Lakhani, Nehal J.

Abstract Background: Zedoresertib (zedo) and lunresertib (lunre) are oral, highly selective WEE1 and PKMYT1 inhibitors, respectively. Inhibition of these targets leads to premature mitotic entry, and in the presence of high replication stress causes mitotic catastrophe. In preclinical models, the combination of the zedo and lunre is synthetically lethal, supporting this first-in-class trial combination (NCT04855656). Methods: In this Phase 1 trial, patients (pts) with advanced solid tumors with CCNE1 amplification (amp), or FBXW7 or PPP2R1A deleterious mutations (mut) were treated with zedo (daily dosing) plus lunre (3 days on/4 days off), guided by preclinical modelling of the pharmacological contributions of WEE1 and PKMYT1 inhibition in achieving tumor regression. Objectives included safety, tolerability, recommended doses (RD), pharmacokinetics (PK), pharmacodynamics (PDy), antitumor activity and molecular response rate (MRR; ≥50% decline in circulating tumor DNA). Results: As of 18 Nov 2025, 54 pts (55.6% female ; prior lines of therapy 1 - 9, main cancer types: ovarian (OC) (35.2%), colorectal (31.5%), pancreatic (7.4%) and breast (5.6%)) were treated at 5 dose levels (DL) from 150 mg to 260 mg of zedo plus 60 mg or 80 mg of lunre. The most common ≥G3 treatment related adverse events (TRAEs) were anemia (9.3%), neutropenia (7.4%) and Palmar Plantar Erythrodysesthesia (PPE) (7.4%). There were no G5 TRAEs. 4 (9.3%) of 54 pts had a dose-limiting toxicity (G3 pain in extremity and G1 rash in same pt (zedo 150 mg / lunre 60 mg), G3 rash (200 mg / 80 mg), G3 PPE (260 mg / 60 mg), G3 vomiting (260 mg / 60 mg)). PK/PDy analyses showed dose-dependent exposures for both zedo and lunre and target engagement in most pts, with reductions in pCDK1 Thr14 and Tyr15 and yH2AX induction. 24 (55.5%) of 44 RECIST v1.1 evaluable pts showed tumor shrinkage (3 cCR, 5 uPR, 15 SD and 1 PD). Of 16 evaluable pts with advanced OC (12 platinum resistant , 2 unknown and 2 platinum sensitive) with CCNE1 amp (13 pts) or FBXW7 mut (3 pts), 13 (81.3%) showed tumor shrinkage (3 cCR, 3 uPR and 7 SD); clinical benefit rate (pts with CR, PR or SD) was 93.8%; 7 (43.8%) OC pts were on treatment for at least 16 weeks; 4 (25%) OC pts achieved GCIG CA-125 responses. Of 23 pts with a post baseline ctDNA analysis, a MRR of 39% was seen across all DLs. Conclusion: We report the first disclosure of clinical data of the first-in-field synthetic lethal combination of WEE1 and PKMYT1 inhibitors in a molecularly defined pt population. The safety profile of zedo and lunre was expected and manageable. Promising antitumor activity was observed in pts with CCNE1 amp or FBXW7 mut solid tumors, especially pts with OC. Further dose optimization of this combination is ongoing. Citation Format: Timothy A. Yap, Rahul Aggarwal, Elisa Fontana, Martin Hojgaard, Benedito A. Carneiro, Linda Duska, Patricia LoRusso, Siddhartha Yadav, Stephanie Lheureux, Cara Mathews, Ryan H. Moy, Nehal Lakhani, Mia Weiss, Joan Tymon-Rosario, Gerardo Colon-Otero, Ignacio Garrido-Laguna, Elisabeth K. Lee, Esteban Rodrigo Imedio, Jonathan Wessen, Luke Piggott, Vito Dozio, Noemie Luong, Christophe Mas, Alison M. Schram. First data disclosure of the Phase I trial of the first in class combination of WEE1 inhibitor zedoresertib with PKMYT1 inhibitor lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT022.

TPS3160 Background: Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (1-3). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (4,5). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods: SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. 1. Bordry 2021. 2. Chakrabarti 2022. 3. Merle 2022. 4. Baudat 2023. 5. Baudat 2024. Clinical trial information: NCT06131840 .

