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.1
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.
Currently, platinum-based chemotherapy plus etoposide remains the first-line standard of care, without a standard second-line option, Lu said.
Patients with NEC originating in the small intestine have a median 5-year survival rate of 26.3%, whereas the median survival is less than 10% for NECs originating elsewhere.
Surufatinib is a novel, oral, angio-immuno kinase inhibitor that selectively inhibits VEGFR1, VEGFR2, VEGFR3, FGFR1, and CSF-1R. Toripalimab is a novel monoclonal humanized antibody that is highly selective for the Kappa subtype of IgG4 and PD-1.
On July 1, 2021, the FDA accepted the filing of a new drug application for surufatinib as a potential therapeutic option for patients with pancreatic and extra-pancreatic NETs; the FDA is slated to decide on the application by April 30, 2022, under the Prescription Drug User Fee Act.2
Prior data demonstrated encouraging antitumor activity with the combination of surufatinib and toripalimab in patients with advanced tumors, including NETs and NECs.
The ongoing, multi-center, single-arm, phase 2 trial enrolled 21 patients with NEC from December 20, 2020, to June 15, 2021. Eligible patients were aged 18 to 75 years with pathologically or cytologically diagnosed advanced NEC. Patients had to have progressed on or been intolerant to prior first-line chemotherapy and have an ECOG performance status (PS) of 0 or 1.
Patients received 250 mg of oral surufatinib once daily plus 240 mg of intravenous toripalimab every 3 weeks until disease progression, unacceptable toxicity, death, or other provisions per protocol. Additionally, treatment with toripalimab was limited to a maximum of 24 months.
The primary end point of the study was investigator-assessed ORR. Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety and immunogenicity, and pharmacokinetic characteristics and efficacy-related biomarkers.
Patients were evaluated for efficacy every 6 weeks following the first dose of treatment for 48 weeks; efficacy was evaluated every 12 weeks thereafter. First complete response or PR needed to be confirmed after 4 weeks of treatment.
Patients were a median age of 60 years (range, 40-67); most patients were male (n = 15; 71.4%) and had an ECOG PS of 1 (n = 19; 90.5%).
Over half of patients (n = 11; 52.4%) had gastrointestinal tract primary lesions. Pathological types included mixed (n = 8; 38.1%), small cell (n = 5; 23.8%), large cell (n = 2; 9.5%), and unknown (n = 6; 33.3%). Liver metastases were present in most patients (n = 13; 61.9%).
One-third of patients (n = 7) had grade 3 tumors, whereas the remainder of patients’ tumor grade was unknown (n = 14; 66.7%). All but 1 patient (n = 20; 95.2%) had stage IV Tumor/Node/Metastasis Staging at screening.
All patients (100%) received prior first-line treatment per the eligibility criteria.
Most patients had a Ki67 index greater than 55% (n = 18; 85.7%) and a PD-L1 combined positive score (CPS) of 1 or greater but less than 10 (n = 13; 61.9%). Four patients each (19%) had a PD-L1 CPS of less than 1 and of 10 or greater but less than 50.
Additional efficacy data revealed that the DCR was 71.4% (95% CI, 47.82%-88.72%) with surufatinib/toripalimab. The median DOR was 4.11 months (95% CI, 2.99-not reached [NR]).
At a median follow-up of 11.07 months (95% CI, 9.46-12.06), the median PFS was 4.14 months (95% CI, 1.45-5.45), and the median OS was 10.32 months (95% CI, 0.07-NR).
The OS data are immature, noted Lu.
Regarding safety, all patients (n = 21; 100%) experienced any-grade treatment-emergent adverse effects (TEAEs) with surufatinib plus toripalimab. Of these, 42.9% of patients (n = 9) had grade 3 or higher TEAEs, and 14.3% of patients (n = 3) had serious TEAEs.
Any-grade treatment-related AEs (TRAEs) related to surufatinib were observed in 100% of patients (n = 21) and TRAEs related to toripalimab were observed in 95.2% of patients (n = 20). Of those related to surufatinib, 42.9% (n = 9) were grade 3 or higher and 4.8% (n = 1) were serious TRAEs. Of those related to toripalimab, 28.6% (n = 6) were grade 3 or higher and 4.8% (n = 1) were serious TRAEs.
One patient (4.8%) experienced a TEAE that led to death. No TEAEs led to treatment discontinuation. More than half of patients (n = 12; 57.1%) had TEAEs that led to treatment interruptions or dose reductions. Additionally, TRAEs that led to treatment interruptions or dose reductions were observed in 42.9% (n = 9) with surufatinib; TRAEs that led to treatment interruptions were observed in 14.3% of patients (n = 3) with toripalimab.
Grade 3 or higher surufatinib-related AEs included hyperglycemia (n = 3; 14.3%), hypertriglyceridemia (n = 2; 9.5%), hypertension (n = 2; 9.5%), upper abdominal pain (n = 1; 4.8%), decreased neutrophil count (n = 1; 4.8%), oral mucositis (n = 1; 4.8%), decreased white blood cell count (n = 1; 4.8%), diabetic ketosis (n = 1; 4.8%), back pain (n = 1; 4.8%), and anemia (n = 1; 4.8%).
Grade 3 or higher toripalimab-related AEs included hyperglycemia (n = 3; 14.3%), hypertension (n = 1; 4.8%), upper abdominal pain (n = 1; 4.8%), diabetic ketosis (n = 1; 4.8%), dermatitis (n = 1; 4.8%), back pain (n = 1; 4.8%), and anemia (n = 1; 4.8%).
The phase 2 trial is ongoing and will evaluate the combination in patients with other advanced solid tumors, such as biliary tract cancer, gastric cancer, thyroid cancer, small cell lung cancer, non–small cell lung cancer, soft tissue sarcoma, endometrial cancer, and esophageal squamous cell carcinoma.3
Patients with NEC who have progressed on or are intolerant to prior first-line chemotherapy are currently being recruited to a randomized phase 3 trial (NCT05015621), which is evaluating surufatinib plus toripalimab vs FOLFIRI chemotherapy.4
Additionally, on July 1, 2021, the FDA accepted the filing of a new drug application for surufatinib as a potential therapeutic option for patients with pancreatic and extra-pancreatic NETs; the FDA is slated to decide on the application by April 30, 2022, under the Prescription Drug User Fee Act.4