Disappointment Over Immunotherapy in Mesothelioma

Liam Davenport

September 30, 2019

BARCELONA — Despite showing promise in phase 2 trials, new results from a randomized phase 3 trial are disappointing in a tumor type that remains a major killer.

In patients with malignant pleural mesothelioma (MPM) who had progressed after first-line chemotherapy, immunotherapy with pembrolizumab (Keytruda, Merck) appears to offer no survival advantages over standard chemotherapy.

The results come from the PROMISE-meso study, presented here at the European Society of Medical Oncology (ESMO) annual meeting.

Sanjay Popat, MD, PhD

Despite "nearly four times more patients" responding to immunotherapy than standard chemotherapy, "unfortunately these responses did not delay progression or improve survival," noted study investigator Sanjay Popat, MD, PhD, thoracic medical oncologist, Royal Marsden Hospital NHS Foundation Trust, London, England.

However, while pembrolizumab "was not superior to chemotherapy, survival was similar, and so pembrolizumab may represent an alternative."

He highlighted that, as in other immunotherapy trials in other cancer types, some of the mesothelioma patients had long responses, which suggests that some patients could "preferentially receive this treatment over chemotherapy."

Popat also suggested that, learning a lesson from lung cancer trials, combining immunotherapy with chemotherapy could have a beneficial effect.

"I would advise clinicians to enroll their patients into one of the large ongoing trials of first-line combination treatment so we can get answers as soon as possible about how to improve mesothelioma treatment," he said.

Commenting for ESMO, Federica Grosso, MD, from the Mesothelioma and Rare Cancers Unit at the Azienda Ospedaliera Nazionale SS Antonio e Biagio e Cesare Arrigo in Alessandria, Italy, said: "Although we did not see better survival with immunotherapy . . . the responses are encouraging."

Grosso explained that treatment of mesothelioma is limited, with the only approved regimen being the combination of pemetrexed and platinum derivatives. Patients generally die within 2 years of diagnosis.

There is currently no standard effective second line therapy for patients with mesothelioma. Those who respond well to pemetrexed- and platinum-based chemotherapy may be given a repeat course, while others are usually offered drugs such as gemcitabine/vinorelbine with response rates of approximately 10%.

Results Were "Disappointing"

Study discussant Nicolas Girard, MD, PhD, Curie-Montsouris Thorax Institute, Institut Curie, Paris, France, said that, overall, the results were "disappointing" despite being in line with findings seen with immunotherapy in phase 2 trials.

Putting the study in context, Girard said that MPM is a rare thoracic malignancy "that is aggressive and difficult to treat."

He noted that the majority of patients are diagnosed with advanced disease, with a median overall survival ranging from 12 to 20 months, and that patients with a nonepithelioid histologic subtype of tumor have a worse outcome.

"Given the aggressiveness of the disease and the absence of standard of care after the failure of platinum-based chemotherapy, immune checkpoint inhibitors represent a new avenue," Girard continued.

He noted that several phase 2, noncomparative trials with immunotherapy — using pembrolizumab, nivolumab (Opdivo, Bristol-Myers Squibb), or avelumab (Bavencio, Merck and Pfizer) — have reported response rates of between 20% and 30%, and disease control rates of 50% to 60%.

Median progression-free survival (PFS) in these trials has ranged from 3 to 5 months, giving overall survival rates in the second- to third-line setting of between 7 to 18 months.

For comparison, the new results from the PROMISE-meso trial show a median PFS of 2.5 months with pembrolizumab and just under 3.5 months with chemotherapy. Overall survival was a median of 10.7 months with pembrolizumab and 11.7 months for chemotherapy (P = .85).

Girard noted that the majority of guidelines do not currently recommend the checkpoint inhibitors in second-line or relapsed settings.

However, the latest National Comprehensive Cancer Network guidelines do suggest pembrolizumab monotherapy or nivolumab with or without ipilimumab (Yervoy, Bristol-Myers Squibb) as among the potential treatment options following first-line chemotherapy.

Details of the PROMISE-meso Study

The PROMISE-meso study recruited a total of 144 patients with MSM between September 2017 and August 2018 in the United Kingdom, Switzerland, and Spain. Accrual was faster than expected, which Girard noted speaks to the high unmet clinical need for this disease.

The median age of the patients was between 69 and 71 years, and between 79.4% and 84.5% were male.

The vast majority of patients (87.3% - 90.4%) had epithelioid tumors, and between 61.7% and 76.1% had a good European Organisation for Research and Treatment of Cancer (EORTC) prognostic score.

