Locally Advanced Malignant Neoplasm

— New data demonstrate efficacy for the oral treatment combination to address MET-driven resistance in EGFR-mutated lung cancer — — MET is a common biomarker in this setting for patients who develop resistance to EGFR targeted therapies — HONG KONG and SHANGHAI and FLORHAM PARK, N.J., Oct. 16, 2024 (GLOBE NEWSWIRE) -- HUTCHMED (China) Limited (“HUTCHMED”) (Nasdaq/AIM:​HCM; HKEX:​13) today announces positive high-level results from the SAVANNAH Phase II trial that showed TAGRISSO® (osimertinib) plus ORPATHYS® (savolitinib) demonstrated a high, clinically meaningful and durable objective response rate (“ORR”) for patients with epidermal growth factor receptor-mutated (“EGFRm”) non-small cell lung cancer (“NSCLC”) with high levels of MET overexpression and/or amplification, defined as IHC90+ and/or FISH10+, whose disease progressed on treatment with TAGRISSO®. These data will be presented at a forthcoming medical meeting and shared with global regulatory authorities. In 2023, TAGRISSO® plus ORPATHYS® received Fast Track designation from the US Food and Drug Administration (FDA) in this setting. ORPATHYS® is an oral, potent, and highly selective MET tyrosine kinase inhibitor (“TKI”) being jointly developed by AstraZeneca and HUTCHMED and commercialized by AstraZeneca. It is approved in China for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. While EGFR-targeted therapy can provide a substantial survival benefit to patients with EGFRm NSCLC, most will eventually develop resistance to their treatment, with MET being a common resistance biomarker.1 Among patients screened for enrollment in SAVANNAH, an estimated 62% had tumors with MET overexpression and/or amplification, and approximately 34% met the defined high MET level cut-off upon clinical progression. Myung-Ju Ahn, MD, PhD, Professor of Hemato-Oncology at the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, and principal investigator in the SAVANNAH Phase II trial, said: “Osimertinib can provide patients with EGFR-mutated lung cancer unprecedented survival and has transformed the treatment landscape, but patients can develop resistance due to genes like MET – a common resistance biomarker. These results show that adding savolitinib, a selective MET-inhibitor, while continuing osimertinib treatment helped to deliver a meaningful response among patients whose disease progressed, providing a potential new treatment option following standard-of-care osimertinib.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “These positive SAVANNAH results show the benefit of a targeted treatment approach in EGFR-mutated lung cancer patients who experience MET-driven resistance. The improved response rates from ORPATHYS® added to TAGRISSO®, which is the backbone EGFR-mutated lung cancer therapy, reinforce the importance of identifying MET aberration and validate our combination strategy to address resistance while allowing continued TAGRISSO® treatment.” Weiguo Su, Chief Executive Officer and Chief Scientific Officer, HUTCHMED, said: “Previous results from the SAVANNAH Phase II trial provided a novel biomarker approach for identifying patients with MET overexpression and/or amplification who are most likely to benefit from a MET-directed therapy, an existing unmet need. These new, positive results affirm our selective, patient-centric approach, which could allow us to deliver the first biomarker-driven targeted therapy combination option in this setting.” The safety and tolerability of TAGRISSO® plus ORPATHYS® was consistent with the known safety profiles of the combination and each treatment alone. No new safety signals were identified. On August 2022, initial positive ORR results from the SAVANNAH trial were presented at the International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer (WCLC). The global SAFFRON Phase III trial sponsored by AstraZeneca will further assess the TAGRISSO® plus ORPATHYS® combination versus platinum-based doublet chemotherapy in patients with EGFRm, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC following TAGRISSO®. Patients are being prospectively selected using the high MET level cut-off identified in SAVANNAH. About