Single-arm, open label study of pemetrexed plus cisplatin in chemotherapy naïve patients with malignant pleural mesothelioma: Outcomes of an expanded access program

Summary

Background

An expanded access program (EAP) provided patient access to pemetrexed prior to its commercial availability. The current report consists of US patients in the EAP who had chemotherapy naïve pleural mesothelioma.

Methods

Eligible patients had a histologic or cytologic diagnosis of malignant mesothelioma that was not amenable to curative treatment with surgery. Study treatment consisted of pemetrexed 500 mg/m² in combination with cisplatin 75 mg/m² once every 21 days. Vitamin B12, folic acid, and dexamethasone were administered as prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilance database for all patients enrolled in the EAP.

Results

Of 1056 patients receiving at least one dose of pemetrexed in the EAP, 728 had chemotherapy naïve pleural mesothelioma. Median age of this group was 70 years (range 23–89 years) and 84% were male. Among 615 patients, overall response rate was 20.5%, including 12 complete responses (2.0%) and 114 partial responses (18.5%). An additional 290 patients (47.2%) had stable disease. Median survival for all 728 patients was 10.8 months (95% CI = 9.8, 12.3; 60.3% censorship) and 1 year survival was 45.4%. The most commonly reported SAEs in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%).

Conclusions

In this large cohort, 67.7% of patients treated with first-line chemotherapy experienced a response or stable disease. Survival time and toxicity from this EAP were promising for this difficult-to-treat disease.

Introduction

Malignant pleural mesothelioma (MPM) is an aggressive and rapidly fatal disease. Global incidence is expected to increase in future decades as a result of widespread use of asbestos during the 20th century and the delayed onset of the disease [1], [2]. Treatment options are limited for patients with unresectable MPM; until recently the absence of any demonstrable survival advantage from single-agent or combination regimens led to the use of chemotherapy with primarily palliative intent. Traditional radiation therapy, as an independent modality, has also failed to influence survival [3].

A new standard of care in first-line MPM was reached following the completion of the largest randomized phase III trial (n = 456) in the disease to date [4]. In this definitive trial, combination treatment with pemetrexed (Alimta^®, Eli Lilly and Company, Indianapolis, IN) plus cisplatin resulted in prolonged median survival time (12.1 months versus 9.3 months, p = 0.020) and time to progression (5.7 months versus 3.9 months, p = 0.001), and improved response rates (41.3% versus 16.7%, p < 0.0001) compared with cisplatin alone. This regimen subsequently became the first to achieve regulatory approval by the US Food and Drug Administration (FDA) for advanced MPM [5].

Pemetrexed is a structurally novel multitargeted antifolate that interferes with nucleotide synthesis by potently inhibiting several key folate-dependent enzymes involved in purine and pyrimidine synthesis, including dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide formyltransferase [6], [7]. This cytotoxic agent has broad anti-tumor activity, as demonstrated by a number of investigational studies in colorectal, pancreatic, breast, and bladder tumor types [8], [9], [10], [11], [12], [13]. Pemetrexed attained its second regulatory approval as a single agent in previously treated advanced non-small-cell lung cancer (NSCLC) on the basis of a phase III trial showing the agent to have equivalent activity but diminished toxicity when compared to docetaxel [14]. The addition of folic acid and Vitamin B12 has improved the tolerability of pemetrexed.

To ensure pemetrexed access to all prospective patients following the completion of the phase III MPM study, Eli Lilly and Company initiated an expanded access program (EAP). Upon FDA approval and commercial release of pemetrexed, this EAP was terminated. Initially, only chemotherapy naïve patients with pleural disease were included, matching the patient population that was evaluated in the phase III registration study. Later, the EAP was expanded to include patients with previously treated pleural disease and peritoneal disease. Results from these separate cohorts have been detailed previously in other reports [15], [16]. This report focuses on the cohort from the EAP of patients with chemotherapy naïve pleural disease. While not as rigorous as a randomized trial, this EAP did provide the opportunity to collect additional tumor response, survival, and basic toxicity information for pemetrexed in large MPM populations.