Olaparib with or without bevacizumab or bevacizumab and 5-fluorouracil in advanced colorectal cancer: Phase III LYNK-003
Abstract
Oxaliplatin-based chemotherapy with a regimen such as FOLFOX with or without targeted therapy is a standard of care option for advanced colorectal cancer; however, long-term exposure to oxaliplatin is associated with cumulative toxicity. Growing evidence suggests maintenance therapy with a less intensive regimen after platinum-based induction therapy can provide continuing benefit with reduced toxicity. We describe the rationale and design of the Phase III LYNK-003 trial, which will evaluate the efficacy and safety of olaparib with or without bevacizumab compared with 5-fluoruracil plus bevacizumab in patients with unresectable or metastatic colorectal cancer that has not progressed on an induction course of FOLFOX plus bevacizumab. The primary end point is progression-free survival by independent central review; secondary end points include overall survival, objective response, duration of response and safety.
Clinical trial registration:NCT04456699
Lay abstract
Commonly used treatments for patients with advanced colorectal cancer are intensive chemotherapy-based combinations. However, long-term treatment with chemotherapy can cause significant toxic effects. To overcome this problem, patients with colorectal cancer are treated with chemotherapy for a short time, followed by a less aggressive maintenance regimen of the chemotherapy drug 5-fluorouracil and the targeted therapy drug bevacizumab. Here, we describe the rationale and design of the LYNK-003 study, which will investigate whether targeted therapy with olaparib alone or olaparib with bevacizumab compared with 5-fluorouracil and bevacizumab is effective and safe in patients with advanced colorectal cancer. Drugs like olaparib or bevacizumab specifically target proteins that promote cancer cell proliferation and have fewer toxic effects than chemotherapy. The results of LYNK-003 may lead to the availability of new chemotherapy-free maintenance options for patients with advanced colorectal cancer.
LYNK-003 trial
The randomized, open-label, Phase III LYNK-003 trial (ClinicalTrials.gov identifier: NCT04456699) will evaluate the efficacy and safety of the PARP inhibitor olaparib, with or without the VEGF inhibitor, bevacizumab, compared with 5-fluorouracil (5-FU) plus bevacizumab in patients with unresectable or metastatic colorectal cancer (CRC) that has not progressed on first-line FOLFOX (folinic acid, 5-FU, oxaliplatin) plus bevacizumab (Figure 1). The current study aims to evaluate whether a chemotherapy-free regimen, composed of either olaparib alone or in combination with bevacizumab, compared with 5-FU-based maintenance can improve outcomes in patients with advanced CRC that has responded to induction therapy with FOLFOX and bevacizumab. The study is funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and AstraZeneca.
†5-FU is administered over 46–48 h.
5-FU: Fluorouracil; BID: Twice daily; CR: Complete response; CRC: Colorectal cancer; ECOG PS: Eastern Cooperative Cancer Group performance status; FOLFOX: Folinic acid, 5-fluorouracil and oxaliplatin; IV: Intravenously; mut: Mutant; PFS2: Time from randomization to second documented disease progression or death due to any cause; PR: Partial response; R: Randomized; SD: Stable disease; Q2W: Every 2 weeks; WT: Wild-type.
Background & rationale
More than 1.8 million cases of CRC were diagnosed in 2018, making CRC the third most common cancer worldwide and accounting for 10% of all cancer diagnoses [1]. Stage at diagnosis is the primary predictor of survival for CRC. The 5-year survival rate for patients with localized disease is 90% [2]. In contrast, the prognosis for patients with advanced disease remains poor, with a 5-year survival rate of only 14% for patients diagnosed with distant metastatic disease [2]. Although significant progress has been made in the management of CRC over the past 2 decades, there remains a need to improve outcomes for patients with advanced CRC [3].
The current standard of care for the first-line treatment of advanced CRC is a chemotherapy backbone including a fluoropyrimidine and oxaliplatin or irinotecan, with or without targeted agents such as the VEGF inhibitor bevacizumab, or antibodies targeting epidermal growth factor receptor such as cetuximab or panitumumab for RAS wild-type disease [4–6].
Such combinations have greatly improved outcomes for patients with advanced CRC, with median overall survival (OS) now reaching 30 months [7–9]. Historically, these regimens were administered until disease progression or unacceptable toxicity occurred [10]. However, these regimens are associated with significant toxicity, which limits their use to patients who can tolerate intensive therapy and also limits the duration of such treatment. Oxaliplatin, in particular, is associated with cumulative toxicity, with peripheral neuropathy as the most common dose-limiting symptom [11]. Consequently, there is interest in alternatives to continuous use of induction regimens, with the aim of reducing toxicity and optimizing health-related quality of life without affecting efficacy.
