Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211)

Author(s): Pamela L. Kunz, MD¹;Noah T. Graham, MS²;Paul J. Catalano, ScD²;Halla S. Nimeiri, MD³;George A. Fisher, MD, PhD⁴;Teri A. Longacre, MD⁴;Carlos J. Suarez, MD⁴;Brock A. Martin, MD⁵;James C. Yao, MD⁶;Matthew H. Kulke, MD⁷;Andrew E. Hendifar, MD⁸;James C. Shanks, MD⁹;Manisha H. Shah, MD¹⁰;Mark M. Zalupski, MD¹¹;Edmond L. Schmulbach, MD¹²;Diane L. Reidy-Lagunes, MD¹³;Jonathan R. Strosberg, MD¹⁴;Peter J. O’Dwyer, MD¹⁵;and Al B. Benson III, MD³

Source: DOI: 10.1200/JCO.22.01013 Journal of Clinical Oncology 41, no. 7 (March 01, 2023) 1359-1369.

Dr. Anjan Patel's Thoughts

Positive study for the combo of TMZ + cape vs. TMZ alone in met-pNET, confirming a regimen that is already widely used. Patients were first-line, and those with MGMT-def had a better response.

PURPOSE

Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies suggest that capecitabine and temozolomide are associated with high response rates (RRs) and long progression-free survival (PFS).

PATIENTS AND METHODS

E2211 was a multicenter, randomized, phase II trial comparing temozolomide versus capecitabine/temozolomide in patients with advanced low-grade or intermediate-grade pancreatic NETs. Key eligibility criteria included progression within the preceding 12 months and no prior temozolomide, dimethyl-triazeno-imidazole-carboxamide or dacarbazine, capecitabine or fluorouracil. The primary end point was PFS; secondary endpoints were overall survival, RR, safety, and methylguanine methyltransferase (MGMT) by immunohistochemistry and promoter methylation.

RESULTS

A total of 144 patients were enrolled between April 2013 and March 2016 to temozolomide (n = 72) or capecitabine and temozolomide (n = 72); the primary analysis population included 133 eligible patients. At the scheduled interim analysis in January 2018, the median PFS was 14.4 months for temozolomide versus 22.7 months for capecitabine/temozolomide (hazard ratio = 0.58), which was sufficient to reject the null hypothesis for the primary end point (stratified log-rank P = .022). In the final analysis (May 2021), the median overall survival was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (hazard ratio = 0.82, P = .42). MGMT deficiency was associated with response.

CONCLUSION

The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared with temozolomide alone in patients with advanced pancreatic NETs. The median PFS and RR observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic NETs. MGMT deficiency was associated with response, and although routine MGMT testing is not recommended, it can be considered for select patients in need of objective response (ClinicalTrials.gov identifier: NCT01824875).

Author Affiliations

¹Yale School of Medicine, New Haven, CT;²Dana-Farber Cancer Institute, Boston, MA;³Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL;⁴Stanford University School of Medicine, Stanford, CA;⁵University of Louisville, Louisville, KY;⁶University of Texas MD Anderson Cancer Center, Houston, TX;⁷Boston University/Boston Medical Center, Boston, MA;⁸Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA;⁹Health East Cancer Care, Lake Elmo, MN;¹⁰The Ohio State University Comprehensive Cancer Center, Columbus, OH;¹¹University of Michigan, Ann Arbor, MI;¹²The Permanente Medical Group, South San Francisco, CA;¹³Weill Cornell Medical College, New York, NY;¹⁴H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL;¹⁵University of Pennsylvania Abramson Cancer Center, Philadelphia, PA

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