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Expert Perspectives on Further Research Needed in NETs

Conference Correspondent 

A research working group was convened during the 3rd Annual International Summit of the Healing NET Foundation (HNF) to explore unmet needs in research, and approaches for meeting those needs. The working group developed a series of discussion questions to bring to all participants at the summit for their input. Unmet research needs identified included defining molecular subsets for well-differentiated grade 3 or poorly differentiated neuroendocrine tumors (NETs), and development of better therapies, including “re-differentiating” agents, immunomodulating therapy, and novel peptide receptor radionuclide therapy (PRRT) targets. In studying high-grade NETs, the working group stated that the following are necessary for patient selection, and no study should be done without them: next-generation sequencing, pooled serum biomarkers/multianalyte assays, and both fluorodeoxyglucose positron emission tomography (PET) and 68Ga-DOTATATE PET. PRRT could be improved by conducting “smart trials” that should consist of efforts to increase somatostatin receptor 2 (SSTR2) expression (histone deacetylase [HDAC] inhibitors, methyltransferase inhibitors, interferon, temozolomide), development of validated surrogate end points, assessing the role of an alpha-emitter linked to SSTR2 antagonist, the impact of immunomodulating agents plus lutetium Lu 177 dotatate (Lutathera), and the utility of novel radiosensitizing agents (eg, poly [ADP ribose] polymerase [PARP] inhibitors, hypoxia-targeted agents).

The first question posed to the summit attendees was, “In well-differentiated NET, PRRT is here. If there is only enough cash left for one more randomized clinical trial, what’s the next experimental arm to compare with Lu-177?” The audience response was divided among the following options: 54% suggested alpha-emitters, 0% somatostatin antagonists, 12% compounds that upregulate SSTR expression, 31% immunotherapy combinations, and 4% chromatin remodeling/DNA repair inhibitors (PARP inhibitors, HDAC inhibitors, etc). Thus, the consensus was clearly in favor of alpha-emitters and immunotherapy combinations as the highest priorities for the next clinical trial approaches for well-differentiated NETs. 

The second question posed was, “In an orphan disease, can a well-maintained and -funded database (ie, ENETS) answer the questions that we have traditionally relied on randomized clinical trials to answer for us?” Nearly three-quarters of the respondents replied, “Yes, of course. It’s time for real-world data to shine,” whereas only 29% said, “No, that data cannot be trusted unless it is in the context of a randomized clinical trial.”   

To make access to NET clinical trials easier, the working group suggested that an updated, curated, and searchable list of NET trials be constructed with industry support, and updated monthly from the National Cancer Institute and the pharmaceutical industry. Information about new trials could be disseminated through social media (a chat room to support navigation and eligibility) and/or a quarterly HNF e-newsletter with trial basics, highlighting new trials. To the question, “What is the best way for Healing NET to facilitate clinical trial participation,” respondents were evenly divided among all 5 choices: nurse navigation/phone liaison; online access to videos explaining clinical trials; create/maintain a searchable trials website for patients and providers; social media; and direct physician and/or patient engagement. The ensuing discussion showed that all these avenues were reasonable ways of increasing patient participation in NET clinical trials. Similarly, respondents were divided in their opinions on what HNF should be doing to impact clinical research, including creating a website for NET clinical trials, establishing a database of patients, creating 1-800-HEAL-NET for nurse navigators with clinical trials information, organizing meetings of NET experts to brainstorm trial concepts and forge collaborations, and directly funding research projects.

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