Sabrina S. Khan

PURPOSE The global, phase 3, open-label, randomized TROPION-Breast01 study assessed the trophoblast cell surface antigen 2–directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer. METHODS Adult patients with inoperable/metastatic HR+/HER2‒ breast cancer, who had disease progression on endocrine therapy, for whom endocrine therapy was unsuitable, and had received one to two previous lines of chemotherapy in the inoperable/metastatic setting, were randomly assigned 1:1 to Dato-DXd (6 mg/kg once every 3 weeks) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine). Dual primary end points were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). RESULTS Patients were randomly assigned to Dato-DXd (n = 365) or ICC (n = 367). Dato-DXd significantly reduced the risk of progression or death versus ICC (PFS by BICR hazard ratio [HR], 0.63 [95% CI, 0.52 to 0.76]; P < .0001). Consistent PFS benefit was observed across subgroups. Although OS data were not mature, a trend favoring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). The rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was lower than ICC (20.8% v 44.7%). The most common TRAEs (any grade; grade ≥3) were nausea (51.1%; 1.4%) and stomatitis (50%; 6.4%) with Dato-DXd and neutropenia (grouped term, 42.5%; 30.8%) with ICC. CONCLUSION Patients receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS and a favorable and manageable safety profile, compared with ICC. Results support Dato-DXd as a novel treatment option for patients with inoperable/metastatic HR+/HER2‒ breast cancer who have received one to two previous lines of chemotherapy in this setting.

Introduction: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a multicenter phase II tissue agnostic trial with 39 treatment arms, that matches a targeted drug to an actionable genetic alteration identified by next-generation sequencing (NGS). It is unique in use of a bioinformatics tool MATCHBox to make patient treatment assignments. The purpose of this review is to offer an update on the current status of NCI-MATCH, and also to discuss the impact of this precision medicine trial on future studies.Areas covered: This review discusses how NCI-MATCH has evolved over time to address the challenges in enrollment as well as to better answer the needs of the wider cancer community. The interim results from the available arms are described, together with a discussion on the future direction of NCI-MATCH.Expert opinion: The NCI-MATCH is generating a unique genetic mutation landscape of relapsed/refractory malignancies, on top of which the future of precision medicine will be built upon. Real-time updates to public databases with new genetic alterations can further optimize treatment assignments for cancer patients. Formation of more definitive trials can study any promising treatments discovered.

3067 Background: M6620 (M), a potent ATR inhibitor, has synergistic activity with cisplatin (C) in multiple preclinical models, resulting in DNA damage and antitumor activity. We hypothesize that inhibition of both homologous recombination and base excision repair through the combination of M6620 and veliparib (V, a potent inhibitor of PARP1/2) would result in accumulation of lethal double stranded breaks induced by cisplatin and increased antitumor activity and initiated a phase-1 dose escalation trial of this combination in patients (pts) with advanced solid tumors (NCT02723864). Methods: This is a standard 3+3 dose escalation design with 21-day cycles. M is given IV day 2 (D2) and D9; V orally twice daily D1-3 and D8-10; C IV D1 (and D8 from dose level 3 [DL3] onwards) at 40 mg/m 2 (with option of holding after cycle 6). Primary objectives: safety; tolerability; maximum tolerated dose (MTD). Secondary objectives: pharmacodynamic (PD) biomarkers; antitumor activity. Dose-limiting toxicity (DLT) evaluated during cycle 1, response using RECIST 1.1. Results: Thirty-seven patients enrolled, median 5 lines of prior therapy (Range 1-12). MTD: V 200 mg, M 210 mg/m 2 , C 40 mg/m 2 (DL6). DLT: grade (gr) 4 thrombocytopenia (DL4), hypophosphatemia (not resolved in 24 hrs., DL3), infusion reaction (DL7). Common gr 3/4 toxicities: anemia (41%), thrombocytopenia (30%), neutropenia (27%), hyponatremia (11%) and hypophosphatemia (8%). Of 34 pts evaluable for response: 2 partial response (PR) (6%, 1 confirmed & 1 transient), 22 stable disease (SD) (65%, median 4 cycles, range 2-11). Of 24 pts with PR/SD, 22 had prior platinum chemotherapy. After July 2018, V was held for gr ≥2 anemia until improved to gr 1, followed by dose reduction. Of 5 pts treated in this period, 3 required V held. PD analysis of circulating tumor cells is underway to elucidate biomarkers of DNA damage and apoptosis. Conclusions: This combination of M6620, veliparib and cisplatin is safe, with activity seen in pts having received prior platinum. The most common toxicity was anemia, which prevented adequate delivery of veliparib. While MTD was established in a heavily pretreated population, consideration should be given to continued dose escalation in pts who have received fewer prior lines of therapy. Funded in part by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT02723864.