A number of approaches have been investigated [12,13]. One is the treatment holiday approach, in which all treatments are halted and restarted. Another is the maintenance therapy or de-escalation approach, which was first described in CRC 15 years ago [14], in which an intensive induction regimen is followed by less intensive maintenance therapy in patients who have responded to initial treatment. A network meta-analysis that evaluated these strategies in metastatic CRC has shown that continuing full induction therapy until disease progression does not provide a benefit in progression-free survival (PFS) or OS compared with observation (no treatment) or maintenance therapy [15]. The study also showed that maintenance with a fluoropyrimidine, bevacizumab, or both was associated with improved PFS compared with observation alone, although this did not translate into an OS benefit [15]. Consequently, maintenance therapy with a fluoropyrimidine with or without a targeted agent is currently the preferred strategy over continuous induction therapy; however, it remains unclear which strategy and which combination of agents provide the optimal outcome for patients who have a response to chemotherapy but may no longer be able to tolerate intensive treatment.
Platinum agents such as oxaliplatin are a mainstay of intensive induction regimens. These agents generate DNA lesions that result in intrastrand and interstrand DNA crosslinks [16,17]. DNA damage occurring in this way leads to cell cycle arrest, and if the damage is too extensive and cannot be repaired, apoptosis eventually occurs [16,17]. Consequently, cancers associated with deficiencies in DNA repair mechanisms are often sensitive to platinum-based therapy [16]. Analysis of The Cancer Genome Atlas dataset has shown that CRC is associated with a particularly high global mutation burden, including driver mutations in 29 DNA damage response and repair genes [18,19]. This analysis suggests that CRC may be amenable to therapeutic approaches that target DNA repair.
One approach to circumvent the toxicity associated with long-term platinum-based therapy is to target the vulnerability of CRC to inhibition of DNA damage response pathways [17]. To date, the most promising of these agents are the PARP inhibitors. PARPs are a family of enzymes that play a key role in the DNA damage response pathway [20]. PARP inhibitors act by trapping PARP at sites of single-strand DNA damage, preventing their repair and leading to double-stand DNA breaks during replication [21,22]. These breaks would normally be repaired by a high-fidelity process known as homologous recombination repair (HRR); however, in tumors cells that are HRR deficient, such as those of BRCA1-mutant breast cancers, this damage cannot be accurately repaired, becoming lethal as genomic rearrangements accumulate [22,23]. HRR-deficient tumors are therefore sensitive to PARP inhibitors, which has been shown in both preclinical models and clinical studies [24–32].
Notably, PARP inhibition alone is insufficient to cause cell death in cells where DNA repair pathways are intact [20]. This concept of synthetic lethality, whereby mutation or blockade of two genes is required to precipitate cell death, can be exploited in cancers with defective DNA repair such as CRC. There is preclinical evidence supporting this concept in CRC. An in vitro study showed that 13% of CRC cell lines enriched for RAS/BRAF mutations were sensitive to PARP inhibition, and response to PARP inhibition correlated with oxaliplatin sensitivity [33]. This cross-sensitivity has been investigated clinically by using PARP inhibitors as maintenance therapy following induction with platinum-based agents. Trials in both ovarian and pancreatic cancer have shown that PARP inhibitors are effective as maintenance therapies in patients with platinum-sensitive and HRR-deficient BRCA1/BRCA2 mutant cancers [29,30,34]. PARP inhibitors are also being investigated in combination with other anticancer therapies, including antiangiogenic agents [20]. The rationale for this approach is that antiangiogenic agents can cause hypoxia-induced deficits in DNA repair, which can sensitize cells to PARP inhibition [35]. This strategy has shown promise for CRC in a preclinical study in which the combination of bevacizumab, a VEGF inhibitor, and olaparib, a PARP inhibitor, resulted in greater tumor regression in a KRAS-mutant CRC xenograft model than either agent alone [36]. There is also clinical evidence to support the use of such combinations in other types of cancer. The Phase III PAOLA-1 trial (Platine, Avastin and OLAparib in first Line) evaluated bevacizumab in combination with olaparib as maintenance therapy in patients with ovarian cancer who had a response to first-line platinum-based chemotherapy plus bevacizumab [31]. Results showed that the bevacizumab plus olaparib provided significant benefit, with a median PFS of 22.1 months for patients receiving the combination compared with 16.6 months for patients receiving bevacizumab alone. Notably, bevacizumab is also known to have antitumor activity in CRC, having been shown to prolong both OS and PFS when used in combination with chemotherapy in patients with metastatic disease [37].
