Keytruda Fails to Improve Profession-Free Survival for Mesothelioma Patients in Phase III European Clinical Trial

Oct 7, 2019 | Cancer, Challenging Results, Keytruda, Lung Cancer, Mesothelioma, Oncology

Keytruda doesn’t improve progression-free survival for mesothelioma patients who progressed after first-line chemotherapy as evidenced from recent Phase III results comparing Merck’s immunotherapy drug to standard chemotherapy.

Background

Mesothelioma is an aggressive malignancy usually affecting the surfaces of body coelomic cavities. It most commonly originates from the pleura with a propensity to the lower parietal pleura and costo-diaphragmatic recess, and is almost always caused by asbestos exposure, with a usual lag time of 30 years between exposure and presentation. Outcomes for most patients are invariably fatal, with median survival from presentation around 9-12 months in most series due to difficulties in achieving a complete microscopic surgical resection and tumour relative chemo-refractoriness. Whilst initially considered rare, due to the demand of asbestos of all varieties associated with industrialization following the Second World War, the background incidence of mesothelioma of 1/million has risen to 40/million in some countries. In the UK, where substantial asbestos exposure continued until the 1970s, the death rate is the highest in the world with a current epidemic of new cases, predicted to continue for another 5-10 years. Two main histological subtypes of mesothelioma are identified. The epitheliod subtype is the commonest, accounting for around 40% of cases, whilst the sarcomatoid subtype is observed in 20% of cases; the latter being typically aggressive and chemorefractory. Around 35% cases have features of both epitheliod and sarcomatoid subtypes and are termed biphasic subtype.

To date Alimta (pemetrexed) and platinum-based chemotherapy (cisplatin or carboplatin) represents the standard-of-care for mesothelioma treatment since 2004.  Keytruda is approved by the FDA to treat non-small cell lung cancer and several other cancers however not mesothelioma.

The PROMISE-meso Study

The disappointing results resulted from the PROMOSE-meso study and presented last week at the European Society of Medical Oncology (ESMO). The study discusses that for patients with pleural mesothelioma, in whom surgery is not considered appropriate, systemic chemotherapy (platinum combined with pemetrexed) remains the international standard of care.

Cisplatin/pemetrexed is associated with a response rate of 41% and confers an OS advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy for mesothelioma in Europe. Despite this, the median survival is 9-12 months from most series in unresectable cases. At relapse, after platinum-based chemotherapy, no anti-cancer systemic therapies are licensed. Whilst several small phase II studies and retrospective series have suggested potential efficacy for chemotherapy with agents including carboplatin/gemcitabine, or vinorelbine, none thus far have demonstrated efficacy benefit in a randomised study, with median PFS rates reported of about 3 months for both gemcitabine and vinorelbine. There is therefore a huge unmet need for effective therapy for patients with relapsed pleural mesothelioma. The largest trial ever performed of systemic therapy in relapsed pleural mesothelioma in 661 patients documented the natural outcome of this group of relapsed mesothelioma patients, reporting a median OS of 27.1 weeks (6 months) and median PFS for 6.1 weeks (1.5 months) for placebo.

Programmed cell death-1 (PD-1) is a co-inhibitory molecule at the immunological synapse that acts as a major regulator of adaptive immunity, and is exploited by tumour cells to result in adaptive immune resistance (tolerance). This occurs when PD-1 binds to the ligands PD-L1 (B7H1) or PD-L2, which are expressed on many tumour types. High PD-L1 expression on tumours is associated with poorer outcomes. Mesothelioma has been shown to express PD-L1, with a small study identifying PDL1 expression in up to 40% of mesotheliomas. Moreover, immunologically-mediated inflammation is known to be a key driver for mesothelioma development via the Nalp3 imflammasome.

Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

There is a need to identify new ways for the systemic therapy of malignant mesothelioma and immune checkpoint inhibition is a promising way forward. Results from the proposed trial will contribute to overcoming tumour-specific immune suppression with immune checkpoint inhibition.

Results

Results from the Phase III clinical trial comparing Keytruda (pembrolizumab) to standard chemotherapy revealed that the immunotherapy is not there yet as an option for malignant pleural mesothelioma. Keytruda failed to improve progression-free survival for mesothelioma patients who progressed after first-line chemotherapy. This was the first randomized clinical trial comparing progression-free survival between an immunotherapy and first-line chemotherapy for mesothelioma (lung cancer) patients reported Asbestos.com. Although the response was to Keytruda was four times higher, the responses failed to delay the tumor progression and hence, improve survival.

Lead Research/Investigator

Sanjay Popat, MD, Royal Marsden NHS Foundation Trust

Alessandra Curioni-Fontecedro, MD University Hospital, Zurich

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