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Surufatinib, is a potent inhibitor of vascular endothelial growth factor receptors 1–3; fibroblast growth factor receptor-1; colony-stimulating factor 1 receptor. This Phase 1/1b escalation/expansion study in US patients with solid tumors evaluated 5 once daily (QD) surufatinib doses (3 + 3 design) to identify maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and evaluate safety and efficacy at the RP2D in 4 disease-specific expansion cohorts including pancreatic neuroendocrine tumors [pNET] and extrapancreatic NETs [epNET]. MTD and RP2D were 300 mg QD (escalation [n = 35]); 5 patients (15.6%) (Dose Limiting Toxicity [DLT] Evaluable Set [n = 32]) had DLTs. Pharmacokinetics were dose proportional. Estimated progression-free survival (PFS) rates at 11 months were 57.4% (95% confidence interval [CI]: 28.7, 78.2) and 51.1% (95% CI: 12.8, 80.3) for pNET and epNET expansion cohorts, respectively. Median PFS was 15.2 (95% CI: 5.2, not evaluable) and 11.5 (95% CI: 6.5,11.5) months. Response rates were 18.8% and 6.3%. The most frequent treatment-emergent adverse events (both cohorts) were fatigue (46.9%), hypertension (43.8%), proteinuria (37.5%), diarrhea (34.4%). Pharmacokinetics, safety, and antitumor efficacy of 300 mg QD oral surufatinib in US patients with pNETs and epNETs are consistent with previously reported studies in China and may support applicability of earlier surufatinib studies in US patients. Clinical trial registration: Clinicaltrials.gov NCT02549937.

Purpose: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both and wild-type and mutant ERα by targeting cysteine 530 and enforcing antagonist conformation. H3B-6545 demonstrated preclinical high activity in breast cancer models with constitutively active ESR1 mutations (Furman C, SABCS 2020) and clinical activity in pretreated women with ER+ breast cancer (Hamilton EP, ASCO 2021). Patients and Methods: The primary objective of the phase II is to estimate the objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and secondary objectives include safety. Results: 94 pts were treated with 450 mg daily, the recommended phase II dose: 11 in the phase I and 83 in the phase II parts of the trial. Patients and tumor characteristics were presented previously (Hamilton EP, ASCO, 2021). As of March 31, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), nausea (17%), fatigue (16%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (39%), hemoglobin decrease (38%), Lymphocytes decrease (37%), ALT increase (14%), AST increase (13%), bilirubin increase (12%), and creatinine increase (12%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 35% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in Table 1. CI: Confidence interval. N: total number of pts in full analysis set, used in PFS analysis. n: number of response-evaluable pts, used in ORR and CBR analysis. Efficacy estimates were consistent across the various subgroups. Responses were demonstrated in heavily pretreated pts, pts with visceral metastases, pts with constitutionally active ESR1 Y537S mutations, and in pts who received chemotherapy in the metastatic setting. Numerically higher response rate and longer PFS were observed in pts with ESR1 Y537s. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was consistent across the various subgroups. Tumors harboring the constitutionally active ESR1 Y537S mutation may present higher ERα activity, and consequently enrich for luminal A traits and demonstrate greater lineage dependence on ERα. Table 1.Consistency of H3B-6545 activity across the key subgroupsEfficacyClinical CharacteristicORR % (95% CI)CBR % (95% CI)Median PFS mo (95% CI)Overall population (N=94, n=72)16.7 (8.9, 27.3)40.3 (28.9, 52.5)5.1 (3.2, 6.2)Liver and/or lung metastases (N=76, n=62)17.7 (9.2, 29.5)41.9 (29.5, 55.2)5.4 (1.8, 7.2)≥3 prior regimens (N=49, n=39)20.5 (9.3, 36.5)48.7 (32.4, 65.2)5.4 (3.5, 7.3)Prior chemotherapy (N=47, n=35)17.1 (6.6, 33.6)51.4 (34.0, 68.6)5.5 (3.6, 7.3)PgR+ (N=38, n=32)15.6 (5.3, 32.8)50.0 (31.9, 68.1)5.4 (2.0, 8.8)ESR1 clonal Y537S (N=10, n=10)30.0 (6.7, 65.2)60.0 (26.2, 87.8)7.3 (0.8, 11.2)ESR1 clonal D538G (N=19, n=17)0.0 (0.0, 19.5)35.3 (14.2, 61.7)5.4 (1.7, 7.2) Citation Format: Erika P Hamilton, Judy S Wang, Timothy Pluard, Aki Morikawa, E Claire Dees, Robert H Jones, Barbara Haley, Anne Armstrong, Adam L Cohen, Pamela Munster, Gail S Wright, Fadi Kayali, Lisa Cantagallo, Manav Korpal, Jenny Long, Jianjun Xiao, Benoit Destenaves, Lei Gao, Tarek Sahmoud, Antonio Gualberto, Dejan Juric. H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer - A phase II 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 P1-17-10.

Background: Engineered toxin bodies (ETBs) are composed of a de-immunized Shiga-like Toxin A subunit genetically fused to an antibody-like binding domain. ETBs can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other therapeutics. MT-5111 is a 55 kD ETB targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of MT-5111 monotherapy in adult pts with advanced HER2+ solid tumors. Secondary objectives are pharmacokinetics (PK), efficacy, and immunogenicity. Using a modified 3+3 design, the dose-escalation part of the study enrolls pts with HER2+ tumors into 7 cohorts: 0.5, 1, 2, 3, 4.5, 6.75, and 10 µg/kg/dose. Three dose-expansion cohorts will follow for HER2+ breast cancer, gastro-esophageal cancer, and other HER2+ tumors. All pts receive MT-5111 weekly as 30-min IV infusions in each 21-day treatment (tx) cycle (C) until disease progression (PD), unacceptable toxicity, death, or withdrawn consent (NCT04029922). Results: Per data cut in June 2021, 21 pts (mean age 64 years, range 34-78; 38% male) in cohorts 1-6 with breast (n=7), biliary (n=6), gastric (n=3), pancreatic (n=2), lung (n=2), and colon (n=1) cancer were treated (Table 1). Pts had a median of 4 prior lines of systemic therapies (range, 1-8) and 2 prior lines of HER2-targeting treatments (range, 0-6). No Grade (G)4 or 5 tx-emergent (TE) adverse events (AEs) occurred. Tx-related AEs occurred in 11 (52%) pts; the most common was fatigue (n=7, 33%). One pt (4.5 µg/kg) had a possibly (per PI) related G3 serious AE (SAE) of dyspnea and hypoxia, but also lymphangitic carcinomatosis and H. influenzae infection. The other related SAE occurred in a pt (6.75 µg/kg) who had a G1 transient troponin increase without concomitant cardiac symptoms or ECG/ECHO changes. All other related AEs were ≤G2. There were no clinically significant changes in cardiac biomarkers (troponin, ECG, left ventricular ejection fraction) nor were there cases of capillary leak syndrome. Two pts (3 µg/kg and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies, and Cmax data at 6.75 µg/kg indicated that current in-human exposure was between the IC50 values of high and medium HER2-expressing cell lines (approximately 10-89 ng/mL). Thus, a dose of at least 10 µg/kg may be required to achieve effective exposure. To date, no dose-limiting toxicities have been observed and the 10 µg/kg/dose cohort is now accruing. Conclusions: MT-5111 was well tolerated with no clinically significant immuno- or cardiotoxicity. Dose escalation is ongoing and nearing levels expected to be required for efficacious exposure. Table 1.Metastatic HER2 status and MT-5111 treatment by cohortDose0.5 µg/kg1.0 µg/kg2.0 µg/kg3.0 µg/kg4.5 µg/kg6.75 µg/kgCohort123456Number of patients treated with MT-5111433335Metastatic HER2 2+ by IHC: ALL/BC1/11/11/01/10/04/0Metastatic HER2 3+ by IHC: ALL/BC3/12/02/12/13/01/1BC, breast cancer. Citation Format: Brian A. Van Tine, Monica Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel Ahn, Joleen Hubbard, Jason Starr, Angela Georgy, Joshua Pelham, Banmeet S. Anand, Thomas Strack, Andrés Machado Sandri, Zev A. Wainberg. Interim results of a phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+tumors [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 P2-13-45.

