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

Abstract

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 (RR) and long progression-free survival (PFS). Patients and Methods E2211 was a multicenter, randomized, phase II trial comparing temozolomide vs. capecitabine/temozolomide in patients with advanced low or intermediate grade pancreatic NETs. Key eligibility criteria included: progression within the preceding 12 months and no prior temozolomide, DTIC, capecitabine or 5-fluorouracil. The primary endpoint was PFS; secondary endpoints were overall survival (OS), RR, safety, and MGMT by immunohistochemistry (IHC) and promoter methylation. Results 144 patients were enrolled between 4/2013 to 3/2016 to temozolomide (n = 72) or capecitabine and temozolomide (n = 72); the primary analysis population included 133 eligible patients. At the scheduled interim analysis in 1/2018, median PFS was 14.4 months for temozolomide vs. 22.7 months for capecitabine/temozolomide (HR = 0.58), which was sufficient to reject the null hypothesis for the primary endpoint (stratified log rank p = 0.022). In the final analysis (5/2021), median OS was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (HR = 0.82, p = 0.42). MGMT deficiency was associated with response. Conclusion The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared to 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. NCT01824875.

Treatment Sequencing Strategies in Advanced Neuroendocrine Tumors: A Review

“…The designs, types of eligible patients, and endpoints assessed differed to varying extents across the nine randomized controlled studies ( Figure 2 ) [ 6 , 7 , 8 , 9 , 10 , 11 , 19 , 23 , 24 , 27 , 28 , 29 , 30 , 31 ]. PROMID was the only study of treatment-naïve patients, although only 16% of the CLARINET population had received prior treatment [ 7 ].…”

“…In contrast, NETTER-1 enrolled patients who had disease progression on first-line SSA therapy [ 11 ]. NETTER-1 ( 177 Lu-DOTATATE vs. high-dose octreotide LAR 60 mg every 4 weeks) [ 11 ] and ECOG E2211 (capecitabine plus temozolomide vs. temozolomide) [ 19 ] were the only trials to use an active comparator as a control. The primary efficacy endpoint was time to tumor progression in PROMID [ 6 ] and progression-free survival (PFS) in the other trials [ 7 , 8 , 9 , 10 , 11 , 19 , 23 , 24 ], where the former metric measured time to disease progression or tumor-related death, and the latter measured time to disease progression or death from any cause.…”

“…Seven of the nine trials showed a benefit in time to tumor progression (PROMID) [ 6 ] or PFS (CLARINET [ 7 ], SUNNET [ 8 ], RADIANT-3 [ 9 ], RADIANT-4 [ 10 ], NETTER-1 [ 11 ], and ECOG E2211 [ 19 ]) in favor of the interventional arm relative to the control arm ( Table 1 ).…”

“…Medline (via PubMed) was searched for articles indexed as randomized clinical trials and their associated secondary analyses, containing the following terms: octreotide long-acting release, lanreotide, everolimus, sunitinib, 177 Lu-DOTATATE, and cytotoxic chemotherapy. Included data pertain only to eight randomized, double-blind, controlled Phase III trials (PROMID [ 6 ], CLARINET [ 7 ], SUNNET [ 8 ], RADIANT-2 [ 23 ], RADIANT-3 [ 9 ], RADIANT-4 [ 10 ], NETTER-1 [ 11 ], and SPINET [ 24 ]) along with one randomized Phase II trial that has changed standard of care over the last 5 years (ECOG E2211) [ 19 ]. Streptozocin-based regimens [ 25 , 26 ] are not cited as preferred regimens in clinical guidelines and thus not reviewed herein.…”

“…SSAs are typically chosen as first-line systemic therapy owing to their antiproliferative effects, capacity to improve carcinoid syndrome, and favorable safety profile [ 5 , 6 , 7 , 15 ]. Potential second-line systemic treatment options depend on individual patient circumstances and include everolimus for pancreatic NETs (pNETs) and nonfunctional NETs of gastrointestinal or lung origin [ 5 , 9 , 10 , 16 ], sunitinib for pNETs [ 8 , 17 ], 177 Lu-DOTATATE for somatostatin receptor-positive gastroenteropancreatic NETs (GEP-NETs) [ 5 , 11 , 12 , 18 ], and capecitabine-temozolomide (CAPTEM) for certain GEP-NETs [ 19 ]. However, customizing the most appropriate treatment program does not always fall neatly into a straightforward linear choice of recommended first-line then later-line therapies [ 5 , 12 , 13 , 20 ].…”