IMMUNOTHERAPY FOR MESOTHELIOMA

VIENNA — Immunotherapy is now offering hope even in one of the most aggressive cancers of all, malignant pleural mesothelioma.

Malignant mesothelioma is usually diagnosed at a late stage and is essentially incurable. The median overall survival is approximately 12 months with first-line chemotherapy, and median survival with second-line therapy, which has not yet been adequately defined, is typically less than 10 months.

Early clinical results with the programmed cell death (PD) inhibitors nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck & Co) show response, yielding survival rates that appear to be improvements on what has been seen historically with chemotherapy.

The new data on immunotherapy are "very promising," commented Cornelius F. Waller, MD, Medizinische Klinik I, Universitätsklinikum, Freiberg, Germany. He added, "We have seen that these drugs have limited side effects, as has been shown in other diseases.

"However, larger randomized trials are needed, because what we have so far are only phase 1b and phase 2 data," he noted.

Intriguingly, the new studies, presented here at the 17th World Conference on Lung Cancer (WCLC), showed that the benefits were achieved independently of expression of the PD-L1 biomarker, which has been predictive of the degree of treatment response in other cancers and has also been shown to be prognostic for patients with mesothelioma.

Dr Waller noted that PD-L1 expression "seems to be a good prognostic marker in mesothelioma, but doesn't seem to have a predictive value in this disease, which points out the necessity to find new biomarkers for mesothelioma."

He also noted, "The question comes up whether the combination of immunotherapy with other immunotherapeutic agents or with chemotherapy or radiation is better than monotherapy with, for example, checkpoint inhibitors."

Dr Waller said that ongoing studies are looking at this question and that "we'll see during the next year or so whether this might be true, that a combination is better than monotherapy."

Speaking to Medscape Medical News after the session, Paul Baas, MD, PhD, Department of Thoracic Oncology, the Netherlands Cancer Institute, Amsterdam, who gave the first presentation, said that there are mainly two possible explanations for the lack of association between PD-L1 expression and treatment outcomes.

"We think that the tumors have a lot of heterogeneity, and it might be that we do not biopsy enough different sites, which would lead to a difference in mutational load, neoantigens, and probably PD-L1," he said.

"Or, and this might be the other explanation, in mesothelioma, this might not be the biomarker of choice. We all know that we have patients who respond to immuno-oncology treatment in non–small cell lung cancer, even when we don't see any expression."

He added: "Maybe this is a sampling error; maybe there's a better biomarker.

Nivolumab Study Details

The study that Dr Baas presented involved 34 mesothelioma patients who had tumors that were accessible for biopsy and who had had experienced disease progression after undergoing at least one prior therapy. PD-L1 expression was absent in 20 patients and was greater than 50% in three patients; for the remainder of patients, PD-L1 expression fell between these two measures.

All patients underwent CT. Biopsies were performed at baseline before treatment. The patients were treated with nivolumab 3 mg/kg once every 2 weeks and underwent a response evaluation with repeat CT and biopsy at 6 weeks.

The primary endpoint was the disease control rate at 12 weeks. The investigators hypothesized that the disease control rate after 12 weeks of nivolumab treatment would increase from 20% to 40%. Median progression-free survival (PFS) was 110 days. Six patients were still receiving therapy at the time of the current analysis. There were no complete responses, but at 12 weeks, there were five partial responses, and 12 patients had stable disease, yielding a disease control rate of 50%.

At 24 weeks, four patients had a partial response, and seven had stable disease, giving a disease control rate of 33%. Progressive disease was seen in 17 patients at 12 weeks and 23 patients at 24 weeks.

There were eight instances of grade 3-4 adverse events. These consisted of nausea and vomiting in two patients each, and pneumonitis, pericardial effusion, infection, and infusion reaction in one patient each.

Analysis of treatment response by PD-L1 status revealed that three of the 20 patients who had no PD-L1 expression had a partial response, and eight had stable disease. Partial responses and stable disease were also seen in patients with PD-L1 expression.

Dr Baas concluded: "I can say that, in this study, nivolumab as a single agent met it's primary endpoint and was very well tolerated by the majority of the patients.

"We did find PD-L1 expression of 29%, which is in agreement with other literature, but mostly they were in the epithelial group. Responses were seen throughout all groups, and the numbers are too small to say anything about the histological subtypes," he aded.

Pembrolizumab Study Details

The pembrolizumab results were presented by Hedy Kindler, MD, professor of medicine and director of the Mesothelioma Program, University of Chicago, in Illinois. She presented results of an interim analysis of a phase 2 trial.

