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Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd demonstrated compelling single-agent antitumor activity in heavily pretreated patients (pts) with metastatic triple-negative BC (Krop, SABCS 2021). This is the first report of results from the TROPION-PanTumor01 study in pts with unresectable or metastatic hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−; including HER2-low and HER2-zero) BC. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part dose-escalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical findings and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with unresectable or metastatic HR+/HER2− BC that progressed on standard therapies. The primary objectives were safety and tolerability. Tumor responses, including ORR (complete response [CR] + partial response [PR]) and DCR (CR + PR + stable disease [SD]), were assessed per RECIST version 1.1 by blinded independent central review. Results: As of the April 29, 2022, data cutoff, 41 pts had received Dato-DXd (median follow-up, 10.9 mo [range, 7-13]); 9 pts were ongoing. The primary cause of treatment discontinuation was disease progression (63%; progressive disease [PD] or clinical progression). Median age was 57 y (range, 33-75); 54% had de novo metastatic disease. Pts were heavily pretreated (Table) with a median of 5 (range, 3-10) prior regimens in the advanced setting; 95% had prior CDK4/6i (adjuvant/metastatic). Median time from initial treatment for metastatic disease to the first dose of Dato-DXd was 42.7 mo (range, 10.2-131.1). Treatment-emergent adverse events (TEAEs; all cause) were observed in 98% (any grade) and 41% (grade ≥3) of pts. Most common TEAEs (any grade, grade ≥3) were stomatitis (80%, 10%), nausea (56%, 0%), fatigue (46%, 2%), and alopecia (37%, 0%). Serious TEAEs were observed in 6 pts (15%); 1 pt died due to dyspnea, which was not considered to be treatment related. Dose reductions occurred in 5 pts due to stomatitis (n=3), fatigue (n=2), keratitis (n=1), and decreased appetite (n=1) (>1 AE per pt); 14 pts had treatment delayed due to stomatitis (n=8), retinopathy (n=1), dysphagia (n=1), fatigue (n=1), malaise (n=1), COVID-19 (n=1), cellulitis (n=1), urinary tract infection (n=1), decreased lymphocyte count (n=1), and nasal congestion (n=1; >1 AE per pt). Three pts discontinued treatment due to keratitis (n=1) and pneumonitis (n=2); 1 case of pneumonitis was adjudicated as grade 2 drug-related interstitial lung disease. The ORR was 29% (11 confirmed PRs; 1 pending confirmation), the DCR was 85% (35/41), and the clinical benefit rate (CR + PR + SD ≥6 mo) was 41% (17/41). Conclusions: Dato-DXd demonstrated a manageable safety profile and encouraging antitumor activity, with high disease control in heavily pretreated pts, the majority having received prior CDK4/6i. Based on these findings, the TROPION-Breast01 (NCT05104866) randomized phase 3 study comparing 2L+ Dato-DXd vs investigator’s choice chemotherapy is currently enrolling pts with HR+/HER2− BC. Prior Therapies in the Adjuvant or Metastatic Setting Citation Format: Funda Meric-Bernstam, Ian Krop, Dejan Juric, Takahiro Kogawa, Erika Hamilton, Alexander I. Spira, Toru Mukohara, Takuya Tsunoda, Senthil Damodaran, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Hong Zebger-Gong, Yui Kawasaki, Rie Wong, Aditya Bardia. PD13-08 Phase 1 TROPION-PanTumor01 Study Evaluating Datopotamab Deruxtecan (Dato-DXd) in Unresectable or Metastatic Hormone Receptor–Positive/HER2–Negative Breast Cancer (BC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-08.

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 mAb covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor selective, tetrapeptide-based cleavable linker. Dato-DXd has previously shown encouraging activity in heavily pretreated patients (pts) with metastatic TNBC (Krop, SABCS 2021). Here we report updated results from the TROPION-PanTumor01 study in pts with advanced/metastatic TNBC. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part dose-escalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with advanced TNBC that relapsed/progressed on standard therapies; 2 pts received 8 mg/kg prior to selection of 6 mg/kg. The primary objectives were safety and tolerability. Tumor responses, including objective response rate (ORR; complete response [CR] + partial response [PR]) and disease control rate (DCR; CR + PR + stable disease [SD]), were assessed per RECIST v1.1 by blinded independent central review. Results: As of April 29, 2022, 44 pts received Dato-DXd (median follow-up, 16.6 mo [range, 13-22]) at the time of data cutoff. The primary cause of treatment discontinuation was disease progression (86%; PD or clinical progression), and 4 pts are still receiving therapy. Median age was 53 y (range, 32-82); 32% had de novo metastatic disease. Pts were heavily pretreated with a median of 3 (range, 1-10) prior regimens in the metastatic setting. Prior treatments included taxanes (91%), anthracyclines (75%), capecitabine (61%), platinum (52%), immunotherapy (43%), Topo I inhibitor–based ADC therapy (32%), and PARPi (18%). Treatment-emergent adverse events (TEAEs; all cause) occurred in 100% (any grade) and 50% (grade ≥3) of pts, respectively. Most common TEAEs (any grade, grade ≥3) were stomatitis (73%, 11%), nausea (66%, 2%), vomiting (39%, 5%), fatigue (34%, 7%), and alopecia (36%, 0%). One pt had grade 3 decreased neutrophil count; no cases of interstitial lung disease (ILD) or grade ≥3 diarrhea were observed. Serious TEAEs were reported in 9 pts (20%); no deaths associated