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Abstract
Objectives To evaluate the maximum tolerated dose/maximum administered dose, safety, pharmacokinetic, and efficacy profiles of ombrabulin combined with paclitaxel and carboplatin in Japanese patients with solid tumors.
Methods Ombrabulin (25, 30, or 35 mg/m2) combined with paclitaxel (175 or 200 mg/m2) and carboplatin (AUC5 or AUC6) was administered by intravenous infusion once every 3 weeks to patients with advanced solid tumors, including cervical, ovarian, and uterine cancers. The maximum tolerated dose/maximum administered dose was defined based on the dose-limiting toxicity at cycle 1. Efficacy was assessed based on Response Evaluation Criteria In Solid Tumors (RECIST).
Results In total, 18 patients were recruited for this dose escalation study. One out of six patients treated with the highest doses of combination of ombrabulin (35 mg/m2), paclitaxel (200 mg/m2), and carboplatin (AUC6) presented a dose-limiting toxicity consisting of grade 3 Escherichia urinary tract infection. This dose was defined as the maximum tolerated dose of ombrabulin. The most frequent treatment-emergent adverse events were alopecia (83.3%), neutropenia and fatigue (72.2% each), decreased appetite, nausea, diarrhea, arthralgia, and myalgia (66.7% each). The grade 3–4 treatment-emergent adverse events included neutropenia (61.1%), Escherichia urinary tract infection, drug hypersensitivity, syncope, pulmonary embolism, and hydronephrosis (one patient each). In efficacy evaluation, seven patients achieved partial response or better (38.9%), including one complete response, and seven of 18 patients had stable disease (38.9%). Pharmacokinetic profiles in this Japanese study were comparable with those observed in the previous study without Japanese patients.
Conclusions Although the maximum tolerated dose/maximum administered dose of ombrabulin (35 mg/m2) with taxane-platinum combination may be tolerable in Japanese patients in the first cycle, the dosages in the repeated treatment should be carefully selected for further study.
Trial registration number NCT01293630.
- uterine cervical neoplasms
- ovarian neoplasms
- uterine neoplasms
- adenocarcinoma
Data availability statement
Data are not available for phase 1 study according to Sanofi’s data-sharing rule. Data are available upon reasonable request. Qualified researchers may request access to patient level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.vivli.org/.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
The tolerability of ombrabulin in combination with chemotherapies was tested for advanced solid tumors in the cohort without Japanese patients. Although ombrabulin in combination with docetaxel and cisplatin is not tolerable in Japanese patients, ombrabulin in combination with paclitaxel and carboplatin has not been tested in Japanese patients.
WHAT THIS STUDY ADDS
In this study, the maximum tolerated/administered dose of ombrabulin in combination with paclitaxel and carboplatin was determined in Japanese patients to confirm no ethnic difference in safety profiles.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Phase II/III studies of ombrabulin for non-small cell lung cancer and soft tissue sarcoma were conducted without Japanese patients but failed to show sufficient clinical benefit, partially because of the lack of predictive biomarkers. Once such biomarkers are identified, further investigation would be allowed with ombrabulin in clinical settings. This Japanese phase I study would be a reference for consideration to include the Japanese cohort in further study of this combination.
INTRODUCTION
The tumor vascular network is essential for the growth and survival of solid tumor cells by delivering oxygen and nutrients; thus, targeting the tumor vascular network can be a treatment of advanced malignant solid tumors.1–3 The agents of such treatments include angiogenesis inhibitors and vascular disrupting agents. Although vascular disrupting agents have not been approved by the Food and Drug Administration, they have shown significant therapeutic potential and are a focus of current research.