Background: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both mutant and wild-type ERα by targeting cysteine 530 and enforcing antagonist conformation. It demonstrated a manageable safety profile and single-agent antitumor activity in heavily pretreated ER+, HER2- mBC patients (pts) (Hamilton et al, ASCO, 2021). Methods: The study aims at determining the recommended phase II doses of the combination of H3B-6545 and palbociclib in pts with ER+, HER2- mBC. Other endpoints include safety, pharmacokinetics, and preliminary efficacy. The escalation phase enrolls pts with at least 2 prior therapies in the metastatic setting. Up to one prior chemotherapy and up to one prior CDK4/6 inhibitor are allowed. Each cohort enrolled 6 pts to ensure availability of sufficient PK data. During the first cycle, H3B-6545 was added to palbociclib on day 9. Dose-limiting toxicities (DLTs) were assessed during the first 28 days starting from the 1st day of adding H3B-6545 to palbociclib (cycle 1 day 9 to cycle 2 day 8). Both drugs were started on day 1 of each of the subsequent cycles. Results: As of June 15, 2021, 14 pts were enrolled: 7 in Cohort 1 (H3B-6545 300 mg QD and palbociclib 100 mg QD) and 7 in Cohort 2 (H3B-6545 300 mg QD and palbociclib 125 mg QD). Median age was 61 years (range: 28-75 years), ECOG performance status was 0 in 7 pts (50%) and 1 in 7 pts (50%) and 9 pts (64%) had lung and/or liver metastases. Median number of prior therapies in the metastatic setting was 3 (range: 1-6). Prior therapy in the metastatic setting included fulvestrant (93%), CDK4/6 inhibitors (79%), aromatase inhibitors (64%), and chemotherapy (29%). One pt in each Cohort was not evaluable for dose limiting toxicity (DLT) assessment and no DLTs were observed in the first 2 Cohorts. Seven pts discontinued study treatment because of progression and 1 pt discontinued due to diagnosis of a second primary cancer during the first cycle. Non-hematological grade 2 or higher adverse events (AE), irrespective of causality, reported in ≥2 pts were: nausea, vomiting, abdominal pain, and bone pain, each observed in 2 pts (14%). Gr. 1 and 2 sinus bradycardia were reported in 6 (43%) and 1 pts (7%), respectively. One pt (7%) had grade 1 QT prolongation. No grade 4 AEs or treatment-related deaths were reported. For hematology and chemistry laboratory abnormalities: gr. 3 and 4 neutropenia in 7 pts (50%) and 2 pts (14%), respectively, gr. 3 thrombocytopenia in 1 pt (7%), gr. 3 anemia in 2 pts (14%). Grade 2 decrease in estimated glomerular filtration rate was observed in 7 pts (50%), all reported irrespective of causality. Co-administration of palbociclib had no meaningful impact on H3B-6545 exposure (15% and 21% increase in geometric means of AUC and Cmax, respectively). Co-administration of H3B-6545 modestly increased palbociclib exposure (49% and 36% increase in geometric means of AUC and Cmax, respectively). Among 6 response-evaluable pts in Cohort 1, 2 pts (33%) had confirmed partial responses and 4 pts (67%) had stable disease. Both responding pts received prior therapy with a CDK4/6 inhibitor and fulvestrant. Cohort 2 efficacy data is not yet mature. Recruitment is currently ongoing in Cohort 3 (H3B-6545 450 mg QD and palbociclib 125 mg QD). Conclusions: The combination of H3B-6545 (up to 300 mg dose) and palbociclib (up to 125 mg dose) was well-tolerated and demonstrated preliminary anti-tumor activity in heavily pretreated pts with ER+, HER2- mBC. ClinicalTrials.gov Identifier: NCT04288089. Citation Format: Stephen Johnston, Timothy J Pluard, Judy S Wang, Erika P Hamilton, Dejan Juric, Catherine R Scholz, Elizabeth Hnitecki, Sara Dar, Lei Gao, Lisa Cantagallo, Manav Korpal, Jianjun Alan Xiao, Lihua Yu, Tarek Sahmoud, Antonio Gualberto. H3B-6545 in combination with palbociclib in women with metastatic estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer, phase 1b 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 P1-17-03.

The Bromodomain and Extra-Terminal (BET) Domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all 4 BET family members (BRD2, BRD3, BRD4, and BRDT). PLX2853 development is continuing at Opna Bio as OPN-2853. Clinical experience with PLX2853 monotherapy in subjects with heavily pretreated solid tumors and lymphoma showed signs of activity. The current study (NCT04493619) was designed as a multicenter, open-label trial with two parallel arms: (1) a phase 2a study of PLX2853 monotherapy in advanced gynecological malignancies with a known ARID1A mutation and (2) a phase Ib/2a combination study of PLX2853 plus carboplatin in platinum resistant OC. The primary objective of the Ib portion of the study was safety and tolerability, with the primary objective of both phase 2a portions being efficacy. In the monotherapy arm, up to 6 patients were treated at 80 mg PLX2853 daily in a safety lead-in, with progression to phase 2a using a Simon 2-stage design if dose limiting toxicities (DLTs) were observed in fewer than 33% subjects. In Stage 1, 6 additional subjects (N=12 total) were planned, with progression to stage 2 if two or more patients responded in stage 1. The combination arm included an escalation phase Ib. Three to six evaluable subjects were planned for each group, with dose escalation pending less than 33% DLT rate. The combination arm defined by the phase 1b portion of the study continued to a planned phase 2a Simon 2 stage design similar to that described for the monotherapy arm. 34 of 37 enrolled patients were evaluable with data from at least 1 post-baseline response (14 monotherapy, 20 combination therapy). Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a partial response (PR) with progression-free survival of 278 days, 5 (35.7%) had stable disease (SD) and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable OC patients on the PLX2843 + carboplatin combination, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD. This study in a larger cohort of gynecologic cancer patients confirmed the safety profile of the agent and demonstrated the feasibility of combination with carboplatin. While these results did not meet the pre-specified response criteria, evidence of clinical activity nevertheless highlights the rationale for further exploration of BRD4 inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway, frequently activated in these cancers. Citation Format: Elizabeth M. Swisher, Linda R. Duska, Erika P. Hamilton, Amit M. Oza, Gini Fleming, Oladapo O. Yeku, Alexander I. Spira, Debra L. Richardson, Robin Guo, Jackie Walling, Kerry Inokuchi, Dmitriy Zamarin. Phase 1b/2a clinical trial of the oral BET inhibitor PLX2853 as monotherapy for ARID1A mutated gynecologic cancers and in combination with carboplatin for platinum resistant ovarian cance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT160.

3025 Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for pts with unresectable or metastatic HER2+ BC with ≥2 prior anti-HER2–based therapies. T-DXd showed improved progression-free survival vs trastuzumab emtansine (T-DM1) as an earlier-line treatment (tx) for pts with HER2+ metastatic BC in the phase 3 DESTINY-Breast03 trial (Cortes J, et al. Ann Oncol. 2021;32:S1283-S1346. Abstract LBA1). Preliminary antitumor activity of T-DXd was shown in heavily pretreated pts with HER2-low advanced/metastatic BC in the phase 1 DS8201-A-J101 trial (Modi S, et al. J Clin Oncol. 2020;38:1887-1896). We report preliminary results from the dose-finding phase of 2 trials investigating T-DXd combination tx in HER2+ or HER2-low metastatic BC. Methods: DB-07 (phase 1b/2; NCT04538742) and DB-08 (phase 1b; NCT04556773) are 2-part, modular, open-label, multicenter trials of T-DXd combined with other anticancer tx in pts with advanced/metastatic BC that is HER2+ (DB-07) or HER2 low (DB-08). Part 1 of each study is an ongoing dose-finding phase; pts must have ≥1 prior tx for metastatic BC. Part 2 of each study is a dose-expansion phase; pts must have no (DB-07) or ≤1 (DB-08) prior tx for metastatic BC. We report preliminary results from the T-DXd + pertuzumab module of DB-07 part 1 (data cutoff: Oct 15, 2021) and T-DXd + anastrozole and T-DXd + fulvestrant modules of DB-08 part 1 (data cutoff: Sep 27, 2021); pts in the DB-08 modules must be hormone receptor positive. The part 1 primary objective was to assess safety and tolerability and determine the recommended phase 2 dose (RP2D) according to the modified toxicity probability interval-2 algorithm. Pts were followed up beyond the 21-day dose-limiting toxicity (DLT) period (28 days for T-DXd + fulvestrant) for safety events. Results: In DB-07, 7 pts were enrolled and received T-DXd 5.4 mg/kg + pertuzumab 420 mg (loading dose: 840 mg) every 3 wk (q3w; not evaluable for DLTs, n = 1). In DB-08, 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + anastrozole 1 mg daily (not evaluable for DLTs, n = 1); another 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + fulvestrant 500 mg every 4 wk (loading dose: 500 mg cycle 1 days 1 and 15). For all 3 modules, no DLTs were reported in any DLT-evaluable pts; the dose levels used in part 1 were approved to be the RP2Ds for use in the dose-expansion part of each corresponding module. No deaths on study or cases of interstitial lung disease/pneumonitis were reported to date. Conclusions: The RP2Ds for the T-DXd combinations were the standard doses for BC of each individual drug. These studies are ongoing, with additional T-DXd combinations being evaluated and further follow-up underway. Clinical trial information: NCT04538742; NCT04556773.

5517 Background: LIO-1 is assessing the oral antiangiogenic, multikinase inhibitor lucitanib in combination with the programmed cell death receptor 1 (PD-1) inhibitor nivolumab. Individualized lucitanib dose titration is being explored to maximize lucitanib exposure and potential clinical benefit of the combination. Here, we present data from stage 1 of a Simon 2-stage design across 4 different types of advanced gynecologic cancers from the phase 2 part of LIO-1. Methods: Patients (pts) with advanced, recurrent, or metastatic endometrial cancer (EC, who received ≥1 prior platinum-based chemotherapy); cervical cancer (CC, who received ≥1 prior platinum-based chemotherapy ± bevacizumab); high-grade ovarian cancer (OC, who received ≥2 prior chemotherapies); or EC/OC with clear-cell histology (EOCC, who received ≥1 prior platinum-based chemotherapy + taxane) were enrolled. Prior PD-1 or programmed cell death ligand 1 (PD-L1) inhibitor treatment was excluded, except for up to 10 pts in the EC cohort. Pts received lucitanib at a starting dose of 6 mg once daily (QD), escalating to 8 mg QD and then 10 mg QD if safety-based titration criteria were met, plus intravenous nivolumab 480 mg every 28 days. The data cutoff was Jan 10, 2022. Results: Across cohorts, 100 pts were enrolled to stage 1; 27 (27%) remain on treatment. To date, 28 (28%) have escalated to lucitanib 8 mg, and 17 (17%) have escalated to the maximum dose of 10 mg. Confirmed responses per RECIST v1.1 have been reported in 5/22 (22.7%; 5 partial responses [PRs]) EC pts, 7/22 (31.8%; 2 complete responses [CRs], 5 PRs) CC pts, 4/33 (12.1%; 4 PRs) OC pts, and 5/23 (21.7%; 1 CR, 4 PRs) EOCC pts. Response duration ranges from 1.9+ to 13.1+ months. Of 5 pts with EC who received prior PD-1 inhibitor, there were 2 PRs, and 1 pt with ongoing stable disease of 7+ months. Grade ≥3 treatment-emergent adverse events (TEAEs) considered related to study treatment were reported in 43 (43%) pts, with hypertension the most frequent (n = 25 [25%]). Forty-six (46%) pts had a lucitanib-related TEAE that led to lucitanib interruption and 12 (12%) had one that led to lucitanib dose reduction. Eleven (11%) and 8 (8%) pts discontinued lucitanib and nivolumab, respectively, due to a treatment-related TEAE. Safety results were generally consistent across tumor cohorts. Conclusions: The combination of lucitanib + nivolumab is active in the treatment of advanced gynecological malignancies and has a manageable safety profile through effective dose titration. Stage 2 enrollment has continued in the CC cohort. Biomarker analysis is ongoing, and more mature efficacy and safety data will be presented at the meeting. Clinical trial information: NCT04042116.

