At the North American Neuroendocrine Tumor Society (NANETS) 2024 Multidisciplinary NET Medical Symposium, several presenters focused on key questions for the field regarding the optimization of systemic therapies in the treatment of advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Following these presentations, featured expert Diane Reidy-Lagunes, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Reidy-Lagunes are presented here.

Fortunately, patients with GEP-NETs can often live for many years after diagnosis, and we want to be calculated about when we use each therapy. The dose, duration, efficacy, and side-effect profile of each treatment may be key considerations in optimizing therapy for individual patients. As more treatments are added to the landscape, I think that there is a need to be mindful of side effects that may be irreversible or that may preclude us from using the next line of therapy. There is a desire, for example, to preserve bone marrow function so that we can successfully provide additional treatment options to patients down the line.

To date, we have not had the kind of therapeutic sequencing trials in GEP-NETs that we often see in other cancers, but we are starting to make some progress. For example, we had a glimpse of this during the “NET Year in Review” presentation at the NANETS 2024 Multidisciplinary NET Medical Symposium by Jennifer Chan, MD, MPH, and in other discussions about cabozantinib, which is a multikinase inhibitor that we hope to have available soon. Cabozantinib was evaluated in the CABINET study, a trial that required at least 1 prior treatment other than SSAs (eg, everolimus and sunitinib). The progression-free survival (PFS) with cabozantinib vs placebo was improved in patients with pancreatic NETs (13.8 months) and in those with extra-pancreatic NETs (8.4 months). Patients in the trial received a 60-mg daily dose of cabozantinib, and there was a fairly high rate of adverse events reported, but I am optimistic that a lower dose may still be able to help our patients while mitigating some of the side effects.

Optimizing systemic therapy was a prominent theme at this year’s NANETS symposium overall. For example, PRRT is a critical tool that we often have to use, and, as noted in several discussions at the conference, both the NETTER-1 and the NETTER-2 trials found significant PFS benefits and hazard ratios in the PRRT treatment arms. However, patients need to have adequate blood counts to receive this therapy. Moreover, although rare, myelodysplasia and secondary malignancy are serious risks of PRRT. Additionally, temozolomide in the capecitabine-plus-temozolomide (CAPTEM) regimen is an alkylator, and we have long known that alkylators can increase the risk of myelodysplastic syndromes. Although the precise effect of prior therapies on the risk of myelodysplastic syndromes in patients after completing PRRT is unknown, there is a concern that prior temozolomide treatment could increase this risk. So, discussions are now ongoing about how best to include CAPTEM and other cytotoxic treatments in view of the bigger picture.

At the NANETS 2024 Multidisciplinary NET Medical Symposium, Shagufta Shaheen, MD, gave a presentation on the varying treatment schedules that have been used with CAPTEM during a session on optimizing dose and duration of systemic therapy. The ECOG-ACRIN Cancer Research Group E2211 study included patients with advanced low- or intermediate-grade pancreatic NETs. Based on this study, the standard duration of CAPTEM treatment is a maximum of 12 months, with a median of approximately 11 cycles. In clinical practice, there is substantial variability in duration of therapy. Dr Shaheen posed the question of whether maintenance CAPTEM should be considered. In my view, this might be considered in some patients when there is concern that stopping therapy will result in a loss of disease control (eg, in those with higher-grade tumors or a high disease burden). However, we do not have prospective data on this yet, and important questions remain, such as how long the patient would need to be on treatment. Dr Shaheen highlighted several additional points for consideration, such as the potential to adjust CAPTEM therapy after maximum response to reduce potential toxicity. She also raised the question of a tailored approach with CAPTEM to balance its efficacy and the risk of prolonged bone marrow exposure.

Other presenters at the NANETS symposium explored similar themes of optimizing therapy and of making the most of our existing options. For example, questions arise regarding when to reintroduce PRRT and whether to go back to the US Food and Drug Administration (FDA)–approved agent ¹⁷⁷Lu-dotatate or consider clinical trials. I think that all of us would highly encourage clinical trial enrollment, provided there is a match in terms of eligibility. If pursuing PRRT retreatment, Delphine Chen, MD, highlighted in her presentation at the NANETS 2024 Multidisciplinary NET Medical Symposium that patients must still have SSTR avidity greater than the liver, and that a 1-year PFS after initial PRRT seems to be a common threshold for considering repeat treatment. Retreatment with PRRT tends to result in a shorter PFS than with initial treatment, although 2 meta-analyses were cited during Dr Chen’s presentation showing encouraging PFS results in this population (ie, a PFS of just over 1 year with PRRT retreatment, which is pretty exciting).

Regarding the broader questions of dosing, scheduling, and duration of therapy, I would emphasize the value of simply looking at your patient and remembering the importance of both quantity and quality of life. When patients have completely asymptomatic disease that is stable, it is worth asking whether they can be monitored closely rather than starting a new treatment that will introduce new symptoms (ie, side effects). However, we need to continue to conduct the clinical studies that will allow us to tailor therapy with more certainty.