Search

425082 Background: KRAS, a mediator of signalling pathways essential for cellular growth, proliferation, and survival, is the most frequently mutated oncogene in cancer. Notably, KRAS mutations occur in ~90% of pancreatic cancers, of which ~2% are KRASG12C mutations. Other gastrointestinal (GI) tumors also harbor KRASG12C mutations, such as biliary tract cancer (BTC; 1%) and appendiceal cancer (3–4%), and they are also seen in non-GI tumors, such as endometrial and ovarian cancer (1–2%). Adagrasib, a covalent KRASG12C inhibitor that irreversibly and selectively binds KRASG12C in its inactive state, was selected for favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system penetration. Methods: KRYSTAL-1 is a multicohort phase 1/2 study (NCT03785249) evaluating adagrasib in patients (pts) with advanced solid tumors harboring a KRASG12C mutation. Here we report data from a phase 2 cohort evaluating adagrasib monotherapy administered orally at 600 mg BID in pts with unresectable or metastatic KRASG12C-mutated solid tumors (excluding non-small cell lung cancer and colorectal cancer), including pancreatic ductal adenocarcinoma (PDAC), BTC, other GI, and non-GI tumors. Study objectives include evaluation of clinical activity (ORR, DCR, DOR, PFS, OS) and safety. Results: As of October 1, 2022, 64 pts with KRASG12C-mutated solid tumors were enrolled and 63 were treated with adagrasib (median follow-up, 16.8 months); of these, 21 pts had PDAC, 12 BTC, 16 other GI tumors (9 appendiceal, 4 gastro-esophageal junction/esophageal, 3 small bowel), and 14 non-GI tumors (5 ovarian, 4 unknown primary, 3 endometrial, 1 breast, 1 glioblastoma). Overall, median age was 65 years, 61% had ECOG PS 1, and median prior lines of systemic therapy was 2. Among 57 pts with measurable disease (blinded independent central review), ORR was 35.1% (20/57; all partial responses); DCR was 86.0% (49/57); median DOR was 5.3 months (n=20; 95% CI 2.8–7.3); median PFS was 7.4 months (95% CI 5.3–8.6); and median OS was 14.0 months (n=64; 95% CI 8.5–18.6). Among 21 pts with PDAC, ORR was 33.3% (7/21); DCR was 81.0% (17/21); median PFS was 5.4 months (95% CI 3.9–8.2); and median OS was 8.0 months (95% CI 5.2–11.8). Among 12 pts with BTC, ORR was 41.7% (5/12); DCR was 91.7% (11/12); median PFS was 8.6 months (95% CI 2.7–11.3); and median OS was 15.1 months (95% CI 8.6–not estimable). Overall (n=63), treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of pts (most commonly [≥20%] nausea [49.2%], diarrhea [47.6%], fatigue [41.3%], vomiting [39.7%]), grade 3 TRAEs in 25.4%, and grade 4 TRAEs in 1.6%. No grade 5 TRAE occurred. Conclusions: Adagrasib is well tolerated and demonstrates promising clinical activity in pretreated pts with PDAC, BTC, and other solid tumors harboring a KRASG12C mutation. Clinical trial information: NCT03785249 .

TPS263 Background: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors (NCT05453825). Cohort A will enroll colorectal cancer (CRC) patients. Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aggressive CRC remains difficult to treat owing to the aberrant activation of oncogenic signaling pathways including the NOTCH pathway. Preclinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway inhibition. We postulate that navicixizumab will demonstrate anticancer efficacy against CRC. Methods: Eligible CRC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 3 prior lines of standard therapy for metastatic disease, including an anti-VEGF monoclonal antibody. Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap ExTra with the Xerna TME Panel where patient samples will be classified into one of four tumor microenviroment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each CRC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort A1) or in combination with irinotecan (180 mg/m2 on Days 1 and 15 of a 28-day cycle, Cohort A2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of