At 6 months, 25.0% of pembrolizumab patients and 27.4% of those in the chemotherapy arm were progression-free, and 68.5% and 72.9%, respectively, were still alive.

Subgroup analysis did not reveal any patients who benefited significantly from one treatment over another, although those with nonepithelioid tumors appeared to fare better with chemotherapy than immunotherapy.

The overall response rate was higher among patients given pembrolizumab than in those treated with chemotherapy, at 22% vs 6% (P = .004), which appeared to be driven by a larger number of patients experiencing a partial response, at 21.9% vs 5.6%.

Surprisingly, the median duration of response with immunotherapy was far shorter for pembrolizumab, at 4.6 months vs 11.2 months for chemotherapy, although this difference was not significant and Popat pointed out that this was due to one chemotherapy patient being an outlier in terms of response duration.

Using predefined cutoffs of 0%, 1%, and 50%, the team were not able to identify a subgroup of patients in terms of their PD-L1 expression who performed better with pembrolizumab or chemotherapy.

This was underlined by a time-to-treatment failure analysis, which showed no significant difference between the two treatment groups, regardless of PD-L1 status.

Treatment-related adverse events were similarly frequent in pembrolizumab- and chemotherapy-treated patients, at 69.4% vs 72.9% overall and 19.4% vs 24.3% for grade 3 to 5 events.

Popat noted that nausea, constipation, oral mucositis, and decreased neutrophil count were significantly more common with chemotherapy treatment than with pembrolizumab, while pruritus, dry skin, and maculopapular rash were significantly more frequent with immunotherapy.

Girard said that, overall, the overall response rates and disease control rates seen with pembrolizumab, as well as the PFS and overall survival results are, in fact, comparable to those seen in past in phase 2 studies with immunotherapy.

However, the lack of benefit relative to chemotherapy means that, "obviously, this is disappointing data for immune checkpoint inhibitors in a late-line setting."

He also added: "I'm not sure that we will be able, from these data, to identify a subset of patients for whom pembrolizumab would provide a long-term benefit."

Mesothelioma: Rare But Fatal Cancer

ESMO notes that mesothelioma is a rare but fatal form of thoracic cancer that is diagnosed in more than 30,000 people per year and kills over 25,000. Most cases (> 80%) arise from exposure to asbestos fibers that cause long-term inflammation in the mesothelial cells of the lung, slowly leading to cancerous changes 20 to 50 years later.

The incidence of mesothelioma has fallen in Australia, the United States, and Western Europe where asbestos or strict regulations were introduced in the 1970s and 1980s. Deaths in the United States have gradually decreased compared with Western Europe, where mortality is relatively stable. However, deaths in Eastern Europe appear to be rising, possibly due to later asbestos bans, and rates are also rising in Japan due to historical asbestos imports.

"The worldwide number of deaths is expected to rise as people exposed to asbestos before it was banned continue to be diagnosed many years later," commented ESMO expert Grosso, who is from Italy.

She noted that there are certain "hotspots" for the disease, for example, at Casale Monferrato in Italy "which had the largest asbestos plant in the world until it was closed in 1987. In a population of 35,000, there are approximately 50 cases per year — an incidence more than 20 times higher than in the rest of the country."

"Mesothelioma is a huge problem because asbestos powder from the plants pollutes large areas. It isn't just people who worked in the plant who are being diagnosed, it is their families and unrelated people, some of whom are only 40 to 50 years old — much younger than we would expect to see with mesothelioma," she pointed out.

"A similar situation of environmental exposure was recently reported in Sibaté [Colombia] where a plant was closed only a few years ago and many cases of mesothelioma are being diagnosed," she added.

"Unfortunately, we can expect to see an increase in mesothelioma in countries where asbestos is still used for many years to come," she added.

The study was funded by MSD, manufacturer of pembrolizumab. Popat reports relationships with Boehringer Ingelheim, Epizyme, BMS, Clovis Oncology, Roche, Lilly, Takeda, AstraZeneca, Chugai, Novartis, Pfizer, Merck Sharp & Dohme, Guardant Health, and Abbvie. Girard reports relationships with Astra-Zeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Hoffmann La Roche, Lilly, Merck Sharp Dohme, Novartis, Pfizer, Pharmamar, Takeda and Trizell.

ESMO Congress 2019: Abstract LBA91_PR. Presented September 30, 2019.

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