Cassier, Philippe A.

Abstract Purpose: TRK-950 is a first-in-class humanized antibody targeting cytoplasmic activation/proliferation-associated protein-1, which is strongly expressed on the cell membrane surface in or on most solid tumors but not in or on normal tissues. This first-in-human study investigated the safety profile, pharmacokinetics (PK), and preliminary antitumor activity. Patients and Methods: Patients with treatment-refractory, locally advanced, or metastatic solid tumors were enrolled in a dose escalation/expansion study. TRK-950 was administered intravenously weekly for 3 weeks in a 28-day cycle, with doses ranging from 3 to 30 mg/kg. Dose expansion included 10 mg/kg weekly and 30 mg/kg biweekly for colorectal cancer and 10 mg/kg weekly for cholangiocarcinoma. The primary objective of this study was to determine its safety, tolerability, and maximum tolerated dose. The secondary objectives were PK, preliminary antitumor activity, and identification of potential biomarkers. Results: Thirty-six patients received at least one dose of TRK-950. In the dose escalation cohort, the maximum tolerated dose was not reached, and no dose-limiting toxicities were observed up to 30 mg/kg. Common adverse events included abdominal pain, fatigue, constipation, back pain, nausea, and decreased appetite. TRK-950 exhibited a PK profile similar to that of other IgG subclass 1 therapeutic antibodies, with linear PK parameters over the 3 to 30 mg/kg dose range. The best response was stable disease. Notably, one patient with cholangiocarcinoma showed signs of cavitation after approximately 8 months, suggesting potential antitumor activity. Conclusions: TRK-950 is safe and well tolerated, has a favorable PK profile, and should be further investigated as a monotherapy and in combination with standard treatment for various types of solid tumors. Significance: TRK-950, a humanized antibody targeting CAPRIN-1, demonstrated good tolerability, no dose-limiting toxicities, a favorable PK profile, and potential antitumor activity in this first-in-human study. Currently, TRK-950 is undergoing Phase Ib and II trials for various cancers, showing promising development potential.

3116 Background: Pralsetinib is an oral tyrosine kinase inhibitor that selectively and potently targets oncogenic RET fusion and mutation proteins. RET fusions or mutations are present in various tumor types. We report the final results from the phase 2 portion of ARROW, a phase 1/2, open-label, multi-cohort, dose-expansion study evaluating the efficacy and safety of pralsetinib (NCT03037385) in patients with RET fusion-positive solid tumors other than non-small-cell lung cancer (NSCLC) and thyroid cancer. Methods: Eligible pts were ≥18 years of age with a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation, had previously received standard of care appropriate for their tumor type, and were not eligible for any other study groups. Overall response rate (ORR) and safety were primary endpoints of the study. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The final database lock was May 20, 2024. Results: Twenty-nine patients were enrolled with 11 different solid tumor histologies. Twenty-six (90%) received prior systemic therapy. Median age was 58 years (range 25-75); 59% were female. Twenty-eight patients were included in the efficacy analysis. ORR (by RECIST) was 46.4% (13/28); 10.7% (3/28) achieved complete response (pancreatic cancer, n=2; cancer of unknown primary, n=1) and 35.7% (10/28) achieved partial response. Median PFS was 7 months (95% CI: 3.9, 12.8). Median DOR was 11.1 months (95% CI: 5.5, 25.1). Median OS was 10.3 months (95% CI: 6.8, 25.2). Twenty-five (86%) patients experienced treatment-related adverse events (TRAEs); 19/29 (66%) reported TRAEs ≥grade 3. The most common TRAEs included increased aspartate aminotransferase (11/29; 38%), increased alanine aminotransferase (10/29; 35%), and anemia (9/29; 31%). Four (13.8%) patients experienced hypertension, and 1 (3.4%) patient had ≥grade 3 hypertension. No new safety risks were identified; AEs remained manageable with supportive care and/or dose modifications. Conclusions: In the phase 2 portion of this trial, responses were observed in many tumor types (Table). Pralsetinib demonstrated robust and durable anti-tumor activity with an ORR of 46.4%. These data validate RET fusions as a tissue-agnostic target with sensitivity to RET inhibition and activity beyond NSCLC and thyroid cancer, further supporting the promising potential of pralsetinib to address the unmet medical need in these patients. Clinical trial information: NCT03037385 . Overall response rate by tumor type. Cancer Type (patient n) ORRn (%) Pancreatic (5) 5 (100) Cancer of unknown primary (1) 1 (100) Neuroendocrine (3) 2 (67) Sarcoma (3) 2 (67) Head and neck (2) 1 (50) Small cell lung (2) 1 (50) Hepatobiliary (4) 1 (25) Colorectal (5), gastric (1), ovarian (1), thymic (1) 0

