Well Differentiated Pancreatic Endocrine Tumor

The FDA on Monday released new draft guidance on conducting multi-regional oncology trials, saying its “paramount consideration” is whether the results apply to the intended use population and standard cancer care practices in the US. The draft’s release coincides with the European Society for Medical Oncology’s conference in Barcelona this week, and it comes more than two years after the FDA shut the door on companies only relying on data from China-based trials for new cancer drug approvals. Back in 2022, the regulator issued a complete response letter to Eli Lilly and Innovent’s sintilimab regarding its China-only data. The agency similarly rejected Hutchmed’s surufatinib, a kinase inhibitor that blocks VEGFR and FGFR, as a treatment of pancreatic and extrapancreatic neuroendocrine tumors, citing similar concerns. While the FDA’s new nine-page draft doesn’t specifically mention China, it notes that there has been a “decreasing proportion of US participants” in cancer drug trials. If a sponsor is planning a multi-regional trial to support a new drug approval, the FDA recommends “that such a trial be conducted across major geographical regions (e.g., across several continents) rather than predominantly in a single country or in a single geographical region (e.g., Asia).” The guidance said sponsors should be aware that if a trial’s participant demographics differ significantly from the US population, “foreign data may not be appropriate to support an FDA regulatory decision.” However, the agency also said there are some circumstances in which it may be acceptable for a sponsor to conduct a multi-regional trial. That includes enrolling “a substantial proportion of participants in a single foreign geographical region if such a trial is conducted as part of an overall program that includes one or more additional pivotal trials in the premarket setting that will enroll a population that is representative of the US population.” For trials of drugs intended to treat cancers that are common in the US like colorectal or breast cancer, the FDA recommends “equal allocation of study participants across the selected major geographical regions, including North America.” Equal allocation is defined as using equal numbers of subjects from each region. And for studies in cancers that occur “much less commonly in the US compared to regions outside the US (e.g., squamous cell esophageal cancer), FDA recommends a proportional allocation approach.” Proportional allocation is defined by the draft as the allocation of subjects to regions in proportion to the size of the region and disease prevalence. The FDA also said companies should take into account patient-related factors like disease risk and genetic background in addition to disease-related and socio-cultural factors, including diet, when deciding if a multi-regional trial is appropriate. Sponsors should request a meeting with the regulator if and when the treatment landscape changes during a trial to determine the most efficient approach to incorporating those changes into an ongoing trial.