1017 Background: The phase 3 ML-2, -3, and -7 trials all demonstrated consistent and statistically significant OS benefit with RIB (starting dose: 600 mg/d 3 wk on/1 wk off) vs PBO in pts with HR+/HER2− ABC. RIB dose mod (reductions and/or interruptions) when needed did not impact OS benefit with RIB + endocrine therapy (ET) in previous analyses of ML-3/-7. Here we present data on the effect of RIB dose mod on OS in postmenopausal pts with HR+/HER2− ABC in ML-2. Methods: ML-2 (NCT01958021) enrolled postmenopausal pts randomized 1:1 to first-line RIB + letrozole (LET) or PBO + LET. Landmark (LM) analyses of OS were performed to evaluate the association between dose reductions (yes vs no) and OS. Multiple LM times were considered to determine the sensitivity of the findings. As an alternative to LM analysis, a Cox proportional hazards model with a time-varying covariate was performed. Two time-dependent variables, dose reduction (with/without mod from 600 mg starting dose) and relative dose intensity 2 (RDI2), were included in the respective model as covariates to explore the association with OS. To account for differences in time to first dose mod, RDI2 reflects the post–dose mod period. Median (m) OS was obtained using a modified Kaplan-Meier method. Results: At data cutoff (June 10, 2021; m follow-up, 49.35 [range, 0-86.7] mo), 209 of 334 pts (62.6%) had ≥ 1 RIB dose reduction and 125 of 334 (37.4%) had 0 RIB dose reduction. LM analyses by dose reduction are presented (Table). mOS was 66.0 (95% CI, 57.6-75.7) mo in pts with ≥ 1 RIB dose reduction vs 60.6 (95% CI, 42.5-79.2) mo in pts with no RIB dose reductions (HR, 0.87 [95% CI, 0.65-1.18]). RDI2 was classified according to tertile: low (< 64.27%), medium (64.27%-95.86%), and high (> 95.86%). In pts with low, medium, and high RDI2, mOS was 62.6 (95% CI, 50.0-80.7) mo, 63.9 (95% CI, 48.8-not reached [NR]) mo, and 65.3 (95% CI, 50.5-NR) mo, respectively (HR low vs high, 0.99 [95% CI, 0.69-1.42]; HR medium vs high, 0.97 [95% CI, 0.62-1.38]). Conclusions: In this exploratory analysis of ML-2, OS benefit was maintained in pts with HR+/HER2− ABC who required mod from the recommended starting dose of RIB (600 mg/d 3 wk on/1 wk off). No relationship was observed between OS and RIB dose reduction or RDI2; OS benefit with RIB was observed in all groups. Clinical trial information: NCT01958021. [Table: see text]

1000 Background: In the DESTINY-Breast03 (NCT03529110) primary analysis (data cutoff [DCO], May 21, 2021), T-DXd showed superiority over T-DM1 in pts with HER2+ mBC, with a significant improvement of progression-free survival by blinded independent central review (HR, 0.284; 95% CI, 0.217-0.373; P < 0.001), and a safety profile consistent with prior studies. This analysis provides updated safety data with longer follow-up. Methods: Pts were randomized 1:1 to T-DXd or T-DM1. Prespecified safety analysis of treatment-emergent adverse events (TEAEs) was conducted; endpoints included time to event, duration of event, and resolution. Results: At DCO (September 7, 2021), 116 (45.1%) pts vs 39 (14.9%) pts remained on treatment in the T-DXd vs T-DM1 arms; median treatment duration was 16.1 mo (range, 0.7-33.0) for T-DXd vs 6.9 mo (range, 0.7-28.5) for T-DM1. Any-grade (G), G≥3, and serious AE (SAE) rates were similar for T-DXd vs T-DM1 (99.6% vs 95.4%; 53.3% vs 49.8%; and 21.0% vs 19.2%), while exposure-adjusted incidence rates (EAIRs; per pt-year) for G≥3 and SAEs were lower for T-DXd vs T-DM1 (0.42 vs 0.70 and 0.17 vs 0.27). Median time to TEAE associated with drug discontinuation or dose reduction was longer with T-DXd vs T-DM1 (224.0 vs 147.0 d and 96.0 v 19.0 d, respectively). Most TEAEs in ≥20% of pts were hematologic or gastrointestinal. Median time to first onset of select any-G TEAEs was 70.0 vs 42.0 d for anemia, 196.0 vs 168.0 d for lymphopenia, 132.0 vs 8.0 d for thrombocytopenia, 22.0 vs 24.0 d for fatigue, 74.5 vs 92.0 d for leukopenia, and 64.0 vs 105.0 d for neutropenia, with T-DXd vs T-DM1, respectively. In both arms, most nausea and vomiting events were G1/2; while G≥3 events with T-DXd vs T-DM1 were 6.6% vs 0.4% for nausea and 1.6% vs 0.8% for vomiting, respectively. Rates of nausea, vomiting, and alopecia were highest in cycle 1 and lower in subsequent cycles for T-DXd. Rates of hematologic events were generally lower in earlier cycles vs cycle ≥8 in both arms. Rates of adjudicated, drug-related ILD/pneumonitis were 10.9% (1 G2 event since previous DCO) with T-DXd vs 1.9% with T-DM1, with no G4/5 events. Median time to first adjudicated, drug-related ILD/pneumonitis event was 5.9 vs 9.5 mo for T-DXd vs T-DM1, respectively; at DCO, most events resolved (57.1% vs 80.0%), and follow-up is ongoing. Conclusions: In this updated safety analysis, T-DXd demonstrated a tolerable safety profile consistent with prior studies. Despite longer treatment duration with T-DXd, EAIRs of G≥3 and SAEs were lower for T-DXd vs T-DM1. Rates of ILD/pneumonitis for T-DXd were similar to those in the previous DCO. Nausea, vomiting, and alopecia rates decreased over time. This longer safety update reinforces the consistent safety profile of T-DXd, supporting the clinical benefit of T-DXd over T-DM1 in patients with HER2+ mBC. Clinical trial information: NCT03529110.

TPS2688 Background: The major histocompatibility complex (MHC) class I-related proteins MICA and MICB are stress-inducible, surface glycoproteins that are up-regulated on human tumors. MICA/MICB are ligands for the activating receptor, Natural Killer Group 2 member D (NKG2D) expressed on Natural Killer (NK) cells, CD8+ T cells, γδ T cells and iNKT cells. Proteases in the tumor microenvironment cleave MICA/MICB from the cell surface which enables tumor cells to evade immune cell recognition and destruction by NKG2D-expressing cells. Increased concentrations of shed MICA have been observed in serum from patients across multiple tumor types and correlate with poor survival. CLN-619 is a humanized, clinical-stage, MICA/MICB-specific IgG1 monoclonal antibody that prevents the proteolytic release of MICA/MICB thereby exposing tumor cells for immune destruction through both NKG2D-mediated and antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody has been shown to restore the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis (AACR Annual Meeting abstract 3506, April 2022). In mice bearing MICA/MICB-expressing human tumor xenografts, CLN-619 treatment yielded robust anti-tumor activity at low doses. MICA/MICB is expressed in a wide range of solid tumors. Therefore, CLN-619 is expected to have broad anti-tumor activity. Methods: CLN-619 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study as monotherapy, and in combination with pembrolizumab, in patients with advanced solid tumors. Cohort expansion in patients with specific indications as monotherapy and in combination with pembrolizumab will be conducted. The phase 1 study explores ascending intravenous doses of CLN-619 as monotherapy (0.1, 0.3, 1.0, 3.0, 6.0 and 10.0 mg/kg) and in combination with pembrolizumab (200 mg) in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Key eligibility criteria include 1) histological or cytological diagnosis of cancer and 2) refractory metastatic disease, or locally advanced disease not amenable to local therapy. At the RP2D, CLN-619 monotherapy will be evaluated in non-small cell lung and cervical cancer. In parallel, a cohort of patients will be administered CLN-619 in combination with pembrolizumab. Serum levels of soluble MICA/MICB, identity of MICA/MICB alleles, phenotypes of peripheral blood mononuclear cells, cytokines and tumor biopsies will be investigated for correlative pharmacodynamic and predictive biomarkers. This clinical trial is in progress (NCT05117476) and has completed accrual of three participants at the first dose level. Clinical trial information: NCT05117476.

