UPDATE 2nd May 2022.
US FDA did not approve.
Commentary from Healthcare New company Global Data.
“On 2 May, the US Food and Drug Administration (FDA) rejected HUTCHMED’s new drug application (NDA) for its lead candidate, Sulanda (surufatinib), for the treatment of advanced neuroendocrine tumours (NETs). Issues pertaining to trial populations were raised in a complete response letter (CRL) and GlobalData expects this case to have wide implications for the whole field of oncology therapeutics.
China-based HUTCHMED received approval for its multi-receptor tyrosine kinase inhibitor Sulanda in China for the treatment of pancreatic and extra-pancreatic NETs in June last year and December 2020, respectively. Following the submission to Chinese authorities, NDAs were also submitted to the FDA and European Medicines Agency (EMA). Two large Phase III studies formed the basis of these submissions, specifically the SANET-p and SANET-ep trials, both of which achieved their primary endpoint of improving progression-free survival (PFS) over placebo. As both of these trials were carried out in China, concerns about how well this data would translate to a Western population necessitated a bridging study. HUTCHMED went with open-label, Phase II trials as bridging studies, specifically the NCT04579679 trial in the EU and NCT02549937 trial in the US.
The FDA’s CRL cited inspection scheduling issues and the requirement of a multinational randomised trial with a more diverse population. It is likely that the rejection was also related to the lack of an active comparator, as in the US, several drugs are already approved and used as standard of care for the same patient populations. Eli Lilly and Innovent recently faced a similar setback when the FDA rejected their application for the marketing of Tyvyt (sintilimab) in non-small cell lung cancer based on data from Chinese populations. A precedent for FDA approval with China-only data does, however, exist; in November 2019, Beigene’s Brukinsa (zanubrutinib) received accelerated approval for relapsed/refractory mantle cell lymphoma based on the NCT03206970 Phase II trial, which took place exclusively in China.
GlobalData had projected Sulanda to reach $97m in US peak annual sales by 2030. This rejection by the FDA could mean a 3–5 year delay to marketing authorisation, or a lack of marketing authorisation altogether, should HUTCHMED decide that a new Phase III multinational trial is not worth the upside. The newfound FDA stringency concerning data from Asian populations will affect a multitude of late-stage pipeline drugs in oncology, and GlobalData expects the FDA to show leniency only in cancers of the highest unmet need. A large number of Chinese companies planned their strategy around a relatively easy US launch based on previous guidance by the FDA, and this news suggests that such a strategy should now be re-evaluated for future NDAs.”
Read more here
The following statement was made by the HutchMed CEO:
“Dr Weiguo Su, Chief Executive Officer and Chief Scientific Officer of HUTCHMED, commented: “Although this decision from the FDA is disappointing, we remain confident about the clinical value of surufatinib for NET patients and committed to making surufatinib available to patients globally. We look forward to working with the Agency to evaluate its feedback. Throughout the duration of the U.S. review process, we have been transparent and collaborative with the FDA. There are very few treatments approved and used in these rare diseases, and patients and physicians would benefit from more options to address the unmet medical need. We look forward to continued engagement with the FDA on developing a plan to bring surufatinib to patients in the U.S.”. Read more here
One question I would have is in regard to the Enhanced Access Program mentioned below. That might still be a way for patients to access this drug. I will update you when I know more.
What is Surufatinib?
Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects.
Update 17th November 2021. Interim findings from a phase 1 dose-escalation and dose-expansion study, which were presented during the 2021 NANETS Symposium, demonstrated antitumor activity with surufatinib in heavily pretreated, United States-based patients with progressive NETs. Moreover, the data were consistent with 2 completed phase 3 studies that were performed with surufatinib in Chinese patients with NETs. Read quick update here.
Update 13th November 2021 Figures in from a Phase II trial on solid tumours with emphasis on Neuroendocrine Carcinoma (i.e. high grade poorly differentiated). See below.
Update: July 1st 2021.
- Hutchmed announces that the FDA has accepted its filing of the New Drug Application (NDA) for surufatinib for the treatment of pancreatic and extra-pancreatic neuroendocrine tumors (NETs).
- The PDUFA goal date assigned by the FDA is April 30, 2022.
- The NDA is supported by data from two positive Phase III studies of surufatinib in patients with pancreatic and extra-pancreatic NET in China (SANET‑p and SANET‑ep), and a surufatinib study conducted in the U.S.
- The data package will also be used to file a Marketing Authorization Application to the EMA.
- HUTCHMED has initiated an Expanded Access Protocol in U.S. to ensure patients with NET with limited therapeutic options have access to this treatment.