Ombrabulin is a water-soluble analog of combretastatin A4 (CA-4) that inhibits polymerization by binding to the colchicine site of tubulin.4 Ombrabulin destroys tumor vasculature, causing blood flow disruption, extensive tumor necrosis, and consequent tumor regression.5 Ombrabulin and other CA-4 analogs have shown potent anti-tumor activities in pre-clinical and clinical studies.6–8 However, tumor repopulation occurs rapidly after a short course of vascular disrupting agent monotherapy from the rim of surviving tumor cells, leading to tumor regrowth following therapy termination.9 10 Therefore, the combination of ombrabulin with other anti-cancer agents is required for effective chemotherapy. The anti-tumor activities of ombrabulin in combination with docetaxel/cisplatin or paclitaxel/carboplatin were demonstrated in a phase I study of non-Japanese patients with cancer.11 In addition, the best synergistic effect was observed in pre-clinical studies, in which ombrabulin was administered prior to, or concomitantly with, other anti-tumor drugs.12 After IV administration, ombrabulin is rapidly converted into its active metabolite, RPR258063. The recommended dose/maximum tolerated dose in the combination therapy was 35 mg/m2 ombrabulin, 200 mg/m2 paclitaxel, and carboplatin AUC6.11 However, the maximum tolerated dose/maximum administered dose, safety, pharmacokinetic, and efficacy profiles of the combination of ombrabulin with paclitaxel and carboplatin have not yet been investigated in Japanese patients with cancer.
The primary objective of this study was to determine the maximum tolerated dose/maximum administered dose based on the incidence of dose-limiting toxicity in Japanese patients with advanced solid tumors treated with ombrabulin combined with paclitaxel and carboplatin administered by IV infusion once every 3 weeks. The secondary objectives were to assess the safety, pharmacokinetic, and efficacy profiles of this combination in these patients.
METHODS
Patients
Eligible patients included those with histologically or cytologically proven advanced solid tumors, such as lung and epithelial ovarian cancer, against which paclitaxel and carboplatin were potentially effective as recommended in the guidelines in Japan; with adequate hematologic, renal, and hepatic function; with an adequate washout period since prior therapy; who had recovered from toxicity; and with a life expectancy of at least 12 weeks.
The following patients were excluded: age less than 20 or above 75 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, or more than one line of previous chemotherapy for advanced or metastatic disease except adjuvant, neo-adjuvant, and targeted agents, allowing taxane-based and/or platinum-based therapy. Other exclusion criteria are described in the Online supplemental material.
Supplemental material
Study Design and Ethics
This phase I study of ombrabulin in combination with paclitaxel and carboplatin was conducted in Japanese patients with advanced solid tumors in two sites following the previous study.11 On day 1 of each cycle, the patients were administered ombrabulin by IV infusion (30 min). Twenty-four hours after the completion of ombrabulin infusion (day 2), paclitaxel was administered by infusion (180 min), immediately followed by carboplatin by IV infusion (30 min). Three or six patients with advanced solid tumors were enrolled in sequential cohort studies and treated with successively higher doses of ombrabulin. The definition of these doses is described in the Online supplemental material. The ombrabulin (25, 30, or 35 mg/m2), paclitaxel (175 or 200 mg/m2), and carboplatin (AUC5 or AUC6) doses were administered at levels 1 to 5 as defined in Online supplemental material.
This study was conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki.13 14 The investigators complied with all applicable regulatory and legal requirements and obtained written informed consent from patients prior to enrollment and any trial-related activity. The study protocol was approved by the ethics committee/institutional review board of the study sites at Hyogo Cancer Center and Saitama Medical University International Medical Center prior to the study.
This study was registered at ClinicalTrials.gov (Identifier: NCT01293630).
Safety Evaluation and Maximum Tolerated Dose/Maximum Administered Dose
The safety assessment was based on physical examinations, treatment-emergent adverse events, serious adverse events, vital signs, 12-lead ECG, chest radiography, echocardiography, cardiac markers, laboratory assessments including hematological and biochemical examinations, and urinalysis. Dose escalation to the next level followed a 3+3 algorithm. The definition of dose-limiting toxicity is described in the Online supplemental material. Twelve-lead ECG evaluations were performed on treatment days 1, 2, 8, and 22 and when clinically relevant. In addition, levels of troponin I, creatine phosphokinase, and creatine kinase-myocardial band isoenzyme cardiac markers were measured on days 2 and 8 of each cycle and when clinically relevant.
The preferred terms for treatment-emergent adverse events and adverse drug reactions were classified according to the Medical Dictionary for Regulatory Activities/Japanese version (MedDRA/J) 16.1. The safety profile evaluation was based on the treatment-emergent adverse event incidence and severity (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 3.0, scale).