NSCLC and MET aberrationsLung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.2,3 Lung cancer is broadly split into NSCLC and small cell lung cancer.4 Each year there are an estimated 2.4 million people diagnosed with lung cancer globally, with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.2,4,5 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.6,7,8 MET is a tyrosine kinase receptor that has an essential role in normal cell development. MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is the primary mechanism of acquired resistance to EGFR TKIs for metastatic EGFRm NSCLC. Among patients who experience disease progression post-osimertinib treatment, approximately 15-50% present with MET aberration.9,10,11,12,13 The prevalence of MET depends on the sample type, detection method and assay cut-off used.14 About SAVANNAHSAVANNAH is an ongoing global, randomised, Phase II trial sponsored by AstraZeneca studying the efficacy of ORPATHYS® added to TAGRISSO® in patients with EGFRm, locally advanced or metastatic NSCLC with MET overexpression and/or amplification who progressed following treatment with TAGRISSO®. Based on the original single-arm trial design, patients were treated with ORPATHYS® 300 or 600 mg once-daily (QD) or 300 mg twice-daily, in combination with oral TAGRISSO® 80 mg QD. In 2022, a registrational component was added to the trial that compared ORPATHYS® 300 mg twice-daily and TAGRISSO® 80 mg QD to ORPATHYS® 300 mg twice-daily and placebo. The trial enrolled over 360 patients in more than 80 centers globally, including in North America, Europe, South America and Asia. The primary endpoint is ORR and key secondary endpoints include progression-free survival and duration of response. About TAGRISSO®TAGRISSO® (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastases. TAGRISSO® (40mg and 80mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore TAGRISSO® as a treatment for patients across multiple stages of EGFRm NSCLC. There is an extensive body of evidence supporting the use of TAGRISSO® as standard of care in EGFRm NSCLC. TAGRISSO® improved patient outcomes in early-stage disease in the ADAURA Phase III trial, locally advanced disease in the LAURA Phase III trial, late-stage disease in the FLAURA Phase III trial, and with chemotherapy in the FLAURA2 Phase III trial. About ORPATHYS®ORPATHYS® (savolitinib) is an oral, potent, and highly selective MET TKI that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression. It is approved in China for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. It is the first selective MET inhibitor approved in China and the first in the National Reimbursement Drug List of China (NRDL). It is currently under clinical development for multiple tumor types, including lung, kidney, and gastric cancers, as a single treatment and in combination with other medicines. In addition to SAVANNAH and SAFFRON, in China the combination of savolitinib and osimertinib in lung cancer is also being studied in the SACHI and SANOVO Phase III trials. About HUTCHMEDHUTCHMED (Nasdaq/AIM:​HCM; HKEX:​13) is an innovative, commercial-stage, biopharmaceutical company. It is committed to the discovery, global development and commercialization of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases. It has approximately 5,000 personnel across all its companies, at the center of which is a team of about 1,800 in oncology/immunology. Since inception, HUTCHMED has focused on bringing cancer drug candidates from in-house discovery to patients around the world, with its first three medicines marketed in China, the first of which is also approved in the US, Europe and Japan. For more information, please visit www.hutch-med.com or follow us on LinkedIn. Forward-Looking StatementsThis announcement contains forward-looking statements within the meaning of the “safe harbor” provisions of the US Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect HUTCHMED’s current expectations regarding future events, including its expectations regarding the therapeutic potential of savolitinib, the further clinical development for savolitinib, its expectations as to whether any studies on savolitinib