3002 Background: Cadherin 6 (CDH6) is part of the cadherin family, which is involved with cell-cell adhesion, organ development, and epithelial-mesenchymal transition. CDH6 is found to be overexpressed in various cancers, particularly RCC and OVC. DS-6000a is an antibody-drug conjugate, comprised of an humanized anti-CDH6 IgG1 monoclonal antibody attached to a topoisomerase I (TOP1) inhibitor payload via a cleavable linker. DS-6000a specifically binds to CDH6 on the surface of tumor cells and is internalized upon binding. The payload is then released, resulting in target cell apoptosis. In preclinical studies, DS-6000a inhibited tumor growth and induced tumor regression in CDH6-expressing RCC and OVC. Here, we report initial results from a phase I trial of DS-6000a in patients (pts) with advanced RCC and OVC (NCT04707248). Methods: This dose-escalation (Part A) and expansion (Part B) study will recruit pts with advanced RCC and OVC. DS-6000a is administered IV as monotherapy on Day 1 of 21-day cycles. Part A assesses safety, tolerability, and maximum tolerated dose or recommended dose for expansion (RDE) using Bayesian optimal interval design; additional pts are enrolled to examine safety and efficacy. The starting dose of DS-6000a is 1.6 mg/kg followed by 3.2, 4.8, 6.4, 8, and 9.6 mg/kg. Part B will assess safety, tolerability and efficacy at the RDE. Results: Part A interim results are presented. At data cutoff (19 NOV 2021), 22 pts had enrolled (7 RCC, 15 OVC). All RCC pts had received an immune checkpoint inhibitor and the majority of OVC had platinum resistant (Pt-R) disease; median age was 63.5 years (range, 41-78); median of 4 (range, 1-12) prior lines of therapy were administered; and median treatment duration was 8.0 wks (range, 3-33.14). Fifteen pts (68.2%) were ongoing at the cutoff date. Treatment-emergent adverse events (TEAEs) occurred in 19 pts (86.4%). Related TEAEs occurred in 17 pts (77.3%). The most common related TEAEs (>20%) were fatigue and nausea (45.5% each), and vomiting (27.3%). Grade ≥3 related TEAEs occurred in 4 pts (18.2%); the most common was neutropenia (13.6%). One patient (4.5%) had a Grade 3 febrile neutropenia. One dose-limiting toxicity of Grade 4 thrombocytopenia (9.6 mg/kg) occurred. There was no study drug discontinuation due to a TEAE. Among 15 evaluable pts, 2 partial responses (PRs; 1 confirmed in RCC and 1 unconfirmed PR in Pt-R OVC) were observed; 9 pts had stable disease. Moreover, 5 out of 11 OVC evaluable pts showed CA-125 responses using GCIG criteria and all CA-125 responders had Pt-R disease. Conclusions: The interim data from dose-escalation of this FIH study showed acceptable tolerability with early signals of efficacy in heavily pretreated pts with advanced RCC and Pt-R OVC, which support further clinical evaluation of DS-6000a in the planned dose-expansion cohorts in advanced RCC and OVC. Clinical trial information: NCT04707248.

1052 Background: Dysregulating mutations in PIK3CA, encoding the PI3K p110α subunit, occur in ̃40% of HR+/HER2– BCs. Inavolisib is a PI3Kα-specific inhibitor that also promotes degradation of mutant p110α. It has demonstrated encouraging preliminary antitumor activity in pts with PIK3CA-mutated HR+ BC as a monotherapy, and in combo with other anticancer agents. Methods: We included pts from NCT03006172 on treatment ≥1 year with inavolisib alone (Arm A), or in combo with palbo + letrozole (letro) (B), letro (C), fulvestrant (fulv) (D), or palbo + fulv (E; + metformin in Arm F for pts with body mass index ≥30 and/or HbA1c ≥5.7%). Inavolisib was administered orally daily (PO QD) at 3, 6, 9, or 12 mg (3+3 dose-escalation design); letro at 2.5 mg PO QD; palbo at 125 mg PO QD for 21/28 days; and fulv at 500 mg intramuscularly every 4 weeks, in 28-day cycles until intolerable toxicity/disease progression. Safety was assessed by NCI-CTCAE v4. Results: 57 female pts were included (cutoff 07/26/21; N = 1, 18, 6, 12, 15, 5 in Arms A–F); median age: 57 years (range 33–80); median lines of prior therapy: 2 (1–7). All but 2 pts, both in Arm B (3 mg), were assigned the 9 mg inavolisib recommended phase 3 dose. Overall median treatment duration: 19 months (range 12–45); median inavolisib cumulative dose intensity, 95%. The most frequent treatment-related adverse events (AEs; in ≥20 pts/35%) were hyperglycemia (68%), stomatitis (68%; grouped terms), neutropenia (58%), diarrhea (51%), nausea (39%), alopecia (35%), and rash (35%; grouped terms). The most frequent treatment-related Grade (G) 3–4 AEs (≥2 pts/4%) were neutropenia (47%), hyperglycemia (16%), leukopenia (9%), thrombocytopenia (9%), lymphopenia (7%), weight decreased, and hypokalemia (4% each). G3–4 neutropenia, leukopenia, thrombocytopenia, and lymphopenia were all reported in palbo arms. One G5 AE of pleural effusion was reported (disease progression-related). 39 pts (68%) had ≥1 AE resulting in study treatment modification (drug interruption/dose reduction/treatment withdrawal); 11 (19%) had an inavolisib dose reduction and 2 (4%) discontinued treatment due to an AE (1 related G2 diarrhea, 1 unrelated G3 cerebrovascular disorder). AEs typically occurred during the first 6 months and tended to be less frequent in later cycles. No new safety signals were observed with long-term inavolisib use. Conclusions: These data indicate acceptable long-term tolerability. The safety profile of pts on study treatment with inavolisib alone or in combo with endocrine-based anticancer therapies for ≥1 year was similar to that reported for the overall study population. Updated data will be presented. A phase 3 study of inavolisib + palbo + fulv is enrolling (NCT04191499; INAVO120). Clinical trial information: NCT03006172.

TPS1124 Background: Targeting constitutively active mutant kinases with selective small molecule inhibitors is a key therapeutic pillar of precision oncology. Phosphatidylinositol-4,5bisphosphate-3 kinase, catalytic subunit alpha ( PIK3CA) mutations leading to oncogenic activation of PI3Kα represent the largest opportunity for this approach in solid tumors. However, there is no selective inhibitor that targets mutant PI3Kα in the clinic. Toxicity related to non-selective inhibition of WT PI3Kα (hyperglycemia) and other PI3K isoforms limits the tolerability, dosing and efficacy of the orthosteric inhibitor, alpelisib, the only approved solid tumor PI3K inhibitor. RLY-2608, a novel oral allosteric PI3Kα inhibitor, is uniquely designed to overcome these limitations via mutant- and isoform-selective PI3Kα inhibition for greater target coverage, improved tolerability and antitumor activity. We initiated a first-in-human (FIH), study to evaluate the clinical activity of RLY-2608 as a single agent in advanced solid tumor patients (pts) with PI3KCA mutations and in combination with fulvestrant in pts with PIK3CAmutant, HR+, HER2- metastatic breast cancer (MBC). Methods: This is a global, multi-center, dose escalation/expansion study (NCT05216432) of RLY2608 as a single agent in adults who have advanced solid tumors and are refractory, intolerant, or declined standard therapy and RLY-2608 in combination with fulvestrant in previously treated pts with HR+/HER2- MBC. Eligibility criteria include presence of PI3KCA mutation (blood or tumor) per local assessment, ECOG performance status 0-1, measurable or evaluable disease per RECIST 1.1 and no prior PI3K inhibitor (except combination group 2). RLY-2608 is administered on a continuous schedule with 4-week cycles. Adverse events (AEs) per CTCAE v5, PK, biomarkers (mutant ctDNAs and insulin pathway markers) and anti-tumor activity are assessed serially. Dose escalation employs a Bayesian Optimal Interval design to identify MTD and RP2D. Following dose escalation, pts will be treated with RLY-2608 at the MTD/RP2D in a monotherapy dose expansion with 5 groups (N = 75, 15 each): 1. Clear cell ovarian carcinoma 2. Head and neck squamous cell carcinoma 3. Cervical cancer 4. Other solid tumors 5. PI3KCA double mutations. In addition, two expansion cohorts will enroll patients with HR+/HER2- MBC treated with RLY-2608 and fulvestrant combination (N = 30, 15 each): 1. No prior PI3K therapy 2. Intolerant to PI3K inhibitors. The primary endpoints are MTD/RP2D and AE profile for single agent and combination; key secondary endpoints are PI3KCA genotype in blood and tumor, PK, biomarkers, and overall response rate. US enrollment began December 2021 and ex-USA startup is underway. Clinical trial information: NCT05216432.

TPS1108 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned. Clinical trial information: NCT05132582.

TPS3158 Background: ELU001 is a novel, first-in-class, new molecular entity described as a C’Dot Drug Conjugate (CDC). ELU001 consists of ̃12 folic acid targeting moieties and ̃22 exatecan topoisomerase-1 inhibitor payloads on Cathepsin-B cleavable linkers covalently bound to the surface of each silicon core/polyethylene glycol C’Dot nanoparticle. CDCs are small in size (̃6 nm), have a greater ability to penetrate into and through tumors as compared to ADCs, and are rapidly eliminated by the kidneys. The rapid systemic elimination is expected to lead to less toxicity than is observed with targeting platforms like ADCs that have a longer half-life in circulation. ELU001’s high avidity is believed to promote internalization into FRα overexpressing cancer cells, selectively delivering it’s ̃22 molecules of payload. The first-in-human clinical trial, ELU-FRα-1, is currently recruiting patients that have advanced, recurrent or refractory FRα overexpressing tumors considered to be topoisomerase 1 inhibitor-sensitive based on the literature, and, in the opinion of the Investigator, have no satisfactory therapeutic options available. Methods: This is a Phase 1 / 2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). In Part 1, patients with cancer types with a high likelihood of having FRα overexpressing tumors based on historical data, (specifically, ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma), will be enrolled to the study. Patients will receive ELU001 on a weekly dose regimen (QW) (once a week for 3 weeks, 1 week rest) or every other week dose regimen (Q2W, with no rest between cycles). Retrospective analysis of FRα expression will be determined. Part 2 uses a Simon’s Two-Stage design to evaluate 4-6 tumor group expansion cohorts, each consisting of patients with specific tumor types (to be identified based on emerging data) that overexpress FRα (prospectively determined prior to enrollment). The primary objective for Part 1 is to identify the MTD/RP2D and for Part 2 is ORR. Dose Escalation will recruit about 25 patients per dose regimen (QW or Q2W). Dose Expansion will recruit about 15 patients per tumor group expansion cohort. Secondary objectives are anti-tumor activity (DOR, PFS, TFST, PFS2, OS), frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. The study is actively enrolling in the US – Cohorts 1-2 have been completed without DLT. Enrollment to Cohort 3 began in December 2021. Clinical trial information: NCT05001282 .