BARCELONA — A new treatment option for a wide range of patients diagnosed with neuroendocrine tumors could be approved in April, as final results of a Phase 3 study on Exelixis’ cabozantinib were presented Monday at the ​​European Society for Medical Oncology. The CABINET study included two cohorts of people with neuroendocrine tumors depending on the tumor location — in the pancreas or outside of it. In 203 patients with extrapancreatic neuroendocrine tumors, cabozantinib lowered the risk of disease progression or death by 62% compared to placebo. In a smaller cohort of 95 patients with pancreatic tumors, Exelixis’ drug cut the risk of disease progression or death by 77%. The study had been stopped early at an interim analysis because of its compelling efficacy findings versus placebo. The trial investigators noted that the early termination of the study “could potentially lead to overestimation of the treatment effect,” though they added the progression-free survival analyses in both cohorts were “relatively mature,” according to a concurrent publication of the results in the New England Journal of Medicine . Exelixis markets cabozantinib as Cabometyx and Cometriq, and last year the company generated $1.8 billion in sales from the tyrosine kinase inhibitor. The drug is approved for kidney cancer, liver cancer and thyroid cancer, and is awaiting an FDA decision in neuroendocrine tumors by April 3 . Neuroendocrine tumors can occur anywhere in the body, meaning existing treatment options vary from patient to patient. Treatment options include somatostatin analogues like octreotide, everolimus, Novartis’ radiopharmaceutical Lutathera, chemotherapy, and the targeted therapy sunitinib — but what’s available to patients depends on their tumor. For example, Lutathera is approved for patients with a certain level of somatostatin receptor expression, while sunitinib is used in patients with pancreatic neuroendocrine tumors only. Gastrointestinal oncologist James Yao from the University of Texas MD Anderson Cancer Center told Endpoints News on the sidelines of the confab that for lung neuroendocrine tumor patients, this approval could be especially impactful because the only current go-to option for them is everolimus. Patients were enrolled in Exelixis’ study regardless of where their primary tumor was, though they were required to have tried at least one previous therapy. The median number of previous treatments was two or three across the study cohorts. “We were looking at a very broad group of patients … and we saw efficacy across the board,” Dana-Farber Cancer Institute neuroendocrine tumor specialist Jennifer Chan said. “This opens up options for a large number of patients. It’s not limited to just a small subset of patients.” Chan, the principal investigator on the study, spoke to Endpoints ahead of her Monday presentation. Yao noted that in China, the tyrosine kinase inhibitor surufatinib is approved for both pancreatic and extrapancreatic neuroendocrine tumors. The drug, developed by Hutchmed, was rejected in the US by the FDA in 2022 as its pivotal clinical trials were run in China. In Exelixis’ Phase 3 study, the median progression-free survival was 8.4 months on cabozantinib compared to 3.9 months on placebo in extrapancreatic tumors. In pancreatic neuroendocrine tumors, the median progression-free survival was 13.8 months compared to 4.4 months for placebo, with p<0.001 in both groups. Also, the response rate was 5% and 19% in extrapancreatic and pancreatic neuroendocrine tumors, respectively, versus 0% with placebo. The most common severe treatment-related adverse events were hypertension, fatigue, diarrhea, and thromboembolic events. Around two-thirds of patients in both the extrapancreatic and pancreatic groups on cabozantinib required dose reductions of the drug, and 31% and 20% of patients in the respective groups discontinued treatment due to adverse events. Exelixis’ medical chief Amy Peterson said that because cabozantinib is already approved in liver cancer, gastrointestinal oncologists are already familiar with the drug. They’re also familiar with the toxicities and dose reductions needed for sunitinib, which is also a VEGF tyrosine kinase inhibitor. In August, Exelixis announced that Cabometyx in combination with Tecentriq did not improve survival in a pivotal prostate cancer trial called CONTACT-02, details of which were shared at ESMO as well. Exelixis’ partner Ipsen, which has rights to Cabometyx outside of the US and Japan, announced Sunday that it does not plan to seek regulatory approvals based on the study. Exelixis confirmed to Endpoints that it still plans to file for approval based on the prostate cancer study this year.

MSD’s – known as Merck & Co in the US and Canada – Welireg (belzutifan) has been recommended with managed access by the National Institute for Health and Care Excellence (NICE) to treat a rare genetic disease that causes tumours in major organs. The take-at-home tablet will be available on the NHS in England and Wales to treat von Hippel-Lindau (VHL) disease in adults who require therapy for VHL-associated renal cell carcinomas, central nervous system haemangioblastomas or pancreatic neuroendocrine tumours, and for whom localised procedures are unsuitable or undesirable. Affecting approximately one in every 70,000 people, VHL disease occurs when a mutation in the VHL gene causes cells to grow abnormally. This can lead to cysts or tumours developing in different parts of the body, including the kidneys, brain and pancreas that can impair function or become cancerous. Until now, the only treatments available have been invasive surgery or radiotherapy, with patients usually requiring multiple surgeries throughout their lives. Benson Fayehun, head of oncology at MSD UK said: “VHL disease is a complex and devastating genetic condition, with patients often acting as carers for their family members, who may also have a VHL diagnosis. Until now, these patients have had few treatment options, typically limited to invasive procedures. “This decision provides a welcome option for patients, reducing the need for and impact of numerous surgeries.” Around 100 people could benefit from Welireg in the first year and approximately 50 people per year thereafter, according to NHS England. NICE’s final draft guidance on the drug, which was enabled by collaboration between NHS England and MSD to provide access through the Cancer Drugs Fund, was supported by clinical trial results showing that 95% of patients did not experience any growth in their tumours in two years of taking the treatment and 56% of patients’ tumours shrunk. However, the agency noted that there are “some uncertainties” and that more evidence is needed before Welireg can be considered for routine use on the NHS, so it has been recommended for use with further data collection. Helen Knight, director of medicines evaluation at NICE, said: “This is a new treatment that has the potential to prevent loss of organ function from repeated tumours and surgeries and improve people’s quality of life at a price that is good value for the taxpayer. We’re therefore pleased to be able to recommend it today while more evidence is collected.”