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]

Background: Rearranged during transfection ( RET ) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET -altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET -mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET -mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET -mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET -mutant MTC and prior C/V, 62 treatment-naïve patients with RET -mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4–68.5] in patients with RET -mutant MTC and prior C/V, 77.4% [95% CI: 65.0–87.1] in treatment-naïve patients with RET -mutant MTC, and 90.9% [95% CI: 70.8–98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET -mutant MTC and prior C/V, not reached in treatment-naïve patients with RET -mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET -altered thyroid cancer safety population ( N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET- altered thyroid cancer. Clinical Trial Registration: NCT03037385

2630 Background: Human papillomavirus 16 (HPV-16) infection is associated with several cancer types with limited treatment options in the locally R/M settings. Furthermore, immune checkpoint inhibitors have limited activity against advanced HPV-cancers. TG4001 is a viral vector vaccine targeting HPV E6 and E7 antigens. We have previously shown in a single-arm, dose finding phase 1 study that TG4001 combined with PD-L1 blockade using avelumab was safe and associated with a response rate of 22%. Herein we report preliminary data on immunogenicity and clinical activity of TG4001 in a randomized phase 2 study comparing TG4001 plus avelumab versus avelumab alone. Methods: Eligibility criteria: R/M HPV16+ anogenital cancer including cervical, vulvar, vaginal, penile, and anal cancers; immunotherapy naïve and with no more than one prior line of chemotherapy. HPV-16 positivity was required and centrally determined using a PCR based assay. Patients were randomly assigned 1:1 to receive either TG4001 plus avelumab (Vaccine arm) or avelumab alone. Randomization was stratified by tumor type (cervical, anal, genital). TG4001 was administered s.c at 5·107 pfu, Q1w for 5 weeks, then Q2w until month 6 followed by Q12w until progressive disease and avelumab i.v at 800 mg Q2w until progressive disease. PBMCwere collected at baseline, day 43 and day 85 to assess T-cell responses against E6 and E7 antigens using ex-vivo IFNg ELISPOT and immunophenotyping of circulating T cells. Vaccine immune response (IR) was defined as onset of a new T-cell response against either antigen or amplification of a pre-existing response under treatment. Tumor response was assessed using RECIST 1.1. Results: 59 pts had been randomized by the time of data cut-off. IR was assessed in 24 pts in the vaccine arm and 16 pts in the avelumab arm. T cells against E6 or E7 antigens at baseline were rare with only 4 pts having a low intensity ELISPOT readout against either target prior to initiation of treatment. 11/24 pts in the vaccine arm had an IR, while none of the patients in the avelumab arm had an IR. Occurrence of IR was detected at day 43 and tended to gain in intensity at D85. In the vaccine arm, IR was associated with tumor response with 3 clinical responders among 11 pts with positive IR versus 1 response observed among the 13 patients without IR. Conversely, only 2 progressive disease pts among 11 positive IR compared favorably to the 6/13 vaccine arm pts with no IR. Remarkably, a complete clinical response was observed in a vaccine treated pt exhibiting the strongest E6 and E7 IR. Conclusions: TG4001 can induce a de novo immune response against HPV-16 antigens E6 and E7 in advanced HPV-16 cancers. The data suggest that these IRs are associated with anti-tumor response and that TG4001 vaccination in combination with ICI has the potential to drive clinical benefit in R/M anogenital cancers. Clinical trial information: NCT03260023 .