TPS1120 Background: ARV-471 is a novel, potent, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader that selectively targets the ER. In xenograft models, ARV-471 demonstrated substantially greater ER degradation and antitumor activity compared with the selective ER degrader fulvestrant. In the phase 1 dose escalation portion (Part A) of the first-in-human phase 1/2 study, ARV-471 monotherapy was well tolerated and showed antitumor activity in patients with ER+/HER2- locally advanced or metastatic breast cancer who had previously received endocrine therapy and a cyclin-dependent kinase (CDK)4/6 inhibitor; the clinical benefit rate (rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26%–56%) in 47 evaluable patients. The phase 2 VERITAC expansion cohort (Part B) is further evaluating ARV-471 monotherapy in this patient population. Palbociclib, a CDK4/6 inhibitor, plus fulvestrant is a standard treatment option for patients with ER+/HER2- breast cancer who have had disease progression on endocrine therapy. ARV-471 plus palbociclib resulted in substantially greater tumor growth inhibition in xenograft models compared with palbociclib plus fulvestrant, supporting further investigation of the ARV-471 plus palbociclib combination in patients with ER+ breast cancer. Here we describe Part C of the phase 1/2 study, which evaluates the safety and clinical activity of ARV-471 plus palbociclib in patients with breast cancer who previously received endocrine therapy. Methods: Eligible patients (aged ≥18 years) have histologically or cytologically confirmed ER+/HER2- advanced breast cancer and have received ≥1 prior endocrine therapy and ≤2 prior chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor therapy is permitted. Patients with known symptomatic brain metastases requiring steroids are excluded. ARV-471 and palbociclib will be administered orally once daily in 28-day cycles; ARV-471 will be given continuously and palbociclib for 21 days followed by 7 days off treatment. Primary objectives are to evaluate the safety and tolerability of ARV-471 plus palbociclib and select the recommended phase 2 dose and schedule of the combination (based on the incidence of dose-limiting toxicities during the first cycle and the frequency and severity of adverse events and laboratory abnormalities). Secondary objectives are to assess preliminary antitumor activity of ARV-471 plus palbociclib (based on overall response rate per Response Evaluation Criteria in Solid Tumors v1.1, clinical benefit rate, progression-free survival, and duration of response) and pharmacokinetic parameters. Clinical trial information: NCT04072952.

1032 Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+, HER2− advanced breast cancer (ABC). Parts A/B (escalation/expansion) assessed camizestrant monotherapy and have been presented previously. Parts C/D examine camizestrant in combination with palbociclib; here we present mature data from camizestrant 75 mg in combination with palbociclib; 75 mg being the camizestrant dose currently under investigation in the Phase 3 studies SERENA-4 (NCT04711252) and SERENA-6 (NCT04964934). Methods: The primary objective was to determine the safety and tolerability of camizestrant once daily (QD) with palbociclib. Secondary objectives included anti-tumor response and pharmacokinetics (PK). Prior treatment with < 2 lines of chemotherapy in the advanced setting was permitted. There was no limit on the number of lines of prior endocrine treatment in the advanced setting; prior treatment with CDK4/6 inhibitors and fulvestrant (F) was permitted. Results: As of 9 September 2021, 25 patients had received camizestrant 75 mg QD in combination with palbociclib. Tolerability of the combination of camizestrant 75 mg and palbociclib was consistent with that of each drug individually. No patient required camizestrant dose interruption/reduction/discontinuation due to a camizestrant-related adverse event (AE); moreover, none experienced a Grade ≥3 camizestrant-related AE. All camizestrant-related heart rate reductions were Grade 1 (asymptomatic). All camizestrant-related visual effects were Grade 1 (mild), apart from one patient who experienced transient Grade 2 (moderate) visual effects that resolved to Grade 1 without dose modification. Camizestrant-related gastrointestinal disorders were all Grade 1, except one instance of Grade 2 nausea lasting one day. PK data for camizestrant 75 mg QD and palbociclib combined were broadly consistent with camizestrant as monotherapy and published palbociclib steady-state PK data, further supporting the use of camizestrant 75 mg QD (Phase 3 dose) in combination with the approved palbociclib doses. In these heavily pre-treated patients (48% prior chemotherapy, 80% prior CDK4/6i, 68% prior F; all in advanced disease setting) and of whom 60% had visceral metastases, the clinical benefit rate at 24 weeks was 7/25 (28%). Conclusions: The PK and safety profile of camizestrant 75 mg QD in combination with palbociclib is favorable in this mature Phase 1 dataset. Despite extensive pre-treatment - including chemotherapies, CDK4/6i, and F - camizestrant 75 mg QD in combination with palbociclib exhibits encouraging clinical activity. The results from the ongoing Phase 3 studies, SERENA-4 and SERENA-6, will further elucidate the role of this combination in the treatment of patients with HR+/HER2− ABC. Clinical trial information: NCT03616587.

TPS4180 Background: SY-5609 is an oral, selective, potent CDK7 inhibitor that targets two fundamental processes in cancer: transcription and cell cycle control. Early results from the Phase 1 dose escalation portion in patients (pts) with advanced solid tumors reported improved tolerability of the intermittent 7 days on followed by 7 days off (7/7) schedule with ongoing dose escalation beyond the continuous daily dosing maximum tolerated dose. Single-agent clinical activity was demonstrated with durable stable disease, target lesion regressions, and reduction in tumor markers observed in multiple tumor types, notably in pancreatic cancer with a disease control rate (DCR) of 38.5% (Sharma 2021). Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 11% (ACS Cancer Facts and figures, 2022) with limited treatment options and therefore, is a disease in need of novel effective therapies. Oncogenic KRAS mutations are prevalent in PDAC. Mutant KRAS is a potent stimulator of mitogenic MAPK signaling and downstream transcriptional programs for cell proliferation. Preclinical studies have shown that CDK7 inhibition via SY-5609 inhibits tumor growth in KRAS mutant PDAC xenograft models, in many cases leading to regressions. SY-5609 also potentiates gemcitabine (gem) activity in PDAC cells in vitro and in xenografts in vivo (Henry 2021). Therefore, combining SY-5609 with gem +/- nab-paclitaxel (nab-pac) offers a potential new treatment strategy for metastatic PDAC (mPDAC). The expansion portion of this Phase 1 study will evaluate SY-5609 in combination with gem +/- nab-pac in mPDAC pts. Gem +/- nab-pac will be administered on a biweekly schedule as it has shown better tolerability and similar clinical activity compared to the standard of care (SOC) administration schedule (Rehman 2020). Methods: This is an ongoing Phase 1, multi-center study in select solid tumors, amended to open expansion cohorts for mPDAC and expected to enroll approximately 80 mPDAC pts who have progressed on SOC treatments. Objectives of the expansion cohorts include evaluation of safety and efficacy of SY-5609 in combination with gem +/- nab-pac. Key objectives of the two parallel safety lead-in cohorts 1) SY-5609 + gem and 2) SY-5609 + gem + nab-pac are safety and determination of the recommended combination dose of the doublet and triplet for subsequent cohort expansions using a 3+3 escalation design. Key objectives of expansion cohorts are to describe efficacy, defined by progression-free survival, overall response rate, and DCR. Additional objectives include evaluation of pharmacokinetics and pharmacodynamics of SY-5609 in combination with gem +/- nab-pac. SY-5609 will be administered orally once daily on a 7/7 regimen and gem +/- nab-pac will be administered intravenously, in a 4-week cycle. The expansion portion is now open to enrollment. Clinical trial information: NCT04247126.

2504 Background: TIM-3 expressed on tumor-infiltrating T cells is associated with T-cell suppression. AMBER (NCT02817633) is evaluating cobolimab (TSR-022/GSK4069889) monotherapy and with PD-1 inhibitors in advanced solid tumors. Methods: Multi-center, open-label study conducted with the following escalation arm (Parts 1A–C primary analysis reported here): (1A) cobolimab (IV Q2W) monotherapy at 7 doses (6 weight-based [0.03–10 mg/kg] and 1 flat [1200 mg] dose); (1B) cobolimab (1 mg/kg) + nivolumab (3 mg/kg IV Q2W); and (1C) cobolimab (100, 300, or 900 mg) + dostarlimab (500 mg IV Q3W). Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D, monotherapy and combination). Results: 104 patients (pts) were included: 1A (n=46), 1B (n=7), or 1C (n=55); 4 pts from 1A crossed over to 1C (included in 1A and 1C safety and efficacy analyses). Most common cancers were non-small cell lung cancer (NSCLC) and melanoma (1A), NSCLC (1B), and NSCLC, skin, and peritoneal mesothelioma (1C). In 1A, 30.4% had ≥5 lines (L) of prior therapy; 42.9% had 3L in 1B; 33.3% had 2L in 1C. Treatment-related treatment-emergent adverse events (TR-TEAE) occurred in 67.4% (1A), 85.7% (1B), and 67.3% (1C); most commonly in 1A (n≥4) fatigue (13.0%) and nausea (8.7%); 1B (n≥3) diarrhea (57.1%) and nausea and vomiting (42.9% each); and 1C (n≥8) fatigue (20.0%) and rash (14.5%). Grade (Gr)≥3 TR-TEAEs occurred in 4.3% (1A), 28.6% (1B), and 14.5% (1C). There were no Gr5 TR-TEAEs or TR-TEAEs leading to dose delay. Serious TR-TEAEs occurred in 2.2% (1A), 0% (1B), and 12.7% (1C). TR-TEAEs led to discontinuation in 2.2% (1A), 28.6% (1B), and 9.0% (1C). Dose limiting toxicities (DLTs) occurred in 3.0% (1/33) in 1A (Gr3 lipase increased [10 mg/kg]); 40.0% (2/5) in 1B (Gr3 diarrhea and ALT and AST elevation); and 0% in 1C. Cobolimab serum exposure increased in a dose proportional manner at the therapeutic dose range. Preliminary mean terminal phase t1/2 ranged from 2.5–5.8 days for 0.03–0.3 mg/kg and 6.9–10.2 days for 1–10 mg/kg doses (1A), 6.9 days for 1B, and 9.5–12.3 days for 1C. Conclusions: Cobolimab + dostarlimab was well tolerated and showed preliminary anti-tumor activity, warranting further investigation of the RP2D + docetaxel in a randomized, phase 2 study. Funding: GSK (213348). Clinical trial information: NCT02817633. [Table: see text]

