Kulkarni, Tejaswini

LBA514 Background: Preclinical and clinical data show that antibody-drug conjugates (ADCs) such as T-DXd may synergize with immunotherapy. Rilvegostomig (R) is a monovalent, Fc-reduced, dual checkpoint bispecific IgG1 monoclonal antibody against PD-1 and TIGIT receptors. R + T-DXd was evaluated as neoadjuvant therapy for up to 4 cycles. Methods: I-SPY2.2 is a phase II neoadjuvant trial with three neoadjuvant sequences (Blocks A/B/C). All HER2-negative subtypes were eligible for R + T-DXd in Block A. Predicted responders at the end of Block A or B could undergo surgery; otherwise, they continued to Block B +/- C. Block B pts received paclitaxel +/- carboplatin +/- pembrolizumab and Block C pts doxorubicin + cyclophosphamide (AC) +/- pembrolizumab, HR+ immune+ received IO in Blocks B/C. Results are analyzed by receptor and response predictive subtypes (RPS), that include expression-based immune, and luminal signatures with hormone receptor (HR) and HER2 status. Some pts were randomized to a control regimen (skipping R + T-DXd in block A and starting in block B). To minimize risk of interstitial lung disease (ILD) that could lead to treatment discontinuation, pts underwent pulmonary function tests and high-resolution chest CTs every 6 weeks. Abnormalities were reviewed in real time. The primary endpoint was pathologic complete response (pCR), within each RPS and HR/HER2 signature, with estimated pCR (EpCR) rates compared to subtype-specific block A goal rates and control pts in those groups. Other endpoints included safety and treatment discontinuation. Results: 105 pts were treated with R + T-DXd in block A, while 31 pts were randomized to the control regimen. Block A EpCR rate was 57% in the 12 HR+Immune+ pts vs a pre-specified goal of 15% (posterior probability, PP > .99). In 35 HR-Immune+ pts EpCR was 52% vs a pre-specified goal of 40% (PP = .87). No other groups (Immune-) had a PP > .85 for their respective pCR goal rate. HER2-IHC was 0 (27.6%), 1+ (49.5%) and 2+ (22.9%) in the treatment arm vs. 37.7%, 37.7%, and 24.7% in the control arm, with no difference in distribution between arms in immune subtypes. The most common adverse events in Block A were fatigue (84.8%), nausea (81.0%) and alopecia (58.1%). ILD was the most common adverse event of special interest in Block A and overall, occurring in 12 pts (11.4%; 7G1, 4G2, 1G3) during Block A and in 3 pts (G1, 2.9%) in other Blocks. 8 pts discontinued T-DXd + R due to ILD and proceeded to the next Block. Conclusions: When considering the full treatment strategy including block B and C regimens, experimental strategies had similar EpCR rates vs. controls in immune+ subtypes but block A rates exceeded pre-defined goal thresholds. This infers that treatment beginning with R + T-DXd has equivalent efficacy to standard of care for immune+ pts, but 64% pts with pCR skip chemotherapy (Block B) and 97% avoid AC (Block C). R + T-DXd participants avoided persistent ILD. Clinical trial information: NCT01042379 .

Abstract Background: Combinations of antibody-drug conjugates and immunotherapy, such as trastuzumab deruxtecan (T-DXd) and rilvegostomig (rilve), respectively, offer promising efficacy but are associated with a heightened risk of drug-induced interstitial lung disease (ILD)/pneumonitis. Early detection and management are critical for optimizing patient safety, yet there are no standard protocols for real-time evaluation. We hypothesized that vigilant monitoring would enable early detection, prevent symptoms, and minimize the chance of treatment delays while testing novel therapeutic combinations that have a potential risk of ILD. Methods: We tested the combination of T-DXd and rilve administered every 3 weeks in the I-SPY2.2 phase 2 platform trial (NCT01042379), which enrolls patients with clinical stage II/III breast cancer commencing neoadjuvant systemic therapy. Given the potential risk of overlapping pulmonary toxicity of these two agents, we added rigorous monitoring with pulmonary function tests (PFTs), six-minute walk test (6MWT), and high-resolution chest CT (HRCT) scanning pretreatment and every 6 weeks thereafter. A real-time safety workflow was implemented, with pre-specified criteria for halting treatment and escalation to the next block of treatment. All abnormal findings reported on chest CT by site radiologist were centrally reviewed in real time by the study pulmonologist (T.K.) and cases of suspected ILD were adjudicated promptly by a safety committee consisting of the pulmonologist and several medical oncologists, enabling early study drug interruption and therapeutic interventions. Toxicity data were evaluated in the first 51 patients treated with T-DXd plus rilve, and a preplanned hold was initiated until safety was ascertained by the data and safety monitoring board. Results: Safety data were evaluated in the first 51 patients receiving T-DXd plus rilve. Eight ILD events were confirmed (15.68% incidence): 5 grade 1, 2 grade 2, and 1 grade 3. One patient had an early chest CT scan because of dyspnea. All cases were identified by HRCT scans; PFTs and 6MWT did not enhance early detection and were subsequently dropped from the monitoring protocol. No patient was symptomatic for more than 24 hours. Radiographic findings resolved within 14-55 days. Patients with grade 2 & 3 ILD were treated with corticosteroids. No cases of ILD required intensive care or escalated therapy beyond steroids. Early treatment escalation to the subsequent block of therapy occurred in 3 patients; all 3 patients were subsequently able to receive appropriate therapy. At the meeting, safety data from all 100 patients treated with this combination will be reported. Conclusion: Real-time, centralized monitoring and adjudication allowed for early detection and prompt management of ILD, which both mitigated severity and supported timely therapeutic management. Among the monitoring tools studied, HRCT scanning performed every 6 weeks proved most effective for early ILD identification; PFT and 6MWT did not enhance early detection. This approach offers a potential framework for future studies assessing pulmonary safety in regimens combining agents that have a known risk for inducing ILD. Citation Format: T. Kulkarni, R. Nanda, H. S. Rugo, C. C. OSullivan, K. M. Kalinsky, J. C. Boughey, P. R. Pohlmann, J. Perlmutter, D. Yee, A. Borowsky, F. Symmans, N. Hylton, L. Van ‘t Veer, C. Yau, L. Esserman. Real-time monitoring for drug-induced interstitial lung disease with Trastuzumab Deruxtecan and Rilvegostomig combination therapy prevents persistent, symptomatic disease: Safety insights from the I-SPY2.2 platform trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-01-09.