Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509

Our plain-English summary of Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509, by L.L. Garland, K. Chansky, A.J. Wozniak, et al (Journal of Thoracic Oncology, 2011).

The study

• Authors: L.L. Garland, K. Chansky, A.J. Wozniak, A.S. Tsao, S.M. Gadgeel, C.F. Verschraegen, M.A. Dasilva, M. Redman, D.R. Gandara
• Journal: Journal of Thoracic Oncology
• Published: 2011;6(11):1938-45
• Cited by: 74 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma (MPM) tumors express vascular epithelial growth factor (VEGF) and VEGF receptors. We conducted a phase II study of the oral pan-VEGF receptor tyrosine kinase inhibitor, cediranib, in patients with MPM after platinum-based systemic chemotherapy.

Methods: Patients with MPM previously treated with a platinum-containing chemotherapy regimen and a performance status 0 to 2 were eligible for enrollment. Cediranib 45 mg/d was administered until progression or unacceptable toxicity. The primary end point was response rate. Tumor measurements were made by RECIST criteria, with a subset analysis conducted using modified RECIST. A two-stage design with an early stopping rule based on response rate was used.

Results: Fifty-four patients were enrolled. Of 47 evaluable patients, 4 patients (9%) had objective responses, 16 patients (34%) had stable disease, 20 patients (43%) had disease progression, 2 patients (4%) had symptomatic deterioration, and 1 patient (2%) had early death. The most common toxicities were fatigue (64%), diarrhea (64%), and hypertension (70%); 91% of patients required a dose reduction. Median overall survival was 9.5 months, 1-year survival was 36%, and median progression-free survival was 2.6 months.

Conclusion: Cediranib monotherapy has modest single-agent activity in MPM after platinum-based therapy. However, some patient tumors were highly sensitive to cediranib. This study provides a rationale for further testing of cediranib plus chemotherapy in MPM and highlights the need to identify a predictive biomarker for cediranib.

In plain English

This phase II trial by the Southwest Oncology Group tested cediranib in people with malignant pleural mesothelioma previously treated with platinum-based chemotherapy. It did not study asbestos exposure. Patients took 45 mg of cediranib daily by mouth until disease worsened or side effects became unacceptable. From November 2005 to April 2008, 54 patients were registered and 47 were analyzed. Of the 47, four (9%) had partial tumor shrinkage and none had a complete response. Sixteen (34%) had stable disease and 20 (43%) had progressive disease. This fell short of the trial's preset 20% response rate of interest. Median overall survival was 9.5 months (95% confidence interval 5.6 to 10.7), 1-year survival was 36% (23 to 50%), and median progression-free survival was 2.56 months (1.74 to 3.68). The most common side effects were hypertension (70%), fatigue (64%) and diarrhea (64%). The dose was lowered in 43 of 47 patients, and there were no treatment-related deaths. The authors concluded that cediranib alone had modest activity, although a small subset of patients' tumors seemed highly sensitive to it.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-arm (uncontrolled) phase II clinical trial with a two-stage design and an early stopping rule; the primary end point was objective response rate
• Who was studied: Adults with unresectable malignant pleural mesothelioma (epithelioid, biphasic or not otherwise specified; no sarcomatoid cases enrolled) previously treated with one platinum-based chemotherapy regimen, at participating SWOG member sites, November 2005 to April 2008. Of 54 registered, 48 were eligible and 47 were analyzed (one refused treatment). Median age was 66.8 years; there were 38 men and 9 women.
• Exposure: Treatment with cediranib, an oral drug that blocks VEGF receptors, given alone at 45 mg daily. Dose reductions to 30 mg and 20 mg were allowed, and to 10 mg in some cases. Asbestos exposure was not studied.
• Main results:
  • No patient had a complete response. Four of 47 patients (9%) had partial responses, including two patients with bulky disease whose tumors shrank by 91% and 56%.
  • Of 47 patients, 16 (34%) had stable disease.
  • Of 47 patients, 20 (43%) had progressive disease, 2 (4%) had symptomatic deterioration and 1 (2%) died early.
  • The 9% response rate did not meet the prespecified 20% response rate of interest.
  • Among all 47 patients, median overall survival was 9.5 months (95% CI 5.6 to 10.7 months) and 1-year survival was 36% (95% CI 23 to 50%).
  • Median progression-free survival was 2.56 months (95% CI 1.74 to 3.68 months), and 1-year progression-free survival was 4% (95% CI 1 to 13%).
  • The most common non-blood side effects were fatigue, hypertension and diarrhea. Table 4 reports hypertension in 70%, fatigue in 64% and diarrhea in 64% of 47 patients.
  • The dose was lowered in 43 of 47 patients.
  • There were no treatment-related deaths. Six patients were removed from the study because of side effects attributed to cediranib.
  • In the 11 patients whose tumors were also measured by modified RECIST, the response assessment matched standard RECIST in every case.
• The authors' conclusion: The authors concluded that cediranib given alone had modest activity in pleural mesothelioma after platinum-based therapy. They also concluded that a small subset of patients had tumors that seemed highly driven by angiogenic signaling and therefore highly sensitive to the drug.
• Limitations the authors state:
  • The trial was uncontrolled. The usefulness of the clinical benefit rate from single-arm phase II studies is limited by the variable natural history of untreated mesothelioma.
  • Cediranib was not well tolerated at the 45 mg daily starting dose.
  • Mesothelioma is difficult to measure accurately. RECIST has documented limitations for assessing response and progression-free survival in this disease.
  • Modified RECIST measurements were collected for only a small subset of patients.
  • Tumor type was classified by local pathologists, without a central pathology review.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Tyrosine Kinase Inhibitor, Chemotherapy, Performance Status, Modified RECIST (mRECIST), Disease Progression, Median Overall Survival, Progression-Free Survival.

Related studies

• Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905) — A.S. Tsao, J. Moon, et al. (2017)
• Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium — N.P. Campbell, R. Kunnavakkam, et al. (2012)
• SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM) — S.H. Ou, J. Moon, et al. (2015)
• Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas — S. Kummar, M.E. Gutierrez, et al. (2013)
• A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma — A.K. Nowak, M.J. Millward, et al. (2012)
• Brief report: a phase II study of sunitinib in malignant pleural mesothelioma. the NCIC Clinical Trials Group — S.A. Laurie, A. Gupta, et al. (2011)

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