11557 Background: Surufatinib is an inhibitor of VEGFR1, 2, & 3, FGFR1, and CSF-1R. A manageable safety profile, and statistically significant improvement in progression-free survival (PFS) in patients (pts) treated with surufatinib have previously been demonstrated in pts with advanced NETs of extrapancreatic (epNET) and pancreatic (pNET) origin in 2 phase 3 randomized trials conducted in China (SANET-ep; NCT02588170 & SANET-p; NCT02589821). Similar safety and efficacy were demonstrated in this phase 1 study (NCT02549937) in pts with NETs. Here we report the results of surufatinib in pts with soft tissue sarcoma. Methods: This study is a phase 1, dose escalation (ESC)/expansion (EXP) study to evaluate the safety and efficacy of surufatinib in the US and Europe (EXP only). ESC previously reported the recommended phase 2 dose as 300mg once daily. Enrollment into advanced, adult, soft tissue sarcoma EXP cohorts is ongoing. The primary endpoint is PFS rate at 4 months (mo). Soft tissue sarcoma histological subtypes include: angiosarcoma (AS), epithelioid sarcoma (ES), leiomyosarcoma (LMS), pigmented villonodular synovitis (PVNS), synovial sarcoma (SS) and undifferentiated pleomorphic sarcoma (UPS). Results: 32 adults with soft tissue sarcoma were enrolled (2 each AS and ES; 10 LMS; 1 PVNS; 9 SS; 8 UPS). The median age across all subtypes was 56.5 years (range 26-77), and the majority of pts were female (68.8%). 59.3% of pts received ≥ 3 prior lines of therapy (Tx) (median lines of Tx: 3 [range 1-6]). As of 15 Nov 2021, 1 pt (PVNS) remained on Tx. The PFS rate at 4 mo was 17.5%. The median PFS was 2.56 mo (95% CI; 0.92-2.92). The median duration on treatment (mDoT) for all pts was 11.2 weeks (wks) (0.4-39.0). The mDoT for LMS pts was 11.6 wks (3.1-36.0), mDoT for SS pts was 11.9 wks (0.4-27.9), and mDoT for UPS pts was 8.2 wks (2.7-27.9). Of 29 pts with ≥ 1 post baseline assessment, 6 pts (20.7%) achieved stable disease of ≥ 8.0 wks from start of Tx. No pts achieved a partial or complete response. The safety profile of surufatinib remains consistent with previously completed trials. All pts (n = 32) reported ≥ 1 adverse event (AE), and 21 pts (65.6%) reported AEs ≥ grade 3. The most common AEs of any grade were fatigue (53.1%), hypertension (43.8%), diarrhea (40.6%), anemia (25.0%), blood bilirubin increase (25.0%), headache (21.9%), and proteinuria (21.9%). The most commonly reported AEs ≥ grade 3 in > 1 pt were hypertension (21.9%), fatigue (12.5%), and anemia (9.4%). AEs leading to Tx discontinuation occurred in 9.4% of pts. Conclusions: Surufatinib demonstrated minimal antitumor activity as a single agent in heavily pretreated pts across various types of soft tissue sarcoma. The safety profile in pts with soft tissue sarcoma remains consistent with previously reported and ongoing studies with surufatinib. Clinical trials are ongoing with surufatinib globally, with active recruitment in PD-L1 combination studies. Clinical trial information: NCT02549937.

1021 Background: Imlunestrant is a novel, orally bioavailable SERD with pure antagonistic properties that result in sustained inhibition of ER-dependent gene transcription and cell growth. In dose escalation, imlunestrant showed favorable safety, pharmacokinetics (PK) and preliminary efficacy in patients with ER+, HER2- aBC and ER+ EEC (Phase 1a EMBER, Jhaveri 2021). Here we present updated data from the dose escalation (Phase 1a) and dose expansion (Phase 1b) of imlunestrant monotherapy in EMBER (NCT04188548). Methods: Phase 1a/1b enrolled patients with ER+ aBC (prior ET sensitivity; ≤3 prior therapies for aBC in Phase 1a following protocol amendment and ≤2 in Phase 1b) and ER+ EEC (prior platinum therapy; no prior fulvestrant or aromatase inhibitor). Premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included recommended phase 2 dose (RP2D) determination, safety and tolerability, PK, objective response rate per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease and ≥1 post-baseline tumor assessment or discontinued prior to tumor assessment, and clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) in patients enrolled ≥24 weeks prior to data cut. Results: As of January 14, 2022, 138 patients (n = 114 aBC, n = 24 EEC) received imlunestrant monotherapy at doses ranging from 200-1200 mg QD. Median age was 62.0 years (range 32-95). Median number of prior therapies for aBC and EEC was 2 (range 0-8) and 1 (0-5), respectively. aBC patients had received a prior ET (94.7%), CDK4/6 inhibitor (92.1%), fulvestrant (50.9%) and chemotherapy (26.3%). No dose-limiting toxicities were observed. Most treatment-emergent adverse events (TEAEs) were grade 1. At the RP2D (400 mg QD, n= 69), the most common all grade TEAE’s were nausea (33.3%), fatigue (27.5%), and diarrhea (23.2%). Across all doses, the incidence of treatment-related grade 3 AEs was low (3.6%). No patient discontinued due to a TEAE. In evaluable aBC patients, ORR was 8.0% (6/75) and CBR was 40.4% (42/104). In evaluable EEC patients, ORR was 5.0% (1/20 had a PR- ongoing pending confirmation) and CBR was 47.1% (8/17). Clinical benefit was observed regardless of baseline ESR1 mutation status as determined by ctDNA sequencing. Additional biomarker analyses will be presented at the meeting. Conclusions: Imlunestrant continues to demonstrate a favorable side effect profile, with no cardiac or opthalmic safety signals, and has continued evidence of clinical activity in heavily pre-treated ER+ aBC and EEC patients. Clinical trial information: NCT04188548.

2648 Background: To characterize the safety and tolerability of PY314, an immunosuppressive macrophage depleting antibody, as a single agent and in combination with pembrolizumab in subjects with advanced refractory solid tumors including subject’s refractory to checkpoint inhibitors if approved for that indication. Methods: Two were evaluated in subjects with advanced solid tumors, single agent PY314 and PY314 in combination with 200 mg of pembrolizumab using a 3+3 dose escalation study design. Dosing was intravenous and administered once every 3-weeks, a defined cycle. Disease assessment by RECIST 1.1 was performed every 6 weeks. Each stratum included 4 dose levels of PY314 (1, 3, 10, and 20 mg/kg). Pharmacokinetics were evaluated at specified time points. Archival tumor tissue was analyzed for TREM2 expression by immunohistochemistry. Based on preclinical evaluation of TREM2 expression, HR+ HER2- and triple negative breast cancer, colorectal cancer, renal cell cancer, non-small cell lung cancer and gynecologic cancers were studied. Results: 28 subjects (median age 60 years [range 26-76], 22 females and 6 ) with an ECOG PS

2583 Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death or withdrawn consent. Results: As of Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUClast data match PK simulations in non-human primate studies. Cmax at 10 µg/kg/dose is ≥5 times the IC50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.

1023 Background: Metastatic triple negative breast cancer (mTNBC) is an aggressive and heterogeneous cancer with limited therapeutic options. PARP inhibitors (PARPi), approved to treat patients with HER2- breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation, have not shown efficacy in homologous recombination repair (HRR) proficient tumors. In pre-clinical models, the BET inhibitor (BETi) ZEN-3694 sensitizes wild-type (WT) BRCA1/2 tumors to PARPi through downregulation of HRR gene expression, providing a rationale for combination therapy. We previously reported results from the Ph 1b portion of the trial evaluating the combination of ZEN-3694 plus talazoparib, in TNBC patients without gBRCA1/2 mutations; here we present results from the completed Ph 1b/2 study. Methods: A Ph 1b dose finding portion (n = 15) was followed by a single arm Ph 2 Simon 2-stage portion (n = 17+20 (37)). The primary endpoint of the Ph 1b portion of the study was safety and recommended Ph 2 dose (RP2D). The secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and clinical benefit rate (CBR = confirmed objective response rate (ORR) + stable disease > 16 weeks). Ph 2 measured CBR as the primary endpoint, ORR and duration of response (DOR) as key secondary endpoints. Eligibility criteria for Ph 1b included TNBC (ER/PR < 10%, HER2-), WT gBRCA1/2, and > 1 prior cytotoxic regimen for mTNBC, and in the Ph2 portion ER/PR < 1% and < 2 prior cytotoxic regimens for mTNBC. Patients were dosed daily in continuous 28 day cycles until disease progression or unacceptable toxicity. Adverse events, PK, and PD in whole blood and tissue biopsies were assessed. Response endpoints were assessed per RECIST 1.1 every 2 cycles. Results: RP2D was determined to be 48mg qd ZEN-3694 plus 0.75mg qd talazoparib. The most common AE for the Ph 1b/2 study was thrombocytopenia (TCP) (55% any grade, 34% G3/4), which was managed with dose holds and reductions. Dose intensity analysis showed average daily doses of ZEN-3694 and talazoparib could be maintained above 40mg and 0.5mg, respectively, over 8 cycles. Robust target engagement was demonstrated using BET-dependent and HRR transcripts assessed in paired tumor biopsies. Ph 2 portion of the trial met its primary endpoint with a CBR of 30% (11/37). For the Ph 1b/2 trial, investgator assessed ORR was 22% (11/50), including 2 CR, CBR was 35% (18/51) and the median DOR was 24 weeks. For the subset of TNBC at diagnosis patients (no history of HR+ disease), ORR was 32% (11/34), and CBR was 44% (15/34). Conclusions: Combination of ZEN-3694 and talazoparib demonstrated anti-cancer activity in pretreated mTNBC WT gBRCA1/2 patients. All confirmed responses were observed in TNBC at diagnosis patients, whose tumors are expected to be more sensitive to the combination due to their basal-like properties. The trial is being expanded to Ph. 2b to accrue an additional 80 TNBC at diagnosis patients. Clinical trial information: NCT03901469.

