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Immunotherapy Flops in Mesothelioma Trial

BARCELONA — The first randomized trial of immunotherapy and chemotherapy for progressive malignant pleural mesothelioma ended in a draw, as neither treatment demonstrated an advantage over the other.

Patients treated with pembrolizumab (Keytruda) had a median progression-free survival (PFS) of 2.5 months as compared with 3.4 months with standard chemotherapy regimens. Median overall survival (OS) also did not differ significantly between treatment groups. More than three times as many patients achieved objective responses with pembrolizumab, but the responses lasted only about a third as long as chemotherapy-induced responses.

Counterintuitively, pembrolizumab performed better in patients with a low total proportional score (TPS) for PD-L1 expression, although the numbers were small, reported Sanjay Popat, MD, of the Royal Marsden Hospital in London, at the European Society for Medical Oncology (ESMO) annual meeting.

“Despite correcting for crossover, an overall survival benefit was not observed,” Popat said. “The pembrolizumab safety profile was consistent with that previously observed. Further exploratory translational work is ongoing to identify subgroups that could benefit from pembrolizumab.”

Pembrolizumab’s performance was in line with previous studies of single-agent anti-PD-1/L1 therapy in mesothelioma, said ESMO invited discussant Nicolas Girard, MD, of the Curie Institute in Paris. A graphic of outcomes from eight studies involving three such checkpoint inhibitors — nivolumab (Opdivo), avelumab (Bavencio), and pembrolizumab — showed median PFS ranging from 2.5 months (as reported by Popat) to 6.1 months. Median OS ranged from 7.2 to 10.7 months in four of six studies that evaluated OS, whereas the KEYNOTE-028 trial with pembrolizumab yielded a median PFS of 18 months and the MERIT trial with nivolumab had a median OS of 17.9 months.

Overall, the current trial — the European Thoracic Oncology Platform (ETOP) PROMISE-meso — provided little insight into strategies to improve the performance of single-agent immunotherapy in progressive mesothelioma.

“I’m not sure from this data whether we will be able to identify a subset of patients for whom pembrolizumab will provide a long-term benefit,” said Girard. “Maybe we need to explore additional characteristics of patients. The discontinuation rate due to toxicity was less than 10%, so perhaps progression.”

In the meantime, clinicians have little guidance about using immunotherapy — if at all — to treat relapsed mesothelioma. Girard noted that neither ESMO nor the American Society of Clinical Oncology include immunotherapy in clinical guidelines. The National Comprehensive Cancer Network guidelines mention pembrolizumab at the bottom of a list of potential options for systemic therapy, beyond recommended first-line therapy.

At relapse after initial platinum-based chemotherapy, patients with malignant pleural mesothelioma have no options that have shown the ability to improve OS. Most patients receive additional chemotherapy, usually vinorelbine (Navelbine) or gemcitabine (Gemzar), said Popat. As pointed out by Girard, single-agent immunotherapy has shown some promise in the setting of relapsed mesothelioma.

To date, results with single-agent immunotherapy came from nonrandomized trials. To address the need for randomized data, ETOP sponsored a multicenter randomized comparison of pembrolizumab and chemotherapy, involving patients from England, Switzerland, and Spain.

Eligibility criteria included any histologic type of mesothelioma, progression after previous platinum-based chemotherapy, measurable or evaluable disease, and availability of tumor tissue for translational studies. Patients received either pembrolizumab or investigator’s choice of gemcitabine or vinorelbine.

Investigators enrolled and randomized 144 patients, giving the trial the statistical power to detect an increase in median PFS from 3.5 months with chemotherapy to 6 months. Median PFS by blinded independent review was the primary endpoint. Objective response rate and OS were among the key secondary outcomes of interest.

The primary analysis produced a hazard ratio of 1.06 for the comparison of pembrolizumab versus chemotherapy (95% CI 0.73-1.53, P=0.76). The proportion of patients who remained progression free at 6 months also did not differ significantly (27.4% with chemotherapy, 25.0% with pembrolizumab). Analysis of predefined subgroups failed to identify any patients who appeared to benefit more from pembrolizumab than chemotherapy.

Neither median survival nor 6-month OS (72.9% with chemotherapy, 68.5% with pembrolizumab) distinguished one treatment from the other. Even after adjustment for crossover from chemotherapy to the PD-1 inhibitor, pembrolizumab did not improve OS, said Popat.

Analysis of PFS by PD-L1 expression status also showed no advantage for pembrolizumab. Median PFS was 4.2 months for patients with TPS <1% versus 4.4 months for the chemotherapy arm and 3.2 months in both treatment arms for patients with TPS ≥1%. The median OS with pembrolizumab also was better in the TPS <1% group (11.7 vs 9.9 months) as compared with the patients who had higher PD-L1 expression (10.7 vs not reached).

Pembrolizumab did induce significantly more objective responses (22% vs 6%, P=0.004), but median duration of response favored chemotherapy (11.2 vs 4.6 months).

Adverse event rates were similar in the two treatment groups. Pembrolizumab was associated with more pruritus, dry skin, and rash, whereas chemotherapy caused more nausea, constipation, mucositis, and neutropenia.

The study was supported by ETOP/Merck.

Popat disclosed relevant relationships with Bristol-Myers Squibb, Takeda, AstraZeneca, Chugai, Novartis, Pfizer, Merck Sharp & Dohme, EMD Serono, Guardant Health, AbbVie, Boehringer Ingelheim, Medscape, Tesaro, OncLive, Elsevier, Clovis Oncology, Roche, Eli Lilly, Epizyme, Ariad, Bayer, Celgene, and Synta.

2019-10-01T17:30:00-0400

Source: MedicalNewsToday.com