Omene, Coral

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 .

625 Background: I-SPY 2 is a multicenter phase II adaptive platform trial evaluating novel agents for stage II-III high-risk breast cancer using response-predictive subtypes (RPS) and a sequential neoadjuvant treatment design of up to three blocks (A/B/C). Investigational regimens are given in Block A, followed by response-guided escalation to standard-of-care (SOC) therapy (tx) in subsequent blocks or early surgery for responders. Topoisomerase I (TOPO1) inhibition plus PARP inhibition may enhance DNA damage and tumor response. DAN-222 is a tumor-targeted polymeric camptothecin conjugate designed to improve the therapeutic index of TOPO1 inhibition. Based on favorable phase 1 safety and preliminary activity in metastatic breast cancer, DAN-222 plus niraparib was evaluated as Block A tx in HER2− disease. Notably, the neoadjuvant regimen used a higher dose of niraparib (200 mg daily) than the prior phase 1 metastatic study. Methods: Patients (pts) with HER2− breast cancer were randomized to DAN-222 plus niraparib for up to 12 weeks in Block A. Response was assessed by serial MRI and biopsy. Inadequate responders escalated early to SOC tx in Blocks B/C. Primary endpoint was pathologic complete response (pCR). Secondary endpoints included residual cancer burden, safety, early discontinuation, and treatment-strategy performance versus subtype-specific SOC tx controls. Given established PARPi sensitivity in BRCA mut disease, the key objective was to assess clinically meaningful activity of DAN-222 plus niraparib in BRCA wt pts. Accordingly, a prespecified Bayesian interim futility analysis focused on BRCA wt and tested the probability of the true pCR rate after Block A alone exceeded 15% after 50 pts. Results: Fifty pts enrolled from Sep to Dec 2024. In BRCA wt (n=47), estimated Block A pCR was 3%, with posterior probability of 0.02 that that true pCR exceeded 15%, meeting futility criteria and prompting arm closure. Across all blocks, pCR rate was 57% (8/14) for HR-HER2−; 11% (4/36) for HR+ HER2−, largely after SOC tx. 2/3 BRCA mut pts achieved pCR. Treatment strategies initiating with DAN-222 plus niraparib underperformed subtype-specific controls. 68% discontinued Block A early, mainly due to toxicity. Grade ≥3 cytopenias were common: neutropenia (n=25; 50%), anemia (24%), and thrombocytopenia (18%). Cystitis occurred in 36% (1 grade ≥3). Conclusions: Neoadjuvant DAN-222 plus niraparib showed insufficient activity and no treatment-strategy benefit in BRCA wt HER2− breast cancer, underscoring challenges for TOPO1–PARP inhibitor combinations. Although not supported for further development in this setting, these results highlight the strength of I-SPY 2 in rapidly enrolling patients and quickly distinguishing ineffective from promising therapeutic strategies to accelerate progress toward improved outcomes for patients with curable breast cancer. Clinical trial information: NCT01042379 .