TPS1111 Background: Tucatinib is an oral reversible small-molecule tyrosine kinase inhibitor highly selective for human epidermal growth factor receptor 2 (HER2). Tucatinib is approved in the US for use in combination with trastuzumab and capecitabine in adult patients with HER2+ metastatic breast cancer (MBC), with and without brain metastases, who have received ≥1 prior anti–HER2-based regimens in the metastatic setting. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) comprising a HER2-directed monoclonal antibody conjugated to a topoisomerase I inhibitor payload, is also approved in the US for patients with HER2+ MBC. In HER2+ breast cancer (BC) xenograft models, tucatinib increased the antitumor activity of a HER2-directed ADC comprising a HER2-directed monoclonal antibody conjugated with 8 exatecan moieties (T-Ex) when compared to T-Ex alone (Kulukian et al 2019). While significant advances have been made in the treatment of patients with HER2+ BC, treatment of metastatic disease remains a clinical challenge due to limited treatment options. Methods: HER2CLIMB-04 (NCT04539938) is a single-arm, open-label, multicenter, phase 2 study evaluating the efficacy and safety of tucatinib plus T-DXd in previously treated patients aged ≥18 years with unresectable, locally advanced, or metastatic (LA/M) HER2+ BC. Patients must have prior treatment with a taxane and trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without pertuzumab). Patients with brain metastases, including active brain metastases, may be enrolled. A safety lead-in portion of the study with 10 patients who were followed for at least 1 cycle has been completed. This portion of the study demonstrated a manageable safety profile so the trial will enroll approximately 60 response-evaluable patients (including the 10 patients from the safety lead-in), evenly distributed between patients with and without brain metastases. The primary endpoint is confirmed objective response rate (cORR) by investigator assessment per RECIST 1.1. Secondary endpoints are progression-free survival (PFS), duration of response (DOR), disease control rate (DCR) by investigator assessment per RECIST 1.1, overall survival, and safety. Exploratory endpoints will include cORR, PFS, DCR, and DOR by independent central review per RECIST 1.1, pharmacokinetic analyses, biomarker analyses, and changes in patient-reported outcomes. Efficacy and safety will be summarized with descriptive statistics. Enrollment in the US began in late 2020. Clinical trial information: NCT04539938.

3097 Background: FF-10832 is a stable liposomal formulation of gemcitabine (GEM) shown to overcome resistance through increased plasma stability and enhanced tumor drug delivery. Macrophage uptake and immune activation in the tumor microenvironment (TME) play a role in the superior efficacy of FF-10832 compared to GEM, with selective, marrow-sparing biodistribution contributing to an improved safety profile. Methods: A 3+3 design determined the safety, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended Phase 2 dose (RP2D). FF-10832 was administered IV once or twice per cycle on a 28 or 21-day schedule until disease progression or unacceptable toxicity. Circulating immune cell populations were measured over time by flow cytometry. Results: Patients (pts) [n = 73, 26M/47F; median age, 64 (range, 26–84); # prior therapies, 3 (1–11); prior GEM, 60%] received FF-10832 on Day 1 and 15 Q28 days (1.2–30 mg/m2), Day 1 and 8 Q21 days (12–23 mg/m2), or Day 1 only Q28 or 21 days (30–55 mg/m2); median # cycles = 2 (1–14) & time on study = 8.3 (4–60) weeks. Common drug-related adverse events were Grade (Gr) ≤2 rash (22%), nausea (22%, 1 Gr 3), and pyrexia (21%, 2 Gr 3). Dose-limiting Gr ≥3 cellulitis/skin ulcers were observed at ≥23 mg/m2 with twice per cycle dosing and those regimens discontinued. Dose frequency was reduced to Day 1 only, which was well-tolerated without significant skin toxicity. Gr ≥3 thrombocytopenia and pneumonitis were observed at 55 mg/m2 Q21 days and the MTD confirmed at 40 (Q21) and 48 mg/m2 (Q28). Median OS = 25.3 (95%CI: 16–27.1) weeks and PFS = 9.6 (95%CI: 7.9–17.6) weeks. Three of 35 evaluable pts achieved a partial response (PR): one pt with gallbladder cancer who previously progressed on GEM achieved a 50%↓ by Cycle 13 at 40 mg/m2 Q28 days & maintains response on study at 60 weeks; two pts with pancreatic cancer had ≥30%↓: one adenocarcinoma after 2 cycles at 4.8 mg/m2 Days 1 & 15 Q28 days, and one acinar cell after 7 cycles at 40 mg/m2 Q28 days who remains on study. Stable disease (SD) was observed in 16 pts; 9 for ≥20 weeks. AUC increased in proportion to dose without accumulation. An extended plasma t1/2 (hrs) for released (39) & total GEM (26) with a free fraction < 1% of total GEM concentrations suggests continuous release in the TME. Pts with PR or SD had dose and time-related log decreases in Ki67+ regulatory T cells relative to total CD4+ cells with increases in anti-tumor CD8+ cells, suggesting a shift to a more immunocompetent environment. Conclusions: FF-10832 was well-tolerated in heavily pre-treated pts with solid tumors, with evidence of anti-tumor activity in pts who progressed on prior GEM. Prolonged, continuous exposure and enhancement of anti-tumor immunity may contribute to improved efficacy. Expansion is ongoing in biliary tract cancer pts treated at the RP2D/schedule of 40 mg/m2 Day 1 of a 21-day cycle. Clinical trial information: NCT03440450.

TPS5622 Background: STRO-002 is a novel FolRα targeting ADC, generated using cell-free antibody production and site-specific conjugation technology. STRO-002 demonstrates potent in vitro cytotoxicity in EOC cell lines and anti-tumor activity in xenograft models, including induction of immunogenic cell death. STRO-002 is currently being studied as a single agent in ovarian and endometrial cancer (Phase 1 Study STRO-002-GM1; NCT03748186). Preliminary efficacy data in relapsed/progressive platinum resistant EOC compared favorably to standard chemotherapy (Naumann W., et al, ASCO 2021). Pre-clinical models tested with STRO-002/bevacizumab combinations demonstrated additive anti-tumor activity compared to monotherapy. This study is a first in human study of STRO-002 plus bevacizumab in patients with advanced ovarian cancer that have progressed on standard therapy. Methods: STRO-002-GM2 is a Phase 1, open-label, multicenter, dose escalation study with a standard 3+3 design with a 21-day dose-limiting toxicity (DLT) assessment period followed by dose expansion. The study will assess safety, establish recommended phase 2 dose (RP2D), and preliminary efficacy of STRO-002/bevacizumab combination in patients with recurrent high-grade EOC. Bevacizumab will be administered at the labeled dose of 15 mg/kg given with STRO-002 starting at 3.5 mg/kg, both administered IV q 3 weeks. Planned dose escalation doses of STRO-002 include 3.5, 4.3, and 5.2 mg/kg and will continue until MTD/MAD is reached. Additional intermediate dose level cohorts may be added for RP2D optimization. Once a cohort is cleared per dose escalation rules, up to 10 additional subjects may be enrolled and treated at that cleared dose level in order to obtain additional safety and efficacy data for RP2D determination and ungating of the expansion stage. Dose expansion will enroll approximately 40 patients treated at the RP2D. The patient population is relapsed high-grade EOC with up to 4 prior regimens. Subjects with primary platinum refractory disease will be enrolled in dose escalation only. Key inclusion criteria include: measurable disease, adequate bone marrow and renal function. Key exclusion criteria include: contraindication to receive bevacizumab and prior treatment with a FolRα ADC or ADC containing a tubulin inhibitor. Efficacy evaluation is per RECIST v1.1. Tumor tissue (archival or fresh biopsy) is required. Study oversight includes a Safety Evaluation Team. Samples will be collected to assess the PK and immunogenicity. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the U.S. Clinical trial information: NCT05200364.

