Pamela Kunz, MD, on Capecitabine-Temozolomide for Advanced Pancreatic NETs

Patients with advanced low- and intermediate-grade pancreatic neuroendocrine tumors (NETs) have few treatment options. Now, results from a randomized phase II trial show significantly improved progression-free survival (PFS) and a clinically meaningful improvement in overall survival (OS) with combined capecitabine-temozolomide compared with temozolomide alone.

Given the current treatment landscape for patients with progressive pancreatic NETs, this combination represents an important option for clinically meaningful tumor shrinkage, said Pamela L. Kunz, MD, of Smilow Cancer Hospital and Yale Cancer Center in New Haven, Connecticut, and colleagues. "These results suggest that the combination of capecitabine and temozolomide should be included as a standard treatment option for patients with advanced pancreatic NETs and is a reasonable comparator arm in future randomized studies."

As the team reported in the Journal of Clinical Oncology, the final analysis of data from the 133 predominantly white, male, non-Hispanic patients enrolled in the ECOG-ACRIN E2211 trial showed that median progression-free survival (PFS) was 23.2 months in the capecitabine-temozolomide arm, and 15.1 months in the temozolomide-only arm. The median follow-up was 59.9 months, and no new safety signals emerged.

There was a statistically significant difference in OS at the planned interim analysis, with a median OS of 38 months for patients treated with single-agent temozolomide and not reached for those in the combination arm. However, this trend did not reach statistical significance in the final analysis, which showed a median OS of 53.8 months in the temozolomide arm and 58.7 months in the capecitabine-temozolomide arm. Time from diagnosis was almost 9 months longer in the combination arm -- "which could have dampened the efficacy results in the combination arm," the authors said.

The response rate (RR) with capecitabine/temozolomide was 39.7% -- higher than that reported with other available therapies. This finding "sets temozolomide-based regimens apart from the others," the researchers said. Notably, response was significantly associated with deficiency in methylguanine methyltransferase (MGMT), a DNA-repair enzyme.

"MGMT deficiency may predict a higher likelihood of objective response to this regimen," the researchers said, noting that this is the first randomized trial to examine MGMT as a biomarker for temozolomide-based chemotherapy. "Although routine MGMT testing is not recommended, it can be considered for select patients in whom cytoreduction is a primary goal of treatment," the team advised.

In the following interview, Kunz, who is director of the Center for Gastrointestinal Cancers and chief of GI medical oncology, discussed the findings in greater detail.

What does this study add to the literature?

Kunz: It represents the first randomized clinical trial of temozolomide and capecitabine in advanced pancreatic NETs. The combination is associated with improved PFS compared with temozolomide alone and is associated with the longest PFS and highest RR reported in randomized trials of pancreatic NETs. For patients in need of tumor shrinkage, this treatment option meets a critical unmet need.

Did any of the findings come as a surprise?

Kunz: Our findings that the combination of temozolomide and capecitabine is more effective confirmed our hypothesis and reinforced findings from retrospective studies. However, I was surprised that temozolomide alone was also associated with a high response rate. This indicates that temozolomide can be considered for some patients who may not be able to tolerate the combination due to other medical comorbidities.

What are your thoughts on why the trend towards improved OS in the interim analysis did not reach statistical significance in the final analysis?

Kunz: A non-significant difference in OS is a very common outcome in NET clinical trials and is due to the indolent nature of the disease and the fact that patients go on to receive many subsequent therapies. In fact, this is one of the reasons that PFS is preferred as primary endpoint in NET clinical trials. Even though the difference is OS in the final analysis was not statistically significant, I believe it is clinically significant, with an absolute difference between the arms of 5 months.

How important is it to determine MGMT deficiency in patients with advanced pancreatic NETs?

Kunz: Although it was very exciting that we saw an association between MGMT deficiency and response, testing for MGMT deficiency is not yet recommended for routine use. MGMT testing may be considered in select patients when response is a primary goal of treatment. We hope to see future studies examining MGMT as a predictive biomarker.

Is the combination of capecitabine and temozolomide included as a standard treatment option for patients with advanced pancreatic NETs treated at your institution?

Kunz: Yes, capecitabine and temozolomide is included as a standard treatment option for patients with advanced pancreatic NETs at my institution. It is also included as an option in the NCCN [National Comprehensive Cancer Network] guidelines, which makes it widely available to most patients in the U.S.

What's next for this research?

Kunz: We plan to examine capecitabine and temozolomide in other indications and thus far have developed two new clinical trials through the National Clinical Trials Network.

One is a randomized phase II trial of postoperative adjuvant capecitabine and temozolomide versus observation in high-risk pancreatic NETs [SWOG 2104, NCT05040360], and the other is a phase II randomized trial of 177Lu-dotatate versus capecitabine and temozolomide in advanced well-differentiated pancreatic NETs [A022001, NCT05247905].

In addition, my team at Yale is examining sex as a biologic variable in patients with NETs -- specifically differences in side effects between male and female patients with pancreatic NETS receiving capecitabine and temozolomide.

Any other comments?

Kunz: The NCI's National Clinical Trials Network is a critical mechanism for conducting cancer clinical trials and often includes trials that answer practical, real-world questions that won't be answered by the pharmaceutical industry. ECOG-ACRIN 2211 is one such trial as capecitabine and temozolomide were both commercially available and off-patent at the time the study was conceived. I am grateful for the support from ECOG-ACRIN, the NCI, and the patients in doing this work.

Read the study here.