3150 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. Current indications for RET mutant disease are limited to MTC. This analysis examined if selpercatinib was effective in non-MTC, RET mutation positive tumors and whether certain RET mutations demonstrated better activity (n=23; data cut-off: 13Jan2023). Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET-altered solid tumors, including pts with RET mutations in tumors other than MTC. Mutations must be known to be activating based on activity in MTC or other published evidence. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Fourteen different tumor types were identified among the 23 pts with non-MTC RET-mutated tumors. This included 8 tumors from the Multiple Endocrine Neoplasia (MEN) syndrome spectrum; adrenal (pheochromocytoma; n=5), paraganglioma (n=2), neuroendocrine (n=1) (Table). Most of the mutations were located in extracellular cysteine-rich domain (CRD) and in the tyrosine kinase domain (TKD) of RET. In 23 efficacy-evaluable pts, confirmed ORR by IRC was 21.7% (5/23, 95% CI: 7.5, 43.7). ORR by IRC for pts with MEN-associated tumors (n=8) was 37.5% while five of these pts (62.5%) had stable disease lasting at least 16 weeks (SD16+). ORR by IRC for the sub-population with pheochromocytoma (n=5) was 40.0% and for pts with tumors manifesting RET extracellular cysteine mutations (n=5) was 60.0%. Of the 15 pts with non-MEN-associated tumors, 2 pts (8.7%; mutation in TKD) had a partial response (both with NSCLC adenocarcinoma, of which one had co-existent MTC). For the overall pts, the median DoR was 12.2 months (95% CI: 3.8, NE) and median PFS was 5.5 months (95% CI: 1.8, 19.4). No new safety signals were identified compared to previous reports. One grade 5 AE, general physical health deterioration, was observed and deemed by INV as not related to selpercatinib. Conclusions: This study suggests that RET-mutated, MEN-associated cancers (adrenal, paraganglioma, neuroendocrine) may benefit from selpercatinib treatment, which could be mediated through mutations in the extracellular CRD. The non-MTC RET-mutated tumor types appear not to derive benefit from selpercatinib. Clinical trial information: NCT03157128 . [Table: see text]

Abstract Background: TIM3 is an inhibitory immunoreceptor linked to decreased activity of immune cells in the tumor microenvironment. S095018 is a human anti-TIM3 IgG2 antibody which blocks binding of phosphatidyl serine to TIM3 promoting the stimulation of T-cells, dendritic cells (DCs) and macrophages. Sym021 is a humanized IgG1 antibody that inhibits binding of PD-1 with its ligands PD-L1 and PD-L2. Preclinical data demonstrated that Sym021 combined with S095018 results in enhanced immunostimulatory antitumor activity. Methods: S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancer whose disease progressed under treatment with at least one line of systemic therapy and who had not received prior treatment with PD-1/-L1 inhibitors (NCT04641871). The dose/schedule of Sym021 and S095018 was 3mg/kg IV Q2W and 10mg/kg IV Q2W, respectively. Primary endpoints included overall response rate (ORR) using RECIST v1.1 and incidence/severity of adverse events. Key secondary endpoints included PK parameters, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results As of 31-Oct-2023, 35 patients with stage IV biliary tract cancer (34 cholangiocarcinoma, 1 gallbladder adenocarcinoma) received S095018 in combination with Sym021. All patients were naïve to prior immune checkpoint inhibitor treatment. Twenty-two patients (62.9%) had received 1 prior antineoplastic systemic treatment for advanced/metastatic disease, 34.3% had received ≥2 prior treatments for advanced/metastatic disease. Overall, 34 patients (97.1%) discontinued treatment, 85.7% due to disease progression. Best overall response was 2 PR (5.7%), 11 SD (31.4%), 18 PD (51.4%) and 4 not evaluable. Median PFS and OS were 1.9 months (90% CI 1.8-3.7) and 13.4 months (90% CI 8.2-27.1) respectively. Disease control rate (CR+PR+SD) with SD≥16 weeks, ≥24 weeks and ≥12 months was 28.6%, 22.9% and 8.6% respectively. Treatment emergent adverse events of any grade occurring in >5% of patients included fatigue, pruritus, alkaline phosphatase increase, amylase increase, IRR (each 8.6%) and hypothyroidism, hyperthyroidism, AST increase, lipase increase and myalgia (each 5.7%). Exploratory biomarker analyses in paired tumor biopsies (N=18) showed an intratumoral increase in CD8 T-cell density, as well as upregulation of gene signatures related to IFNg signaling, antigen presentation, T-cell activation and cytotoxicity upon treatment. Baseline tumor biopsies from the two patients who achieved confirmed PR showed high PD-L1 expression. Conclusions: S095018 in combination with Sym021 exhibited antitumor activity in patients with advanced/metastatic recurrent biliary tract cancer who had not received prior treatment with PD-1/-L1 inhibitors. The combination was well tolerated without new safety signals. Further biomarker analysis is ongoing. Citation Format: Francois Ghiringhelli, Richard Kim, Teresa Macarulla, Irene Moreno, Albiruni Razak, Jordi Rodon, Chih-Yi Liao, Thomas Marron, Judith Raimbourg, Helene Kaplon, Julia Geromini, Najah Harouki, Christelle Rodrigues, Pauline Darcel, Niels Jorgen Skartved, Rikke Hald, Daleen Lopez-Ravnborg, Peng He, Xenophon Ianopoulos, Vasileios Askoxylakis, Nehal J. Lakhani, Sarah Davis, Amit Mahipal. A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT133.

Background Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. Methods In this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. Results Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. Conclusions Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. Trial registration number NCT02475213.

