Tourneau, Christophe Le

Abstract Background: Digital Drug Assignment (DDA) is a computational reasoning model that scores cancer therapies based on the complete molecular profile of a tumor, and stratifies them by predicted efficacy (Petak et al., 2021). In a prior study of 111 lung cancer patients, DDA-derived high-score molecularly targeted agents (MTAs) were associated with improved clinical outcomes (Dirner et al., 2025). Here, we extend this analysis to the GENIE BPC NSCLC cohort to assess the broader clinical validity of DDA. Methods: From the GENIE BPC NSCLC cohort data available on Synapse, we included 1,078 patients with a single-sample genomic profile, available primary treatment data and survival outcomes (total 2,103 treatment lines, therapies included: afatinib, erlotinib, osimertinib, crizotinib, nivolumab, pembrolizumab, atezolizumab, bevacizumab+chemo, ramucirumab+chemo; and chemotherapy alone). DDA scores were generated for all cases, and the individual score of the administered MTAs (incl. immune checkpoint inhibitors) was used to stratify outcomes into low (<0), intermediate, and high DDA-score (≥1000) tiers. Progression-free survival (PFS, by imaging) and overall survival (OS) were analyzed using Kaplan-Meier statistics. Results: Median PFS and OS differed significantly across DDA score tiers, increasing with higher scores (see table). Intermediate-tier drugs had similar mPFS values as chemotherapies (3.9 vs 4.2 months). Six-month PFS and twelve-month OS rates increased with DDA-tiers and were all significantly different by χ2 test. DDA-high therapies provided greater benefit across treatment types than lower-score counterparts. Conclusions: Across a large, real-world NSCLC cohort, DDA effectively distinguished therapies with higher clinical efficacy based on the full molecular profile of each patient. These results reinforce the potential of DDA to enhance personalized treatment selection based on NGS diagnostics in precision oncology. Citation Format: Barbara Vodicska, Eniko Kispeter, Dora Lakatos, Gabor Gy Kalmar, Robert Doczi, Dora Gorog-Tihanyi, Anna Dirner, Reka Szalkai-Denes, William T. Beck, Arkadiusz Z. Dudek, Christophe Le Tourneau, Istvan Petak. Molecularly-informed prediction of treatment efficacy in the GENIE BPC NSCLC cohort using computational reasoning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7.

PURPOSE There is growing scientific interest in incorporating patient-reported outcomes (PROs) in early phase dose-finding oncology trials (DFOTs) to assess tolerability, inform dose selection, and guide later stage trial design. However, research indicates that PRO objectives in DFOTs are often unclear. The Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Research Objectives Recommendations (OPTIMISE-ROR) project was established to support trialists to effectively incorporate PROs into DFOTs. METHODS Using the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework, guideline development included the following: (1) a methodological review of published DFOTs incorporating PROs; (2) candidate item generation, refined through expert consultation; (3) a two-round international multistakeholder Delphi survey (N = 109 in Round 1 [October 2024]; N = 96 in Round 2 [December 2024]); and (4) an independently chaired virtual consensus meeting (N = 31; January 2025) where multidisciplinary, international experts reviewed and voted to finalize items for inclusion. RESULTS Consensus was reached on six recommendations emphasizing three core PRO tolerability concepts: overall side effect impact, symptomatic adverse events, and overall health-related quality of life. The integration of PROs to inform final dose recommendations in dose escalation and optimization trials should be considered, regardless of trial design. The recommendations highlight the importance of PRO data analysis over time and across dose levels, defining PRO research objectives as descriptive or statistically powered, and assessing PRO-related end points to guide end point selection for subsequent studies. CONCLUSION This foundational guidance outlines key PRO research objectives in DFOTs. By facilitating the systematic integration of PROs, this guidance supports the utilization of patient-centered evidence for the tolerability and efficacy assessment of therapies to inform dose escalation, optimization, and regulatory evaluation—ultimately contributing to the development of safer, more effective therapies.

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 .

