Dumbrava, Ecaterina E.

Abstract Purpose: Intratumoral injection of Clostridium novyi-nontoxic (C. novyi-NT), lacking alpha-toxin, germinates and subsequently replicates in the tumor hypoxic regions, causing cell lysis and inflammation. This phase Ib study investigated the safety and synergistic effects of pembrolizumab and C. novyi-NT in advanced solid tumors. Patients and Methods: Patients with injectable solid tumors received one intratumoral C. novyi-NT injection (day 8) across four dose cohorts (3 × 104 to 100 × 104 spores) with pembrolizumab (200 mg intravenously every 3 weeks, day 0–24 months). Sixteen patients were enrolled with a median age of 62.5 years, and the most common tumor types were breast cancer and melanoma. Results: The combination therapy demonstrated a manageable safety profile, with one grade 3 dose-limiting toxicity of abscess formation and the remainder of treatment-related adverse events in ≥10% of patients being grade 1 or 2 injection site reaction (25%), pyrexia (19%), pruritus (13%), leukopenia (13%), and anemia (13%). The maximum tolerated dose was determined to be pembrolizumab intravenously at 200 mg every 3 weeks and a single dose of 100 × 104C.novyi-NT spores intratumorally on day 8. The confirmed overall objective response rate of 25% was observed among four patients with nonkeratinizing undifferentiated nasopharyngeal squamous carcinoma, human papilloma virus–positive squamous cell carcinoma of the base of the tongue, vulvar melanoma, and chordoma. Among these patients, we obtained three partial responses and one complete response. The median duration of the response was 10.93 months, and stable disease was observed in 69% of patients. Conclusions: This study highlights the potential of the C. novyi-NT and pembrolizumab combination as a promising therapeutic strategy for treatment-refractory solid tumors.

Abstract Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T-cells and natural killer (NK) cells. TIGIT inhibits T and NK cell function by binding to CD155 and CD112. SEA-TGT is an investigational human, nonfucosylated monoclonal antibody directed against TIGIT, blocking TIGIT's interaction with CD155 and CD112. SGNTGT-001 (NCT04254107) is a phase 1, open-label, multicenter study of SEA-TGT in patients (pts) with advanced malignancies (solid tumors and lymphomas). In this abstract, we present data from the dose-escalation phase (Part A). Methods: Pts received SEA-TGT ranging from 0.01 to 6.0 mg/kg of body weight intravenously every 3 weeks (Q3W). The primary objectives were to evaluate the safety and tolerability of SEA-TGT and identify the maximum tolerated dose (MTD) or the recommended dose and schedule of SEA-TGT. The optimal biological dose was defined using the Clinical Utility Index. Secondary objectives included the evaluation of antitumor activity, pharmacokinetics (PK) and immunogenicity. Antitumor activity was based on Response Evaluation Criteria in Solid Tumors version 1.1 or the Lugano classification criteria with Lymphoma Response to Immunomodulatory Therapy Criteria. Results: From June 12, 2020, to October 5, 2022, 41 pts were enrolled (2, 4, 5, 11, 12, and 7 pts in the 0.01, 0.1, 0.3, 1, 3, and 6 mg/kg cohorts, respectively). Among the 39 pts who were treated 23 pts had solid tumors and 16 had lymphomas. The median number of prior therapies across all cohorts was 5. Treatment emergent adverse events of any grade were reported in 100% of pts, and treatment-related adverse events (TRAEs) of any grade were reported in 69.2%. TRAEs seen in ≥10% of the pts were infusion-related reaction (38.5%), chills (25.6%), pyrexia (17.9%), fatigue (12.8%), maculopapular rash (12.8%), and rash (10.3%). Seven pts (17.9%) reported TRAEs grade ≥3, and rash (5.1%) was the most frequently reported. No grade 4 or 5 TRAEs were reported. One dose-limiting toxicity, pruritic rash, was observed in 1 pt in the 6 mg/kg cohort, and MTD was not exceeded. Based on the PK and pharmacodynamic data, 1 mg/kg Q3W was selected as the optimal biological dose for the expansion cohorts. One partial response was observed in a pt with gastric cancer, and 2 partial metabolic responses were seen in a pt with Hodgkin’s lymphoma and a pt with diffuse large B-cell lymphoma. Conclusions: Overall, clinical data for SEA-TGT from the SGNTGT-001 trial suggest a manageable and tolerable safety profile. Preliminary antitumor activity warrants further clinical evaluation of SEA-TGT. SGNTGT-001 is ongoing and evaluating monotherapy and combination therapies. Citation Format: Elena Garralda Cabanas, Elisa Fontana, Honey Kumar Oberoi, Nataliya V. Uboha, Ecaterina E. Dumbrava, Emiliano Calvo, Giuseppe Curigliano, Diwakar Davar, Bridget K. Keenan, Vincent K. Lam, Sudhir Manda, Amitkuma Mehta, Anna Minchom, Alison Moskowitz, Ravi Paluri, Vincent Ribrag, Donald Richards, Lillian Siu, Paul Swiecicki, Trisha Wise-Draper, Jasmine Zain, Andres Forero-Torres, Ping Xu, Stephen Ansell. Phase 1 dose-escalation study of SGN-TGT monotherapy in patients with advanced malignancies [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 CT265.

