit, Nawale Hajjaji, Eric-Charles Antoine, Marc-Antoine Benderra, Michel Gozy, Cyril Foa, Jean-Loup Mouysset, Julien Grenier, Mireille Mousseau, Audrey Mailliez, Mahasti Saghatchian, Emma Lachaier, Isabelle Desmoulins, Audrey Hennequin, Patricia Maes, Delphine Loirat, Francesco Ricci, Véronique Diéras, Dominique Berton, Florence Lai Tiong, Luis Teixeira, Nadine Dohollou, Christelle Lévy, Thomas Bachelot, Jean-Yves Pierga. Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-26.

Background HER2-targeted therapies have substantially improved survival in patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization-positive) advanced or metastatic breast cancer. Despite significant advancements, patients ultimately develop resistance to standard-of-care HER2-targeted therapies. Therefore, a need remains for regimens that prolong disease control and survival in these patients. T-DXd is a HER2-targeted antibody-drug conjugate containing a linker selectively cleaved in tumor cells and a topoisomerase I inhibitor payload with high cell-membrane permeability. T-DXd has been approved by the FDA for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥ 2 prior anti-HER2-based regimens in the metastatic setting and by Japan’s Ministry of Health, Labour and Welfare for use in patients with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy (use limited to patients refractory to or intolerant of standard treatments). Results from the phase 2 DESTINY-Breast01 trial demonstrated an objective response rate (ORR) of 60.9% per independent central review and a median progression-free survival (PFS) of 16.4 months in a heavily pretreated population (median of 6 prior lines of therapy) of patients with HER2-positive advanced or metastatic breast cancer treated with T-DXd (Modi S, et al. N Engl J Med. 2020;382:610-621). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd combinations in patients with HER2-positive advanced or metastatic breast cancer. Study Description DESTINY-Breast07 is a global, multicenter, open-label, phase 1b/2 dose-finding and dose-expansion trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd in combination with other therapies in patients with HER2-positive advanced or metastatic breast cancer. Patients will be enrolled globally at ≈ 110 sites in ≈ 10 countries. The study will initially consist of 4 combination modules, each with 2 parts: dose finding (part 1) and dose expansion (part 2), and a T-DXd monotherapy module (part 2 only). The 4 combination modules will enroll patients for treatment with (1) T-DXd + durvalumab, (2) T-DXd + pertuzumab, (3) T-DXd + paclitaxel, or (4) T-DXd + durvalumab + paclitaxel. New combination treatment modules may be added via protocol amendment. Part 1 of each combination module will enroll patients who have had disease progression on ≥ 1 prior line of therapy in the metastatic setting. In part 2, patients who have received no prior therapy for metastatic disease will be randomized to receive a combination regimen or T-DXd monotherapy. Antitumor activity will be evaluated based on investigator assessment according to RECIST 1.1. The primary endpoint is to assess the safety and tolerability of T-DXd combinations and determine the recommended phase 2 doses. Secondary endpoints include ORR, PFS, duration of response, overall survival, pharmacokinetics, and immunogenicity. Citation Format: Fabrice Andre, Erika Hamilton, Sherene Loi, Peter Schmid, Tinghui Yu, Shiyao Lu, Sarice Boston, Celina D'Cruz, Pia Herbolsheimer, Komal Jhaveri. Trastuzumab deruxtecan (T-DXd; DS-8201) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2 open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-04.

Trastuzumab Beyond Progression in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: UK Practice now and in the Future

