Phase I study of intratumoral administration of CV8102 in patients with advanced melanoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the head and neck, or adenoid cystic carcinoma

Abstract

Background: CV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death protein-1 (PD-1) therapy-naïve or anti-PD-1 therapy-refractory cutaneous melanoma (cMEL) and in patients with advanced cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma and adenoid cystic carcinoma.

Methods: This open-label, cohort-based, phase I dose escalation study aimed to establish the maximum tolerated dose (MTD), recommended dose (RD), safety and preliminary efficacy of CV8102 as monotherapy or in combination with a PD-1 inhibitor. The preliminary efficacy of the RD was assessed in patients with cMEL in the expansion cohorts.

Results: Between September 2017 and October 2022, 98 patients were enrolled in monotherapy and combination therapy dose escalation and dose expansion cohorts. Two patients in the CV8102 monotherapy dose escalation cohort experienced relevant toxicities at the 900 µg dose level. One patient had Grade 3 aspartate transaminase/alanine aminotransferase elevation which met dose-limiting toxicity (DLT) criteria. Another patient experienced Grade 3 immune-mediated pneumonitis. No DLTs occurred in the combination therapy dose escalation cohort. The MTD was not formally reached and the RD for expansion was 600 µg. Common treatment-emergent adverse events were fever (57%), chills (37%) and fatigue (25%). In the dose escalation part, objective responses occurred in 3/33 patients treated with CV8102 as monotherapy and in 2/25 patients treated with CV8102 plus a PD-1 inhibitor. In the expansion cohorts in patients with anti-PD-1 therapy-refractory melanoma, 0/10 patients treated with CV8102 as monotherapy and 5/30 patients (17%) treated in combination with a PD-1 inhibitor experienced objective responses.

Conclusions: IT CV8102 was generally well tolerated with preliminary signs of efficacy as monotherapy and in combination with a PD-1 inhibitor.

Trial registration number: NCT03291002.

Keywords: Head and Neck Cancer; Immunotherapy; Intratumoral; Skin Cancer.

Figure 1. (A) Treatment schedule. (B) Trial profile for the monotherapy and combination therapy dose escalation and dose expansion parts. PD-1, programmed cell death protein-1. ^aPatients in the monotherapy dose expansion and dose escalation cohort and the combination dose escalation cohort, and anti-PD-1 refractory patients in the combination dose escalation cohort. with evidence of clinical benefit received further injections until progression. ^bNivolumab (2-weekly CV8102 administration both for 2- and 4-weekly nivolumab schedule). ^cPembrolizumab.^dOnly patients who did not show any signs of tumor progression after completion of treatment when treated with single-agent CV8102 received subsequent intratumoral CV8102 after the eight injection for the planned duration of the study at 4-weekly intervals. RCD, recommended combination dose; RD, recommended dose.

Figure 2. Treatment response per Response Evaluation Criteria in Solid Tumors V.1.1 in patients with anti-PD-1 therapy-refractory cutaneous melanoma in the combination therapy dose expansion cohort at the recommended dose of 600 µg (N=30). (A) Longitudinal change of target lesions from baseline. The per cent change in the sum of diameter from the baseline is shown. The dashed lines at 20% and −30% represent the boundary for the determination of PD and PR. (B) Overall response related to time on treatment. Each patient is represented by a bar and the treatment responses from baseline in target lesions are shown as colored dots. CR, complete response; NE, not evaluable; PD, progressive disease; PD-1, programmed cell death protein-1; PR, partial response.

Figure 3. Melanoma lesions in an anti-programmed cell death protein-1 therapy-naive patient with stage IIIC melanoma with multifocal in-transit metastases in the 150 µg monotherapy dose escalation group at: (A) Pretreatment, (B) week 6 post-treatment (five injections of CV8102), (C) week 12 post-treatment (eight injections of CV8102), and (D) at end of study.

Figure 4. Analysis of the tumor microenvironment in paired biopsies from responders before and after CV8102 treatment. (A) Quantification of tumor and immune cell populations at baseline, Day 36 and EOT (all paired samples obtained from responders are shown, n=3). (B) Clinical evolution and treatments received by a patient with partial response melanoma in the dose escalation (combination cohort) and representative ROIs from biopsies collected at baseline and Day 36, from a non-injected subcutaneous lesion of the right upper limb. The patient was anti-PD-1 therapy-refractory prior to entering the trial and received 900 µg of CV8102 in combination with nivolumab for the complete treatment period of 8 injections. (C) Targeted gene expression profiling in paired samples of the same patient as in B, wheel plots showing the IO360 signatures at baseline and after treatment. (D) Results for all signature scores calculated for the sample in C. (E) Clinical evolution and treatments received by a patient with complete response melanoma in the dose expansion (combination cohort) and representative ROIs from biopsies collected at baseline and Day 36, from an injected lesion on the medial surface of the right lower leg (skin). The anti-refractory patient received 600 µg of CV8102 in combination with pembrolizumab and remained on treatment for a total of 19 injections. The zoom-in image in the post-treatment sample shows activated T cells with Granzyme B (GZMB) granules oriented towards tumor cells. DAPI, 4',6-diamidino-2-phenylindole; EOT, end of treatment; PD, progressive disease; PD-L1, programmed death-ligand-1; PR, partial response; TIS, tumor inflammation signature.