4009 Background: Oncogenic FGFR2 alterations (fusions/rearrangements (f/r), amplifications, mutations) represent a broad therapeutic opportunity as they drive multiple solid tumors, particularly cholangiocarcinoma (CCA). However, off-isoform toxicity and on-target resistance limit the benefit of approved pan-FGFR inhibitors (FGFRi). RLY-4008 is the first potent, highly selective, oral FGFR2 inhibitor designed to overcome these limitations by targeting FGFR2 driver alterations and resistance mutations. Here, we present updated dose escalation results from ReFocus (NCT04526106), a seamless Phase I/II, open label study evaluating the safety and preliminary efficacy of RLY-4008 in patients (pts) with advanced, FGFR2-altered solid tumors. Methods: Adult pts received RLY-4008 BID, QD, QD discontinuous on a 4-week (wk) cycle following a Bayesian Optimal Interval design. Treatment-related adverse events (TRAEs), PK, ctDNA and anti-tumor activity (RECIST v1.1) were assessed. Results: As of 30 Jan 23, 116 pts (82 f/r, 27 mutation, 6 amplification) received RLY-4008 at doses of 20-200 mg/day, including 91 with CCA. 50% had prior FGFRi, and median lines of prior therapies was 3 (1-15). 28/46 ct-DNA-evaluable pts with CCA with prior FGFRi had ≥1 baseline resistance mutation, most commonly at FGFR2 N549X (23/46) or V564X (17/46). RLY-4008 had favorable PK with doses ≥40 mg QD providing FGFR2 occupancy ≥90%. 70 mg QD was the RP2D based on PK, safety, anti-tumor activity and exposure-dependent tumor regressions in FGFRi-naïve CCA f/r pts. Anti-tumor activity was observed in CCA and solid tumors across doses and FGFR2 alterations with radiographic tumor reductions in 74 (64%), SD/PR in 83 (72%), including 4/4 (100%) FGFRi-naïve CCA f/r pts at RP2D achieving confirmed PR. Clinically meaningful disease control and durable responses were observed in pts with FGFR2 f/r CCA. Overall, median treatment duration was 24 wks (range <1-108 wks). 105 pts discontinued (PD (81%), AE (3%), other (7%)). Across doses, most common TRAEs were low-grade PPE (57%), stomatitis (56%), dry mouth (38%), alopecia (28%), and dry eye (22%). No grade 4/5 TRAEs were observed. Conclusions: These encouraging dose escalation data confirm the broad therapeutic potential of highly selective FGFR2 targeting with RLY-4008 by demonstrating encouraging initial efficacy across FGFR2-altered solid tumors and genomic alterations, with a differentiated safety profile that avoids FGFR1- and FGFR4-related toxicity. Phase 2 of ReFocus continues across solid tumors and with registrational intent in FGFRi-naïve, FGFR2 f/r CCA. Clinical trial information: NCT04526106 . [Table: see text]

