Abstract LB198: A first-in-human, open-label, multicenter study of intratumoral SAR441000 (mixture of cytokine encoding mRNAs), as monotherapy and in combination with cemiplimab in patients with advanced solid tumors (2023)

Abstract Background: SAR441000 is an intratumoral (IT) therapy consisting of a mixture of mRNAs encoding the cytokines IL-12, IFN-α 2b, GM-CSF, and IL-15sushi. SAR441000 is hypothesized to induce a local and systemic immune response with reduced toxicity, and potentially enhance anti-tumor response when combined with checkpoint inhibitors. Methods: We conducted a phase 1 dose escalation and expansion study (NCT03871348) in patients with advanced/metastatic solid tumors to investigate SAR441000 as monotherapy (QW) and in combination with cemiplimab (350mg Q3W). The recommended dose (RD) of SAR44100 in combination with cemiplimab was further investigated to confirm the anti-tumor activity in patients with metastatic melanoma who had previously exhausted all standard of care options and failed treatment with anti-PD-(L)1 therapies. Serum samples and tumor biopsies were collected at baseline and post-treatment to characterize the PK/PD profile, and immune cell tumor infiltration. Tumor assessment was performed per RECIST 1.1 and iRECIST, where ≥1 non-injected lesion was considered as target lesion. Analysis was triggered after the last treated patient underwent their 2nd tumor assessment. Results: 77 patients were treated, 36 in escalation phase (21 in monotherapy, 15 in combination therapy) across eight dose levels (8µg-4000µg) and 41 in expansion phase. No dose limiting toxicities were observed. During escalation phase, 1 patient (6%) achieved confirmed complete response (iCR), 1 (6%) partial response (iPR), and 3 (20%) stable disease (iSD) as per iRECIST in combination therapy. Paired biopsies from the iPR patient showed significant increases in CD3+ and CD8+ immune cells in both injected and non-injected lesions compared to baseline. Increase of peripheral PK and PD (IFN-γ and IP-10) cytokines were observed post-treatment but no clear dose response relationship was established. Based on the overall data, 4000µg was chosen as the RD. During expansion phase, 2 (5%) melanoma patients achieved confirmed iPR and 12 (29%) achieved iSD as best overall response. Although clinically meaningful responses of injected and/or non-injected lesions were observed in 13 (32 %) patients, responses were mostly limited to loco-regional disease and no significant distant non-injected lesion response was seen. Post-treatment biopsies showed increased CD3+ and CD8+ immune cells in approximately 50% and 40% of injected and non-injected tumors, respectively. Most frequent (&amp;gt;10%) related TEAEs observed in expansion phase included injection site pain (26.8%), fatigue, diarrhea, pruritus, and asthenia (each 12.2%). Conclusion: IT with SAR441000 in combination with cemiplimab was generally well tolerated and demonstrated anti-tumor activity and immune cell infiltration in both injected and non-injected tumors. Citation Format: Oliver Bechter, Carmen Loquai, Stephane Champiat, Jean Francois Baurain, Jean-Jacques Grob, Jochen Utikal, Sylvie Rottey, Alfonso Berrocal, Jessica Hassel, Ana Arance, Miguel F. Sanmamed, Marye Boers-Sonderen, Brian Gastman, Christoffer Gebhardt, Brant Delafontaine, Ugur Sahin, Özlem Türeci, Giovanni Abbadessa, Gianfranco Di Genova, Patrick Brueck, Rahul Marpadga, Helen Lee, Céleste Lebbe. A first-in-human, open-label, multicenter study of intratumoral SAR441000 (mixture of cytokine encoding mRNAs), as monotherapy and in combination with cemiplimab in patients with advanced solid tumors [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 LB198.