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Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial

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Summary

Background

Single-drug checkpoint inhibition has shown efficacy in patients with recurrent malignant pleural mesothelioma. Here, we assessed the safety and efficacy of the combination of nivolumab, an anti-programmed cell death 1 antibody, plus ipilimumab, an anti-cytotoxic T-lymphocyte protein 4 antibody, in patients with previously treated and relapsed malignant pleural mesothelioma.

Methods

INITIATE was a prospective single-centre, single arm, phase 2 trial. Patients with malignant pleural mesothelioma who progressed after at least one line of platinum-containing chemotherapy were enrolled. Key eligibility criteria were measurable disease according to the modified Response Evaluation Criteria in Solid Tumours for mesotheliomas, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received intravenous nivolumab (240 mg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks up to four times). Treatment was continued for up to 2 years or until confirmed progression or unacceptable toxicity. The primary endpoint was disease control at 12 weeks. All patients who received at least one dose of therapy were included in safety analysis and all patients who received one dose of therapy and at least one radiological assessment were included in the primary analysis. This trial is registered at ClinicalTrials.gov, number NCT03048474.

Findings

Between Oct 5, 2016, and Aug 3, 2017, 38 patients were enrolled in the study, of which two patients were excluded because they were not eligible for a biopsy. Of 36 eligible patients, one deteriorated before the start of the study so was not included in any analyses and one withdrew consent after one treatment cycle before radiological assessment so was included in the safety population only. 34 patients were evaluable for response assessment at 12 weeks. Of these, ten (29%) patients had a partial response and 13 (38%) patients had stable disease; thus, disease control was achieved by 23 (68%, 95% CI 50–83) of 34 patients. Treatment-related adverse events were reported in 33 (94%) patients. The most common adverse events were infusion-related reactions, skin disorders, and fatigue. Grade 3 treatment-related adverse events were reported in 12 (34%) of 35 patients.

Interpretation

In this single-centre phase 2 trial, the combination of nivolumab plus ipilimumab showed marked efficacy in patients with recurrent malignant pleural mesothelioma. The safety profile was consistent with known data on the combination regimen. Our results warrant further investigation of this combination in a phase 3 trial.

Funding

Bristol-Myers Squibb.

Introduction

Malignant pleural mesothelioma is an aggressive tumour originating from the mesothelial cells of the pleura. Asbestos exposure is the major risk factor for malignant pleural mesothelioma, with latency time from exposure to diagnosis varying from 20 years to more than 50 years.1, 2

The approved first-line treatment option for patients with malignant pleural mesothelioma who are not eligible for surgery is platinum-based chemotherapy with an antifolate.3, 4 This treatment leads to a median overall survival of about 12–16 months, increasing to almost 19 months with the addition of the angiogenesis inhibitor bevacizumab.3, 5 No approved second-line therapy exists yet. Responses with chemotherapy vary between 10% and 20% of patients and median overall survival ranges from 5·6 months to 10·9 months.6, 7, 8, 9, 10

A few studies using a single-drug checkpoint inhibitor for second-line treatment of patients with malignant pleural mesothelioma have been published. The programmed cell death 1 (PD-1) checkpoint inhibitors pembrolizumab and nivolumab were used in KEYNOTE-02811 (pembrolizumab) and NivoMes12 (nivolumab), with partial responses achieved by five (20%) of 25 patients and nine (26%) of 34 patients, disease control achieved by 18 (72%) of 25 patients and 16 (47%) of 34 patients, and survival at 12 months of 63% (95% CI 40–79) and 50% (36–70).11, 12 In the Javelin phase 1b trial with programmed cell death ligand 1 (PD-L1) checkpoint inhibitor avelumab, five (9·4%) of 53 patients had an overall response.13 But the randomised, double-blind, placebo-controlled phase 2 DETERMINE trial14 analysing second-line treatment with the single-drug cytotoxic T-lymphocyte protein 4 (CTLA-4) checkpoint inhibitor tremelimumab in 571 patients with mesothelioma did not show benefit.

Research in context

Evidence before this study

Few treatment options are available for patients with malignant pleural mesothelioma after chemotherapy. We searched PubMed for studies published between Jan 1, 2010, and June 1, 2018, with the following terms: “mesothelioma” AND “PD-1” OR “PD-L1” OR “CTLA-4” OR “checkpoint”. We also searched clinical trial registers (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform). We found several studies of immune checkpoint inhibitor monotherapy for malignant pleural mesothelioma and ongoing studies for combination checkpoint inhibitors. In phase 1 and phase 2 studies, monotherapy with a programmed cell death 1 or programmed cell death ligand 1 antibody has shown efficacy and an acceptable safety profile, in contrast to cytotoxic T-lymphocyte protein 4 monotherapy, which didn't show clinical efficacy versus placebo in a phase 2B study. Combination therapy with durvalumab and tremelimumab showed encouraging results. No phase 3 trials on immunotherapy for malignant pleural mesothelioma have been published.