Background: There is no uniform standard of care for HER2-positive breast cancer (BC) after disease progression on ado-trastuzumab emtansine (T-DM1). [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is a novel HER2-targeted antibody-drug conjugate (ADC) with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker and a drug-to-antibody ratio of 7 to 8. It was designed with the goal of improving critical attributes of an ADC. In a phase 1 study, T-DXd showed promising antitumor activity in subjects with HER2-positive BC previously treated with T-DM1 with a confirmed objective response rate (ORR) of 59.5% (Tamura et al, Lancet Oncol, 2019). Results from the pivotal, phase 2 study of subjects with HER2-positive BC previously treated with T-DM1 (DESTINY-Breast01) confirmed the activity observed in the phase 1 study and will be presented at the meeting (Krop, et al). Here, we describe the phase 3 confirmatory trial evaluating T-DXd in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received T-DM1. Study Description: DESTINY-Breast02 is a multicenter, open-label, phase 3 trial that is comparing the efficacy and safety of T-DXd with those of the investigator’s choice of therapy in subjects with centrally confirmed, HER2-positive (IHC 3+ or ISH+), unresectable and/or metastatic BC that progressed on or after T-DM1. The trial started in August 2018 and is recruiting subjects from ≈ 190 sites in North and South America, Europe, and Asia. Approximately 600 subjects will be randomized (2:1) to T-DXd or the investigator’s choice of treatment (trastuzumab + capecitabine or lapatinib + capecitabine). Randomization is stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. T-DXd (5.4 mg/kg) will be administered intravenously once every 3 weeks. Progression-free survival (PFS) based on blinded, independent central review using RECIST v1.1 criteria is the primary efficacy endpoint; overall survival (OS) is the key secondary endpoint. Other secondary efficacy endpoints are ORR, duration of response, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health-related quality of life will also be measured. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or trial closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥ 1 dose of trial treatment. For further information on this trial, visit ClinicalTrials.gov (NCT03523585). Citation Format: Fabrice André, Javad Shahidi, Caleb Lee, Kongming Wang, Ian E Krop. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) vs investigator’s choice of treatment in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received T-DM1: A randomized, phase 3 trial (DESTINY-Breast02) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-07-04.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial

Ado-trastuzumab emtansine (Kadcyla—Genentech) has received FDA approval for the management of human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer. The therapy is specifi cally indicated for those who have already undergone unsuccessful treatment with trastuzumab (Herceptin—Genentech) and a taxane. Trastuzumab emtansine is an antibody–drug conjugate comprising the antibody trastuzumab and the chemotherapy drug DM1 attached using a stable linker.

DESTINY-Breast03 trial: some questions remain – Authors' reply

BackgroundTrastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.MethodsIn this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.ResultsOverall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).ConclusionsTrastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.)

Background [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a HER2 antibody, peptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. In a phase 1 trial, the objective response rate (ORR) was 59.5% (66/111) and median progression-free survival (PFS) was 22.1 mo in subjects with HER2-positive metastatic breast cancer (BC) previously treated with T-DM1 (Tamura, Lancet Oncol, 2019). DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 registration study of T-DXd in subjects with centrally confirmed HER2-positive metastatic BC. Methods Part 1 of this 2-part study was performed in 2 stages (pharmacokinetics and dose finding; T-DXd 5.4, 6.4, 7.4 mg/kg) and served to identify the recommended Part 2 dose (RP2D). In Part 2, subjects were treated at the RP2D. Subjects in Parts 1 and 2a were required to have metastatic BC that progressed on or after T-DM1. Subjects in a small additional cohort (Part 2b) had discontinued T-DM1 for reasons other than progression. The primary endpoint was ORR (complete response [CR] + partial response [PR]) per independent central review (ICR). Additional endpoints included disease control rate (DCR; CR + PR + stable disease [SD]), duration of response (DOR), and PFS. Abstract results represent 6 mo of follow-up from the date the last subject enrolled in the study. Results As of data cutoff (March 21, 2019), 253 subjects were enrolled and 184 received the RP2D (5.4 mg/kg), 4 of which were enrolled in Part 2b. All subjects were female, 55% were white, and 38% were Asian. Median age was 55 y (range, 28-96 y; ≥ 65 y, 24%); 53% were hormone receptor (HR) positive and 45% were HR negative. Median number of prior treatment regimens was 6 (range, 2-27), including trastuzumab (100%), T-DM1 (100%), pertuzumab (66%), and other HER2-targeted regimens (54%). The reported best response to T-DM1 before enrollment was 22% CR or PR, 21% SD, and 36% progressive disease (PD); 21% were not evaluable. At data cutoff, 60% of subjects remained on T-DXd treatment; primary reasons for discontinuation were PD (21%) and treatment-related adverse events (TEAEs, 8%). The confirmed ORR by ICR in subjects treated at the RP2D in Parts 1, 2a, and 2b was 60% (111/184 [95% CI, 53%-68%]). ORRs were consistent across subgroups, including those with prior pertuzumab (64%) and those with ≥ 3 prior regimens (59%). The DCR was 97% (95% CI, 94%-99%); only 5 of 184 subjects did not have SD or better at the time of first post-baseline scan. As of the data cutoff, median DOR and PFS had not been reached; median duration of follow up was 7.2 mo (range, 0.7-17.2 mo). In the 184 subjects, the median treatment duration was 6.9 mo (range, 0.7-16 mo); 70% had > 6 mo of treatment. TEAEs occurred in 99% of subjects (grade ≥ 3, 51%); the most common any-grade TEAEs were gastrointestinal (nausea [77%], vomiting [45%], constipation [34%], decreased appetite [29%], and diarrhea [27%]), alopecia (48%), fatigue (48%), and hematologic (decreased neutrophil count [31%] and anemia [26%]). Most common grade ≥ 3 AEs were decreased neutrophil count (17%), nausea (7.6%), anemia (6.5%), decreased lymphocyte count (5.4%), and fatigue (5.4%). 15 subjects (8.2%) had interstitial lung disease (ILD) adjudicated as ILD related to T-DXd by an independent adjudication committee; ILD was primarily grade 1 or 2 (6.0%; no grade 3 or 4; 2.2% grade 5). [Additional follow up and first DOR/PFS data will be presented at the meeting.] Conclusion Overall, T-DXd treatment demonstrated clinically meaningful and durable activity in a heavily pretreated patient population with HER2-positive metastatic BC. T-DXd had a generally manageable safety profile, with ILD identified as a risk warranting proactive awareness and management. Citation Format: Ian E Krop, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice André, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara Hurvitz, Javier Cortes, Caleb Lee, Shuquan Chen, Lin Zhang, Javad Shahidi, Antoine Yver, Shanu Modi. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-03.

