Phase 2 Clinical Trial of CRS-207, Keytruda Combo for MPM is Discontinued

A combination of the immunotherapies Keytruda (pembrolizumab) and CRS-207 is safe, but has no evidence of clinical activity in adults with malignant pleural mesothelioma who failed prior lines of therapy, a Phase 2 study shows.

Based on the findings and on additional data from CRS-207’s program, the therapy’s clinical development has been discontinued.

The data was recently presented at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium, held in San Francisco, California, Feb. 28-March 2. The study was titled “A phase II single-arm study of CRS-207 with pembrolizumab (pembro) in previously treated malignant pleural mesothelioma (MPM).”

Malignant pleural mesothelioma is an aggressive cancer that occurs in the thin layer of tissue that covers the lungs, and usually has a poor prognosis. There currently is no disease-modifying therapy that effectively increases the survival of these patients, but both CRS-207 and Keytruda separately have shown some effectiveness in these patients.

CRS-207, developed by Aduro Biotech, is an immunotherapy that uses a Listeria monocytogenes bacterium engineered to express mesothelin protein — which is over-expressed in a large variety of tumors, including mesothelioma — and trigger strong immune responses against this protein.

Keytruda, by Merck (known as MSD outside the U.S. and Canada), is an immune checkpoint inhibitor meant to help the immune system recognize and fight cancer. It binds to a protein called PD-1 on immune T-cells, preventing interaction with its ligand, PD-L1, produced by cancer cells to avoid immune surveillance.

In prior Phase 1 trials, these immunotherapies have shown promising response rates in mesothelioma patients, and a study in a lung cancer mouse model suggested that anti-PD-1 therapies like Keytruda could enhance CRS-207 responses.

So, Aduro and Merck designed a Phase 2 trial (NCT03175172) to determine if combining the treatments could improve response rates among malignant pleural mesothelioma patients.

The trial included 10 patients who had received one or two prior lines of therapy and had progressed on standard chemotherapy — Alimta (pemetrexed) and platinum-based therapy. They received the combination every three weeks for four cycles, after which Keytruda remained in a once-every-three-weeks schedule and CRS-207 was given every six weeks.

In addition to the overall response rate, researchers also aimed to assess duration of response, the number of patients with at least stable disease, time to disease progression or death, and overall survival.

At the time of the analysis, nine patients were evaluable for responses, none of whom achieved a response to treatment. Only one patient had their disease stabilized, and the time patients lived without disease worsening ranged from 3.4 to 8.9 weeks.

CRS-207 also lingered very little in circulation, with no signs of treatment four days after the injection, and with all urine, fecal, and saliva samples testing negative for the treatment at all intervals.

The treatment was safe, with the most common treatment-related adverse side effects being chills, fever, and nausea, which was consistent with safety data from each agent alone.

“The toxicity profile of CRS-207/pembro combination was consistent with the safety profile of each component alone [but] no evidence of clinical activity was observed,” researchers concluded. “Based on the results and an overall evaluation of the program, the clinical development of CRS-207 was discontinued.”