Abstract P5-03-04: The effectiveness of post-T-DXd treatments in patients with HER2-positive metastatic breast cancer: A nationwide Japanese cohort study (EN-SEMBLE)

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Abstract Background: Trastuzumab deruxtecan (T-DXd) is a new standard of care for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer after treatment with anti-HER2 antibody and taxane. In clinical practice, some patients (pts) discontinue T-DXd treatment due to progressive disease (PD) or adverse events (AEs). Thus, an unmet medical need remains to determine optimal post-T-DXd treatment regimens. The EN-SEMBLE study investigated post-T-DXd treatments in terms of effectiveness and incidence/exacerbation of interstitial lung disease (ILD) in the Japanese real-world (rw) setting. Methods: This study was a multicenter cohort study (jRCT1030220506). Among pts who received T-DXd from May 25, 2020, to November 30, 2021, and had been registered for the Japanese post-marketing all-patient surveillance, this study enrolled pts who discontinued T-DXd and received subsequent anti-tumor therapy for metastatic breast cancer from May 25, 2020, to May 31, 2023, and were followed up until November 30, 2023. The endpoints were the distribution of post-T-DXd treatment regimens, effectiveness (rw progression-free survival [rwPFS], rw time to next treatment [rwTTNT], overall survival [OS], etc.) and ILD incidence/exacerbation rate by subsequent anti-tumor therapies. Reasons for T-DXd treatment discontinuation were also analyzed. Results: A total of 664 pts were registered from 222 sites nationwide in Japan: median age, 60.0 (range 30–89) years; female, 99.5%; ECOG-PS ≥2, 8.6%; visceral and brain metastasis, 79.7% and 23.0%; de novo stage IV and recurrent breast cancer, 37.7% and 59.3%. The median treatment line for T-DXd was 4th regimens (range 2–43). The most common reason for T-DXd discontinuation was PD, 67.5% (448/664), followed by ILD, 22.0% (146/664), and AEs other than ILD, 5.1% (34/664). The subsequent regimens (1st post-T-DXd treatment) after T-DXd discontinuation were anti-HER2 antibody (trastuzumab, pertuzumab)–containing regimens, 54.4% (361/664); anti-HER2 TKI–containing regimens (lapatinib, other anti-HER2 TKIs), 17.0% (113/664); ADC (trastuzumab emtansine), 1.8% (12/664); and others, 26.8% (178/664). In overall population, anti-HER2 antibody, anti-HER2 TKI, and ADC regimens, rwPFS were 4.1 (3.9–4.5), 4.1 (3.8–4.6), 4.3 (3.8–6.2), 2.6 (1.0–4.7); rwTTNT, 5.0 (4.6–5.5), 5.1 (4.5–5.7), 5.3 (4.4–6.8), 3.0 (1.0–5.9); and OS, 16.2 (13.8–17.2), 17.2 (15.1–19.8), 16.3 (12.2–18.7), 9.3 (4.3–not reached) (respectively; all shown as median [95% CI] months). The HR (95% CI) for anti-HER2 TKI to anti-HER2 antibody was 1.06 (0.84–1.34) for rwPFS, 1.07 (0.85–1.35) for rwTTNT, and 1.17 (0.88–1.54) for OS. Among the anti-HER2 antibody–containing regimens, the HR (95% CI) for a trastuzumab + pertuzumab–containing regimen (n=203) to a trastuzumab-containing regimen (n=157) was 0.94 (0.74–1.20) for rwPFS, 1.00 (0.79–1.26) for rwTTNT, and 0.98 (0.73–1.30) for OS. For pts who discontinued prior T-DXd treatment due to PD or AEs including ILD, rwPFS were 3.5 (3.0–3.8), 7.3 (5.7–10.3), rwTTNT, 4.2 (3.8–4.6), 8.3 (6.2–11.3), and OS 12.0 (10.9–13.6), 32.4 (22.3–not reached), respectively (median [95% CI] months). The incidence of ILD was observed in 10 pts during the first post-T-DXd treatment: 4 pts were new onset, 5 pts were recurrent or exacerbation (3.4%, 5/146), and 1 pts was unknown. Conclusion: About half of the pts received anti-HER2 antibody regimens in the 1st treatment after T-DXd. No differences were observed between anti-HER2 antibody and TKI-based regimens in terms of rwPFS, rwTTNT, or OS. Post-T-DXd treatments were generally safe in pts who had discontinued T-DXd due to ILD, with 3.4% of exacerbation. Citation Format: Kazuki Nozawa, Hiroji Iwata, Toru Mukohara, Tetsuhiko Taira, Shigenori E. Nagai, Jun Hashimoto, Kazuo Matsuura, Toshiro Mizuno, Yoshiaki Shinden, Mitsugu Yamamoto, Saori Kawai, Makoto Wakahara, Hirohumi Terakawa, Takashi Yamanaka, Yasuyuki Kojima, Takahiro Nakayama, Yuji Hirakawa, Kiyoka Kuge, Ayumi Tanabe, Junji Tsurutani. The effectiveness of post-T-DXd treatments in patients with HER2-positive metastatic breast cancer: A nationwide Japanese cohort study (EN-SEMBLE) [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 P5-03-04.

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