Pancreatic neuroendocrine tumours: Capecitabine plus temozolomide gives longer PFS than temozolomide alone

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Published: 6 Jun 2022
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Dr Pamela Kunz - Yale Cancer Center, New Haven, USA

Dr Pamela Kunz speaks to ecancer about a randomised study, E2211, of temozolomide vs temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumours.

The drug combo gave the longest progression-free survival rates and highest response rates that have been seen in any trial of this type for pancreatic NETs.

The phase II trial, which included 144 patients, showed 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.

E2211 is a randomised phase II study that is done through the ECOG-ACRIN National Clinical Trial Network. It was designed because there are not many agents that yield tumour shrinkage for patients with advanced pancreatic neuroendocrine tumours. The only cytotoxic chemotherapy that is approved for this disease is streptozocin, it’s an IV chemotherapy associated with a fair number of side effects, and temozolomide is an oral alkylating agent, so in the same class as streptozocin, and it has clear advantages over streptozocin, including fewer side effects, it can cross the blood-brain barrier, it’s oral, so it’s quite a bit more practical for patients.

Over the years preceding the development of this study there had been some small prospective and retrospective studies using capecitabine and temozolomide that suggested really high response rates. So we based this study on that. So it’s a study of capecitabine temozolomide versus temozolomide alone. We used temozolomide alone as the control arm because there was great interest, we figured both arms would actually provide us with really useful information because this was felt to be a really active agent.

The eligibility criteria were patients with low and intermediate grade advanced pancreatic neuroendocrine tumours. Patients were stratified by having had either prior everolimus, prior sunitinib, which are both FDA approved agents in the disease, or concurrent somatostatin analogue. They were randomised 1:1, there were 144 patients studied, so 72 on each arm, to either temozolomide as a single agent, that was dosed at 200mg/m2 days 1 through 5, so only five days out of a 28 day cycle, versus capecitabine and temozolomide together. So capecitabine was dosed at 750mg/m2 b.i.d. for two weeks and then the temozolomide came in at days 10 through 14 out of that two week period, also a 28 day cycle. Patients could receive a maximum of 13 cycles for the study and the primary endpoint was progression free survival by local review. Secondary endpoints were response rate, overall survival and toxicity. 

Then the other important thing that we reported out at this study were correlative analyses. So central path review we did after the study was completed and then looked at methylguanine methyltransferase, which is a DNA repair enzyme that in glioblastoma is a predictive marker for response to temozolomide. So we looked at that by two methodologies – immunohistochemistry and promoter methylation. 

We had previously presented the interim analysis data in 2018. So that data we met the primary endpoint of progression free survival. The capecitabine temozolomide combination arm had a longer PFS of about 22 months versus 14 months so it was about an 8 month absolute difference favouring the combination arm. The hazard ratio was 0.59 with a statistically significant p-value. What was updated was the overall survival. We found that there was no statistically significant difference in OS, likely due to the fact that the median OSs were in the 53-58 month time frame. So actually those are the longest median overall survivals reported in any prospective trial for advanced PNETs. There was a five month absolute difference so that’s a clinically meaningful difference but did not meet statistical significance.

This is a real challenge in neuroendocrine tumour studies for patients with grade1 or 2 low-grade neuroendocrine tumours. Likely it’s because patients go on to get many other therapies after they go off. So patients could get a year of treatment and they had an overall survival that extended to four or 4½ years.

The other data that we presented were on MGMT. We found that MGMT was associated with response. MGMT, this study was not designed to look at MGMT as a predictive biomarker because both arms contained temozolomide. So in GBM we know that it’s predictive of response to temozolomide, however, we had no non-temozolomide containing arm. But we did see that it was clearly associated with response by both methodologies, by both IHC and promoter methylation. But then when we looked at the patients that had both tests, so there were 55 patients that had both IHC and promoter methylation, we found that all of the patients who were promoter methylation positive were also IHC positive but the reverse was not true. So the large majority of patients were IHC positive. So what that likely indicates is that promoter methylation is probably not sufficient as a biomarker for pancreatic NETs and there are likely other mechanisms for downregulating MGMT other than just methylation.

So capecitabine temozolomide has really, since 2018, become more commonly used for advanced pancreatic NETs, it really belongs as a standard treatment in guidelines. It’s listed in some of the guidelines but this hopefully will strengthen that data. Then in terms of MGMT it is probably not recommended for routine use but for patients that need an objective response, that subset of patients we can consider doing MGMT testing. Then confirmatory testing is really needed in future studies. We already are seeing capecitabine temozolomide used as a comparator arm in a number of ongoing studies and we will have the opportunity, hopefully, to look at that and answer that question.