would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates and the timing and availability of subjects meeting a study’s inclusion and exclusion criteria; changes to clinical protocols or regulatory requirements; unexpected adverse events or safety issues; the ability of savolitinib, including as a combination therapy, to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions and to gain commercial acceptance after obtaining regulatory approval; the potential market of savolitinib for a targeted indication; and the sufficiency of funding; and AstraZeneca’s ability to successfully develop and commercialize savolitinib.. In addition, as certain studies rely on the use of other drug products such as osimertinib as combination therapeutics with savolitinib, such risks and uncertainties include assumptions regarding the safety, efficacy, supply and continued regulatory approval of these therapeutics. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see HUTCHMED’s filings with the US Securities and Exchange Commission, The Stock Exchange of Hong Kong Limited and on AIM. HUTCHMED undertakes no obligation to update or revise the information contained in this announcement, whether as a result of new information, future events or circumstances or otherwise. Medical InformationThis announcement contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. Inside InformationThis announcement contains inside information for the purposes of Article 7 of Regulation (EU) No 596/2014 (as it forms part of retained EU law as defined in the European Union (Withdrawal) Act 2018). CONTACTS Investor Enquiries+852 2121 8200 / ir@hutch-med.com Media Enquiries Ben Atwell / Alex Shaw, FTI Consulting+44 20 3727 1030 / +44 7771 913 902 (Mobile) / +44 7779 545 055 (Mobile) / HUTCHMED@fticonsulting.comZhou Yi, Brunswick+852 9783 6894 (Mobile) / HUTCHMED@brunswickgroup.com Nominated Advisor Atholl Tweedie / Freddy Crossley / Rupert Dearden, Panmure Liberum+44 (20) 7886 2500 1 Del Re M, et al. Understanding the Mechanisms of Resistance in EGFR-Positive NSCLC: From Tissue to Liquid Biopsy to Guide Treatment Strategy. Int J Mol Sci. 2019;20(16): 3951. 2 World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at: https://gco.iarc.who.int/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf. Accessed September 2024. 3 World Health Organization. International Agency for Research on Cancer. World Fact Sheet. Available at: https://gco.iarc.who.int/media/globocan/factsheets/populations/900-world-fact-sheet.pdf. Accessed October 2024. 4 LUNGevity Foundation. Types of Lung Cancer. Available at: https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed September 2024. 5 Cheema PK, et al. Perspectives on treatment advances for stage III locally advanced unresectable non-small-cell lung cancer. Curr Oncol. 2019;26(1):37-42. 6 Keedy VL, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients with Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 2011:29;2121-27. 7 Szumera-Ciećkiewicz A, et al. EGFR Mutation Testing on Cytological and Histological Samples in 11. Non-Small Cell Lung Cancer: a Polish, Single Institution Study and Systematic Review of European Incidence. Int J Clin Exp Pathol. 2013:6;2800-12. 8 Ellison G, et al. EGFR Mutation Testing in Lung Cancer: a Review of Available Methods and Their Use for Analysis of Tumour Tissue and Cytology Samples. J Clin Pathol. 2013;66:79-89. 9 Soria JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113-125. 10 Mok TS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017;376(7):629-640. 11 Hartmaier R, et al. Tumor genomics in patients (pts) with advanced epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib therapy in the Phase II ORCHARD study. Cancer Res 15 June 2022; 82 (12_Supplement): LB078. 12 Piotrowska, et al. MET amplification (amp) as a resistance mechanism to osimertinib. Journal of Clinical Oncology 2017 35:15_suppl, 9020-9020. 13 Hartmaier, et al. Detection of MET-mediated EGFR tyrosine kinase inhibitor (TKI) resistance in advanced non-small cell lung cancer (NSCLC): biomarker analysis of the TATTON study. Cancer Res (2019) 79 (13_Supplement): 4897. 14 Coleman N, et al. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open. 2019;6(6).