Abstract Background: (Z)-endoxifen (ENDX) is an oral SERM that dually targets ERα (> 5 ng/ml) and PKCβ1 (>500 ng/ml). It has been tested in the endocrine resistant setting at doses of 20-360 mg/day; however, the optimal dose in an endocrine naïve population is not defined. We explored 10 mg/day dose of neoadjuvant ENDX in the Endocrine Optimization Pilot (EOP) of I-SPY2. Methods: EOP eligibility included pts with Stage II/III HR+ HER2- breast cancer, MammaPrint (MP) low. Pts with MP High1 scores were eligible if clinically node-negative. Pts received ENDX 10 mg orally once daily for 6 cycles (each cycle = 28 days). Premenopausal pts started ovarian function suppression on cycle 2, day 1. ENDX was continued until the day prior to surgery. The primary study endpoint was feasibility, defined as >75% of pts completing >75% of ENDX. Baseline (T0), 3-wk (T1) biopsies, and the surgical specimen (T3) were assessed centrally for Ki-67. Rates of modified preoperative endocrine prognostic index (mPEPI) 0 were reported, defined as pT1-2 pN0, Ki67< 2.7%, or pathologic complete response. A genomic index for sensitivity to endocrine therapy (SET) index was done at T0. Breast MRI measurement of functional tumor volume (FTV) was performed at T0, T1, 12 weeks (T2), and pre-operatively (T3). Blood was collected for tumor informed ctDNA at T0, T1, T2, T3 and for pharmacokinetic (PK) steady state concentrations (Css) at T1. Safety data using CTCAE V5 is reported. Results: Between March 2023 and May 2024, 20 pts were enrolled in this arm. The median age was 52.5 years (range 32 -73), 13 (65%) were premenopausal, and 55% had clinically positive lymph nodes. Tumors were MPHigh1 in 3 pts (15%) and SET2,3 index high in 16 pts (80%). The primary endpoint was met with 95% of study participants completing ≥75% of therapy. The T0 median Ki-67 was 10.5% (range 2-60%). At T1 (n=19) and T3 (n=18), median Ki-67 was 5% (range 0-35%) and 5% (range 0-45%), respectively. The 3-week rate of Ki-67 ≤10% at T1 was 61.5% in premenopausal and 71.4% in postmenopausal women. The rate of Ki-67 ≤10% at surgery was 81.8% in premenopausal and 57.1% in postmenopausal women. An mPEPI score of 0 was observed in 1 (5%) of participants. The median T0 FTV was 8.9 ccs (range 0.9 to 251.1). The median T3 FTV was 1.3 ccs (range 0 to 11.2) and the median change in FTV from T0 to T3 was -72.0% (range -88.5% to -61.6%). ctDNA analysis was performed in 17 pts longitudinally across 64 blood samples.10 pts had positive ctDNA at T0, with 7 converting to ctDNA undetectable during treatment with ENDX. 1/7 pts who was ctDNA negative at T0 became positive at T1 and then reverted to undetectable ctDNA. The other 6 pts remained ctDNA negative at all timepoints. The median ENDX T1 Css was 79.3 ng/mL (range 73.6 - 906.4 ng /mL). The most common side effects reported were Grade 1 hot flush (70%), nausea (40%), fatigue (40%), and insomnia (35%). Grade 2 side effects included fatigue (15%) and night sweats (5%). No dose reductions or discontinuations due to toxicity occurred. Conclusions: ENDX at 10 mg was well tolerated and demonstrated reductions in Ki-67, MRI FTV, and ctDNA. The ISPY2 EOP is currently enrolling patients to ENDX 40 mg/day (intended to dually target ERα and PKCβ1) in combination with abemaciclib (with and without OFS). Citation Format: K. V. Giridhar, M. P. Goetz, C. Yau, A. M. Wallace, C. Falkson, J. Boughey, M. Arora, E. Stringer-Reasor, C. Nangia, C. Gallagher, A. Elias, A. Zimmer, M. S. Trivedi, C. Omene, L. van 't Veer, L. Brown Swigart, G. L. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, C. Vakalvas, M. Wei, J. M. Reid, S. Alhafaji, N. Chen, R. M. Mukhtar, L. Huppert, O. Opopade, L. J. Esserman, A. Chein. Low dose (Z)-endoxifen in the I-SPY2 Endocrine Optimization Pilot [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 PS3-07-10.