3584 Background: Patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed on ≥2 prior therapies have limited treatment options, with median OS ranging from 6-9 months (mo). In the dose-escalation phase of this first-in-human multicohort study (NCT02720068), the anti-lymphocyte activation gene (LAG)-3 antibody favezelimab (fave) was well tolerated alone and with pembrolizumab (pembro) across all dose levels (Lakhani, SITC, 2018, abstract O26). Here, we evaluate the safety and efficacy of fave alone or in combination with pembro in pts with advanced MSS CRC from the dose confirmation phase. Methods: Eligible pts with MSS PD-1/PD-L1-treatment-naïve mCRC that progressed on prior standard-of-care (3L+) were enrolled (cohort A) to receive the RP2D of 800 mg fave alone (Arm 1), 800 mg fave + 200 mg pembro (Arm 2C), or 800 mg fave + 200 mg pembro (MK-4280A) co-formulation (Arm 5), all Q3W. Treatment continued for 35 cycles or until progression, unacceptable toxicity, or investigator/pt decision. Pts with confirmed progression per irRECIST v1.1 on fave alone could crossover to 800 mg fave + pembro. Safety was assessed in all treated pts; efficacy in the full analysis set (FAS) of all treated pts with baseline scan. Objectives included safety (primary), ORR (RECIST v1.1 by investigator [secondary]), and DOR, PFS, and OS (exploratory). Interim analysis data cut-off was: Oct. 23, 2020. Results: A total of 20 pts received fave (Arm 1); 89 pts (including 9 crossover) received fave + pembro (Arms 2C+5); 12 pts (Arm 1) and 36 pts (Arms 2C+5), had PD-L1 CPS ≥1 tumors. At data cut-off, median follow-up was 5.8 months (mo) in Arm 1 and 6.2 mo in Arms 2C+5. Treatment-related adverse events (TRAEs) were 65% with fave (Arm 1) and 65.2% with fave + pembro (Arms 2C+5). Grade ≥3 TRAEs were 15% (Arm 1), and 20% [Arms 2C+5]). No grade 5 TRAEs were reported. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15%) with fave, and fatigue (16.9%) with fave + pembro. Confirmed ORR was 6.3% (4PR, 1CR) with fave + pembro (Arms 2C+5). No pt receiving fave alone responded. In Arms 2C+5, median DOR was 10.6 mo (range, 5.6-12.7). ORR, OS and PFS by PD-L1 status are reported in the Table. Conclusions: Favezelimab alone or in combination with pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, including with MK-4280A, compared with monotherapy most notably in pts with PD-L1 CPS ≥1 tumors. Clinical trial information: NCT02720068. [Table: see text]

8017 Background: LAM-002 is a selective inhibitor of PIKfyve that disrupts lysosomal homeostasis, inducing cytotoxicity in B-cell lymphoma models as monotherapy or with anti-CD20 or anti-PDL1 antibodies (Gayle et al., Blood 2017;129(13):1768). Methods: In this study, patients received LAM-002 orally 2-3 times per day (BID or TID) in a 3+3 escalation. Additional patients received LAM-002 125 mg BID as monotherapy; with rituximab 375 mg/m2 intravenously (IV) and or subcutaneously weekly (Q1W) x 4 → Q8W x 4; or atezolizumab 1200 mg IV Q3W until disease progression or unacceptable toxicity. Pharmacokinetics (PK) were assessed for 8 hours postdose on Days 1 and 8. Efficacy was evaluated Q6-12W. Results: The study enrolled 62 patients (M:F n = 32/30); median [range] age = 69 [46-89] years; with diagnoses (n) of diffuse large B-cell lymphoma (25), follicular lymphoma (19), marginal zone lymphoma (8), mantle cell lymphoma (5), or chronic lymphocytic leukemia (5) to receive LAM-002 alone (n) at 50 mg BID (3), 100 mg BID (8), 150 mg BID (8), 75 mg TID (4), or 125 mg BID (20); LAM-002/rituximab (12); or LAM-002/atezolizumab (7). During LAM-002 dose-ranging (50 mg BID → 100 mg BID → 150 mg BID → 75 mg TID → 125 mg BID) transient, reversible nausea and/or diarrhea occurred at 150 mg BID and 75 mg TID, resulting in a LAM-002 recommended Phase 2 dosing regimen (RP2DR) of 125 mg BID. Among 39 patients receiving LAM-002, 125 mg BID, alone or in combination for up to 22 cycles (1.9 years), adverse events were typically low-grade. LAM-002 PK showed rapid absorption, dose proportionality, minimal accumulation, and no substantive changes with rituximab or atezolizumab coadministration. In patients with follicular lymphoma and median [range] prior therapies = 3 [1-9] treated with the RP2DR, objective response rates were 2/7 (29%; 1 complete response [CR], 1 partial response [PR]) with LAM-002, 5/8 (63%; 1 CR, 4 PRs) with LAM-002/rituximab, and 2/2 (100%; 2 PRs) with LAM-002/atezolizumab. Conclusions: LAM-002, the first clinical PIKfyve inhibitor, is safe alone or with full-dose anti-CD20 or anti-PD-L1 inhibition. LAM-002 does not cause the myelosuppressive or immune adverse events associated with lenalidomide or PI3K inhibitors. Promising efficacy supports registration-directed Phase 2/3 testing of LAM-002 monotherapy and combination therapy for patients with previously treated follicular lymphoma. Clinical trial information: NCT02594384 .