9月7日-10日，由国际肺癌研究协会（IASLC）举办的2024世界肺癌大会（WCLC）在美国召开。免疫治疗作为NSCLC领域的重要治疗手段之一，在本次大会中公布了多项突破性成果。其中，由天津医科大学肿瘤医院王长利教授领衔的 AK112-205研究以口头报告的形式重磅发布。作为第二代免疫治疗药物，全球首个PD-1/VEGF双特异性抗体 依沃西单抗在围手术期的探索引发了广泛关注。基于此特邀王长利教授参与访谈，深入解析 AK112-205研究的亮点及临床意义，视频及访谈内容精粹如下。     王长利 教授   ·天津医科大学肿瘤医院肺部肿瘤科 主任医师，教授，博士生导师 ·天津医科大学肿瘤医院外科教研室主任 ·天津市肺癌诊治中心主任 ·中国抗癌协会肺癌专业委员会名誉主任委员 ·国家卫生健康委能力建设和继续教育肿瘤学专家委员会副主任委员 ·CSCO非小细胞肺癌专业委员会副主任委员 ·《中国肿瘤临床》杂志副主编 ·获天津市科学技术进步一等奖、中国抗癌协会科技奖一等奖等多项奖项       【围术期免疫治疗再攀高峰！依沃西单抗：超越过往，铸就历史新篇章】   Q1：今年WCLC大会上，由您牵头开展的AK112-205研究结果以口头报告的形式重磅公布，引起广泛关注。作为主要研究者，请您分享一下开展AK112-205研究的初衷和背景？   王长利 教授：   近年来，围手术期免疫治疗的临床研究数据引起了广泛关注。从2021年CheckMate- 816研究公布了主要研究终点，再到2023年RATIONALE-315研究公布研究终点，前后两年多的时间，共有6项Ⅲ期随机对照研究相继发布成果，给我们带来了许多惊喜。 目前，驱动基因阴性非小细胞肺癌的围手术期治疗已经正式进入了免疫时代。   然而，在庆祝这些成就的同时，我们也意识到 在围术期的大部分研究之间，pCR率和EFS等关键指标上的差异并不显著。 因此我们进一步思考，免疫治疗是否还能够提升到新的高度，能否有新的产品或疗法为围手术期NSCLC的免疫治疗带来更大的突破，为患者带来更好的pCR率和EFS结果？   正是在这样的背景下，我们聚焦于依沃西单抗这一新型免疫治疗药物， 其作为双特异性抗体展现出了独特的治疗潜力。因此我们与康方生物合作，启动了这一探索性研究，旨在评估依沃西单抗在围手术期治疗中的疗效和安全性。   经过两年多的精心筹备与努力，我们筛选了超过130名患者，入组100余例患者，设立了单药与联合化疗两个治疗队列进行探索， 最终得到了非常亮眼的结果——依沃西单抗在围术期NSCLC中的疗效得到了验证，并且数据更是超越了以往的记录，再次创造了历史。因此，在追求新辅助免疫治疗最优解的道路上，我们的探索应当是永无止境的。依沃西单抗的探索和超越，是围术期免疫治疗向前迈进的又一坚实步伐。     【一药双靶创新突破，挑战高难度基线人群】   Q2：近年来，免疫治疗在NSCLC围术期治疗中的探索如火如荼。您认为AK112-205研究作为对新型免疫治疗方案的探索，有哪些亮点或特色？   王长利 教授：   AK112-205研究是基于我们对PD-1单抗与PD-(L)1单抗在新辅助及全程免疫治疗领域的深入探索而展开的。现有6项研究的成果虽令人瞩目，却仍激发了我们超越现状的渴望。于是，这项创新研究应运而生。   AK112-205研究是全球首个PD-1/VEGF双特异性抗体在围手术期的首个探索性研究，对照组采用的是含依沃西单抗方案。 作为新一代免疫治疗药物，依沃西单抗单个药就能同时靶向PD-1和VEGF两个靶点，具有独特的创新性。   从入组人群上看，我们聚焦于临床分期为II至III期的患者，尤其值得注意的是，有78%的患者已处于III期，且鳞癌患者占比75%，N+分期占比90%（N2占比70%），这一基线情况颇具挑战性，并且充分反映了中国局部晚期肺癌患者的临床实际。   研究设计分为两个队列：队列一采用依沃西单抗单药治疗，而队列二则是依沃西单抗与化疗的联合治疗方案。最终，总计90例患者的数据在本次世界肺癌大会上首次公布，再次刷新了疗效的新高度。     【迄今最高pCR率！依沃西进军围术期治疗，未来可期】   Q3：请您结合AK112-205研究的主要结果，谈谈该研究对围手术期NSCLC临床治疗及未来研究探索的价值及意义。   王长利 教授：   评估一个研究的价值，首要考量的是其结论的成效。一个积极且显著的结论，无疑将赋予该研究深远的意义，不仅体现在其直接成果上，更预示着未来潜在的巨大影响与应用前景。   我们的这项Ⅱ期探索性研究取得了非常亮眼的结果。 依沃西单抗单药组的MPR率高达60%，pCR率更是达到30%，这一数据在单药治疗中极为难得，甚至超越了众多以往Ⅲ期研究的联合治疗组的表现。   在依沃西单抗联合化疗的队列中，pCR率也达到了43.6%，MPR率高达71.8%（截至2024年8月，数据进一步更新，MPR率提高至72.7%，pCR率达到52.7%） ，创造出了历史新高。   尤为值得一提的是，在鳞癌这一亚组人群中，pCR率更是提高至63.6%，MPR率达 84.1%，预示着依沃西单抗在鳞癌治疗上的巨大潜力。   当然，大家可能会提出疑问：pCR率高就一定意味着疗效好吗，OS会获益吗？实际上， 过往的6项Ⅲ期随机对照研究已明确揭示了pCR率与EFS及OS之间的强相关性，pCR率的提升将直接关联到患者后续治愈率的提高，这正是我们研究的魅力所在，也是其备受瞩目的根本原因。我们将持续随访，期待后续为大家公布更多的数据。     【新辅助免疫治疗：未增加手术难度，促进疗效升级】   Q4：新辅助治疗对手术结局的影响是围术期免疫治疗策略探索中饱受关注的重点。请您从外科专家的视角，谈谈您对于依沃西单抗在NSCLC围手术期治疗中应用的体会？   王长利 教授：   近年来，随着新辅助免疫治疗在外科领域的逐步渗透，其对于外科手术的影响成为了业界热议的话题。实际上，多项研究一致表明，新辅助免疫治疗或围手术期的免疫治疗对手术的影响是非常积极的。   外科同行常常会有疑虑，担心新辅助免疫治疗会增加手术难度—— 在临床实践中确实会遇到手术难度较大的病例，但这更多源于患者本身的病情阶段而非新辅助免疫治疗， 关键在于患者的疾病分期。对于原本无法手术的患者而言，新辅助免疫治疗往往能够创造条件，使原本无法实施的手术变得可行，尽管手术过程可能依旧具有挑战，但其对治疗的正面贡献不容忽视。   从我个人及团队的研究经验来看，新辅助免疫治疗并未增加手术难度，也并没有引发新的问题， 无论是手术切除率还是R0切除率，均保持在较高水平，与未接受新辅助免疫治疗的患者相比，并未出现额外的困难。尽管个别患者可能会遇到特定挑战，但考虑到我们研究中纳入的大多是病情较晚期的患者（如AK112-205研究中，III期患者占比高达70%以上），这一结果尤为难能可贵。   回顾以往的多项Ⅲ期随机对照研究，我们可以得出明确的信息：新辅助免疫治疗在手术率和手术完全切除率上的表现均不逊于甚至优于化疗。 这一发现强有力地证明了新辅助免疫治疗非但未对手术造成不利影响，反而可能通过改善肿瘤微环境、缩小肿瘤体积等方式，为手术创造更有利的条件，从而提高手术成功率和患者的预后。   因此，我认为，对于符合条件的患者而言，新辅助免疫治疗是安全且有效的治疗选择，不仅能够改善手术条件，还可为患者的长期生存带来积极的影响。 而第二代免疫治疗药物——双特异性抗体的出现，更是为新辅助免疫治疗提供了新的武器。   【结语】   综上所述，新辅助免疫治疗在外科领域的应用不仅未增加手术难度，反而通过其独特的机制为晚期肺癌患者带来了前所未有的治疗机遇。随着研究的深入，我们愈发坚信其在提高手术切除率、改善患者预后方面的巨大潜力。特别是双特异性抗体等新型免疫治疗药物的涌现，更是为这一领域注入了新的活力。未来，我们期待更多高质量的研究数据，以进一步验证和优化新辅助免疫治疗策略，为肺癌患者带来更加精准、有效的治疗选择。 转载自：肿瘤医生

