Surufatinib is a Potential New Option in Advanced Pancreatic NETs

The ESMO Virtual Congress 2020 is packed with an increasing number of clinical trials reported in endocrine and neuroendocrine tumours (NETs): promising results from a tyrosine-kinase inhibitor for pre-treated patients, novel peptide receptor radionuclide therapy strategies and latest data on immunotherapy

Results from the phase III Chinese SANET-P study, presented yesterday, revealed that the vascular endothelial growth factor receptor-, FGFR- and CSF-1R-targeting tyrosine kinase inhibitor (TKI), surufatinib, is the first of the new TKIs to show statistically significant benefit in pancreatic NETs (Abstract 1156O).

Earlier this year, a US phase I/II study presented at the American Society of Clinical Oncology (ASCO) annual meeting showed promising results of surufatinib in a cohort of US patients with GI and panNETs pre-treated with everolimus and/or sunitinib, by mirroring the results of the SANET-P Chinese population.

Surufatinib was shown to significantly improve progression-free survival (PFS) and response rate (RR) compared with placebo in the Chinese population, with a median PFS – the primary endpoint – of 10.9 months with surufatinib versus 3.7 months with placebo (hazard ratio 0.491; 95% confidence interval 0.319–0.755; p=0.0011). “The impact of surufatinib on PFS and RR was similar to that of sunitinib in its phase III regulatory trial. However, an important difference is that a proportion of patients in SANET-P had previously received everolimus, compared with none in the sunitinib trial,” comments Dr Nicola Fazio from the European Institute of Oncology (IEO), Milan, Italy. “SANET-P provides the first evidence in a phase III trial that a TKI is effective after progression on an mTOR inhibitor.”

In the study, the most common grade ≥3 treatment-emergent adverse events occurring in ≥5% in either arm for surufatinib and placebo, respectively, were hypertension (38.9% versus 8.5%) and proteinuria (9.7% versus 1.7%). “Although hypertension is a well-known, category-related adverse event, the rate of grade ≥3 events (39%) was not negligible,” adds Fazio. “The authors did not report the clinical implications of hypertension and its impact on study drug discontinuation, but they concluded that toxicity was clinically manageable, similarly to the US colleagues’ conclusion in their phase I-II study. Therefore, I do not believe this is a concrete reason to avoid this drug but, of course, it should be considered when selecting the right patients for surufatinib.” He continued: “There would also be a keen interest in studies of surufatinib in combination with other agents, such as checkpoint inhibitors”.

Neuroendocrine neoplasms (NENs) encompass a broad range of clinical and pathological properties, from poorly-differentiated neuroendocrine carcinomas (NECs) to well-differentiated NETs. Following decades of poor progress, with somatostatin analogues (SSAs), interferon and chemotherapy as the only options, recent years have seen the introduction of new treatments, including everolimus, the TKI sunitinib and peptide receptor radionuclide therapy (PRRT) for panNETs and everolimus and PRRT for gastrointestinal (GI) NETs. Additionally, two SSAs, octreotide long-acting repeatable (LAR) and lanreotide depot are now available for gastroenteropancreatic (GEP) NETs as antiproliferative agents. Options of treatment are more limited for lung carcinoids with everolimus as the only approved systemic therapy. For NECs, the standard treatment is platinum/etoposide-based chemotherapy. However other treatments can be utilised in clinical practice for advanced NETs, including surgical and non-surgical, locoregional procedures and some alkylating agent- or fluoropyrimidine-based chemotherapies. Due to these advances in treatment, the survival of patients, particularly those with distant GI and distant pancreatic NETs, has improved, but much more needs to be done. A clear unmet need is also to understand the role of immunotherapy in this setting.

Additional relevant data on potential new therapies were presented during yesterday’s Proffered Paper session on NETs, including results with PRRT involving the somatostatin antagonist 177Lu-satoreotide tetraxetan (Abstract 1160O) and those from the phase I/II ARROW trial of anti-RET pralsetinib in RET mutation-positive medullary thyroid cancer (Abstract 1913O). Findings from the DUNE trial of durvalumab plus tremelimumab in advanced GEP or lung neuroendocrine neoplasms were less encouraging (Abstract 1157O), softening the results of the DART trial of ipilimumab plus nivolumab in patients with rare tumours including NETs, in which tumour response was reported earlier this year.

Last but not least, the well-recognised challenge in NETs of adequate and timely diagnosis was again highlighted during the Congress. Results of a survey suggest that misdiagnosis is worryingly common and threatens to jeopardise the advances made in the research of new and more effective treatments (Abstract 1168P). Including 2,795 healthcare professionals, patients with NETs and their carers from 68 countries, the study reported that 44% of patients had been misdiagnosed. Overall, only one-third of patient cases were reviewed by a multidisciplinary team (MDT) in the previous 12 months, with even fewer patients being reviewed by an MDT in North America (29%) and Asia (22%). “Sadly, this survey reveals the reality for patients with NETs globally,” admitted Fazio. “Because of the rare and heterogeneous nature of NETs, the ideal approach for any patient is to have access to a NET-dedicated MDT. These findings should provide the impetus for scientific societies to work towards providing a dedicated MDT for every patient, regardless of their geographical location,” said Fazio.

“While on the one hand I believe that NET expertise should be focused in centralised sites, offering multimodal, high-level clinical and technical management, on the other hand, I would also like to see dispersal of knowledge from referral centres to community practices, so that misdiagnoses or delays in diagnoses are avoided, and appropriate therapeutic approaches are followed right from the start,” he concludes. “The best treatment is directly correlated to the accurate diagnosis and characterisation of the disease. Maximal clinical benefit for the patient depends in most cases on the global therapeutic strategy rather than a single therapy, thus the MDT and its co-ordination are arguably much more important than the expertise of a single specialist.”

Abstract and session details

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