TPS277 Background: There is a need to develop novel immunotherapeutic approaches to enhance responses to immune checkpoint blockade. REGN7075 is a human costimulatory bispecific antibody designed to bridge epidermal growth factor receptor (EGFR)-expressing tumor cells with CD28-positive T cells to support further T-cell activation by endogenous tumor antigens. Methods: This is an open-label, Phase 1/2, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab (anti-programmed cell death [PD]-1) in patients with advanced solid tumors (NCT04626635). This study includes a dose-escalation (Bayesian optimal interval design; Part 1) and a dose-expansion phase (Part 2). Patients must have a protocol-defined advanced solid tumor, have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naive to anti–PD-1/anti–PD-ligand(L)1 therapy in the dose-expansion phase. In Part 1, heavily pre-treated patients with advanced solid tumors receive a lead-in of REGN7075 monotherapy every week for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Planned dose levels (DLs) of REGN7075 are 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, and 900mg. Once the recommended Phase 2 dose is determined in Part 1, five tumor-specific expansion cohorts will be opened in Part 2: colorectal cancer (microsatellite stable [MSS-CRC]), non-small cell lung cancer (NSCLC, PD-L1 ≥50%), triple-negative breast cancer, cutaneous squamous cell carcinoma, and head and neck squamous cell carcinoma (PD-L1 combined positive score ≥1). Patients with MSS-CRC with RAS or BRAF wild type mutations must have received anti-EGFR therapy or anti-vascular endothelial growth factor (VEGF therapy). Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. For Part 2, a secondary objective is to assess the effect of REGN7075 on patient-reported outcomes as measured by several validated instruments including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and EORTC QLQ-CR29 (CRC patients only). Approximately 400 patients will be enrolled in this phase 1/2 study, including ~80 patients in Part 1 and ~320 patients in Part 2 (including ~70 in the CRC cohort). As of September 13, 2022, 30 patients were treated in the dose-escalation phase, up to the 300 mg DL for REGN7075 in combination with cemiplimab. This study is ongoing and currently open to enrollment. Clinical trial information: NCT04626635 .

738 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating diagnosis with an overall 5-year survival rate of ~10%. Therapies targeting KRAS G12D, a prevalent molecular driver of PDAC, represent an active area of investigation with many agents currently in clinical development. This study characterizes the real-world clinico-genomic landscape of patients with KRAS G12D-mutated PDAC to inform ongoing therapeutic development and clinical trial design. Methods: We conducted a retrospective, records-based analysis of 2,805 patients with PDAC from across 299 community-based oncology clinics. All patients had broad-panel next generation sequencing (NGS) from commercial vendors performed as standard of care. Patients were stratified into KRASWT (26%), KRASG12D (31%), and KRASnon-G12D (43%) cohorts according to NGS results and assessed for co-mutations, overall survival, and time to chemotherapy failure. Results: The KRASG12D and KRASnon-G12D cohorts exhibited similar mutational landscapes with frequent alterations in TP53, CDKN2A, and SMAD4 ( > 20% frequency occurrence) and infrequent actionable co-mutations (i.e. ATM, MTAP, BRCA1/2, PIK3CA, and MYC; < 5% frequency occurrence). KRASG12D exhibited significantly decreased overall survival compared to KRASWT (m (95% CI); 32.4 months (27.6-37.6 months) [ KRASWT], 20.1 months (17.0-22.7 months) [ KRASG12D], 21.7 months (20.0-25.0 months) [ KRASnon-G12D]; Cox model p-value < 0.001) as well as significantly shortened time to chemotherapy failure compared to both KRASnon-G12D and KRASWT (m (95% CI); 10.8 months (9.6-11.6 months) [ KRASWT], 7.8 months (7.3-8.7 months) [ KRASG12D], 9.8 months (8.8-11.1 months) [ KRASnon-G12D]; Cox model p-value < 0.01). Within the KRASG12D cohort, no co-mutations were significantly associated with overall survival. Conclusions: This study demonstrates the acute need for KRAS G12D-targeted agents in the clinic, as patients with KRAS G12D-driven PDAC experience particularly poor patient outcomes and lack alternative molecular targets.

