Rationale and design of a multicenter, randomized phase II trial of durvalumab with or without multitarget tyrosine kinase inhibitor as maintenance treatment in extensive‐stage small‐cell lung cancer patients (DURABLE study)

Abstract Introduction Durvalumab is a check‐point inhibitor against programmed death ligand‐1 (PD‐L1), and anlotinib is a new orally administered multitarget tyrosine kinase inhibitor (TKI). Both agents have been approved in China. Preclinical and clinical trials have suggested that antiangiogenic therapy has the potential to alleviate immunosuppression and showed synergetic effect when combined with ICIs. However, it is unclear that whether this combination is effective when initiated as maintenance treatment in ES‐SCLC patients. Methods This is a multicenter, randomized, phase II study. A total of 64 eligible patients who do not experience disease progression after four cycles platinum‐based chemotherapy combined with durvalumab will be randomized to durvalumab with anlotinib or durvalumab alone until disease progression, withdrawal of consent, or unacceptable toxicity. The primary endpoint is PFS (from randomization); secondary endpoint was OS and PFS (from diagnosis), objective response rate (ORR); disease control rate (DCR) and duration of response (DOR), safety and tolerability assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Discussion We conduct a phase II study to investigate the safety and efficacy of durvalumab combined with anlotinib as maintenance treatment in ES‐SCLC patients.


| INTRODUCTION
Lung cancer has been the most common cancer in the world for several decades, accounting for 11.6% of the total new cases in 2018, and was also the leading cause of cancer-related death (18.4% of the total cancer deaths). 1 Small-cell lung cancer (SCLC) represents approximately 13%-15% of all newly diagnosed lung cancers. 2 SCLC is characterized by a highly aggressive disease with its rapid doubling time, high growth fraction and early metastasis. 2 The prognosis of extensive-stage small cell lung cancer (ES-SCLC) is very poor.The median OS was 7 months, and only less than 7% of patients remain alive at 5 years after diagnosis. 3our to six cycles of platinum-based chemotherapy have been the standard care for patients with ES-SCLC for the past 25 years. 4,5Until the advent of check-point inhibitors (ICIs), immunotherapy has been integrated into the clinical management of these patients.CASPIAN study suggested that the addition of durvalumab to firstline chemotherapy resulted in significantly longer overall survival (OS) than chemotherapy alone. 6The updated results of this study sustained OS improvement versus platinum-etoposide. 7In addition, IMpower-133 study also demonstrates that chemotherapy combined with another programmed death ligand-1 (PD-L1) inhibitorsatezolizumab, can confer survival benefit. 8,9nti-angiogenesis agents are important treatment strategy in non-small cell lung cancer when initiated as first-line or maintenance treatment. 10,11But series clinical trials have demonstrated that bevacizumab 12,13 and other anti-angiogenesis treatment including rhendostatin, 14 sunitinib 15 and pazopanib 16 failed to show survival benefit in SCLC patients.In addition, maintenance treatment with nivolumab plus ipilimumab did not prolong OS in these patients. 17Thus, consolidating maintenance therapy represents a largely unmet need.
Anlotinib (AL3818) is a new orally administered tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR) and c-kit. 18In a randomized, phase II trial, anlotinib showed longer PFS (4.1 vs. 0.7 m hazard ratio [HR] 0.19, p < 0.0001) and OS (7.3 vs. 4.9 m; HR = 0.53, p = 0.0029) compared with placebo when administered as third-or further-line treatment, thus has been approved as standard treatment in these patients. 19oth preclinical and clinical trials have suggested that antiangiogenic therapy has the potential to alleviate immunosuppression via inhibiting Treg differentiation and promoting the maturation of dendritic cells, thus showing synergetic effect. 20,21Based on these results, we proposed our hypothesis that durvalumab combined with anlotinib may serve as a potential maintenance treatment in ES-SCLC patients (Durvalumab Combined with Anlotinib as Maintenance Treatment In Extensive Stage Small Lung Cancer Patients (DURABLE)).

| Study design
This is an open-label, randomized, multicenter, phase II study.Eligible patients will be treated with durvalumab combined with up to four cycles of etoposide and platinum-based chemotherapy (EP/EC).Patients who complete the four cycles of durvalumab plus EP/EC treatment and do not have progressive diseases (non-PD patients) will be randomized in a 1:1 ratio to receive maintenance treatment durvalumab with anlotinib (Arm 1) or durvalumab alone (Arm 2) until confirmed PD, unacceptable toxicity or withdraw of written consent.Prophylactic cranial irradiation (PCI) is allowed at the investigators' discretion (Figure 1).Patients will attend a safety follow-up visit 90 days after the last dose of durvalumab.The first eligible patient has been recruited at the end of September 2021.This study has been registered with clinicaltrial.gov, and the registration number is NCT04985851.The study was conducted in accordance with the Declaration of Helsinki.The study protocol and informed consent documents were approved by the ethical committees of Shanghai Chest Hospital (IS2150).Written informed consent is obtained from all participants.

| Research point
The primary endpoint of the study was to assess the efficacy of durvalumab with anlotinib as maintenance therapy in terms of median progression-free survival (PFS, from randomization); secondary endpoint was OS and PFS (from diagnosis), objective response rate (ORR); disease control rate (DCR) and duration of response (DOR), safety and tolerability assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.The exploratory endpoint of the study was to investigate potential biomarker based on peripheral blood and tumour tissue.

