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961 Preliminary results of a phase 2 study of intratumoral administration of BO-112 with pembrolizumab in patients with advanced melanoma that have progressive disease on anti-PD-1-based therapy
  1. Iván Márquez Rodas1,
  2. Philippe Saiag2,
  3. Luis de la Cruz Merino3,
  4. Caroline Dutriaux4,
  5. Juan Rodríguez-Moreno5,
  6. Caroline Robert6,
  7. Ana Arance7,
  8. Eduardo Castañón Álvarez8,
  9. Pablo Cerezuela-Fuentes9,
  10. Henry Montaudie10,
  11. Miguel Sanmamed8,
  12. María González Cao11,
  13. Julie Charles12,
  14. María Pilar López Criado13,
  15. Alfonso Berrocal14,
  16. Enrique de Miguel1,
  17. Elisa Funk-Brentano2,
  18. Sorilla Prey15,
  19. Roberto Huertas7,
  20. Delvys Rodríguez Abreu16,
  21. Eva Muñoz Couselo17,
  22. Juan Martin-Liberal18,
  23. Javier Sánchez López19,
  24. Helena Escuin-Ordinas19,
  25. Marisol Quintero19,
  26. Sonia Maciá19,
  27. Marya Chaney20 and
  28. Stephane Dalle21
  1. 1Hospital Universitario Gregorio Marañón, madrid, Spain
  2. 2Hôpital Ambrois Pare, Paris, France
  3. 3Hospital Universitario Virgen Macarena, Sevilla, Spain
  4. 4Hôpital Saint-André, Bourdeaux, France
  5. 5Hospital Universitario Sanchinarro-Clara, Madrid, Spain
  6. 6Hôpital Gustave Roussy, Villejuif-Paris, France
  7. 7Hospital Clínic Barcelona, Barcelona, Spain
  8. 8Clínica Universidad de Navarra, Madrid, Spain
  9. 9Hospital Clínico Universitario Virgen de, Murcia, Spain
  10. 10Centre Hospitalo-Universitaire de Nice, Nice, France
  11. 11Hospital Universitari Dexeus, Barcelona, Spain
  12. 12Centre Hospitalier Universitaire Grenobl, Grenoble, France
  13. 13MD Anderson, Madrid, Spain
  14. 14Hospital General Universitario de Valenc, Valencia, Spain
  15. 15Hôpital Saint-André Bourdeaux, Bourdeaux, France
  16. 16Hospital Universitario Insular de Gran C, Las Palmas de Gran Canaria, Spain
  17. 17Hospital General Universitario Vall d’He, Barcelona, Spain
  18. 18Catalan Institute of Oncology (ICO), Barcelona, Spain
  19. 19Highlight Therapeutics, Valencia, Spain
  20. 20Merck and Co., Inc, Kenilworth, NJ, USA
  21. 21Hôpital Lyon Sud, Lyon, France


Background Intratumoral immunotherapies are being tested in different solid tumors. They trigger local and systemic responses.1 2 BO-112 is a double stranded RNA nanoplexed with polyethyleneimine (PEI), which mimics a viral infection and mobilizes the immune system.

In preclinical models and in a first in human clinical trial BO-112 activated dendritic cells, induced CD-8 infiltration, apoptosis and enhancement of immunogenic cell death and achieved an objective response in 2 out of 10 patients with melanoma with primary resistance to antiPD-1.3 4

Methods In this phase 2 study, BO-112 plus pembrolizumab is evaluated in patients with advanced melanoma, who have developed progressive disease while on or within 12 weeks after anti-PD1/PD-L1 based therapy (either as first line or as adjuvant treatment). BO-112 is administered intratumorally once weekly in 1 to 8 tumor lesions, total dose 1 to 2 mg, for the first 7 weeks and thereafter every three weeks; pembrolizumab 200 mg is administered intravenously every three weeks. Overall response rate (ORR) is analyzed as primary endpoint by independent reviewer. Secondary objectives include disease control rate (DCR), duration of response and progression free survival (PFS); response assessment is done by RECIST 1.1 and iRECIST; in addition, CD-8 and PD-L1 IHC, NGS, itRECIST and radiomics signatures are prospectively assessed. Key eligibility criteria include cutaneous or mucosal melanoma with known BRAF status; at least one lesion RECIST 1.1 measurable and amenable for IT injection. Enrollment has been completed on 26th August.

Results With 26 evaluable patients with a first response assessment, seven have progressive disease (PD), five have partial response (PR) and fourteen patients show stable disease (SD). Preliminary ORR is 19.2% and DCR is 73.1% at week 8. Three patients with PR at week 8 have undergone a second assessment at week 16, with further decrease in sum of diameters (SOD) in both injected and non-injected lesions. Three out of five patients with SD and a second assessment maintain SD, showing a decrease in SOD in two cases (figure 1). In addition, two patients with only skin lesions have a pathological complete response. CD8 and PD-L1 have increased in 8 and 7 out of 13 patients with paired biopsies, being related with clinical benefit (figure 2).

Abstract 961 Figure 1

Swimmer plot, efficacy data for evaluable patients undergoing at least one response assessment

Abstract 961 Figure 2

Immunohistochemistry data for CPS and CD8 data from paired biopsies

Conclusions Despite these data being preliminary, there is a trend for benefit in terms of ORR and also in long lasting stable diseases. BO-112 is able to increase PD-L1 expression in tumor cells and increase CD8-T cell infiltrates.

Acknowledgements Merck, Pivotal SLU, Quibim radiomics, Pangaea laboratories, all participating sites and patients

Trial Registration NCT04570332


  1. Aznar MA, Planelles L, Perez-Olivares M, et al. Immunotherapeutic effects of intratumoral nanoplexed poly I:C. J Immunother Cancer. 2019 May 2;7(1):116.

  2. 5. Hamid O, Ismail R, Puzanov I. Intratumoral immunotherapy-update 2019. The Oncologist 2020;25:e423–438.

  3. Márquez-Rodas I, Longo F, Rodríguez-Ruiz M, et al. Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors. Sci Transl Med 2020 Oct 14;12(565):eabb0391.

  4. Kalbasi A, Tariveranmoshabad M, Hakimi K, Kremer S, et al. A. Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma. Sci Transl Med 2020 Oct 14;12(565):eabb0152.

Ethics Approval The study obtained ethics approval by Spanish Health Agency (AEMPS), on 11th December 2020, and French Health Agency (ANSM) on 27th January 2021; study obtained approval from two Ethics Committee: Vall D’Hebron, Barcelona, Spain on 7th December 2020 (number 467), and Centre Léon Bérard, Lyon, France, CPP on 11th February 2021.

For each study patient, written informed consent is obtained prior to any protocol-related activities. As part of this procedure, the principal investigator or one of his/her associates must explain orally and in writing the nature, duration, and purpose of the study, and the action of the study drug in such a manner that the patient is aware of the potential risks, inconveniences, or adverse effects that may occur. They should be informed that the patient may withdraw from the study at any time. They will receive all information that is required by the regulatory authorities and ICH guidelines. The ICF has been signed by the patient and a copy provided to them.

Consent N/A

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