Marianne E. Pavel, MD
Based on the final results of ECOG-ACRIN E2211, invited discussant Marianne E. Pavel, MD, of Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany, concluded: “Capecitabine/temozolomide is a preferred regimen…, but temozolomide can still be an option in patients who do not tolerate capecitabine.”
Putting the study into context with previous prospective randomized studies in pancreatic neuroendocrine tumors, Dr. Pavel noted that temozolomide with or without capecitabine has produced the best response rates and overall survival among evaluated therapies in patients with progressive pancreatic neuroendocrine tumors. Now, in ECOG-ACRIN E2211, capecitabine/temozolomide has resulted in “the best response rates, the most durable progression-free survival, and the best overall survival ever reported in this patient population,” she said.
Questions Remain
According to Dr. Pavel, several key questions remain: Is the combination superior to temozolomide monotherapy? Where should temozolomide-based chemotherapy be placed in the treatment algorithm? Should clinicians perform MGMT testing for treatment selection?
“If you look at the primary endpoint, yes, the combination is superior to monotherapy (median progression-free survival of 22.7 months vs 14.4 months)—but with a caveat. One significant prognostic factor, namely World Health Organization grade 1 vs 2 disease, was more favorable in the combination-therapy arm, and this might have impacted the outcome,” Dr. Pavel proposed. “Long-term prognosis is excellent for grade 1 neuroendocrine tumors, worse for grade 2, and very bad for the classic grade 3.”
Objective response rates did not significantly differ between the arms: 40% with the combination and 34% with the single agent. Median overall survival was “long” in both arms (> 53 months), so Dr. Pavel wondered what subsequent therapies the patients received. Certainly, the single agent was more tolerable.
Ongoing research may help to define the optimal care of these patients. One study of particular interest is comparing capecitabine/temozolomide to lutetium-177 dotatate, the radiolabeled somatostain analog approved for somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (ClinicalTrials.gov identifier NCT05247905). Meanwhile, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) indicate that capecitabine/temozolomide is the preferred option when tumor response is needed for symptoms or debulking. But given the very good results from the ECOG-ACRIN study, temozolomide and capecitabine should be an upfront treatment unless patients are candidates for somatostatin analogs, as exemplified by the ESMO treatment guidelines from 2020 for gastroenteropancreatic neuroendocrine neoplasms.
The Controversy Surrounding MGMT Status
“Should we look into MGMT [O(6)-methylguanine-DNA methyltransferase] status? This is a question we have been discussing for nearly 10 years, and it’s controversial because the data have been conflicting,” stated Dr. Pavel. “The study has now confirmed the association of response and MGMT deficiency, though it was not designed to test MGMT as a predictive biomarker, and so the question remains unanswered. Currently, we cannot recommend MGMT testing based on the data, but it can be a consideration for selected patients for whom response is a primary goal.”
Dr. Pavel concluded: “Capecitabine/temozolomide should be the preferred therapy in advanced pancreatic neuroendocrine tumors grade 2, in consideration of these very good results, also with respect to overall survival. This is also supported by a very good safety profile. Somatostatin analogs are the preferred therapy in somatostatin receptor–positive neuroendocrine tumors grade 1 or low grade 2 tumors with low-volume and/or stable disease.”
DISCLOSURE: Dr. Pavel reported financial relationships with Advanced Accelerator Applications, Boehringer Ingelheim, Hutchison MediPharma, Ipsen, Lilly, and Riemser.