Abstract Background: Head and Neck (HNSCC) and Ovarian cancer (OC) are two indications for which immunotherapy had limited impact so far. Current treatments achieve high rates of initial success through surgery and adjuvant chemo/radiotherapy, but patients (pts) remain at high risk of relapse in both indications. Immune stimulation using a vaccine is a promising strategy to a clinically meaningful improvement. Herein we report phase I data of TG4050, a vaccine engineered to carry a pt tailored antigen payload, in pts with HNSCC (NCT04183166) or OC (NCT03839524). Methods: Tumor specific variants are identified using next generation sequencing of tumor and normal samples whereby immune relevant mutations are predicted using a machine learning algorithm factoring in parameters known to affect immunogenicity including MHC binding, level of expression, prevalence across clones, and antigen processing. DNA sequences of the mutations of interest, typically 30 per pt, are cloned in a viral vector (Modified Vaccinia Virus Ankara). Following curative intent treatment, HNSCC pts in complete remission were randomized to an immediate vaccination arm to receive weekly doses of TG4050 for 6 weeks followed by a maintenance period of one dose every 3 weeks for up to 20 doses or to a delayed vaccination arm where the same vaccination regimen is initiated at relapse. OC pts received the vaccine upon onset of signs of relapse. PBMC were collected at Baseline and after 6 doses of vaccine. Primary endpoint was vaccine safety and secondary endpoints included feasibility, immunogenicity. Results: 18 pts received TG4050 (5 OC and 13 HNSCC) treatment with no related grade ≥ 3 adverse events. Tumor mutational burden (TMB) was on average 3.00±0.98 and 2.43±0.69 mutations per megabase for HNSCC and OC respectively. Despite this low TMB, all pts had sufficient cancer specific neoantigens to design a vaccine. Ex-vivo ELISPOT was completed for 7 pts at the time of submission. A mean of 44% of selected mutations were associated with a reactive T cell responses either spontaneously or after TG4050 stimulation ranging from 6 to 22 mutations per pt. Vaccination induced a stimulation of T cell response in all tested pts on an average of 10 targeted mutations, induction of de novo responses was seen in all 7 tested pts and amplification of pre-existing response in 6/7 pts. None of the evaluable HNSCC pts receiving TG4050 immediately after first line treatment had relapse after a median follow-up of 7 months while 2 pts had relapse in the delayed vaccination arm. Furthermore, in OC pts treated at early relapse, TG4050 has normalized disease markers (ctDNA and/or CA-125) for 2/4 pts with stable disease for 9 and 11 months. Conclusion: TG4050 treatment is feasible and immunogenic in pts with low to moderate TMB. It is effective in inducing T cell responses and first signs of antitumor activity are encouraging for the continuation of development. Citation Format: Ana Lalanne, Camille Jamet, Christian H. Ottensmeier, Jean-Pierre Delord, Christophe Le Tourneau, Matthew S. Block, Gerardo Colon-Otero, Keith L. Knutson, Annette Tavernaro, Gisele Lacoste, Benoit Grellier, Xavier Noiriel, Thierry Huss, Bernard Burtin, Yoshiko Yamashita, Kousuke Onoue, Kazuhide Onoguchi, Brandon Malone, Olivier Lantz, Oliver Baker, Naoko Yamagata, Yuki Tanaka, Eric Quemeneur, Maud Brandely, Kaidre Bendjama. Feasibility and immunogenicity of adjuvant TG4050, a patient tailored cancer vaccine in head and neck and ovarian cancer [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 LB205.

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.

