TKIs, New Targets Serve as Active Areas of Exploration in Pancreatic and Extrapancreatic NETs

Yoomi Lee, MD

Tyrosine kinase inhibitos (TKIS) such as sunitinib (Sutent) and, more recently, surufatinib, have demonstrated promising efficacy in patients with pancreatic and extrapancreatic neuroendocrine tumors (NETs), although a number of questions need to be addressed to optimize their benefit in these populations, according to Yoomi Lee, MD.

“[One] question that is really important to bring up in the context of the new data on surufatinib is the role of TKIs,” Lee said. “We know that sunitinib has been effective in [patients with] pancreatic NETs [and that] surufatinib is effective in [both] pancreatic NETs and extrapancreatic NETs. But [what is] the role of TKI therapy? What is the best TKI to use? Also, can we use other important targets, beyond the VEGF receptor, to really maximize [the benefits of] these treatments for patients?”

In the phase 3 SANET-ep trial (NCT02588170), patients with extrapancreatic NETs experienced a median progression-free survival (PFS) of 9.2 months with surufatinib vs 3.8 months with placebo.¹ Similarly, in the phase 3 SANET-p trial (NCT02589821), surufatinib elicited a median PFS benefit of 10.9 months vs 3.7 months with placebo in patients with pancreatic NETs.² Importantly, surufatinib is the first agent to demonstrate an improvement in PFS in patients who have extrapancreatic NETs, according to Lee.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Lee, a specialty care physician at Inova Medical Group, discussed the safety profile of surufatinib and highlighted future directions for patients with pancreatic and extrapancreatic NETs.

OncLive®: What is on the horizon for the treatment of gastroenteropancreatic NETs?

Lee: [One focus] has to do with the sequencing of treatments for these tumors, which is very important in a population who we expect to have a long life. In these patients, I always think of this as more of a marathon than a sprint. It is important to get as much mileage out of each treatment regimen as you can; take into account important adverse effects [AEs] and tolerability of these medications, and, obviously, prioritize quality of life [QOL]. The second question [has to do with developing a better understanding regarding] the role of TKIs.

What factors do you take into consideration when you are sequencing agents for this population?

The most important factors are individualized for the patient. For example, in someone who is younger and has a lower intermediate–grade NET, you want to get as much mileage out of the somatostatin analogue as you can. I personally try not to reach for peptide receptor radionuclide therapy [PRRT] too early in the course [of treatment] because we know that there is a 2% risk of [developing] myelodysplastic syndrome with PRRT. That is a major concern for young patients who we expect to have a long survival.

What evidence has read out to support the use of PRRT in these patients?

There has been a lot of clinical experience with PRRT, [which has] been available for the past 20 years. The phase 3 NETTER-1 trial [NCT01578239] was the first to look at PRRT in a systematic way. The PFS proved to be longer in patients who receive PRRT compared with high-dose octreotide [Sandostatin]. The data also indicate that there will be an overall survival benefit. Obviously, that is a significant advance in the treatment of these [patients].

PRRT was very well tolerated. The most common AEs were nausea and vomiting, which is related to the amino acid infusions that are given for renal protection. The other AEs [were] fatigue, abdominal pains, and asthenia. The most significant grade [3 or higher] AEs were neutropenia, thrombocytopenia, and lymphopenia. [These are] important toxicities to keep in to keep in mind for patients who have been heavily pretreated with chemotherapy or any other regimens that cause cytopenias.

You mentioned remaining questions regarding TKIs. Could you expand on the efficacy of surufatinib and how it relates to other available options in the paradigm?

In the SANET-p and the SANET-ep trials, surufatinib demonstrated an improvement in PFS in both pancreatic and extrapancreatic NETs. It is the first TKI to show PFS improvement in extrapancreatic NETs, so that is a significant advance in this patient population. The response rate in [patients with] pancreatic neuroendocrine tumors was 19%, which compares favorably with sunitinib. In the study that led to approval of sunitinib, the response rate was 9%. [As such], there is an indication that surufatinib may be even more effective than sunitinib.

Have the safety data reported with surufatinib differed from those of other TKIs?

The AEs with surufatinib have been pretty consistent with what we have seen with other TKIs, with hypertension, proteinuria, and hypertriglyceridemia being the most important grade 3 [or higher] AEs. Some lower-grade AEs that you typically associate with TKI therapy were also reported, such as diarrhea, nausea, fatigue, and abnormal liver function abnormalities. The only QOL score that was different between the surufatinib group and the placebo group was diarrhea.

Beyond surufatinib, what work is being done with TKIs?

In terms of TKI therapy, it is clear that VEGF is not the only target that is important. We know that sunitinib and surufatinib are effective in GEP-NETs. Some recent data presented at the 2021 Gastrointestinal Cancers Symposium suggested that axitinib [Inlyta] did not provide a PFS benefit. However, other TKIs are being evaluated in the space, such as cabozantinib [Cabometyx]. It will become clear which targets are most important in this particular patient population.

References

1. Xu Jianming, Shen L, Zhou Z, et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(11):1500-1512. doi:10.1016/S1470-2045(20)30496-4
2. Xu Jianming, Shen L, Bai C, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(11):1489-1499. doi:10.1016/S1470-2045(20)30493-9