Pharmacokinetic Evaluation
The main objective was to evaluate the pharmacokinetic profiles of ombrabulin, its active metabolite RPR258063, paclitaxel, and free/total carboplatin (as free/total platinum) in patients treated with ombrabulin in combination with paclitaxel and carboplatin. Blood samples (2 mL) for the evaluation of ombrabulin and RPR258063 were collected before ombrabulin infusion; at 30 min (end of the infusion); and at 5, 10, 25, and 45 min and 1, 2, 4, 6, 8.5 hours (day 1), and 24 hours (day 2) after ombrabulin infusion during cycle 1. Blood samples (2 mL) for the evaluation of paclitaxel were collected before ombrabulin infusion; at 90 min after the initiation of paclitaxel infusion (180 min); at 30 min after paclitaxel infusion; and 1, 2, 4, 6 hours (day 2), and 24 hours (day 3) after paclitaxel infusion during cycle 1. In addition, 5.5 mL blood samples for total/free carboplatin evaluations were collected before ombrabulin infusion; at 30 min (end of carboplatin infusion); and at 30 min, 1.5 hours, 3.5 hours (day 2), and 23.5 hours (day 3) after carboplatin infusion. The pharmacokinetic parameters, including maximum plasma concentration, area under the curve (AUC), clearance/body surface area, volume of distribution at steady-state/body surface area, and terminal elimination half-life for ombrabulin, RPR258063, paclitaxel, and total/free carboplatin were determined at each sampling point during cycle 1 using WinNonlin (version 5.2, Pharsight Corp., Mountain View, California, USA).
Efficacy evaluation
The tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria. These assessments were conducted at a frequency of at least every two cycles or less. Best overall response is defined as the best response across all time points. Stable disease was evaluated based on the measurement of target lesions at least 4 weeks after the start of cycle 1 but during cycle 2. For patients who had only small lesions that did not meet the criteria of measurable disease, tumor response was evaluated as non-complete response/non-progressive disease instead of stable disease.
Statistical analysis
Cohorts of three or six patients were screened and treated at each dose level. The actual sample size varied and depended on the incidence of dose-limiting toxicity during cycle 1. The primary objective was to determine the maximum tolerated dose based on the incidence of dose-limiting toxicities and maximum administered dose of ombrabulin in combination with paclitaxel and carboplatin. Therefore, the evaluable population for dose-limiting toxicities was defined as all patients who received at least one infusion of ombrabulin, paclitaxel, or carboplatin and had no major protocol deviations during cycle 1. The safety analysis was targeted at summarizing the treatment-emergent adverse events by dose level among all treated patients. The adverse events were summarized with respect to the incidence and severity (NCI-CTCAE v. 3.0). All adverse events were coded using MedDRA version 16.1. All serious adverse events were documented. The pharmacokinetic parameters were summarized using descriptive statistics. The anti-tumor activity assessed by the best overall response according to RECIST 1.1 criteria was descriptively presented based on the actual dose level received.
RESULTS
Patient Characteristics
A total of 18 patients were enrolled to be evaluable for dose-limiting toxicities as well as safety, pharmacokinetic, and efficacy between January 2011 and October 2013. The median age at baseline was 56.5 (range 40–74) years, the primary tumor sites included the cervix (four patients), uterus and ovaries (three patients each), others (peritoneum in two patients, thymus and duodenum in one patient each), muscle/soft tissue tumor in two patients, brain/central nervous system (one patient), and missing data in one patient. Histological analysis confirmed the presence of adenocarcinomas in 11 patients. Two patients had squamous cell carcinoma and five had other histology types (two unspecified carcinomas, one unclassified spindle and round cell sarcoma, one leiomyosarcoma, and one intracranial hemangiopericytoma). The median numbers (range) of organs involved were 3 (range 1–6). Almost all (17 patients, 94.4%) had metastatic tumors at baseline and one patient had locally advanced disease. The previous therapies received by the patients included chemotherapy (15 patients, 83.3%), surgery (12 patients, 66.7%), radiotherapy (4 patients including two cervix, one uterus, and one brain, 22.2%) but no bevacizumab (Table 1). No patient was treated as primary adjuvant therapy in this study.