| Inclusion criteria
Only patients who meet all of the following criteria will be enrolled in this study: • absolute neutrophil count ≥1.5 Â 10 9 /L, platelet count ≥100 Â 10 9 /L, haemoglobin ≥9.0 g/dL (no blood transfusion or no erythropoietin dependence within 7 days before enrollment); • biochemical test results should meet the following criteria: serum bilirubin ≤1.5 times the upper limit of normal value (ULN); ALT and AST ≤2.5 Â ULN; in case of liver metastases, ALT and AST ≤5 Â ULN; creatinine clearance (CCr) >60 mL/min for patients on cisplatin and >45 mL/min for patients on carboplatin, as determined by Cockcroft-Gault (using actual body weight).
13. international normalized ratio (INR) and prothrombin time (PT) ≤1.5 times ULN for patients not receiving therapeutic anticoagulation; 14. women of child-bearing age should agree to take contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study and within 6 months after the study; nonbreast-feeding patients whose serum or urinary pregnancy test should be negative; male patients should agree to take contraceptive measures during the study and within 6 months after the study; and 15. patients are voluntarily enrolled into the study, sign the informed consent form and have good compliance.

| Exclusion criteria
Patients who meet any of the following criteria will be excluded: 1. patients who were diagnosed with mix SCLC or limited stage SCLC; 23. patients who are the subjects or their sexual partners cannot or refuse to take effective contraceptive measures during the clinical trial; 24.patients who are pregnant or breast-feeding women; and 25. patients in other situations who are evaluated by the investigator to be ineligible to be enrolled.

| Randomization
Non-PD patients who completed four cycles of durvalumab with chemotherapy will be randomized into maintenance phase.Once the patient is confirmed to be eligible to enter maintenance phase, the investigator or suitably trained delegate will obtain a unique randomization number via the interactive voice response system or interactive web response system (IVRS/IWRS).The system will randomize the eligible patient to one of the two treatment arms.

| Treatment, dose and assessment
Durvalumab 1500 mg will be administered for all patients concurrently with chemotherapy every 3 weeks, starting on Week 0 for four cycles.Non-PD patients who completed the four cycles of the combination treatment will be randomized 1:1 into Arm 1 or Arm 2. Eligible patients should begin continuous treatment in 3 days after randomization.In Arm 1, durvalumab 1500 mg monotherapy will be continued every 4 weeks.Anlotinib will be orally administered 12 mg once a day, 14 days-on and 7 days-off.Anlotinib is available at three dose levels, 12, 10 and 8 mg.Patients in Arm 2 will be treated with durvalumab monotherapy.Dose reduction may take place whenever toxicity is not controlled with optimal supportive care during the study.If a subject subsequently tolerates treatment well at that level in the judgement of the investigator, the dose may be increased to the next dose level.If a subject cannot tolerate treatment after dose reduction to 8 mg, treatment will be discontinued.Efficacy assessment will be performed every 6-8 weeks.After discontinuation of study treatment, patients will continue to be followed for survival via phone calls or email every 3 months to study end.The survival status (including cause of death) and the date of death or last follow-up date will be collected.

| Rationale for setting the number of enrolled participants
The study will randomize approximately 64 eligible patients 1:1 to durvalumab with anlotinib and durvalumab monotherapy group.The primary analysis of PFS (from randomization) will occur when approximately 50 progression events have been observed in the 64 randomized patients.If the true PFS HR for the comparison of durvalumab plus anlotinib versus durvalumab is 0.6 (5 vs. 3 m), 50 progression events will provide 70% power to demonstrate a statistically significant difference in PFS at a 20% two-sided significance level.And assuming about 20% patients will experience disease progression in the first four cycles treatment (from CASPIAN) and 5% patients will lose of follow-up, the overall sample size is 80.

| Population to be analysed
Efficacy will be analysed based on the intention-to-treat (ITT) population and per-protocol set (PPS).Safety will be analysed based on safety analysis set (SAS).
ITT: all randomly assigned patients.PPS: all the participants in the ITT except patients with violation of inclusion/exclusion criteria or violation for prohibited concomitant drugs/therapies.SAS: patients who received at least one dose of study drugs.

| Statistical methods
Baseline characteristics, incidence and severity of adverse events will be summarized.The number and percent of subjects achieving objective responses (CR or PR) will be summarized along with corresponding two-sided 95% CI using binomial distribution.Median PFS and OS will be calculated based on the Kaplan-Meier method and compared by log-rank test.Cox proportional hazard regression model will be used to identify independent prognostic factors.

| DISCUSSION
The advent and administration of ICIs have revolutionized the first-line treatment in ES-SCLC patients. 6,8espite the ORR is encouraging, but the survival benefit is not sustained.Thus, efficient treatment of these patients still represents a formidable challenge.
Anlotinib monotherapy has been approved as thirdor further-line treatment in ES-SCLC patients. 19The synergetic effect of antiangiogenic agent and ICIs support the combination strategy as maintenance treatment.To the best of our knowledge, this is the first study to investigate the safety and efficacy of durvalumab with anlotinib as maintenance treatment in these patients. 20,21The first patient has been enrolled at the end of September 2021 and is expected to take 36 months.

| CONCLUSION
The results of the DURABLE study will provide new data about safety and efficacy about multitarget tyrosine kinase inhibitor as maintenance treatment in ES-SCLC patients.