438 Background: HER2 overexpression has been found in invasive UC, suggesting a role for HER2 in disease progression and prognosis (Kruger Int J Oncol 2002). T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. Preclinical models showed that T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572). Methods: Pts aged ≥18 y had pathologically documented advanced/metastatic UC with centrally confirmed HER2 expression by immunohistochemistry (IHC) 2+/3+ (cohort 3; high expression) or IHC 1+ (cohort 4; low expression) who received prior platinum-based therapy with documented progression. Pts received T-DXd at 5.4 mg/kg and nivo 360 mg IV every 3 weeks (recommended dose for expansion). The primary endpoint was confirmed objective response rate (ORR) assessed by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints (assessed by ICR) included duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS), and safety. Results: At the primary analysis data cutoff (July 22, 2021), 34 pts (cohort 3, n = 30; cohort 4, n = 4) received T-DXd and nivo. Median age was 70.9 y (range, 41.4-80.5), 88.2% were male, 61.8% received ≥1 prior regimens for locally advanced/metastatic disease, and 26.5% had a history of liver metastases. Median treatment duration (all pts) was 3.2 mo (range, 1-21) for T-DXd and 4.1 mo (range, 1-20) for nivo. In cohort 3, ORR by ICR was 36.7% (95% CI, 19.9-56.1; complete response, 13.3%; partial response, 23.3%), median DOR was 13.1 mo (95% CI, 4.1- NE), median PFS was 6.9 mo (95% CI, 2.7-14.4), median TTR was 1.9 mo (range 1.2-6.9), and median OS was 11.0 mo (95% CI, 7.2-NE). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 73.5% of all pts (44.1% related to T-DXd; 26.5% related to nivo). TEAEs leading to drug discontinuation occurred in 32.4% of all pts (17.6% related to T-DXd; 23.5% related to nivo). The most common any-grade TEAEs were nausea (73.5%), fatigue (52.9%), and vomiting (44.1%). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.5% of all pts (2 G1; 4 G2; 1 G3; 1 G5). Conclusions: T-DXd combined with nivo showed antitumor activity in pts with high-expressing HER2 UC. The safety profile was consistent with prior studies for T-DXd in other indications and nivo monotherapy in UC pts. Adjudicated ILD/pneumonitis was within the range observed in other T-DXd monotherapy studies. Ongoing clinical trials are further exploring T-DXd in this population. Clinical trial information: NCT03523572.

TPS375 Background: In normal conditions, Claudin (CLDN)18.2 is a tight junction protein with expression strictly confined to differentiated epithelial cells in gastric mucosa. CLDN18.2 has been found to be upregulated, and involved in tumor development and progression in a variety of tumor types such as gastric, pancreatic, and bile duct cancer (BTC). The biological characteristics of CLDN18.2 suggest it is an ideal therapeutic target for cancer drug development. IMAB362 is the first anti-CLDN18.2 monoclonal antibody (mAb) of high potency to have been tested in humans and it revealed clinical efficacy in gastric cancer in a phase II study. TST001, a humanized IgG1 mAb, binds to a distinct epitope of CLDN18.2 with higher affinity and mediates CLDN18.2 expressing cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) in comparison with IMAB362; Furthermore, TST001 is produced using an optimized glycoengineering process to increase affinity to FcR. The enhanced binding to CLDN18.2 on tumor cells and FcR on NK cells results in more efficient engagement of the tumor cells with NK cells and antibody mediated cellular cytotoxicity. In preclinical xenograft studies, TST001 displayed potent anti-tumor activities in the tumor models with medium to high level of CLDN18.2 expression and synergy anti-cancer effect with checkpoint inhibitor. A mAb specific for CLDN18.2 was also developed as an IHC based biomarker for patient enrollment in the clinical trials. Methods: This is an open-label, multi-center, phase I clinical trial to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK) profile and preliminary anti-cancer effect of TST001 in patients with locally advanced or metastatic solid tumors. (NCT04396821) The study consists of two parts: Part A is a 3+3 dose escalation design with sequential dose cohorts of 1, 3, 6, 10mg/kg in Q2W and Q3W schedules. Based on the emerging safety data, higher doses may be proposed for testing. About 27-54 patients will be enrolled. Dose expansion (Part B) will utilize doses of TST001 based on the emerging data from Part A. In Part B, up to 20 patients with CLDN18.2 overexpression per tumor specific cohort will be enrolled to 3 cohorts: A: TST001 single agent in gastric/gastroesophageal junction (G/GEJ) cancer; B: TST001 + nivolumab in G/GEJ cancer; C: TST001 single agent in pancreatic cancer or BTC. All patients in Part B will be selected by CLDN18.2 expression by central lab testing. The safety, anti-tumor activity, and PK will be further assessed in Part B. Enrolment began in July 2020 in the USA and is ongoing in multiple sites. As of 20 September, 2021, 23 subjects were dosed in Part A and the dose of 10mg/kg is being tested. Another phase I study of TST001 single agent and in combination with chemotherapy in patients with metastatic solid tumor is also ongoing in China (NCT04495296).

297 Background: MT-5111 is a 55 kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction and does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: This is a phase 1 study in adult pts with advanced HER2+ solid tumors. The dose-escalation portion (modified 3+3 design) enrolls pts into sequential cohorts followed by expansion cohorts for HER2+ breast cancer (BC), gastric or gastroesophageal junction adenocarcinoma (GEA), and other HER2+ tumors. MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. Results: As of Sep 2021 (contains preliminary data), 24 pts (mean age 64 yrs) were treated, 13 (54%) of whom had gastrointestinal (GI) tumors (6 biliary, 3 GEA, 2 pancreatic, 2 colo/rectal) (Table). Pts with GI tumors had a median of 3 prior systemic tx and 1 prior HER2-targeting tx. No Grade (G) 4/5 tx-emergent adverse events (AEs) occurred. Tx-related AEs occurred in 13 (54%) pts, most commonly fatigue (n=7, 29%). One pt with biliary cancer and concurrent lymphangitic carcinomatosis and H. influenzae infection (4.5 µg/kg) had a possibly related G3 serious AE (SAE) of dyspnea, which resolved 9 days later. Another related SAE occurred in a pt with GEA (6.75 µg/kg) who had a G1 transient troponin increase that resolved during hospitalization, with no clinical symptoms or ECG/ECHO changes; the pt withdrew from study before further dosing. All other related AEs were ≤G2. No other clinically significant changes in cardiac biomarkers (troponin, ECG, LVEF) or cases of capillary leak syndrome occurred. Two pts (3 and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies. Cmax data at 10 µg/kg indicate that current in-pt exposure was between IC50 values of high and medium HER2-expressing cell lines (approx 10-89 ng/mL). Thus, at least 10 µg/kg may be required to achieve effective exposure. No dose-limiting toxicities have been observed. The 10 µg/kg cohort is now accruing. Following this cohort, an expansion cohort for pts with BC will open. Conclusions: MT-5111 was well tolerated with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing and is nearing levels expected to be required for efficacious exposure. Clinical trial information: NCT04029922. [Table: see text]

Background: Addition of CDK 4/6 inhibitors to endocrine therapy has provided significant improvements in outcomes for patients (pts) with metastatic breast cancer (mBC). However, acquired resistance to front-line therapy remains a challenge, and response to late lines of therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα) H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins, including Y537S. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα).Methods: This is a multicenter phase I/II trial. The primary objective of the phase I is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) in pretreated pts with ER+, HER2- mBC. Secondary objectives include safety and antitumor activity. The primary objective of the phase II is to estimate the objective response rate (ORR) and secondary objectives include clinical benefit rate (CBR), progression-free survival (PFS) and safety. The trial was designed to exclude a lower limit of ORR of 5% at one-sided level of significance of 0.05 and a power of 90%. Results: Between August 2017 and February 2020, 130 pts were enrolled; 47 in the Phase I part and 83 in the Phase II part of the trial. A total of 105 pts, including 73 patients on 450 mg, were response-evaluable. The phase I evaluated once daily doses from 100 to 600 mg. No dose-limiting toxicities (DLT) were observed at doses up to 450 mg and 2 DLTs were observed in 2 (grade 3 fatigue and grade 3 drug eruption) of 7 pts on the 600 mg cohort. Consequently, the dose of 450 mg was selected as the RP2D. Median age was 62 years (range: 31 to 87 years), 82% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 10), with 41% of the pts receiving ≥ 4 prior therapies in the metastatic setting. Prior CDK4/6 inhibitors, fulvestrant, and chemotherapy were received by 87%, 71%, and 54% of the pts, respectively. 75 pts (58%) had detectable ESR1 mutations. As of May 31, 2020, grade 2 or higher adverse events reported in ≥10% were anemia (20%), fatigue (16%), nausea (14%), diarrhea (11%) and AST increase (11%). Three cases of grade 4 AE were reported (serum bilirubin, urinary tract obstruction, and hyponatremia), all considered related to disease progression. Grade 1 sinus bradycardia (asymptomatic) was reported in 35% and grade 2 (symptomatic, no intervention needed) was reported in 4%. Grade 2 and 3. QTcF prolongation were reported in 2 and 3 patients, respectively. There were no treatment-related deaths. In the response-evaluable group, 13 confirmed partial responses (PR, 12%. 90% confidence limits: 7.5%-19%), including 11 PRs (15%, 90% confidence limits: 8.7%-23.7) on 450 mg dose, were observed, thus achieving the primary objective of the trial. Stable disease (SD) and clinical benefit rates (≥23 weeks) were 45% and 33% respectively at 450 mg and 46% and 34%, respectively on all doses. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, prior CDK4/6 inhibitor, and/or prior chemotherapy, in the metastatic setting. Three PRs (25%) and 4 SDs were observed in 12 pts in whom clonal ESR1 Y537S was the main ERα driver. Median PFS, in all pts and in pts with clonal ESR1 Y537S was 3.7 months and 7.3 months, respectively. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients including those with a constitutively active clonal ESR1 Y537S mutation. Citation Format: Erika P Hamilton, Judy S Wang, Timothy Pluard, Stephen Johnston, Aki Aki Morikawa, Claire E Dees, Robert H Jones, Barbara Haley, Anne Armstrong, Adam L Cohen, Pamela Munster, Gail Wright, Fadi Kayali, Manav Korpal, Lihua Yu, Lisa Cantagallo, Benoit Destenaves, Zhaojie Zhang, Lei Gao, Marc J Pipas, Tarek Sahmouud, Antonio Gualberto, Dejan Juric. Phase I/II trial of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-06.