Antitumor activity of SS1P with pemetrexed and cisplatin for front-line treatment of pleural mesothelioma and utility of serum mesothelin as a marker of tumor response.

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7026 Background: SS1P is an immunotoxin targeting mesothelin, a tumor antigen highly expressed in malignant mesothelioma (MM). Preclinical studies showed marked synergy between SS1P and chemotherapy, leading to this frontline trial in pleural MM. Methods: Patients with no prior treatment, advanced disease, ECOG 0-2, and good organ function received pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 every 3 weeks for 6 cycles. SS1P dose escalation was: 25 µg/kg; 35 µg/kg; 45 µg/kg and 55 µg/kg on days 1, 3 and 5 of cycles 1 and 2. CT scans were performed every 2 cycles. Results: Nineteen patients (16 males, 3 females) have been treated, with median age of 68 y (51 to 78 y). One patient at 55 µg/kg had Grade 3 fatigue, considered dose-limiting. The maximum tolerated dose (MTD) of SS1P with chemotherapy was 45 µg/kg. Adverse events possibly or probably related to SS1P included Grade 3 hypoalbuminemia (n=6), pain (n=3), and hypotension (n=2); and Grade 2 hypoalbuminemia (n=11), fatigue (n=9), edema (n=6), hypotension (n=5), and pain (n=5). One patient died from neutropenic sepsis during cycle 1. Of the 14 evaluable patients treated at all dose levels, 7 had partial response (PR), 3 stable disease (SD) and 4 progressive disease (PD). Of 7 patients treated at MTD, 5 had PR, 1 SD and 1 PD. Of the 10 patients whose serum mesothelin levels were evaluated before and at completion of treatment all 5 patients with PR had significant decrease in serum mesothelin (63-83%). Two of 3 patients with PD had increased mesothelin levels (16%-34%), while 1 pt had a slight decrease (7%). Two patients with SD had discordant responses (17% increase and 60% decrease). Conclusions: SS1P with pemetrexed and cisplatin is well tolerated and results in significant anti-tumor activity with 5 PRs, and 1 SD among the 7 patients treated at MTD. Serum mesothelin responses correlate with the radiological response with all patients who obtained a PR having significant decrease in serum mesothelin levels.