Patient baseline characteristics
Patients in all treatment groups received a median of 11 (range 1–24) cycles of treatment. The mean±SD numbers of dosing cycles in patients treated with levels one, two, three, four, and five dose regimens were 4.0±2.0, 3.0±0.0, 5.7±4.5, 9.3±6.1, and 12.0±9.1, respectively. The number of cycles of ombrabulin at 35 mg/m2 was greater than those for ombrabulin at 25 or 30 mg/m2 (117 cycles in 12 patients treated with ombrabulin 35 mg/m2 compared with 21 cycles in six patients treated with ombrabulin 25 or 30 mg/m2). The number of cycles in three patients who were exposed to pelvic radiation was nine cycles. The treatment was discontinued in 10 patients due to adverse events, in seven patients with disease progression, and in one patient for personal reasons.
Dose-Limiting Toxicity
One out of six patients administered the highest dose level of ombrabulin (35 mg/m2), paclitaxel (200 mg/m2), and carboplatin (AUC6) experienced one dose-limiting toxicity of Escherichia urinary tract infection grade 3. Therefore, this dose regimen of ombrabulin combined with paclitaxel and carboplatin was considered the maximum administered dose/maximum tolerated dose in Japanese patients. This patient recovered 11 days later following adequate treatments, and therapy with the investigational products was continued.
Safety
The safety profiles of ombrabulin in combination with paclitaxel and carboplatin in the present study are shown in Table 2. All 18 patients developed at least one treatment-emergent adverse event and 15 patients had a grade 3–4 treatment-emergent adverse event. Two serious adverse events (grade 3 drug hypersensitivity and pulmonary embolism, 1 patient each) were observed. No deaths were reported in this study. Nine patients (50%) discontinued study treatment because of treatment-emergent adverse events.
Main related adverse events of ombrabulin in combination with paclitaxel and carboplatin
The most frequently reported treatment-emergent adverse events were alopecia (83.3%), neutropenia and fatigue (72.2% each), decreased appetite, nausea, diarrhea, arthralgia, and myalgia (66.7% each). The grade 3 or 4 treatment-emergent adverse events were neutropenia (61.1%), Escherichia urinary tract infection, drug hypersensitivity, syncope, pulmonary embolism, and hydronephrosis (5.6% each). The most common adverse drug reactions (treatment-emergent adverse event related to investigational products) in all ombrabulin-treated groups were alopecia (83.3%); neutropenia, and fatigue (72.2% each); decreased appetite, arthralgia, myalgia, nausea, and diarrhea (66.7% each); and dysgeusia and constipation (50.0% each).
Vascular disorders occurred in eight patients, including four patients who developed hypertension (no corrective treatment) at grade 1 or 2, and which were considered to be drug-related. One patient treated with ombrabulin (35 mg/m2) in combination with carboplatin (AUC6) and paclitaxel (175 mg/m2) had a grade 3 related pulmonary embolism that led to permanent treatment discontinuation, an event that occurred concomitantly with hypertension. Evaluation of cardiac markers revealed one patient (5.6%) with transient troponin I values higher than the upper limit of normal (0.9 ng/mL). This patient was treated with ombrabulin (35 mg/m2) in combination with paclitaxel (200 mg/m2) and carboplatin (AUC6), but no concomitant abnormality was observed in ECG or cardiac examinations. The increase in troponin I resolved 1 week later. Assessment of creatine phosphokinase revealed four patients (22.2%) with grade 1 abnormalities—one patient (5.6%) with abnormalities at baseline that did not resolve, and three patients (16.7%) with transient abnormalities. Among these three patients, one patient each (5.6%) had abnormalities in ECG or cardiovascular examinations. These abnormalities were not concomitant with creatine phosphokinase abnormalities. Creatine kinase-myocardial band abnormalities were reported in 10 patients (55.6%) from baseline to the end of the study. No medical history of cardiac disease or concomitant treatment-emergent adverse event was reported in these patients. The blood pressure abnormalities were observed in different cycles and mainly on the day that treatment was administered. These abnormalities were transient, and all patients recovered.