- Recently, HCM’s surufatinib was OK’d in China for treatment of advanced pancreatic neuroendocrine tumors.
Read here to understand the expanded access protocol in US.
Expanded Access // HUTCHMED (hutch-med.com)
Expanded Access Program of Surufatinib – Full Text View – ClinicalTrials.gov
Update: December 30, 2020 – The China National Medical Products Administration has approved surufatinib for the treatment of patients with non-pancreatic neuroendocrine tumors. Read more here. In China, the drug is known as Sulanda.
An extremely interesting drug in the pipeline which has been featured at ENETS, NANETS, ESMO and ASCO.
– Company plans to complete rolling submission in the first half of 2021 –
– The pivotal Phase III SANET-ep trial demonstrated surufatinib reduced risk of progression or death by 67%, extending PFS of non-pancreatic NET patients with an acceptable risk/benefit ratio –
– The pivotal Phase III SANET-p trial demonstrated surufatinib reduced risk of progression or death by 51%, extending PFS of pancreatic NET patients with an acceptable risk/benefit ratio –
– First NDA submission by Chi-Med in the United States –
HONG KONG, SHANGHAI, China and FLORHAM PARK, N.J., Dec. 28, 2020 (GLOBE NEWSWIRE) — Hutchison China MediTech Limited (“Chi-Med”) (Nasdaq/AIM: HCM) today announces that it has initiated the filing of a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) – the first portion of a rolling submission for surufatinib for the treatment of pancreatic and non-pancreatic neuroendocrine tumors (“NET”). Chi-Med plans to complete the NDA submission in the first half of 2021, which would be the company’s first NDA in the U.S.
The Fast Track Designation granted earlier this year by the FDA permits the company to submit sections of the NDA on a rolling basis.
Additionally, Chi-Med has received advice from the European Medicines Agency’s (EMA) to submit a marketing authorization application (MAA).
PRESS RELEASE: LONDON, June 01, 2020 (GLOBE NEWSWIRE) — Hutchison China MediTech Limited (Chi-Med) today announces that it has held its pre-New Drug Application (NDA) meeting with the U.S. Food and Drug Administration (FDA) for surufatinib for the treatment of patients with advanced neuroendocrine tumors (“NET”). Chi-Med has reached an agreement with the FDA that the completed SANET-ep (non-pancreatic NET) and SANET-p (pancreatic NET) studies, along with existing data from surufatinib in U.S. non-pancreatic and pancreatic NET patients, could form the basis to support a U.S. NDA submission.
The FDA granted Fast Track Designation status to surufatinib for the non-pancreatic and pancreatic NET development programs in April 2020. Chi-Med has initiated preparatory work for the U.S. NDA and intends to utilize a rolling submission under Fast Track Designation Status. The rolling NDA allows completed portions of an NDA to be submitted and reviewed by the FDA on an ongoing basis. Filing acceptance of the NDA is subject to FDA review of the complete application. The planned start of the NDA submission is late 2020.
On 9th August 2020, Chi-Med announced that it received scientific advice from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) for surufatinib for the treatment of patients with advanced neuroendocrine tumors (NET). Based on the CHMP advice, we have concluded that the completed SANET-ep (non-pancreatic NET) and SANET-p (pancreatic NET) studies, along with existing data from surufatinib in U.S. non-pancreatic and pancreatic NET patients, could form the basis to support a marketing authorization application (MAA). Given that no filing issues were identified, the MAA submission is planned for 2021, following submission for the U.S. Food and Drug Administration (FDA) new drug application (NDA)
Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects.
Chi-Med currently retains all rights to surufatinib worldwide.
NET in the U.S., Europe and Japan: In the U.S., surufatinib was granted Fast Track Designations for development in pancreatic and non-pancreatic (extra-pancreatic) NET in April 2020, and Orphan Drug Designation for pancreatic NET in November 2019. A U.S. FDA NDA submission is being prepared. Regulatory interactions in Europe and Japan are also underway to confirm the clinical development strategy and potential path to registration. All such interactions are based on the robust data from the two positive Phase III studies of surufatinib in NET in China, and the ongoing multi-cohort Phase Ib study in the U.S. that began in November 2015 (clinicaltrials.gov identifier: NCT02549937).
Non-pancreatic neuroendocrine tumors in China: In November 2019, a NDA for surufatinib for the treatment of patients with advanced non-pancreatic NET was accepted for review by the China National Medical Products Administration (NMPA) and granted Priority Review status in December 2019. The NDA is supported by data from the successful SANET-ep study, a Phase III study of surufatinib in patients with advanced non-pancreatic neuroendocrine tumors in China for whom there is no effective therapy. A 198-patient interim analysis was conducted in June 2019, leading the Independent Data Monitoring Committee (IDMC) to determine that the study met the pre-defined primary endpoint of progression-free survival (PFS) and should be stopped early. The positive results of this trial were highlighted in an oral presentation at the 2019 European Society for Medical Oncology Congress (clinicaltrials.gov identifier:NCT02588170).