2651 Background: Etigilimab (etig), a humanized IgG1 monoclonal antibody, blocks TIGIT interaction with PVR (poliovirus receptor) and inhibits downstream signalling with target cell killing. Etig +/- nivolumab (nivo) showed acceptable safety and preliminary activity in a FIH Phase 1a/b study in solid tumors. ACTIVATE, an open-label Phase 1b/2 basket study is evaluating further efficacy, safety, tolerability and PK/PD of etig+nivo. This is a preliminary efficacy and safety analysis from ACTIVATE. Methods: Subjects with advanced/metastatic solid tumors without curative/standard of care therapies are given IV etig+nivo Q2W until disease progression or intolerable toxicity. Six open cohorts are enrolling in parallel: endometrial cancer (post-front-line platinum), endometrial cancer (2-3 prior lines), PD-L1+ checkpoint-inhibitor-naïve (CPI-n) cervical cancer, rare cancers (germ cell tumor (GCT), sarcoma, uveal melanoma), ovarian cancer (post-front-line platinum) and TMB-h/MSS, (TMB >10mut/mb) tumors. Tumor assessments are done every 8 weeks following baseline scan. Primary endpoint is investigator-assessed ORR by RECIST 1.1. Secondary endpoints include duration of response and safety. Results: Of 27 efficacy-evaluable subjects enrolled in the 6 open cohorts with minimum 1 staging scan or radiological/clinical progression at data cut-off of 02/10/22, 12 had clinical benefit with 1 complete response (CR), 2 partial responses (PRs) and 9 stable diseases (SDs) and 15 had radiological/clinical progressive disease (PD), with an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Conclusions: Etig+nivo is safe and well tolerated with no new safety signals. Early efficacy was noted in cervical cancer (1CR, 1PR and 1SD) and uveal melanoma (3 SDs >20 weeks). Encouraging activity was also noted in ovarian cancer and post-CPI treated TMB-H/MSS NSCLC. These early data support continued evaluation of the combination of etig+nivo. Clinical activity was notable as below. Clinical trial information: NCT04761198. [Table: see text]

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

2549 Background: BDC-1001 is a novel ISAC consisting of an investigational trastuzumab biosimilar chemically conjugated to a TLR 7/8 agonist with a non-cleavable linker. BDC-1001 was designed to activate the innate immune system, eliciting antibody-mediated effector functions (eg, antibody-dependent cellular phagocytosis) and a durable adaptive immune response. In preclinical tumor models resistant to anti-HER2 treatments, BDC-1001 demonstrated potent and durable immune-mediated antitumor efficacy. Methods: A 4-part, phase 1/2 dose-escalation/expansion study was initiated to evaluate BDC-1001 ± PD1 inhibitor pembrolizumab in pts with HER2-expressing solid tumors who had progressive disease on standard of care (NCT04278144). Preliminary results of the monotherapy dose escalation (Part 1) are reported. Pts with advanced metastatic HER2-expressing (IHC2/3+) or amplified solid tumors received BDC-1001 IV q3w in a 3+3 design w/ 12 pts/cohort backfill allowed. Primary objectives were to evaluate safety, tolerability, dose-limiting toxicities (DLTs) and determine a phase 2 dose; secondary objectives were to assess pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity. Results: As of Jan 29, 2021, 20 pts w/ a median age of 65 (46-85) have enrolled in 4 dose levels (0.15mg/kg to 5 mg/kg). Cancer types include breast, biliary, cervical, colorectal (CRC), lung, gastroesophageal, salivary, urinary tract and endometrial. Pts had received a median of 4 (1-7) prior therapies; 65% received >1 prior anti-HER2 therapy. All pts completed the 21-day DLT period; no DLTs or drug-related serious adverse events (AEs) have been observed. AEs deemed related to BDC-1001 have been mild to moderate including infusion-related reactions. The MTD has not been reached (treatment duration 5-17+wk); enrollment is ongoing. PK evaluations showed Cmax levels consistent with predicted modeling based on non-human primates (NHP). One pt with microsatellite stable (MSS) HER2+ CRC with lung metastases had a confirmed partial response after 4 cycles and remains on study; 2 additional pts with metastatic MSS HER2+ CRC had stable disease (SD) and a pt with heavily pretreated MSS endometrial cancer with lung metastases had confirmed SD and remains on treatment 17+ wk; 3 of these pts had received 2 prior anti-HER2 therapies. Conclusions: In this first-in-human study, BDC-1001 appears to be well-tolerated up to the dose tested to date (5 mg/kg), with Cmax levels achieved as predicted by NHP modeling. Evidence of clinical activity have been observed, including in pts previously treated with anti-HER2 therapy. Dose escalation is ongoing and will be followed by combination dosing with CPI and the phase 2 component in selected tumors. Clinical trial information: NCT04278144.