PARIS, France I October 04, 2024 I TheraVectys, a biotechnology company that designs and develops lentiviral vector-based vaccines and immunotherapies against infectious agents and cancers, announces that the first patient has been enrolled in the Phase I/IIa clinical trial evaluating the onco-therapeutic vaccine Lenti-HPV-07 for the treatment of human papillomavirus (HPV)-induced cancers. This study will include 36 patients in a dose-escalation protocol conducted at several cancer centers in the United States. Selection and inclusion of these patients are already underway. The Lenti-HPV-07 vaccine is based on the lentiviral vector technology platform developed by Pasteur-TheraVectys Joint Laboratory and pioneered by TheraVectysfor for nearly 20 years. The highly promising preclinical studies results on the Lenti-HPV-07 vaccine candidate, published in September 2023 in EMBO Molecular Medicine (1) and in June 2024 in NPJ Vaccines (2), showed that after a single intramuscular injection the vaccine was able to induce a strong cellular immune response against the E6 and E7 antigens of HPV16 and HPV18, resulting in: Aims and methodology of the human trial The open-label Phase I/IIa trial will evaluate the safety of ascending doses of Lenti-HPV-07, determine its immunogenicity profile and assess the preliminary efficacy through the Objective Response Rate. It will include two groups of patients with oropharyngeal or cervical cancers induced by HPV-16 or HPV-18, all of whom will be clinically and immunologically followed for one year. Group A will consist of patients with recurrent/metastatic cancers who have not responded to multiple lines of treatment, including immunotherapies. These patients will receive two intramuscular injections of Lenti-HPV-07, one month apart. Group B will be composed of patients with newly diagnosed, treatment-naïve, locally advanced cancers. Patients in Group B will receive a single intramuscular injection of Lenti-HPV-07. The trial comprises 2 parts: a dose escalation and dose expansion. In the dose escalation portion participants are enrolled successively to receive increasing doses of Lenti-HPV-07. Safety will be carefully monitored after each dose and before proceeding to enrolment at a higher dose. Enrolment and dose escalation in each arm A and B will be conducted independently. In each arm, when 18 participants will have received Lenti-HPV-07 treatment in the dose-escalation portion and the safety results will be satisfying, a dose-expansion portion of the trial will be open to treat 18 additional patients at the Optimal Biological Dose . In total, 72 patients with HPV + cancer will be enrolled in this Phase I/IIa clinical trial. In terms of safety, TheraVectys has already completed a Phase I clinical trial on a therapeutic HIV-1 vaccine based on an integrative lentiviral vector. Over a 5-year follow-up, this clinical trial revealed no notable side effects or genotoxicity. The ongoing Lenti-HPV-07 clinical trial