Abstract Background: Immune checkpoint inhibitors targeting the PD1/PD-L1 axis have made a breakthrough in advanced solid tumors, leading to improved overall survival (OS) in several cancer types. However, only a minority of patients experience durable responses, requiring further development of anti-tumoral immunotherapies to overcome tumor immune escape. We hypothesized that priming the immune system with TG4001, a vaccine using the highly attenuated Modified Vaccinia virus Ankara as vector expressing the HPV16 E6 and E7 proteins (rendered non-oncogenic) and interleukin-2, would increase the clinical benefit associated with PD-L1 blockade in HPV16+ cancer patients. In the single-arm part of the trial evaluating the combination of TG4001 and avelumab in terms of response rate, the overall response rate (ORR) was 22%. Presence of liver metastases had a profound impact on outcome in terms of ORR and Progression Free Survival (PFS). In patients (pts) without liver metastases an ORR of 32% was observed versus 0% in pts with liver metastases, warranting further development of this combination in this patient population (SITC 2020, Abstract ID 793). Methods: We have designed a randomized open-label two-arms trial evaluating the efficacy of the combination of TG4001 and avelumab versus avelumab alone (NCT03260023). Eligible pts have R/M HPV-16 positive anogenital cancer including cervical, vulvar, vaginal, penile, and anal cancers with no more than one prior line of chemotherapy for R/M disease and no previous exposure to cancer immunotherapy. HPV-16 positivity is determined in a central laboratory. Patients are randomly assigned 1:1 to receive either TG4001 plus avelumab or avelumab alone. Randomization is stratified by primary tumor type (cervical, anal, genital). TG4001 is administered subcutaneously (SC) at 5 × 107 plaque forming units (pfu) Q1w for 5 weeks, Q2w until month 6 and Q12w until progressive disease and avelumab intravenously (IV) at 800 mg Q2w until progressive disease. A total of up to 140 pts are currently being recruited into two cohorts (A and B) in France, Spain, and USA. For Cohort A, consisting of pts without liver metastases at Baseline (BL), a 2-stage sample size adjustment design is used with PFS by RECIST 1.1 as primary endpoint. Plans are to accrue 120 patients following Interim Analysis and Independent Data Monitoring Committee (IDMC) review. Cohort B recruits pts with liver metastases at BL. To be eligible, hepatic disease is restricted in terms of extent and number of lesions. A total of 20 pts will be recruited and analyzed for the percentage of early progressors. Secondary endpoints include overall survival, objective response rate according to RECIST1.1, duration of response, disease control rate. Exploratory endpoints comprise analyses of blood-based parameters and tumor-based proteins and RNA expression and their impact on clinical outcomes. Citation Format: Christophe Le Tourneau, Frédéric Rolland, Amaury Daste, Philippe Cassier, Sébastien Salas, Luis Manso Sánchez, Gerardo Colon-Otero, Lauriane Eberst, Olivier Lantz, Ana Lalanne, Annette Tavernaro, Hakim Makhloufi, Kaïdre Bendjama, Maud Brandely, Jean-Pierre Delord. A randomized phase II trial of TG4001 plus avelumab versus avelumab alone in recurrent/metastatic (R/M) human papilloma virus (HPV)-16 positive anogenital cancers [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 CT045.

6080 Background: Alterations in RET are targetable oncogenic drivers in TC. Pralsetinib is a highly potent, selective RET inhibitor, with demonstrated efficacy in pts with RET-altered TC. In a previous analysis of the Phase I/II ARROW trial (NCT03037385; data cutoff: 22 May 2020), overall response rates [ORR; measurable-disease population] with pralsetinib at 400 mg once daily (QD) were 60% (33/55) and 71% (15/21) in pts with RET-mutant medullary TC ( RET-mutant MTC) who had received prior multikinase inhibitors cabozantinib and/or vandetanib (C/V), and those who were treatment naïve, respectively, and 89% (8/9) in pts with previously treated RET fusion-positive TC ( RET-fp TC). Here we report an updated analysis of these cohorts in the intention-to-treat (ITT) population. Methods: Adult pts with RET-altered locally advanced/metastatic TC who had enrolled in ARROW and initiated pralsetinib at 400 mg QD, were included. Phase II primary endpoints: ORR (by blinded independent central review, per RECIST v1.1) and safety. Efficacy endpoints for this analysis were assessed in the ITT population. Safety was assessed in all pts with RET-altered TC who initiated pralsetinib at 400 mg QD. Enrolment cutoff: 23 August 2020 for the ITT population; data cutoff: 12 April 2021. Results: The ITT population comprised 145 pts with RET-mutant MTC (with or without prior systemic therapy, including C/V) and 22 pts with RET-fp TC, 21 of whom had received prior systemic therapy (including multikinase inhibitor[s] and/or radioactive iodine). In pts with RET-mutant MTC who had received prior C/V (n = 67), ORR was 51% (34/67; 95% CI 38–63; 2 complete responses [CR]; 32 partial responses [PR]), median duration of response (DoR) was 25.8 months (95% CI 18.0–not reached [NR]) and median progression-free survival (PFS) was 24.9 months (95% CI 19.7–31.2). In treatment-naïve pts with RET-mutant MTC, ORR was 72% (48/67; 95% CI 59–82; 4 CR; 44 PR), and median DoR and median PFS were not reached. In pts with previously treated RET-fp TC, ORR was 86% (18/21; 95% CI 64–97; 3 CR; 15 PR), median DoR was 17.5 months (95% CI 16.0–NR) and median PFS was 19.4 months (95% CI 13.0–NR). Median overall survival (OS) was not reached in any of the cohorts. The safety population comprised 172 pts with RET-altered TC treated at 400 mg QD. The most common treatment-related adverse events (TRAEs) were increased aspartate aminotransferase (n = 67; 39%), anemia (n = 60; 35%), hypertension (n = 57; 33%) and decreased white blood cell count (n = 52; 30%). Serious TRAEs were reported in 27 pts (16%); the most frequent was pneumonitis (n = 5; 3%). Nine pts (5%) discontinued pralsetinib due to a TRAE and one patient ( < 1%) died due to a TRAE ( pneumocystis jirovecii pneumonia) following 44 days ( < 3 cycles) on pralsetinib. Conclusions: In this updated analysis including more pts, pralsetinib continues to be efficacious with a manageable safety profile in pts with RET-altered TC. Clinical trial information: NCT03037385.