Pharmacokinetics
The plasma concentration–time profile of ombrabulin and RPR258063 are shown in Figure 1. The pharmacokinetic parameters of ombrabulin, RPR258063, paclitaxel, and carboplatin are shown in Online supplemental tables 1 and 2. The results of the maximum plasma concentration confirmed that ombrabulin was rapidly converted to its active metabolite RPR258063. The median time to maximum plasma concentration (tmax) values of 0.5 hour and 0.58 hour, respectively, for ombrabulin and RPR258063 at 35 mg/m2 ombrabulin. Ombrabulin had high clearance/body surface area (51.5–52.8 L/h/m2), high volume of distribution at steady-state/body surface area (16.2–19.7 L/m2), and short terminal elimination half-life (17.5–21.4 min), with no observable dose effects. The terminal elimination half-life of RPR258063 was significantly longer than that of ombrabulin in all dosage populations (terminal elimination half-life values of ombrabulin and RPR258063 of 17.5 min and 9.68 hours, respectively, for 35 mg/m2 ombrabulin). No dose effects in clearance/body surface area and volume of distribution at steady-state/body surface area values were observed for ombrabulin, RPR258063, paclitaxel, and carboplatin.
Plasma concentration-time profiles of ombrabulin and RPR258063 in Japanese patients with cancer. LOQ, limits of quantification.
Efficacy
Tumor responses are shown in Table 3. Of the 18 patients evaluated, seven achieved partial response or better (39.9%), including one complete response (5.6%). Non-complete response/non-progressive disease was observed in two patients (11.1%). Stable disease was observed in seven patients (38.9%) and two patients (11.1%) exhibited progressive disease. Complete response was observed in one patient with ovarian cancer who received 24 cycles of ombrabulin (35 mg/m2) in combination with paclitaxel (200 mg/m2) and carboplatin (AUC6). The partial responses were observed in six patients with primary tumor sites of cervix, peritoneum (two patients each), and ovaries and muscle/soft tissue (one patient each). One patient with ovarian cancer who achieved partial response received 20 cycles of ombrabulin (35 mg/m2) in combination with paclitaxel (200 mg/m2) and 8 cycles of carboplatin AUC6 (stopped due to hypersensitivity reaction). After another chemotherapy and surgery for a localized lesion (para-aorta lymph node at the left renal artery level), the patient is free from any evidence of disease and long-term toxicity 7 years after study entry.
Tumor responses to ombrabulin in combination with paclitaxel and carboplatin
In summary, for 10 patients with gynecologic tumors the efficacy was as follows: one complete response with ovarian cancer; three partial responses with two cervical and one ovarian cancer; three stable diseases with cervical, ovarian, and uterine cancer; one progressive disease; and two non-progressive diseases/non-complete responses in cervical and uterine cancer.
DISCUSSION
Summary of Main results
Our study showed that there was maximum tolerated dose and one dose-limiting toxicity (grade 3, Escherichia urinary tract infection) in one patient at the dose combination of ombrabulin (35 mg/m2), paclitaxel (200 mg/m2), and carboplatin (AUC6). The most frequently reported treatment-emergent adverse events in this study were alopecia, neutropenia, fatigue, decreased appetite, arthralgia, myalgia, nausea, and diarrhea. Although all 18 patients experienced at least one treatment-emergent adverse event including hypertension observed in three patients (8.1%, grade 3–4 in one person), the safety profile in this study was consistent with the one in the previous study.11 In the efficacy evaluation of 18 patients, including 10 patients with gynecologic tumors, seven showed a partial response or better, including one complete response with ovarian cancer and three partial responses with cervical or ovarian cancer.