Abstract BACKGROUND: EOP is an I-SPY2 sub-study designed to test novel endocrine-based strategies in patients (pts) predicted to have modest benefit from chemotherapy. Vepdegestrant is a selective oral PROTAC estrogen receptor (ER) degrader that has demonstrated efficacy in mutant ER+ HER2-negative MBC. METHODS: EOP eligibility included pts with Stage 2/3 HR+ HER2-negative, MammaPrint (MP) Low Risk BC. Patients with MP High1 signatures were eligible if clinically node-negative or SET 2,3 High. Pts were randomized to one of 3 oral treatment (tx) arms: vepdegestrant 200 mg/d (V), vepdegestrant 200 mg/d +letrozole (VL), vepdegestrant 200 mg/d + abemaciclib 150 mg bid (VA). Pts received tx for six 28-day cycles followed by surgery. Premenopausal (PreMN) pts received ovarian function suppression (OFS) starting C1D1 in the VL arm, and C2D1 in the V and VA arms. The primary endpoint was feasibility, defined as >75% of pts completing >75% of study therapy. Breast MRI functional tumor volume (FTV) and ctDNA (tumor-informed assay) were assessed at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). Ki67 and ER/PR by IHC were centrally assessed from tumor biopsies at T0, T1, and the surgical specimen. Results: Between 4/2023 and 1/2025, 121 pts were enrolled: 40 in V, 41 in VL, and 40 in VA. Median age was 54 years, 50% preMN. 60% of pts had ductal, 35% lobular, 5% mixed histology. 55% were cN+, and 59% were not breast conservation surgery (BCS) candidates at baseline. Mean baseline Ki67 was 12.5%, 85.1% had MP Low Risk signature, 79.3% were SET 2,3 High. All 3 tx arms met the primary endpoint with 88%, 88%, and 83% completing > 75% study therapy in V, VL, and VA (thus far), respectively. Most common all grade (AG) TRAEs in V and VL arms include fatigue (53% V, 71% VL), hot flashes (48% V, 71% VL), arthralgias (33% V, 49% VL), all G1 or G2 except for 1 G3 fatigue in VL arm. G2 and G3 neutropenia was seen in 1 pt each in V and VL arms. The most common AG TRAEs in VA include diarrhea (80%), fatigue (65%), nausea (58%), hot flashes (50%), neutropenia (43%). High grade TRAEs in VA include neutropenia (23% G3, 5% G4), ovarian cyst requiring surgery (5% G3), diarrhea (15% G3), nausea (3% G3), transaminitis (3% G3), thromboembolic event (8% G3), acute kidney injury (3% G3). Table 1 summarizes key response endpoints by tx arm. CONCLUSION: Six months of neoadjuvant vepdegestrant, alone or in combination with letrozole or abemaciclib, is feasible and demonstrates robust ER/PR degradation. Encouraging anti-tumor activity through reduction of Ki67 and MRI FTV, ctDNA clearance, and achievement of BCS was seen in pre- and postMN women. The neoadjuvant setting provides a rich platform to identify the dynamic range of response and non-response using a multi-modal approach and can be leveraged to inform future trial design and adjuvant therapy. Citation Format: J. Chien, R. M. Mukhtar, C. Yau, A. D. Elias, A. M. Wallace, N. Chan, C. Omene, N. Chen, J. Tseng, M. S. Trivedi, E. Stringer-Reasor, D. Yee, A. S. Clark, A. Thomas, H. Han, M. Arora, C. Nangia, K. Albain, C. Falkson, C. Isaacs, A. Zimmer, M. Rozenblit, L. van't Veer, L. Brown Swigart, G. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, S. Alkhafaji, K. V. Giridhar, C. Vaklavas, M. Wei, M. P. Goetz, O. Olopade, L. Huppert, C. Wu, L. J. Esserman. I- SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant vepdegestrant monotherapy or in combination with letrozole or abemaciclib in molecularly selected patients with stage 2/3 HR+ HER2-negative breast cancer (BC) [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 PD10-02.