Added value of this study

Results from our phase 2 INITIATE trial show that the combination of nivolumab plus ipilimumab has significant clinical efficacy for patients with malignant pleural mesothelioma after at least one line of chemotherapy and a safety profile that is consistent with previously reported data.

Implications of all the available evidence

The clinical efficacy shown by our study and others suggests that combination checkpoint inhibition for malignant pleural mesothelioma should be tested in phase 3 studies in the second-line setting. A phase 3 trial comparing first-line nivolumab plus ipilimumab with platinum-based chemotherapy plus pemetrexed is ongoing (NCT02899299).

Preclinical data suggest a synergistic effect of CTLA-4 and PD-1 checkpoint inhibitors.15 The ongoing first-line CheckMate 743 phase 3 randomised controlled trial (NCT02899299) in patients with malignant pleural mesothelioma is comparing platinum-based chemotherapy plus pemetrexed with nivolumab plus ipilimumab. In the phase 2 single-arm NIBIT-MESO-1 trial,16 patients received a combination of tremelimumab (anti-CTLA-4 antibody) and durvalumab (anti-PD-L1 antibody) in the first-line or second-line setting. 11 (28%) of 40 patients had an immune-related objective response and 25 (63%) achieved disease control. Median progression-free survival was 5·7 months (IQR 1·7–9·7) and median overall survival was 16·6 months (13·1–20·1).16 The MAPS2 randomised phase 2 trial by Scherpereel and colleagues17 assessed nivolumab with or without ipilimumab in patients with relapsed malignant pleural mesothelioma and showed similar results for the combination treatment and monotherapy, although a formal comparison was not done.17

Patients with mesothelioma usually have moderate expression of PD-L1, with 20–40% of tumours expressing PD-L1 in more than 1% of cells. PD-L1 expression is more common in the non-epithelioid histological subtype than in the epithelioid subtype. In cohorts of patients who have not been treated with checkpoint inhibitors, patients with PD-L1-positive tumours have a substantially worse prognosis (median survival 4·8 months) than those with negative tumours (16·3 months), independent of histology (epithelioid or non-epithelioid subtypes). The heterogeneity of tumour biopsy procedures in malignant pleural mesothelioma, and non-uniformity of staining procedures, including differences in cutoff levels, makes comparison between studies difficult.18, 19, 20, 21

In line with our previous study on nivolumab monotherapy, here we report the efficacy and safety data of our INITIATE trial assessing the combination of ipilimumab and nivolumab in the treatment of malignant pleural mesothelioma, including results of PD-L1 expression.

Section snippets

Study design and participants

INITIATE is a prospective single-centre, single-arm, phase 2 trial for patients with unresectable malignant pleural mesothelioma who have disease progression or recurrence after at least one line of platinum-containing systemic therapy. The study was approved by the institutional review board and in accordance with the Declaration of Helsinki. All patients provided written informed consent before enrolment.

Patients were aged at least 18 years, had an Eastern Cooperative Oncology Group (ECOG)

Results

Between Oct 5, 2016, and Aug 3, 2017, 38 patients with progression of malignant pleural mesothelioma after at least one line of chemotherapy gave informed consent. Of these, 36 patients were eligible for inclusion (figure 1). One patient deteriorated quickly and could not begin immunotherapy at the planned start of treatment so was excluded from analyses.

Most patients in the cohort were men (27 [77%] of 35) and most had the epithelioid subtype (30 [86%]); the median age was 65 years (IQR 62–71;

Discussion

Our study shows that the combination of nivolumab and ipilimumab has marked clinical efficacy in previously treated relapsed patients with malignant pleural mesothelioma. The regimen was well tolerated and toxicity was reversible and considered manageable when adhering to protocol guidelines.

Four (31%) of the 13 patients who achieved a partial response did so by the 6-week assessment, six (46%) did so by the 12-week assessment, and three (23%) did so after 12 weeks. The median time to response

Data sharing

Individual participant data will be available after deidentification to investigators who provide a written request in accordance with General Data Protection Regulation, starting immediately and ending 10 years after publication.

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