Background Preoperative chemotherapy in combination with trastuzumab and pertuzumab is a preferred regimen for treating patients (pts) with HER2-positive, invasive, early breast cancer (BC). Pts who have received such treatment but still have residual invasive disease in the breast or lymph nodes at surgery are at greater risk for disease recurrence or death than those with a pathological complete response. The antibody-drug conjugate (ADC) T-DM1 is approved as a postneoadjuvant treatment for pts with residual invasive disease (in the breast and/or axillary nodes) after optimal neoadjuvant chemotherapy and trastuzumab (or trastuzumab with pertuzumab). T-DXd is a potent HER2-targeted ADC with a humanized HER2 antibody attached to a membrane-permeable topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker and a drug-to-antibody ratio of ≈8. T-DXd is approved globally for the treatment of adult pts with HER2-positive, unresectable or metastatic BC who have received ≥2 prior anti-HER2-based regimens in the metastatic setting or had prior chemotherapy and are refractory to or intolerant of standard treatments. These approvals have been supported by results from DESTINY-Breast01, an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2-positive metastatic BC. In an updated data cutoff (June 8, 2020), T-DXd demonstrated an objective response rate (ORR) of 61.4% (113/184 pts) and a duration of response of 20.8 months in pts with HER2-positive (IHC 3+ or ISH+), unresectable or metastatic BC previously treated with T-DM1 (Modi et al. Cancer Res. 2021;81[4 suppl]:PD3-06). Yet, further unmet need exists in patients who do not achieve pathologic complete response to neoadjuvant treatment, as these patients have increased risk of recurrence. Here, we describe a randomized phase 3 trial evaluating T-DXd vs T-DM1 as postneoadjuvant treatment for high-risk pts with HER2-positive primary BC who have residual invasive disease following neoadjuvant therapy. Study Description DESTINY-Breast05 is a multicenter, open-label, randomized, phase 3 trial comparing the efficacy and safety of T-DXd with those of T-DM1 in pts with HER2-positive (IHC 3+ or ISH+, centrally confirmed on pretreatment biopsy), invasive BC with pathologic evidence of residual invasive disease in the breast or axillary lymph nodes after neoadjuvant therapy. Additionally, pts must have a higher residual risk for recurrence, following standard T-DM1, defined as either presenting with inoperable disease (clinical stages T4, N0-3, M0 or T1-3, N2-3, M0) or operable BC at presentation (clinical stages T1-3, N0-1, M0) with axillary node-positive disease after neoadjuvant chemotherapy and anti-HER2 treatment. Approximately 1600 pts will be randomly assigned (1:1) to T-DXd or T-DM1 from ≈ 400 sites globally. Randomization is stratified by operative status at presentation, hormone receptor status, pathologic nodal status following neoadjuvant therapy, and type of HER2-targeted neoadjuvant therapy (single vs dual). T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg will be administered intravenously once every 3 weeks for 14 cycles. Invasive disease-free survival based on investigator assessment is the primary efficacy endpoint. Secondary endpoints are overall survival, disease-free survival, distant recurrence-free interval, and brain metastasis-free interval. The pharmacokinetics of T-DXd, biomarkers, and health-related quality of life will also be evaluated (NCT04622319). Citation Format: Charles E Geyer, Jr, Michael Untch, Aleix Prat, Priya Rastogi, Naoki Niikura, Elton Mathias, Lee Anne McLean, Yibin Wang, Sibylle Loibl. Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer after neoadjuvant therapy: A randomized, phase 3 trial (DESTINY-Breast05) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-03.

