Addition of Cediranib to Cisplatin/Pemetrexed in Chemotherapy-Naive Unresectable Malignant Pleural Mesothelioma


Key Points

  • The addition of cediranib to platinum/pemetrexed produced a small benefit in progression-free survival.
  • Patients treated with cediranib experienced greater toxicity.  

In the phase II SWOG S0905 trial reported in the Journal of Clinical Oncology, Tsao et al found that the addition of the epidermal growth factor receptor and platelet-derived growth factor receptor inhibitor cediranib to cisplatin/pemetrexed was associated with limited benefit and greater toxicity in chemotherapy-naive patients with unresectable malignant pleural mesothelioma.

In the double-blind trial, 92 patients with disease of any histologic subtype were randomly assigned between October 2011 and February 2016 to receive cediranib at 20 mg/d (n = 45) or placebo (n = 47) plus six cycles of cisplatin (75 mg/m2) plus pemetrexed (500 mg/m2) every 3 weeks (carboplatin could be substituted for cisplatin in case of cisplatin intolerance) followed by maintenance cediranib or placebo.

The primary endpoint was progression-free survival on Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Analysis of the difference in progression-free survival was performed at a one-sided 10% level, with statistical significance defined as P < .10. Disease histology was epithelioid in 75% of patients and biphasic or sarcomatoid in 25%.

Progression-Free Survival

Median follow-up was 31 months in surviving patients. Median progression-free survival on RECIST v1.1 was 7.2 months in the cediranib group vs 5.6 months in the control group (hazard ratio [HR] = 0.71, 80% confidence interval = 0.54–0.95; P = .062). Overall response rates on RECIST v1.1 were 26% vs 15% (P = .15).

Median progression-free survival on modified RECIST criteria was 6.9 months vs 5.6 months (HR = 0.77; P = .12). Overall response rates on modified RECIST criteria were 50% vs 20% (P = .006). Median overall survival was 10 months vs 8.5 months (HR = 0.88; P = .28).

Adverse Events

Adverse events of any grade that occurred more frequently in the cediranib vs control group included anorexia (51% vs 38%), diarrhea (47% vs 17%), hypertension (44% v 15%), myelosuppression (44% vs 30%), peripheral neuropathy (20% vs 11%), and epistaxis (13% vs 0%). Grade 3 or 4 adverse events occurred in 69% vs 57% of patients, with hypertension (20% vs 0%), dehydration (9% vs 4%), weight loss (9% vs 0%), and diarrhea (4% vs 0%) being more common in the cediranib group.

There were two cases of sinus bradycardia and one case of supraventricular tachycardia in the cediranib group vs none in the control group. More patients in the cediranib vs control group switched from cisplatin to carboplatin (13% vs 4%), required dose reduction of cediranib vs placebo (13% vs 2%), and discontinued cediranib vs placebo due to toxicity (29% vs 17%).

The investigators concluded, “The addition of cediranib to platinum/pemetrexed improved [progression-free survival] by RECIST v1.1 and response rate by modified RECIST in patients with unresectable [malignant pleural mesothelioma]. Whereas adding antiangiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes additional development in [malignant pleural mesothelioma].”

Anne S. Tsao, MD, of the Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

