An ongoing open-label, phase 2 trial of RP2 Or RP3 oncolytic immunotherapy in combination with atezolizumab and bevacizumab for the treatment of patients with advanced colorectal carcinoma

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality worldwide. PD-1/PD-L1 inhibition, in combination with other modalities, has demonstrated clinical benefit in patients with microsatellite instability-high or mismatch repair–deficient CRC, but little or no benefit in patients with microsatellite stable (MSS) or mismatch repair–proficient (pMMR) CRC. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), human granulocyte-macrophage colony-stimulating factor (GM-CSF), and an anti–CTLA-4 antibody-like molecule; RP3 additionally expresses 4-1BB and CD40 activating ligands but does not express GM-CSF. Preliminary data from phase 1 studies have demonstrated promising safety and efficacy of either agent in patients with solid tumors. This open-label, nonrandomized, phase 2 study will evaluate safety and efficacy of RP2 or RP3 in combination with atezolizumab and bevacizumab in patients with advanced MSS and pMMR CRC (NCT05733611).

Patients with a histologic diagnosis of unresectable and/or metastatic CRC, documented MSS or pMMR status, and previously treated with up to 3 standard-of-care systemic regimens will be enrolled in the RP2 + atezolizumab + bevacizumab or RP3 + atezolizumab + bevacizumab treatment groups (30 patients per group). Further key inclusion criteria include having at least 1 measurable and injectable tumor (≥1 cm), Eastern Cooperative Oncology Group performance status 0–1, and adequate hepatic, renal, and hematologic function. RP2/RP3 will be injected into tumors by direct (including via colonoscope) or image-guided injection. Patients will receive 8 total doses of up to 10 mL of RP2/RP3, with a first dose concentration of 1 × 10 6 plaque-forming units (PFU)/mL, followed by 3 doses of 1 × 10 7 PFU/mL every 2 weeks, and then 4 doses of 1 × 10 7 PFU/mL every 3 weeks. Patients may receive a second course of up to 8 injections of RP2/RP3 with or without bevacizumab and atezolizumab if protocol-specified criteria are met. Bevacizumab will be administered starting on day 1 (with the first dose of RP2/RP3); bevacizumab + atezolizumab will be administered starting at week 7 (fourth dose of RP2/RP3) within 72 hours of administration of RP2/RP3. The primary endpoint is objective response rate; secondary endpoints are safety, overall survival, progression-free survival, duration of response, duration of clinical benefit, and complete response rate. Exploratory endpoints include the assessment of health-related quality of life, changes in biomarkers, and the biodistribution/shedding of RP2/RP3. Antitumor activity will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 as modified for this study. Patients will undergo radiologic evaluation at screening and then every 8 weeks until confirmed disease progression; tumor assessments will also be conducted whenever clinically significant progressive disease is suspected. Safety will be assessed by physical examination, clinical laboratory evaluations, vital signs, and monitoring for adverse events (AEs; including serious AEs). AE severity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

NCT05733611.

Medical writing and editorial support were provided by Marita Chakhtoura, PhD, of AlphaBioCom, LLC, a Red Nucleus Company (King of Prussia, PA, USA) and were funded by Replimune Inc. (Woburn, MA, USA).

Replimune Inc.

Replimune Inc.

E. Élez: Honoraria (self): Amgen, Bayer, Hoffman La - Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, Seagen International GmbH, Servier.; Advisory / Consultancy: Amgen, Bayer, Hoffman La - Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, Seagen International GmbH, Servier.; Research grant / Funding (institution): Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc.; Travel / Accommodation / Expenses: Amgen, Bayer, Hoffman La - Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, Seagen International GmbH, Servier.; Non-remunerated activity/iesA: American Society of Clinical Oncology (ASCO), Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy., European Society for Medical Oncology (ESMO), Other, Speaker of the ESMO Academy., Sociedad Española de Oncología Médica (SEOM), Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants.. D. Shepard: Advisory / Consultancy: Replimune. T. Bekaii-Saab: Honoraria (self): Royalties: Uptodate; Advisory / Consultancy: CConsulting (to institution): Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merus, Merck KGA and Merck., CConsulting (to self): Stemline, AbbVie, Blueprint Medicines, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, Beigene, Kanaph, Astra Zeneca, Deciphera, Zai Labs, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine and Sanofi., IDMC/DSMB: The Valley Hospital, Fibrogen, Suzhou Kintor, Astra Zeneca, Exelixis, Merck/Eisai, PanCan and 1Globe. Scientific Advisory Board: Imugene, Immuneering, Xilis, Replimune, Artiva and Sun Biopharma.; Research grant / Funding (institution): Research Funding (to institution): Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS. ; Licensing / Royalties: WO/2018/183488: HUMAN PD1 PEPTIDE VACCINES AND USES THEREOF – Licensed to Imugene, WO/2019/055687: METHODS AND COMPOSITIONS FOR THE TREATMENT OF CANCER CACHEXIA – Licensed to Recursion. J. Jac: Shareholder / Stockholder / Stock options: Replimune; Full / Part-time employment: Replimune. The author has declared no conflicts of interest.