TPS764 Background: Kirsten rat sarcoma (KRAS) G12D is a point mutation observed in various cancer types including pancreatic ductal cancer, colon adenocarcinoma, and lung cancers. ASP3082 is a novel small-molecule proteolysis-targeting chimeric degrader that binds to, and selectively targets, the KRAS G12D-mutated protein for degradation via recruitment of E3 ubiquitin ligase proteins. In preclinical studies, ASP3082 selectively degraded the KRAS G12D-mutated protein and showed growth inhibitory activity in KRAS G12D-mutated cancer cells but not in KRAS -wildtype cancer cells. Notable antitumor effects of ASP3082 have been demonstrated when intravenously administered weekly in mice xenografted with KRAS G12D-mutated cancer cells. Methods: This first-in-human, open-label, multicenter, phase 1 study evaluates the safety and tolerability of ASP3082 in patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer or other solid tumors. Participants with unresectable, locally advanced, or metastatic solid tumor malignancy with documented KRAS G12D mutation are eligible for enrollment. Part 1 consists of dose-escalation cohorts of 3−12 patients receiving intravenous administration of ASP3082 in a 21-day cycle. Part 2 consists of random assignment of ≤20 patients into 2 cohorts with different ASP3082 dose levels to determine the recommended phase 2 dose. Additional tumor-specific expansion cohorts may enroll ≤20 participants per tumor type. Primary endpoints will evaluate safety and tolerability as noted by dose-limiting toxicities, adverse events, serious adverse events, laboratory test results, electrocardiograms, vital signs, physical exams, and Eastern Cooperative Oncology Group performance status. Secondary endpoints will evaluate objective response rate, duration of response, disease control rate per Response Evaluation Criteria in Solid Tumors version 1.1, pharmacokinetics of single and repeated doses of ASP3082, and changes in KRAS G12D in tumor samples. Exploratory objectives will evaluate potential biomarkers that may correlate with treatment outcomes. Tumor assessment follow-up will continue for ≤45 weeks or until progressive disease. Enrollment in Cohort 1 is complete, and enrollment to Cohort 2 began in September 2022. Clinical trial information: NCT05382559 .

TPS3179 Background: To survive harsh tumor microenvironments, cancer cells actively utilize ISR as an adaptive stress response and survival mechanism. General control nonderepressible 2 (GCN2), a serine-threonine kinase is essential for maintaining cellular homeostasis in amino acid stress conditions. HC-7366 is a novel, highly selective, and potent GCN2 kinase modulator. Single agent HC-7366 has demonstrated potent anti-tumor activity resulting in regression and complete responses in several pre-clinical tumor models. Methods: This is a first in human, multicenter, open label, Phase 1a/b dose escalation and expansion study to establish the maximum tolerated dose, evaluate safety and tolerability, and determine the recommended Phase 2 dose of daily oral dosing of HC-7366 in patients (pts) with advanced solid tumors. Up to 36 pts with squamous cell carcinoma of the head and neck (SCCHN), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), or transitional cell carcinoma of the bladder (TCC) will be enrolled into Phase 1a; other solid tumors are eligible if selection criteria are met (capped at 50%). A 3+3 design will be employed and dose escalation determined by occurrence of dose limiting toxicities (DLT) within Cycle 1 (21 days). A Safety Monitoring Committee will review each cohort when the planned number of pts complete the DLT period. Six dose levels (10, 20, 40, 75, 125, 150 mg) of HC-7366 will be evaluated. Phase 1b will be an expansion of up to two Phase 1a dose levels and enroll 15 pts per cohort. Secondary endpoints include ORR, DOR, TTF, PFS, and OS. Pharmacokinetic data will be profiled. Exploratory objectives include evaluation of pharmacodynamic markers in tumor biopsies and immunophenotyping in blood samples. Main inclusion criteria include: SCCHN, CRC, NSCLC, TCC or other solid tumors; >1 radiologically measurable lesion per RECISTv1.1; >1 biopsiable lesion at baseline; no immune checkpoint inhibitor within 4 weeks (wks) of 1st dose; ECOG 0 or 1; st dose & serum albumin >3 g/dL; and normal/adequately controlled pan-endocrine function. Main exclusion criteria include: autoimmune disease, organ transplant, retinitis or photosensitive skin disorders; history of interstitial lung disease or pneumonitis within 1yr; and overt or latent disorders of the exocrine pancreas. Formal hypothesis testing will not be performed. Descriptive statistics of parameters of interest will be presented by dose level and safety parameters will be summarized. The trial is sponsored by HiberCell, Inc. Approximately 9 US sites will participate. Clinical trial information: NCT05121948.