with adverse events (AEs) were observed. Dose reductions occurred in 8 pts (18%) due to stomatitis (n=3), fatigue (n=2), dry eye (n=1), retinal exudates (n=1), and dysgeusia (n=1); 12 pts (27%) delayed treatment due to stomatitis (n=5), dry eye (n=1), keratitis (n=1), blurred vision (n=1), fatigue (n=1), bronchitis (n=1), skin infection (n=1), musculoskeletal chest pain (n=1), dysgeusia (n=1), chronic obstructive pulmonary disease (n=1), and dyspnea (n=1; >1 AE per pt). One pt (2%) discontinued treatment due to grade 1 pneumonitis (which was centrally adjudicated as not ILD). ORR in all pts was 32% (1 CR, 13 PRs), DCR was 80% (35/44), and clinical benefit rate (CR + PR + SD ≥6 mo) was 34% (15/44). Median duration of response was not yet reached; median progression-free survival (mPFS) was 4.3 mo (95% CI, 3.0-7.3), and median overall survival (mOS) was 12.9 mo (95% CI, 10.1-14.7). In the subset of pts without prior Topo I inhibitor–based ADC therapy and with measurable disease at baseline, ORR was 44% (12/27). Among all pts without prior Topo I inhibitor–based ADC therapy (n=30), mPFS was 7.3 mo (95% CI, 3.0-NE), and mOS was 14.3 mo (95% CI, 10.5-NE). Conclusions: Dato-DXd continues to demonstrate encouraging and durable antitumor activity, along with a manageable safety profile, in heavily pretreated pts with metastatic TNBC. Based on these findings, the phase 3 randomized TROPION-Breast02 (NCT05374512) trial comparing Dato-DXd vs chemotherapy as 1L therapy for pts with metastatic TNBC is currently underway. Citation Format: Aditya Bardia, Ian Krop, Funda Meric-Bernstam, Anthony W. Tolcher, Toru Mukohara, Aaron Lisberg, Toshio Shimizu, Erika Hamilton, Alexander I. Spira, Kyriakos P. Papadopoulos, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Hong Zebger-Gong, Yui Kawasaki, Rie Wong, Takahiro Kogawa. Datopotamab Deruxtecan (Dato-DXd) in Advanced Triple-Negative Breast Cancer (TNBC): Updated Results From the Phase 1 TROPION-PanTumor01 Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-03.

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Preliminary results from the phase 1 TROPION-PanTumor01 study demonstrate that Dato-DXd has encouraging antitumor activity and a manageable safety profile in patients with non-small cell lung cancer (NSCLC) (Meric-Bernstam, ASCO 2021) and those with triple-negative breast cancer (TNBC) (Bardia, ESMO BC 2021). Updated results from the TNBC cohort are presented here. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multi-center, open-label, 2-part study evaluating Dato-DXd in previously treated patients with solid tumors. Based on the dose-escalation results in patients with NSCLC, Dato-DXd 6 mg/kg intravenously every 3 weeks is being evaluated in patients with advanced/metastatic TNBC and HR+/HER2− breast cancer who relapsed/progressed on standard therapies. Two patients with TNBC received Dato-DXd 8 mg/kg prior to selection of 6 mg/kg for dose expansion. Safety and efficacy were assessed, including objective response rate (ORR) per RECIST version 1.1 by blinded independent central review (BICR). Results: As of the April 6, 2021, data cutoff, 43 patients with TNBC had received ≥1 dose of Dato-DXd, with 27 patients (63%) continuing and 16 patients (37%) discontinuing treatment all due to disease progression. The median age was 53 years (range, 32-82 years). Forty-one patients (95%) had received ≥2 prior lines of therapy; 19 patients (44%) had received prior immunotherapy and 7 (16%) had received prior sacituzumab govitecan. The median duration of treatment was 2.8 months (range, 0.7-6.9 months). The median follow-up was 3.9 months (range, 0.3-9.2 months). Among 38 patients evaluable for response, the ORR by BICR was 39% (15 partial responses [PR]), with 12 confirmed and 3 pending confirmation. The disease control rate was 84% (32/38). The median time to response was 1.35 months (1.2-3.2 months) for the 12 confirmed PRs. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 95% and 35% of patients, respectively; 2 events were grade 4 and 0 grade 5. The most common TEAEs (any grade [≥30%], grade ≥3) included nausea (58%, 0%), stomatitis (53%, 9%), alopecia (35%, N/A), vomiting (35%, 2%), and fatigue (33%, 7%). One patient had grade 3 decreased neutrophil count; no cases of grade ≥3 diarrhea were observed. No cases of treatment-related interstitial lung disease as adjudicated by an independent committee were reported. Serious TEAEs were observed in 5 patients (12%); no TEAEs were associated with death. Dose reductions occurred in 9 patients due to stomatitis, fatigue, mucosal inflammation, dry eye, retinal exudates, and blurred vision (multiple counts per TEAE). Three patients had dose interruptions due to stomatitis, mucosal inflammation, bronchitis, and musculoskeletal chest pain. No patients discontinued treatment due to adverse events. Conclusions: Preliminary results showed that Dato-DXd demonstrates promising antitumor activity with a manageable safety profile in patients with previously treated advanced/metastatic TNBC; confirmatory studies in patients with breast cancer are warranted. Citation Format: Ian Krop, Dejan Juric, Toshio Shimizu, Anthony Tolcher, Alexander Spira, Toru Mukohara, Aaron E. Lisberg, Takahiro Kogawa, Kyriakos P. Papadopoulos, Erika Hamilton, Senthil Damodaran, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Ferdinand Guevara, Takahiro Jikoh, Yui Kawasaki, Funda Meric-Bernstam, Aditya Bardia. Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: Results from the phase 1 TROPION-PanTumor01 study [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 GS1-05.