Novel Drug Combination Demonstrates Promising Results in Treating Pancreatic Neuroendocrine Tumors

Very few treatment options are available to patients with advanced pancreatic neuroendocrine tumors (NETs), but researchers at the Yale Cancer Center and Yale New Haven Health’s Smilow Cancer Hospital found that patients treated with a combination of capecitabine and temozolomide had longer progression-free survival rates than those treated with temozolomide alone.[1]

The findings were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held from June 3-7, 2022 in Chicago, Il, and are based on the results of a multicenter, randomized, phase II trial comparing temozolomide (200 mg/m2 PO QD days 1-5) vs. capecitabine/temozolomide (capecitabine 750 mg/m2 PO BID days 1-14; temozolomide 200 mg/m2 PO QD days 10-14) in patients with advanced pancreatic NETs. [1]

Pancreatic Neuroendocrine Tumors
Advanced pancreatic neuroendocrine tumors (NETs), also known as Islet Cell Tumors, are rare tumors with about 1,000 new cases per year in the United States. [2] The disease, which accounts for less than 2% of pancreatic malignancies, has an overall better prognosis than the more common pancreatic exocrine tumors. [2][3]

The diagnosis of these tumors is difficult and requires a careful history and examination combined with laboratory tests and radiologic imaging.

Combination treartment
This combination of drugs yielded the longest progression-free survival rates and highest response rates that have been seen in any study of this type for patients with pancreatic NETs,” said Pamela Kunz, associate professor of internal medicine (medical oncology) at Yale School of Medicine, director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center, and principal investigator of the clinical trial.

The trial, which included 144 patients, was a randomized, phase 2 clinical trial comparing the effects of temozolomide alone (n = 72) with those of temozolomide in combination with capecitabine (n = 72).

The primary endpoint of the study was Progression Free Survival (PFS); secondary endpoints were Overall Survival (OS), RR, safety, and MGMT as evaluated by immunohistochemistry (IHC) and promoter methylation.

The efficacy analysis showed a median PFS of 14.4 months for temozolomide vs. 22.7 months for capecitabine/temozolomide (HR = 0.58), which was sufficient to reject the null hypothesis for this final primary endpoint (stratified log rank p = 0.022. In the final analysis, median OS was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (HR = 0.82, p = 0.42) and the response rate (RR) was 34% for temozolomide and 40% for capecitabine/temozolomide (p = 0.59).

Overall, the study demonstrated that the combination of capecitabine and temozolomide produced longer progression-free survival rates, higher response rates, and longer overall survival rates than temozolomide alone.

In addition, deficiency of the DNA repair enzyme methylguanine methyltransferase (MGMT) in the tumor tissue, was found to be associated with increased responses.

Adverse events
Capecitabine/temozolomide was associated with higher rates of grade 3-4 AEs (45% vs. 22%, p = 0.005). MGMT deficiency, defined as either low IHC or positive promoter methylation, was associated with greater odds of response (OR [95% CI] = 6.38 [2.19, 18.60] and 9.79 [1.09, 87.71], respectively).

“This clinical trial is practice-changing and the combination of capecitabine and temozolomide should be included as a standard treatment option for patients with advanced pancreatic NETs,” Kunz noted.

“In addition, MGMT testing can be considered for select patients receiving temozolomide for whom response is a primary goal of treatment. However, testing is not recommended for routine use as confirmatory studies are needed.”

The findings are part of the ECOG-ACRIN E2211 trial, conducted through the National Cancer Institute and the National Clinical Trial Network.

Clinical trial
Temozolomide With or Without Capecitabine in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors – NCT01824875

Highlights of Prescribing Information
Capecitabine (Xeloda; Genentech/Roche)(Prescribing Information)
Temozolomide (Temodar®; Merck & Co) (Prescribing Information)

Reference
[1] Kunz PL, Graham N, Catalano PJ, Nimeiri H, Fisher GA, Longacre TA, Suarez CJ, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: Final analysis of efficacy and association with MGMT (ECOG-ACRIN E2211). J Clin Oncol 40, 2022 (suppl 16; abstr 4004) | DOI:
10.1200/JCO.2022.40.16_suppl.4004
[2] Davies K, Conlon KC. Neuroendocrine tumors of the pancreas. Curr Gastroenterol Rep. 2009 Apr;11(2):119-27. doi: 10.1007/s11894-009-0019-1. PMID: 19281699.
[3] Phan GQ, Yeo CJ, Hruban RH, Littemoe KD, Pitt HA, Cameron JL. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: Review of 125 patients. J Gastrointest Surg. 1998 Sep-Oct;2(5):473-82. doi: 10.1016/S1091-255X(98)80039-5. PMID: 18335273.

Featured image: Annual Meeting (2017)  of the American Society of Clinical Oncology at McCormick Place in Chicago, Ill. Photo courtesy: © 2017 – 2022, ASCO. Used with permission.