LBA612 Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) status to evaluate novel neoadjuvant agents in high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Oral Paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar. Dostarlimab (D) is an intravenous (IV) PD-1 inhibitor. Methods: Women with tumors ≥ 2.5cm and MP high risk cancers (MP1 = MP high; MP2 = MP ultra-high) were treated starting Oct 5, 2020. Treatment included OPE (Oral P 205mg/m2 + encequidar 12.9mg) on days 1-3 weekly x 12 and D 500 mg IV given q 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q 2-3 weeks x 4. Patients with HER2+ disease received IV weekly trastuzumab (T) during the first 12 weeks. The control arm was weekly IV P x 12 with or without trastuzumab followed by AC q 2-3 weeks x 4. OPE + D was eligible to graduate [85% chance of success in a 300-person phase 3 neoadjuvant trial with a pCR endpoint] in any of the pre-defined signatures. Results: 113 (78 HR+HER2-, 17 HR-HER2- and 18 HER2+ patients) received OPE + D +/- T. The control arm included 388 historical controls (201 HR+Her2-, 156 HR-HER2-, 31 HER2+). 77 patients (70 HR+ and 7 HR-) were MP1 and 36 patients (24 HR+ and 12 HR-) were MP2. Safety events of note for OPE + D versus IV P include increased rates of nausea (85% vs. 72%) diarrhea (77% vs. 41%). There was no significant difference in rates of neutropenia (23% vs.17%). Peripheral neuropathy (37% vs. 64%) and alopecia (59% vs. 66%) were significantly decreased. Immune related adverse events (irAEs) were lower than expected. Conclusions: Although both OPE and D have both been shown to have efficacy in other settings, combination therapy with OPE + D did not graduate in any of the predefined subtypes. In the HR+ signature where we would not expect a benefit of D, we see equal response to OPE with decreased rates of peripheral neuropathy and alopecia, which suggest this oral agent may be an attractive alternative to IV P in this subgroup and is under consideration in ISPY 2.2. We did not observe the expected improvement in pCR rates seen with PD-1 inhibitors in the HR- or MP2 subtypes (over P alone historic control). In addition, the irAEs were less than expected. Together these findings suggest interference of OPE with D. A potential mechanism of interference could be change in microbiome with the use of OPE vs. IV P, as the microbiome is known to influence the efficacy of immunotherapy. The source of interference is being investigated. Clinical trial information: NCT01042379 . [Table: see text]

LBA520 Background: I-SPY 2 is a multicenter trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) risk to evaluate novel neoadjuvant agents in high-risk breast cancer. Oral paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar, to enhance gastrointestinal (GI) absorption. Dostarlimab (D) is an anti-PD-1 monoclonal antibody. Methods: Women with tumors ≥ 2.5cm and MP high-risk cancers were screened and treated starting Oct 5, 2020. Treatment included Oral Paclitaxel 205mg/m2 and encequidar 12.9 mg on days 1-3, Carboplatin (Cb) AUC 1.5 on day 1 weekly x 12, and Dostarlimab (D) 500 mg every 3 weeks x 4, followed by doxorubicin/ cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was IV P weekly x 12 followed by AC every 2-3 weeks x 4. For patients with HER2+ disease, weekly Trastuzumab (T) was administered during the first 12 weeks. The arm was eligible for graduation [> 85% chance of success in a 300-person phase 3 neoadjuvant trial with a pathologic complete response (pCR) endpoint] in 10 predefined signatures. Results: 106 patients (44 HR+HER2-, 56 HR-HER2- (TN), 6 HER2+) received OPE/Cb/D ± T. The control arm included 388 historical controls (201 HR+HER2-, 156 TN, 31 HER2+). 22 patients (20 HR+, 2 HR-) in OPE/Cb/D were MP1 (MP high) and 84 patients (29 HR+, 55 HR-) were MP2 (MP ultra-high). OPE/Cb/D graduated in the TN signature and accrual was stopped. Conclusions: OPE/Cb/D graduated in the TN signature with a higher predicted pCR rate compared to control. OPE and D have been, individually, shown to have efficacy in other settings. The lower-than-expected pCR rate and lower irAEs with triplet therapy (taxane, platinum, immune checkpoint inhibitor [ICI]) in TN compared to prior IV chemo + ICI arms on I-SPY 2 suggests a possible interference of OPE with ICI. Changes in gut microbiome is being investigated as an explanation. Clinical trial information: NCT01042379 . [Table: see text]