Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer - The PICCASSO phase I trial.

Georg Martin Haag, Christoph Springfeld, Barbara Grün, Leonidas Apostolidis, Stefanie Zschäbitz, Mareike Dietrich, Anne-Katrin Berger, Tim Frederik Weber, Inka Zoernig, Marina Schaaf, Lisa Waberer, Daniel Wilhelm Müller, Salah-Eddin Al-Batran, Niels Halama, Dirk Jaeger

Journal: European journal of cancer (Oxford, England : 1990) 2022;167():112-122

PMID: 35427833

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

PD-1/PD-L1 inhibitors do not show activity in mismatch repair proficient (MMRp) colorectal cancer. Inhibition of C-C motif chemokine receptor 5 (CCR5) leads to an antitumoral activation of macrophages, affecting immune cell infiltrates. PICCASSO is a phase I trial exploring safety and efficacy of pembrolizumab and maraviroc in refractory MMRp CRC.

METHODS

Twenty patients received pembrolizumab and maraviroc (core period, eight cycles), followed by pembrolizumab monotherapy. Primary endpoint was the feasibility rate (patients without treatment-related grade ≥3 immune-related adverse events, treatment-related grade ≥4 adverse events, or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Optional biopsies of liver metastases were performed for analyses of the micromilieu.

RESULTS

The feasibility rate was 94.7% [90% CI 77.4-99.7%], with one grade 4 hyperglycemia and no additional ≥ grade 3 treatment-related toxicities. ORR according to RECIST was 5.3%. Median PFS according to RECIST was 2.10 months [95%CI 1.68-2.30], median OS 9.83 months [95% CI, 5.59-20.02]. Disease control rate of poststudy salvage treatment was >70%. Translational analyses showed an increase of antitumoral chemokines during treatment; eotaxin, a chemokine involved in chemotaxis, was identified as a biomarker linked to OS.

CONCLUSIONS

Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MMRp CRC patients was limited with prolonged disease stabilizations observed in single patients. Efficacy of poststudy salvage treatment and OS was higher than expected in this heavily pretreated population. THIS TRIAL IS REGISTERED AT CLINICALTRIALS.GOV: NCT03274804.

Address: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor-Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: [email protected].; Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.; Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany.; IKF Klinische Krebsforschung GmbH am Krankenhaus Nordwest, Frankfurt, Germany.; University Cancer Center Frankfurt, Institut für Klinisch-Onkologische Forschung and IKF Klinische Krebsforschung GmbH am Krankenhaus Nordwest, Frankfurt, Germany.; Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany; Department of Translational Immunotherapy, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor-Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.

DOI: 10.1016/j.ejca.2022.03.017

Link outs

Free resources

Medical:

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-CD274-1

Subscription / membership required

Full Text Sources:

MeSH Terms: Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Colorectal Neoplasms, DNA Mismatch Repair, Humans, Immune Checkpoint Inhibitors, Maraviroc, Microsatellite Repeats