Novel Vaccine Added to Chemotherapy Improves Patient Outcomes in Mesothelioma

Thierry M. Jahan, MD

The first report of results from a phase Ib clinical trial evaluating CRS-207, a live, attenuated, double-deleted Listeria monocytogenes (LADD) vaccine, in combination with pemetrexed and cisplatin, demonstrated the effectiveness of this approach for patients with malignant pleural mesothelioma (MPM), according to findings presented at the 2016 European Lung Cancer Conference (ELCC).

CRS-207 was designed to activate both innate and adaptive immunity by directing expression of the tumor-associated antigen mesothelin, which is overexpressed in virtually all epithelioid histology but not in sarcomatoid cases of mesothelioma.

The standard of care for firstline treatment was established as pemetrexed and cisplatin in 2003 in a trial showing an objective response rate (ORR) of 41%, median time to progression of 5.7 months, and overall survival of 12.1 months.

“In our early studies, CRS-207 induced an anti-mesothelin response and cellular tumor -specific immunity in patients with mesothelin-expressing tumours,” said Thierry M. Jahan, MD, clinical professor in the Department of Medicine at the University of California San Francisco. “We also have data suggesting that this immunotherapy works synergistically with chemotherapy, so testing the effect of this immune-targeting agent with chemotherapy was a natural step.”

Of the 38 patients enrolled in this trial as of August 2015, 30 had completed the full treatment course, and 19 of completing patients had received at least 1 maintenance treatment with CRS-207.

Data were evaluable for 34 patients that showed a best overall response of partial response in 20 (59%) patients, and stable disease in 12 (35%) patients. One patient experienced progressive disease. Tumor shrinkage was confirmed in 85% of patients. The overall disease control rate was 94%.

Following treatment of CRS-207 combined with chemotherapy, the median progression-free survival (PFS) was 8.5 months and median overall survival had not been reached.

“Malignant pleural mesothelioma is an aggressive disease with a poor prognosis; most patients are not candidates for surgical resection,” Jahan noted.

CRS-207 has already been evaluated in phase I and II clinical trials in various combinations and tumor types, according to Jahan. “More than 300 patients have received more than 30 doses of LADD immunotherapy, either alone or in combination with other agents with no additive or long-term effects.”

The study enrolled chemotherapy-naïve patients with unresectable MPM, an ECOG performance status 0-1, and adequate organ function. Patients were required to have epithelial or biphasic MPM; however, in patients with biphasic tumor, the sarcomatoid component of the tumor could not exceed 50%. The mean patient age was 70 (range, 51-82 years), and 89% of patients were male; 87% of patients had epithelioid histology, 11% had biphasic, and 1 patient had other histology.

Patients received two CRS-207 infusions (1×109 CFU) 2 weeks apart, 6 cycles of pemetrexed at 500 mg/m2 plus cisplatin at 75 mg/m2 3 weeks apart, followed by two additional CRS-207 infusions 3 weeks apart. Eligible patients received maintenance therapy with CRS-207 every 8 weeks; all patients were evaluated every 8 weeks until disease progression. Immune analyses were done using multiplexed immunohistochemistry (IHC) of tumor-infiltrating lymphocytes (TILs), flow cytometry analysis of peripheral blood mononuclear cells, and Luminex analysis of serum biomarkers.

Aims of the study objectives were safety, immunogenicity, tumor response, and tumor marker kinetics.

“There was an expansion of all immune cell compartments, specifically CD8+ T cells, macrophages, and natural killer cells, following CRS-207,” Jahan commented, “There was no expansion of T-regulatory cells.”

IHC data were available from 3 patients and revealed an increase in TILs following treatment, as well as increased immune cell recruitment and activation in the tumor microenvironment.

There was 1 report of a severe, grade 3, CRS-207 infusion—related adverse event (AE) of fever, 2 cases of chills/rigors, and 1 report of hypotension.

"CRS-207 in combination with chemotherapy appears to be well tolerated with no additive or cumulative toxicities. Recruitment and expansion of TILs and changes in circulating immune cells and serum biomarkers were observed post-CRS-207," Jahan said.

Jahan concluded: “CRS-207 is an exciting agent for patients with mesothelioma. Our preliminary results are encouraging, suggesting superior clinical activity when added to standard chemotherapy. This supports assessing the impact of CRS-207 in a randomised trial, which is currently in the planning stages and should be underway within this calendar year.”

Rolf A. Stahel, professor of oncology at the University Hospital Zurich, who was not involved in this research, commented: “The findings suggest that the addition of this type of immunotherapy improves the response rate, and provides a longer progression- free survival, compared to what would be expected with chemotherapy alone. This supports the hypothesis of benefit of this vaccination which will be examined in a randomized trial to prove or disprove the survival benefit of vaccination added to chemotherapy.”

Jahan T, Hassan R, Alley. CRS-207 with chemotherapy (chemo) in malignant pleural mesothelioma (MPM): results from a phase Ib trial. Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract 208O.

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