Abstract Background: Cancer mutations acquired during carcinogenesis are not subject to central tolerance and thus, are cornerstone in cancer immunosurveillance. The use of mutation-derived neoepitopes to design cancer vaccines is an unprecedented opportunity to target efficient antigens, but the stochastic occurrence of mutations implies that a tailored vaccine needs to be designed and manufactured for each patient. We used next generation sequencing, machine learning based genomic data analysis and advances in genome editing to systematically identify private neoepitopes in high-risk HPV negative HNSCC and relapsing OvC patients. Methods: Mutations were identified by DNA and RNA sequencing and putative epitopes were selected for vaccine design on their likelihood to elicit a class I or II response based on HLA binding, allelic frequency, prediction of processing and expression at RNA level. The vaccine was a recombinant virus of the modified Vaccinia Ankara (MVA) strain encoding for up to 30 sequences of 29 amino acids centred on the predicted epitope and flanked with the normal germline sequence in case of missense mutations, and of the mutated protein sequence in case of frameshift mutations. The viral vaccine was amplified under GMP conditions and administered to patients after curative intent treatment in two phase I trials. Treatment was started for OvC patients at relapse defined as elevation of CA-125 or onset of suspicious radiological findings and, after first line therapy for HNSCC patients with locally advanced disease with either extracapsular extension or positive resection margins following upfront surgery. The vaccine was administered for 6 weeks and a booster dose every three weeks over a year, in absence of other cancer therapy. Results: Six patients (4 OvC and 2 HNSCC) were treated and experienced only mild related adverse events. After 6 doses of vaccine, we measured immunoreactive T cells in PBMCs against each of the targeted epitopes using an ex vivo IFNγ ELISPOT showed robust responses in all evaluable patients. Positive responses to vaccination were observed for a total of 46 epitopes over 115 tested with a median of 11 epitopes (6 to 18) per patient. Responses were directed against both class I and II epitopes and were either de novo responses (64%) or amplification of pre-existing responses (36%). In parallel, phenotyping of patient PBMCs showed, in all treated patients, a decline in naïve CD4 and CD8 cells and the onset of effector CD27- CD4 and CD27-/CD57+ CD8; similarly, CD56dim NK cells increased suggesting a stimulation of antitumor innate immunity. In one ovarian cancer patient, these immune changes correlated with a normalization of CA-125 that lasted 7 months. Conclusions: These data show that the personalized approach with TG4050 is feasible, safe and immunogenic. The two phase I trials are ongoing. Citation Format: Matthew S. Block, Jean-Pierre Delord, Christian H. Ottensmeier, Christophe Le Tourneau, Ana Lalanne, Olivier Lantz, Keith L. Knutson, Gisèle Lacoste, Annette Tavernaro, Maud Brandely, Nathalie Silvestre, Benoit Grellier, Yoshiko Yamashita, Onoue Kousuke, Naoko Yamagata, Eric Quemeneur, Kaidre Bendjama. Phase I trials of personalized cancer vaccine TG4050 in surgically treated high-risk head and neck squamous cell carcinoma (HNSCC) and relapsing ovarian cancer (OvC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT182.

2637 Background: Mutation-associated neoantigens (MANAs) constitute attractive antigens for the design of cancer vaccines. However, clinical implementation remains challenging because of the patient specific nature of MANAs, hereby requiring that a bespoke vaccine is designed for each subject. We developed a pipeline for the genomic characterization and the design of tailored vaccine using a modified vaccinia Ankara viral vector. Methods: Immunogenicity, safety and early clinical activity of personalized cancer vaccines are being assessed in two phase I trials, respectively in high grade serous OC and HPV-negative HNSCC. Patients (Pts) at high risk of relapse are enrolled in the study being in remission following surgical primary treatment. High risk is defined as stage IIIC or IVA for OC and stage III or IVA for HNSCC. A vaccine is manufactured for each patient. OC pts are treated at asymptomatic relapse based on radiological finding or elevation of CA-125 with the vaccine alone; HNSCC pts in complete remission after surgery and adjuvant therapy are randomized to receive the vaccine either at the end of locoregional treatment or in combination with standard of care at relapse. The vaccine was administered weekly for 6 weeks and a booster dose every three weeks over a year or until progression, whichever occurred first. Results: At the time of the data cut-off, a total of 8 pts were treated: 4 relapsing OC pts, 3 HNSCC pts in complete remission and 1 relapsing HNSCC pt. AE attributable to the vaccine were mainly grade 1 injection site reactions and fatigue. One OC pt displayed an objective response 6 weeks after initiation of vaccine and for 9 months with a normalization of CA-125 until death from an unrelated cause; 1 other OC pt remains on treatment with a stable radiological disease for 11 months. The 2 other OC progressed at the first evaluation on day 43. HNSCC pts treated in complete remission received respectively 20, 15 and 4 doses, and remain on treatment and disease free. One HNSCC patient received 9 doses of vaccine after relapse in conjunction with chemotherapy and anti-PD-1 therapy and remains on treatment with stable disease after 5 months. Immune monitoring demonstrates priming of a polyepitopic T cell response against class I and II antigens. Responses were observed regardless of HLA and without cross-reactivity to the germline protein. Adaptive response was associated with a shift of CD4 and CD8 T cells toward an effector phenotype and innate cellular immunity was activated with a strong maturation and activation of NK cells. Immune changes were stronger in pts with controlled disease versus progressors. Conclusions: Data demonstrate that TG4050 is safe, well tolerated and able to induce T cell responses whatever the HLA haplotype. Early signs of clinical activity were observed in OC pt. These data pave the way for further development and synergistic immunotherapeutic combinations. Clinical trial information: NCT04183166.