Combined PD-1 inhibition (Pembrolizumab) and CCR5 inhibition (Maraviroc) for the treatment of refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC): First results of the PICCASSO phase I trial.

Abstract

3010 Background: Checkpoint inhibition using PD-1/PD-L1 inhibitors does not show clinically relevant activity in MSS/pMMR (Mismatch Repair Proficient) colorectal cancer. Previous work showed that inhibition of CCR5 (C-C chemokine receptor type 5) leads to a macrophage re-polarization towards M1 macrophages within the tumor microenvironment which directly affects immune cell infiltrates. The current phase I trial explores a combined modification of the innate immune system (by CCR 5 blockade) and the adaptive immune system (by PD-1 inhibition) in the treatment of MSS CRC. Methods: 20 patients with metastatic MSS/pMMR colorectal cancer with failure of fluoropyrimidines, oxaliplatin, irinotecan, VEGF antibodies and EGFR antibodies (in ras WT patients) received pembrolizumab 200 mg q21d and maraviroc 300 mg bid cont. for 8 cycles, followed by pembrolizumab monotherapy for a maximum of 24 additional cycles. Imaging was performed every nine weeks (RECIST and irRECIST criteria). Primary endpoint was the feasibility rate (rate of patients receiving the protocol treatment during the core treatment without special event: treatment-related Grade ≥ 3 immune-related abnormalities, treatment-related Grade ≥ 4 AEs or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, ORR, PFS and OS. Results: 20 patients were enrolled. The median number of applied cycles was 3.5 for pembrolizumab and 3.5 for maraviroc. Two patients completed the core treatment period with pembrolizumab and started maintenance treatment. The feasibility rate was 94.7% (90% CI 77.4 to 99.7%), with one patient experiencing a special event. Except this grade 4 event (hyperglycemia) no ≥ 3 treatment-related toxicities were observed. According to irRECIST criteria one patient showed a partial response and one a stable disease as best response, resulting in an irDCR of 10.5%. Median PFS according to irRECIST was 2 months (CI 95%, 2 to 3), median OS 9 months (CI 95%, 6 to 20). Conclusions: Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MSS CRC patients was limited, however prolonged disease stabilizations were observed in single patients and overall survival was higher than expected in this heavily pretreated population. Clinical trial information: NCT03274804 .

The Role of Macrophages in Cancer Development and Therapy

“…However, they are potential candidates to target TAMs in cancer therapy. Recently, Maraviroc was used in Phase 1 clinical trial in combination with Pevrolizumab in the treatment of metastatic colorectal cancer with a good toxicity profile [ 99 ] ( Table 1 ) and is currently used in a clinical trial with nivolumab and ipilimumab for the treatment of metastatic colorectal and pancreatic cancers (clinical trial: NCT04721301). Leronlimab is currently studied in Phase 1 in combination with carboplatin in the treatment of triple-negative breast cancer [ 101 ] and in Phase 2 for the treatment of solid metastatic tumors (NCT0450494).…”

CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis

“…The combination of MVC and pembrolizumab was used to treat 20 patients with refractory microsatellite stable (MSS) metastatic colorectal cancer in a phase I trial (ClinicalTrials.gov Identifier: NCT03274804), while in a phase II clinical trial, the efficacy of MVC was examined in the prophylaxis of graft-versus-host disease (GVHD) in patients with hematologic malignancies (NCT01785810). Results from the phase I trial supported the feasibility of combined MVC and pembrolizumab treatment and good toxicity, with higher-than-expected overall survival [ 30 ]. The results of the phase II trial are awaited.…”

Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

“…Importantly, maraviroc has shown promising results in a clinical trial (MARACON), reducing cell growth in colorectal cancer patients that were refractory to standard chemotherapy [145], while two other clinical trials evaluating the combined PD-1 inhibition (Pembrolizumab) with Maraviroc or Vicriviroc, respectively, for the treatment of refractory MSS, revealed prolonged disease stabilisation and a higher survival rate than expected [143,161]. Additional clinical trials with CCR5 + metastatic cancer patients are currently underway to evaluate the combination of either a CCR5 antagonist with a biologic, or of leronlimab with a conventional chemotherapeutic agent [162].…”