Pancreatic neuroendocrine tumors in China: In 2016, we initiated the SANET-p study, which is a pivotal Phase III study in patients with low- or intermediate-grade, advanced pancreatic NET in China. A second NDA for surufatinib for the treatment of patients with advanced pancreatic NET is being prepared for submission, following an interim analysis review conducted in January 2020 by the IDMC that recommended the registrational study be terminated early as the pre-defined primary endpoint of PFS had already been met (clinicaltrials.gov identifier: NCT02589821). Study results will be submitted for presentation at an upcoming scientific conference.
Biliary tract cancer in China: In March 2019, we initiated a Phase IIb/III study comparing surufatinib with capecitabine in patients with advanced biliary tract cancer whose disease progressed on first-line chemotherapy. The primary endpoint is overall survival (OS) (clinicaltrials.gov identifier NCT03873532).
Immunotherapy combinations: We have entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with anti-PD-1 monoclonal antibodies, including with tislelizumab (BGB-A317), Tuoyi® (toripalimab) and Tyvyt® (sintilimab), which are approved in China.
See below for more links to clinical trial info.
I first heard about this drug at ENETS Barcelona 2017 and then again in 2018. It’s now starting to be discussed in USA including at the 2019 ASCO and more recently in the 2019 ESMO conference. It was known then as Sulfatinib but for reasons unclear to me it was changed later to Surufatinib. It’s a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity (TKI) associated with vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies. Surufatinib, manufactured by Hutchinson China MediTech Ltd (Chi-Med), is in proof-of-concept clinical trials in the USA and several proof-of-concept and late-stage clinical trials in China.
If you’ve heard of VEGFR and TKI before, you may be thinking of a known NET drug called Sutent (Sutininib) which works in a similar fashion – although Surufatinib looks more thorough and complex in its method of operation. Interestingly, no anti-angiogenic treatment is yet approved for extrapancreatic neuroendocrine tumors (NETs). Extrapancreatic simply means outside the pancreas, i.e. anywhere except the pancreas. Worth noting for context, Sutent (Sutininib) is only approved for pNETs. This type of drug, along with something called mammalian Target Of Rapamycin (mTOR) inhibitor used in Everolimus (Afinitor) are collectively known as ‘Targeted Therapy’ – they are not a type of chemotherapy.
The Phase Ib/II Clinical Trial
In the single-arm phase Ib/II study of surufatinib in advanced NETs, clinicaltrials.gov identifier: NCT02267967, the following outcome was reported:
Experimental Design: Patients with histologically well-differentiated, low or intermittent grade, inoperable or metastatic NETs were enrolled into a pancreatic or extrapancreatic NETs cohort. Patients were treated with surufatinib 300 mg orally, once daily. The primary endpoints were safety and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (version 1.1). Results: Of the 81 patients enrolled, 42 had pancreatic NETs, and 39 had extrapancreatic NETs. Most patients had radiological progression within one year prior to enrollment (32 patients in each cohort). In the pancreatic and extrapancreatic NETs cohorts, ORRs were 19% (95% CI 9-34) and 15% (95% CI 6-31), disease control rates were 91% (95% CI 77-97) and 92% (95% CI 79-98), and median progression-free survival was 21.2 months (95% CI 15.9-24.8) and 13.4 months (95% CI 7.6-19.3), respectively. The most common grade ≥3 treatment-related adverse events were hypertension (33%), proteinuria (12%) hyperuricemia (10%), hypertriglyceridemia and diarrhea (6% for each), and increased alanine aminotransferase (5%). Conclusions: Surufatinib showed encouraging anti-tumor activity and manageable toxicities in patients with advanced NETs. Two ongoing phase III studies, validating the efficacy of surufatinib in patients with NETs, will contribute to the clinical evidence.
The Phase III Clinical Trial (non Pancreatic NETs)
SANET-ep is a Phase III study in China of surufatinib in patients with low- or intermediate-grade. SANET-ep is an acronym for “Surufatinib Advanced NET (ExtraPancreatic) aimed at patients for whom there is no effective therapy. ExtraPancreatic’ simply means outside the pancreas, i.e. anywhere except the pancreas.