4009 Background: Survival outcomes are historically poor in patients (pts) with advanced/metastatic iCCA, with median overall survival (mOS) times of approximately 1 year with first-line gemcitabine plus cisplatin and approximately 6 months with second-line chemotherapy. Futibatinib, a highly selective, irreversible FGFR1–4 inhibitor, demonstrated efficacy with durable responses in pts with iCCA harboring FGFR2 fusion/rearrangements in the pivotal FOENIX-CCA2 phase 2 study (NCT02052778). At the primary analysis of this trial (data cutoff: October 1, 2020), an objective response rate (ORR) of 41.7% was observed, with a median duration of response (mDOR) of 9.7 mo. Here, we report updated efficacy (including mature OS data) and safety data from the final analysis with an additional 8 mo of follow-up. Methods: FOENIX-CCA2 was a single-arm phase 2 study that enrolled pts with advanced/metastatic iCCA with FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; including gemcitabine plus platinum-based chemotherapy). Pts received futibatinib 20 mg once daily until PD/intolerability. The primary endpoint was ORR per RECIST v1.1 by independent central review. Secondary endpoints were DOR, disease control rate (DCR), progression-free survival (PFS), OS, safety, and patient-reported outcomes. Results: At the time of the final data cutoff (May 29, 2021), median follow-up was 25.0 mo, and 96/103 pts (93%) had discontinued tx. The median number of tx cycles was 13.0 for a median tx duration of 9.1 mo. The confirmed ORR was 41.7% (43/103) and thereby the same as of the primary analysis, as was the DCR (at 82.5%). The ORR was consistent across pt subgroups. The mDOR was 9.5 mo, and 74% of responses lasted ≥6 mo. mPFS was 8.9 mo, with a 12-mo PFS rate of 35.4%. Mature mOS was 20.0 mo, with a 12-mo OS rate of 73.1% . No new safety signals were identified. Common tx-related adverse events (TRAEs) included hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). TRAEs resulted in tx discontinuation in 4 pts (4%). No tx-related deaths occurred. Quality of life was maintained from baseline to tx cycle 13. Conclusions: Findings from the final analysis of FOENIX-CCA2 confirm the results of the primary analysis and reinforce the durable efficacy and continued tolerability of futibatinib in previously treated pts with advanced/metastatic iCCA harboring FGFR2 fusion/rearrangements. Mature OS data were consistent with data from the primary analysis and far exceed historical data in this patient population. Clinical trial information: NCT02052778.