uses a non-integrative lentiviral vector, which reinforces the safety of the approach. It should be noted that since group B patients are newly diagnosed and untreated, their immune systems will not have been affected by other chemo- or radiotherapy treatments. These patients will receive standard care, often including anti-PD1 treatments, one month after treatment with Lenti-HPV-07. TheraVectys has shown in animal models that the Lenti-HPV-07 vaccine acts synergistically with treatments such as anti-PD1, increasing the efficacy of anti-PD1 immunotherapy alone by a factor of 4 (1, 2). Professor Christian Bréchot, Medical Director of TheraVectys commented: “ The inclusion of the first patient in the Phase I/IIa trial represents a key milestone for TheraVectys. It is the achievement of more than 2.5 years of preparation, from first interaction with the FDA, production of the vaccine, performance of the preclinical studies, review and approval by the regulatory authorities till sites preparation. The careful selection of adequate partners and the development of a cooperative relationship have been key in successfully building the project.” Pierre Charneau, head of the Pasteur-TheraVectys Joint Laboratory and founder of TheraVectys, said : “With the launch of this study, we are proud to bring our product to a new phase of its development. We expect the preliminary results on safety and immunogenicity a couple of months after all patients in one group will have received their last injection.” HPV causes almost all cervical cancers, as well as many oropharyngeal and anogenital cancers. The preventive HPV vaccines currently available essentially induce HPV-neutralizing antibodies and thus prevent infection, but have no effect on chronic HPV infections or established tumors. In comparison to Lenti-HPV-07, the immunotherapeutic potential of mRNA-based vaccine technology has only been shown to be effective against very small HPV-related tumors, with early relapse in almost 50% of treated animals (3). In contrast, in the preclinical study conducted by Pasteur-TheraVectys Joint Laboratory, Lenti-HPV-07 immunotherapy was active against large tumors, which are notoriously more difficult to control, demonstrating the superior efficacy of the lentiviral vector-based vaccine platform. A recent publication of a cross-sectional comparison of the most relevant vaccine strategies tested to date in preclinical anti-HPV immuno-oncotherapy showed that lentiviral vector-based approaches were the most effective at eliminating tumors, while providing the longest-lasting memory (4). About lentiviral vector technology TheraVectys is Institut Pasteur’s exclusive licensee for all human and animal vaccine applications of lentiviral vectors worldwide. Thanks to its interaction with dendritic cells, this technology stimulates the body’s natural immune defenses, particularly T cells, more effectively than other vaccine strategies. The technology is based on the natural attraction of lentiviral vectors for dendritic cells and on their ability to induce directly in these cells a sufficiently long-lasting and highly effective endogenous antigenic