Part A of the trial was designed to determine the objective response rate of pembrolizumab in an unselected group of malignant mesothelioma patients and to assess the optimal PD-L1 cutoff. The intention of part B was to use that cutoff, if identified, to enroll patients. Part B employed a biomarker enrichment strategy.

In presenting results from part A, Dr Kindler said that they enrolled 34 patients with histologically confirmed malignant mesothelioma and disease progression on or after treatment with pemetrexed plus a platinum-based therapy. Patients had an ECOG performance status of 0 or 1.

The majority of patients (n = 25, 74%) had epithelioid-type disease. The disease site was the pleura in 29 patients (85%). For 20 patients (59%), pembrolizumab was the second-line therapy; for 14 patients (41%), it was the third line.

Pembrolizumab was given at a dose of 200 mg intravenously every 21 days. CT scans were performed every 9 weeks. The median number of cycles was nine, and the range was 1 to 22.

Dr Kindler reported that 56% of patients experienced a decrease in tumor size from baseline. The median PFS was 6.2 months, and the median overall survival was 11.9 months

A partial response was seen in seven patients, and 20 had stable disease, giving a disease control rate of 80%. The median duration of response was not reached. Among 12 patients treated beyond progression, one achieved a partial response, and two had stable disease, giving a disease control rate of 25%.

The most common grade 3-4 adverse events were fatigue (6%), pneumonitis (6%), and adrenal insufficiency (6%). Colitis, confusion, neutropenia, hepatitis, and hyponatremia were seen in 3% of patients each.

PD-L1 expression was found in 47% of patients, almost exclusively on tumor cells. Although the response rate was lower in patients without PD-L1 expression compared with those with expression, at 12% and 27%, there was no significant difference in PFS (P = .38) or overall survival (P = .25) between the two groups.

Dr Kindler said, "Pembrolizumab has robust activity in PD-L1 unselected, previously treated mesothelioma patients, with a response rate of 21% and a disease control rate of 80%."

She added: "Although an optimal PD-L1 threshold could not be established, the sample size was still too small to draw any definitive conclusions. The second stage is currently enrolling an additional 30 patients without PD-L1 preselection; to date, 31 patients have been enrolled."

The third presentation was given by Evan W. Alley, MD, PhD, codirector of the Penn Mesothelioma and Pleural Program, Penn Medicine, Philadelphia, Pennsylvania, who reported data from the KEYNOTE-028 study. In that study, patients with malignant mesothelioma who were positive for PD-L1 expression and had failed or were unable to receive standard chemotherapy were given pembrolizumab 10 mg/kg intravenously every 2 weeks.

Response assessments were made every 8 weeks for the first 6 months and every 12 weeks thereafter. Patients with a complete or partial response or with stable disease were treated for 24 months or until progression or intolerable toxicity. For those with confirmed progression or intolerable toxicity, pembrolizumab therapy was discontinued.

The mean age of the 25 patients included in the study was 65.0 years; 18 (72%) had epithelioid-type disease. Fifteen patients (60%) had received one prior line of therapy, and eight (32%) had received two prior therapy lines.

Dr Alley noted that for 60.9% of patients, there was a decrease in tumor volume from baseline with treatment. The median PFS was 5.4 months, and the median overall survival was 18.0 months. The upper limit of the 95% confidence interval was not reached.

There were no complete responses, but five patients had a partial response, and 13 had stable disease, giving a disease control rate of 72%. The median duration of response was 12.0 months.

An objective response was seen in 20% of patients. Clinical benefit, defined as a complete or partial response or stable disease lasting at least 6 months, was observed in 40% of patients.

During a median follow-up of 18.7 months, five patients experienced at least one adverse event of grade 3 or higher, one each consisting of appetite decrease, dyspnea, iridocyclitis, neutrophil count decrease, pyrexia, thrombocytopenia, and an increase in alanine transaminase level.

"In summary, single-agent pembrolizumab has substantial clinical activity in patients with PD-L1-positive malignant pleural mesothelioma and, at least numerically, seemed to improve on the historical 10-month median overall survival for chemotherapy," said Dr Alley.

The Nivolumab study was partly funded by the Mesothelioma Applied Research Foundation. The KEYNOTE-028 study was supported by Merck & Co. Dr Kindler has served in a consultant/advisory role for and has received research funding from a number of companies, including AstraZeneca, Bayer, Bristol-Meyers Squibb, and GlaxoSmithKline. The other speakers have disclosed no relevant financial relationships.

17th World Conference on Lung Cancer (WCLC). Abstracts OA13.01, OA13.02, and OA13.03. Presented December 6, 2016.