In this study, patients are randomized at a 2:1 ratio to receive either 300 mg of surufatinib orally daily or placebo, on a 28-day treatment cycle. The primary endpoint of the study is to evaluate the progression free survival (PFS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DoR), overall survival (OS), safety, and tolerability. Additional details may be found at clinicaltrials.gov, using identifier NCT02588170.
London: Friday, June 14, 2019: Hutchison China MediTech Limited today announces that the independent Data Monitoring Committee (IDMC) of the Phase III pivotal study of SANET has completed a planned interim analysis. The IDMC determined that the study has already met the pre-defined primary endpoint of PFS and as a result the study will be stopped. (note: results detail awaited).
Chi-Med will now arrange for a pre-New Drug Application (NDA) meeting with the China National Medical Products Administration (NMPA) to discuss the preparation of the NDA for surufatinib for this indication. We intend to submit the results of the SANET-ep study for presentation at an upcoming scientific conference.
Any Trials for Pancreatic NETs?
In 2016, the manufacturer initiated the SANET-p study, which is a pivotal Phase III study in patients with low- or intermediate-grade, advanced pNETs. They expect an interim analysis in late 2019 and enrollment to complete in 2020 – clinicaltrials.gov identifier: NCT02589821.
Any Trials for other types of Neuroendocrine Neoplasm?
There’s one trial showing called “Study of Sulfatinib in Treating Advanced Medullary Thyroid Carcinoma and Iodine-refractory Differentiated Thyroid Carcinoma” – see NCT02614495
Any Trials for other cancers?
There’s another clinical trial of surufatinib in Biliary tract cancer in China: In March 2019, the manufacturer initiated a Phase IIb/III study comparing surufatinib with capecitabine in patients with advanced biliary tract cancer whose disease progressed on first-line chemotherapy. The primary endpoint is overall survival (OS) – see – NCT03873532
Any combo surufatinib with immunotherapy?
In November 2018, the manufacturer entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with checkpoint inhibitors. This included a global collaboration to evaluate the combination of surufatinib with Tuoyi®, a PD-1 monoclonal antibody approved in China in late 2018 by Shanghai Junshi Biosciences Co. Ltd. Check out this clinical trial entitled “Trial of Sulfatinib (sic) Combined With JS001 in the Treatment of Advanced Solid Tumors” – NCT03879057. As at 14th Jan 2020, they’re also recruiting for the phase 2 trial – click here.
Interest point – incidence of Neuroendocrine Tumours in China
Some of my research indicated that the manufacturer estimates there were approximately 67,600 newly diagnosed neuroendocrine patients in 2018 and, considering the U.S. incidence to prevalence ratio, potentially as many as 490,000 patients living with the disease. Authors note: Many specialists agree that the US figures are under-reported so the Chinese estimates are probably also under-reported and possibly have excluded Neuroendocrine Carcinomas from their figures. In fact, given the population of China compared to USA, the prevalence figure is more likely to be nearer one million and the annual incidence rate is likely to be closer to 90,000 (extrapolated and based on 2012 published figures of 23,000 annual incidence rates and a 171,321 prevalence figure). Read more about the incidence and prevalence of Neuroendocrine Neoplasms in my running article – Not as rare as you think.
Please note the above clinical trials documents do not list USA as a trial location but I have at least one person from USA in my closed Facebook group on one of the trials.
What about Neuroendocrine Carcinomas (poorly differentiated)
The combination of surufatinib and toripalimab demonstrated promising clinical activity with a manageable safety profile when used as second-line treatment for patients with advanced neuroendocrine carcinoma.
The combination of surufatinib and toripalimab demonstrated promising clinical activity with a manageable safety profile when used as second-line treatment for patients with advanced neuroendocrine carcinoma (NEC), according to findings from a phase 2 study (NCT04169672) that were presented during the 2021 North American Neuroendocrine Tumor (NET) Society (NANETS) Multidisciplinary NET Medical Virtual Symposium.
Among 21 evaluable patients, the confirmed investigator-assessed overall response rate (ORR) was 23.8% (95% CI, 8.22%-47.17%) with the combination and was comprised of all partial responses (PRs; n = 5). Additionally, 47.6% of patients (n = 10) had stable disease. Six patients (28.6%) had progressive disease.
Patients with NEC have limited treatment options to reduce their poor prognosis, explained lead study author Ming Lu, of the Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, in Beijing, China, in a virtual presentation of the data.
General Clinical Trials Disclaimer
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided in the clinical trials document. It’s very important to check the trial inclusion and exclusion criteria before making any contact. If you need questions, the articles here is very useful Questions to Ask About Clinical Trials | Cancer.Net
The inclusion of any trial within this blog should not be taken as a recommendation by Ronny Allan.
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