presentation of the antigens encoded by the vector. Dendritic cells programmed in this way play a key and unique role in the development of T cell responses, the main effectors against tumor cells. About TheraVectys TheraVectys Biotech, specialist in immunotherapy, is based on more than 20 years of research on lentiviral vectors and brings an innovative technology to the field of vaccinology. Research is carried out in the Pasteur-TheraVectys Joint Laboratory under the scientific direction of Pierre CHARNEAU , inventor and pioneer of lentiviral technology, and Laleh MAJLESSI , Director of Research in Immunology. Christian BRECHOT , the former General Director of Institut Pasteur and INSERM, is the Medical Director of TheraVectys. Estelle BESSON , Director of Clinical Operations, coordinated and supervised the preparatory work required to obtain FDA approval, including production of the vaccine, regulatory preclinical studies, preparation of the IND filing, selection and implementation of the clinical trial in collaboration with TheraVectys’ partners. The biotech’s work is based on a proprietary platform for delivering cytotoxic T-cell vaccines in response to critical unmet medical needs. The technology used is at a clinical stage. TheraVectys’ technology and its worldwide license area address a broad spectrum of infectious diseases, cancers and viral cancers, positioning it at the origin of a genuine revolution in the field of vaccination. Our aim: To make profound improvements to global health. Our approach: Strategic industrial partnerships to take our vaccine candidates from proof of concept to clinical trials and marketing. TheraVectys S.A. 28 rue de Dr Roux, Institut Pasteur, Paris, France Chairman TheraVectys: Jean CHALOPIN – Scientific Director: Pierre CHARNEAU 1 Immune checkpoint inhibitors; PD1 = programmed cell death protein-1 References 1. Douguet L*, Fert I*, Lopez J*, Vesin B*, Le Chevalier F, Moncoq F, Authié P, Nguyen TM, Noirat A, Névo F,Blanc C, Bourgine M, Hardy D, Anna F, Majlessi L £ , Charneau P £ . (2023) Full Eradication of Pre-clinical Human PapillomaVirus-Induced Tumors by a Lentiviral Vaccine. EMBO Mol Med . *Co-first authors, £ Senior authors. https://www.embopress.org/doi/full/10.15252/emmm.202317723 2. Fert I*, Douguet L*, Vesin B*, Moncoq F, Noirat A, Authié P, Ciret S, Le Chevalier F, Blanc C, Vitrenko Y, Charneau P £ , Majlessi L £ , Anna F £ . (2024) T-cell immunity induced and reshaped by an anti-HPV immuno-oncotherapeutic lentiviral vector. NPJ Vaccines. *Co-first authors, £ Senior authors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164992/ 3. Ramos da Silva J, Bitencourt Rodrigues K, Formoso Pelegrin G, Silva Sales N, Muramatsu H, de Oliveira Silva M, Porchia B, Moreno ACR, Aps L, Venceslau-Carvalho AA et al (2023) Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice. Sci Transl Med 15: eabn3464 4. Demidova A*, Douguet L*, Fert I*, Wei Y*, Charneau P, Majlessi L. (2024) Comparison of preclinical efficacy of immunotherapies against HPV-induced cancers. Exp Rev Vacc. *Co-first authors. https://www.tandfonline.com/doi/full/10.1080/14760584.2024.2374287 . SOURCE: TheraVectys