8623 Background: ILD is a potentially serious adverse event seen with many cancer therapies, including checkpoint inhibitors. Factors like smoking and disease pathophysiology have been suspected to potentially increase ILD risk. Dato-DXd, a TROP2-directed antibody drug conjugate, is being evaluated in multiple tumor types. We describe ILD incidence and severity across 5 studies of Dato-DXd in pts with advanced solid tumors. Methods: Pts with non-small cell lung cancer (NSCLC) or breast cancer (BC) who received 6 mg/kg Dato-DXd monotherapy in the TROPION-Lung01, -Lung05, -Breast01 and -PanTumor01 studies were pooled. Additional pts with other solid tumor types (prostate, esophageal, gastroesophageal, pancreatic, small cell lung, urothelial, ovarian, endometrial, colorectal, and biliary tract cancers) receiving Dato-DXd monotherapy in TROPION-PanTumor01 and -PanTumor03 were analyzed separately. An independent adjudication committee retrospectively reviewed potential ILD/pneumonitis cases using imaging and clinical data to assess if the event was drug-related ILD. Adjudicated drug-related ILD events are reported. Results: 927 pts with NSCLC (484) or BC (443) were included in the pooled analysis. Median (range) duration of treatment was 5.5 (0.7, 29.9) months. Overall adjudicated drug-related ILD incidence was 5% (43 pts; 28 grade [Gr] 1-2, 15 Gr 3-5); this was largely driven by the NSCLC pt subgroup (Table). Median (range) time to first onset and duration of first event were 44.0 (7.0, 237) and 39.0 (4.0, 96)days, respectively. ILD associated with dose reduction, drug interruption, or drug withdrawal occurred in 3 (<1%), 13 (1%), and 24 (3%) pts, respectively. In pts with NSCLC, 8 fatal events were observed (7 in TROPION-Lung01, 1 in TROPION-Lung05), 5 of which were attributed to disease progression by investigator. An additional 9 cases of ILD have been reported in 272 pts (3%; Gr 3-5, 2%) across multiple tumor indications enrolled in TROPION-PanTumor01 and -PanTumor03 (Table). Conclusions: Cases ofadjudicateddrug-related ILD seen with Dato-DXd monotherapy were mainly low grade. Gr ≥3 events have been reported, highlighting the need for careful monitoring and adherence to management guidelines. ILD incidence was numerically higher in NSCLC; risk factors for Dato-DXd-related ILD are under investigation. Clinical trial information: NCT05104866 ; NCT05374512 ; NCT05489211 ; NCT04656652 ; NCT03401385 . Adjudicated drug-related ILD, n (%) NSCLC + BC (N=927) NSCLC a (n=484) BC b (n=443) Other Tumors c (N=272) Any 43 (5) 33 (7) 10 (2) 9 (3) Gr 1-2 28 (3) 21 (4) 7 (2) 4 (1) Gr 3-5 15 (2) 12 (2) 3 (1) 5 (2) Gr 5 9 (1) 8 (2) 1 (<1) 1 (<1) Associated with dose reduction 3 (<1) 2 (<1) 1 (<1) 0 (0) Associated with drug interruption 13 (1) 11 (2) 2 (<1) 4 (1) Associated with drug withdrawal 24 (3) 20 (4) 4 (1) 3 (1) a TROPION-Lung01 (n=297); TROPION-Lung05 (n=137); TROPION-PanTumor01 (n=50). b TROPION-Breast01 (n=360); TROPION-PanTumor01 (n=83). c TROPION-PanTumor01 (n=137); TROPION-PanTumor03 (n=135).

1006 Background: In the primary analysis of the Phase 3 TROPION-Breast01 study (NCT05104866), Dato-DXd showed a statistically significant and clinically meaningful improvement in progression-free survival vs investigator’s choice of CT (ICC) (HR 0.63 [95% CI 0.52‒0.76]; p<0.0001) (Bardia et al, ESMO 2023). Here we report PROs from TROPION-Breast01. Methods: Patients with inoperable or metastatic HR+/HER2‒ BC, with disease progression on endocrine therapy and for whom endocrine therapy was unsuitable and who had received 1‒2 prior lines of systemic CT, were randomized 1:1 to Dato-DXd (6 mg/kg Q3W, n=365) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine, n=367). PROs were measured at prespecified timepoints, including secondary PRO endpoints of time to deterioration (TTD) in global health status (GHS)/QoL, physical functioning, and pain based on EORTC QLQ-C30, and exploratory PRO endpoints based on additional questionnaires. Results: PRO questionnaire compliance was 82.5% at baseline in both arms and remained similar across arms over time. TTD was delayed in Dato-DXd vs ICC arms for all secondary endpoints. In an analysis of time to first deterioration (primary analysis), median TTD (HR [95% CI]) in GHS/QoL was 3.4 vs 2.1 months (0.85 [0.68–1.06]), physical functioning was 5.6 vs 3.5 months (0.77 [0.61–0.99]), and pain was 3.5 vs 2.8 months (0.85 [0.68–1.07]); in an analysis of time to confirmed deterioration (sensitivity analysis), median TTD in GHS/QoL was 9.0 vs 4.8 months (0.76 [0.58–0.98]), physical functioning was 12.5 vs 6.2 months (0.77 [0.59–1.01]), and pain was 9.0 vs 5.5 months (0.72 [0.55–0.94]). The Table shows TTD in other selected functioning and symptom scales from EORTC. Patient-reported symptomatic AEs (measured by PRO-CTCAE and EORTC) were generally consistent with clinician-reported safety data, and patient-reported treatment tolerability (measured by PGI-TT) was comparable between arms. Conclusions: In TROPION-Breast01, TTD was delayed in the Dato-DXd vs ICC arms for GHS/QoL, physical functioning, pain, and most other symptoms and functioning scales. PRO data complement the improvement in efficacy and manageable safety profile demonstrated with Dato-DXd vs ICC in the primary analysis, supporting Dato-DXd as a potential new, well tolerated therapeutic option in this setting. Clinical trial information: NCT05104866 . [Table: see text]