Background: The clinical activity of antibody-drug conjugates (ADCs) when used sequentially remains uncertain. Given the increasing utilization of ADCs in both HER2-positive and HER2-negative metastatic breast cancer, our aim was to assess the efficacy of sequential ADC treatments in metastatic breast cancer patients across subtypes. Methods: We conducted a retrospective analysis using data from the Dallas Metastatic Breast Cancer Study, which encompasses all metastatic breast cancer patients treated at multiple hospitals within a single academic medical center. Clinical data were gathered through retrospective chart reviews. Progression-free survival (PFS) was defined from the initiation of ADC treatment to disease progression or death. Results: At our institution, 156 metastatic breast cancer patients were treated with ADCs between March 21, 2013 and March 29, 2024. Among these, 35 patients received sequential ADC treatments. In our analysis, we included 32 patients who switched to a second ADC after disease progression on their first ADC. Patients who switched ADCs due to side effects were excluded from our analysis. The median age at metastatic diagnosis was 52 years (range: 34-75 years). The cohort consisted of 21 patients with HER2-positive breast cancer and 13 patients with HER2-negative breast cancer. Of the patients with HER2-negative disease, six patients had hormone receptor positive disease and 12 had HER2-low disease. Overall survival for the entire cohort was 17 months (range: 6-78 months). In the HER2-positive subgroup, 15 patients initially treated with trastuzumab emtansine (T-DM1) had a median PFS of 4 months (95% CI: 0.44-7.55). Subsequent treatment with trastuzumab deruxtecan (T-DXd) resulted in a median PFS of 8 months (95% CI: 3.41-12.58). Four patients initially treated with T-DXd had a median PFS of 4.5 months (95% CI: 0-26.67) and subsequent treatment with T-DM1 resulted in a median PFS of 4 months (95% CI: 0-11.98). In the HER2-negative subgroup, eight patients initially treated with sacituzumab govitecan (SG) had a median PFS of 7.5 months (95% CI: 3.84-11.15). Subsequent T-DXd treatment resulted in a median PFS of 4.5 months (95% CI: 2.01-6.98). Looking closer specifically within the HER2-low subset, the median PFS of SG remained at 7.5 months (95% CI: 3.31-11.68), while subsequent PFS on T-DXd was slightly higher at 5 months (95% CI: 1.65-8.34). Five patients initially treated with T-DXd had a median PFS of 5 months (95% CI: 0-11.00) and subsequent treatment with SG resulted in a median PFS of 2 months (95% CI: 0-14.70). Conclusions: Our findings indicate that in the HER2-positive metastatic setting, treatment with T-DXd, despite sequential use after disease progression on T-DM1, results in a longer PFS compared to the initial T-DM1 treatment. This suggests that T-DXd retains its efficacy even after disease progression on T-DM1 despite both treatments targeting the same HER2 antigen. Conversely, in the HER2-negative metastatic setting, the sequential use of SG and T-DXd, which share the same payload, resulted in a lower PFS compared to initial treatment with SG or T-DXd. These data suggest and contribute to growing evidence that payload resistance may reduce clinical benefit across subtypes instead of antigen resistance. Future studies into novel ADC development should focus on using different payloads. Citation Format: Hannah Chang, Katherine Lei, Flavia Soares Fernandes, Mayuri Vaish, Sai Movva, Christine Hodgdon, Julia Maues, Isaac Chan. Sequential ADC Treatments in Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-09-30.