Results in the context of published literature
The combinations of a vascular disrupting agent with other anti-cancer agents including chemotherapies and anti-vascular endothelial growth factor antibody has been investigated in the treatment of patients with advanced cancers.2 3 This therapeutic strategy can reduce the regrowth of tumor cells remaining after termination of vascular disrupting agent monotherapy.8 9 Antitumor activity and moderate tolerability of ombrabulin in combination with taxane and platinum agents have been reported in the phase I study with no Japanese cohort included.11 Thus, tolerability tests of ombrabulin in combination with docetaxel and cisplatin or paclitaxel and carboplatin were conducted in Japanese patients. The combination with docetaxel and cisplatin was not tolerable even with the lowest dose in the dose escalation study.15 In contrast, the combination with paclitaxel and carboplatin was tolerable as the dose escalations of ombrabulin reached the same doses in the previous study. The pharmacokinetic profiles of ombrabulin and its active metabolite RPR258063 in Japanese patients were comparable to those shown in the previous phase I study with no Japanese cohort.11
Since the phase III study with the combination of ombrabulin and cisplatin did not show significant benefit in advanced soft-tissue sarcoma, a further phase III trial was not conducted.16 However, fosbretabulin has been reported to be possibly beneficial in combination with anti-angiogenic agents in phase II studies.17 18 Additionally vascular disrupting agents, including plinabulin and CKD-516, were under investigation in combination with immune checkpoint inhibitors.2
Strengths and Weaknesses
This phase I study showed that ombrabulin (35 mg/m2) in combination with paclitaxel and carboplatin in Japanese patients with advanced solid tumors was tolerable with the assessment of dose-limiting toxicity at cycle 1 The tolerability of same dose level as used in the previous study in Caucasian patients was confirmed, whereas the other phase I study on Japanese patients showed that the combination with docetaxel and cisplatin was not tolerable.15 The limitation of this study follows the limitation of the traditional 3+3 design.19 The estimate of the maximum tolerated dose is biased and the recommended dose selected for the further studies is often lower than the optimal dose. In addition, this study is designed to stop the dose escalation at the highest dose level predefined in the protocol, which was determined to be the maximum tolerated dose in Caucasian patients. The further dose escalation of ombrabulin was not performed, although the highest dose level was well tolerated. The true maximum tolerated dose of Japanese patients may be higher than that shown in this study.
Implications for Practice and Future Research
Although one patient treated with ombrabulin combination was free from recurrence after another chemotherapy and surgery in the follow-up, further rationale including predictive biomarkers is necessary for further investigation of ombrabulin in combination with chemotherapies or immune checkpoint inhibitors.
CONCLUSIONS
Ombrabulin in combination with paclitaxel and carboplatin was well-tolerated in Japanese patients; partial response or better was observed in 7 of 18 patients (39%). The combination of ombrabulin (35 mg/m2), paclitaxel (200 mg/m2), and carboplatin (AUC6) may be tolerable and should be evaluated in future studies in Japanese patients.
Data availability statement
Data are not available for phase 1 study according to Sanofi’s data-sharing rule. Data are available upon reasonable request. Qualified researchers may request access to patient level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.vivli.org/.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by AVE8062-TCD11270IRB of Saitama Medical University International Medical Center institutional review board of Hyogo Cancer Center. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors thank Kazuo Sugio of Honyaku Center, Inc. for their assistance with the drafting and editing of the manuscript. This assistance was funded by Sanofi.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors All authors have contributed to the study conceptualization, validation of the data, writing original draft of the manuscript. YS contributed to the curation and formal analysis of the data. KM and KF were responsible for investigation and resources. EE-F was responsible for the management and coordination of the study. KM, YS, and KF were guarantor. All authors have reviewed, revised, and approved the manuscript for publication.
Funding This study was funded by Sanofi.
Competing interests KM reports grants from Sanofi, during the conduct of the study; grants from ICON Japan; grants and personal fees from MSD, Chugai, Novartis, ONO, Astra Zeneca, and Eisai; personal fees from Taiho, Eli Lilly, Kyowa Kirin, Pfizer, and AbbVie, outside the submitted work. YS reports personal fees and other from Sanofi, outside the submitted work. EE-F reports personal fees from Sanofi, during the conduct of the study. KF reports grants from Sanofi, during the conduct of the study; grants and personal fees from Astra Zeneca, Chugai-Roche, Eisai, MSD, Taiho, Zeria, Nano Carrier, and Takeda; grants from Immunogen, Oncotherapy, Regeneron, Genmab; personal fees from Daiichi Sankyo, Kyowa Kirin, and Mochida, outside the submitted work.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.