Irinotecan and Avastin and/or carboplatinfor GBM – pro

Lay Summary: Irinotecan and Avastin is a promising new combination for gliolastoma. Ongoing trials are expected to move if forward to the standard of care. Avastin alone is still experimental.

Glioblastoma is a disease for which there were few options available until recently. The past several years brought several new potentially promising treatments and one, Temodar, has been FDA approved for this indication. One of these promising approaches is Avastin and irinotecan. Stark-Vance recently reported that, among 21 patients with recurrent malignant glioma treated with bevacizumab plus irinotecan (Camptosar®; Pfizer Pharmaceuticals), one patient achieved a complete response, eight achieved partial responses, and 11 achieved stable disease. Overall, the regimen was reported as well tolerated, although two deaths occurred on treatment, including one patient with an intracranial hemorrhage and one patient with bowel perforation. A formal, single-arm phase II study of bevacizumab plus irinotecan is being performed at the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center for patients with recurrent malignant glioma. Preliminary analyses of results of this trial reveal that this regimen is well tolerated among malignant glioma patients and is associated with a highly exciting rate of radiographic response. Further investigation of the regimen of bevacizumab plus irinotecan is planned. Currently there are 11 sites nationally to participate in the pivotal clinical trial of bevacizumab and irinotecan (Avastin) in recurrent glioblastoma; this combination has been reported to shrink tumors in 63% of patients with recurrent glioblastoma in one small study.There are also other phase II trials combining Avastin with carboplatin, etoposide and other drugs. In late November 2007, Genetech announced preliminary results of its randomized phase II study with two arms, Avastin vs. Irinotecan/Avastin. The latter arm has a higher TTP and response rate. However, when updated at 2008 ASCO, the Avastin arm had survival of 9.2 months in a bevacizumab-alone group versus 8.7 months with irinotecan, The study is ongoing. There are no reported phase III trials or guideline recommendations for Avastin or Camptosar + Avastin. Avastin alone is in an ongoing phase II trial.

NCCN lists the combination with irinotecan and footnotes it to a 2007 phase II trial. Based on the NCCN recommendation, irinotecan/avastin should not be considered any longer to be investigational, even in the absence of phase III trials; however, because there are no phase III trials, individual insurers may be justified in rejecting NCCN recommendation.

Regarding Avastin alone:

Genentech, Inc. (NYSE: DNA) announced in November 2008 that the company submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) for Avastin® (bevacizumab) as a therapy for people with previously treated glioblastoma. If accepted by the FDA, the application would be considered for an accelerated approval that allows provisional approval of medicines for cancer or other life-threatening diseases based on preliminary evidence suggesting clinical benefit.

The Avastin application is based on a Phase II clinical trial (BRAIN) in previously treated glioblastoma that evaluated Avastin as a single agent or in combination with irinotecan chemotherapy. When Avastin was evaluated as a single agent, the study showed that at six months 43 percent of patients lived without their disease advancing, as defined by progression-free survival (PFS). In the study, 28 percent of patients responded to Avastin, meaning tumors decreased in size by at least 50 percent. Patients receiving Avastin had a median overall survival of 9.3 months, a secondary endpoint in the study. Most adverse events related to Avastin in this trial appeared to be similar to those previously reported in other Avastin studies. The most common severe (Grade 3 or greater) toxicities in the Avastin-only arm were hypertension (8 percent) and convulsion (6 percent). There were two deaths associated with adverse events in the Avastin-only arm. These data, along with those from the combined Avastin and irinotecan study arm, were presented earlier this year at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO).
NCCN has incorporated this regimen into its guideline.

WIth carboplatin: A 2012 study by Readon found that the addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naïve, recurrent GBM patients. ( number NCT00953121).

 Glioblastoma: Rationale and Potential Role of Targeted Agents The Oncologist, Vol. 11, No. 2, 152-164, February 2006

Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neurooncol 2005;7:369.

Cloughesy T, et al “A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM)” J Clin Oncol 26: 2008; May 20 suppl; Abstract 2010b., brain cancers, p.38

Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.

Olson JJ, Fadul CE, Brat DJ, et al. Management of newly diagnosed glioblastoma: guidelines, development, value and application. J Neurooncol. 2009;93:1-23.

Reardon DA, Desjardins A, Peters KB, Gururangan S, Sampson JH, McLendon RE, Herndon JE 2nd, Bulusu A, Threatt S, Friedman AH, Vredenburgh JJ, Friedman HS. Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma.J Neurooncol. 2012 Mar;107(1):155-64.

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