Olaparib
Olaparib (Lynparza®) is a first-in-class oral PARP inhibitor with activity against the PARP1, PARP2 and PARP3 enzymes [38]. Initially approved for use in ovarian cancer, olaparib is now approved for several additional tumor types, including breast, pancreatic and prostate cancers (Table 1) [38,39]. The recommended dosage of olaparib for the tablet formulation is 300 mg taken orally (PO) twice daily (BID) with or without food [38]. Olaparib is rapidly absorbed, achieving peak plasma concentrations approximately 1.5 h after dosing [38]. The mean terminal plasma half-life is 14.9 ± 8.2 h, and plasma clearance is 7.4 ± 3.9 l/h following a single 300 mg dose. Olaparib is principally metabolized by CYP3A, and consequently, coadministration of olaparib and strong CYP3A inhibitors and inducers should be avoided.
| Tumor type | Monotherapy/combination | Details of indication |
|---|---|---|
| Ovarian cancer [38] | Monotherapy | Maintenance treatment of patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy |
| Combination with bevacizumab | Maintenance treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who experience complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency† | |
| Monotherapy | Maintenance treatment of recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer in patients with complete or partial response to platinum-based chemotherapy | |
| Monotherapy | Patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with ≥3 prior lines of chemotherapy | |
| Breast cancer [38] | Monotherapy | Patients with deleterious or suspected deleterious germline BRCA-mutated, HER2- metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting‡ |
| Pancreatic cancer [38] | Monotherapy | Maintenance treatment of patients with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on ≥16 weeks of first-line platinum-based chemotherapy |
| Prostate cancer [38] | Monotherapy | Patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer who have progressed following prior treatment with enzalutamide or abiraterone |
A pivotal Phase I trial evaluating olaparib in 60 patients with advanced solid tumors of whom a substantial portion were carriers of a BRCA1 or BRCA2 mutation demonstrated that olaparib was generally well tolerated [26]. Notably, objective responses were observed only in carriers of a BRCA1 or BRCA2 mutation and responses were durable. The US FDA initially approved olaparib for the treatment of BRCA-mutated ovarian cancer, including as maintenance therapy for patients with complete or partial response to first-line platinum-based chemotherapy (Table 1). Subsequently, olaparib was approved for a number of additional tumor types, including breast, pancreatic and prostate cancers (Table 1) [38].
To date, two clinical trials have investigated olaparib for the treatment of CRC, both of which employed continuous olaparib treatment in second line or beyond. The Phase I Canadian Cancer Trials Group IND 187 study evaluated the safety and tolerability of olaparib combined with irinotecan in 25 patients with previously treated advanced CRC [40]. Continuous dosing of olaparib plus irinotecan was poorly tolerated and although intermittent dosing was associated with reduced toxicity, efficacy was limited with intermittent dosing. No patient had partial or complete response and nine patients had stable disease [40]. A Phase II trial investigated olaparib monotherapy in 33 patients with disseminated CRC who had received ≥2 prior lines of therapy [41]. After a median follow-up of 31.5 months, no responses were observed (5 patients had stable disease). Median PFS was 1.81 months for patients with microsatellite stable disease and 2.00 months for patients with microsatellite instability high disease; median OS was 9.3 and 8.1 months, respectively. The most common adverse events were gastrointestinal disorders (94%), mainly nausea and vomiting, cytopenias, and fatigue (39%). Whereas the results of these trials demonstrated limited efficacy, there is precedent from studies of relapsed, high-grade serous ovarian cancer; relapsed, high-grade, BRCA1/2-mutated ovarian cancer; newly diagnosed, advanced, high-grade ovarian cancer; and germline BRCA1/2-mutated metastatic pancreatic cancer showing that olaparib is effective as maintenance therapy in patients who have responded to or not progressed on platinum-based chemotherapy [27,29,31,34]. As a result, olaparib has been approved as monotherapy and in combination with bevacizumab for maintenance treatment of patients with ovarian cancer that has responded to platinum-based chemotherapy and for maintenance treatment in patients with germline BRCA-mutated pancreatic cancer that has not progressed on first-line platinum-based chemotherapy (Table 1) [38].
LYNK-003 study design
The Phase III LYNK-003 study has been designed to compare targeted therapy with olaparib alone or olaparib plus bevacizumab with standard-of-care chemotherapy-based treatment with 5-FU plus bevacizumab in patients with advanced CRC that has responded to induction therapy with FOLFOX plus bevacizumab. Eligible patients will be randomized centrally using an interactive response technology system in a 1:1:1 ratio to open-label treatment with olaparib 300 mg PO BID plus bevacizumab 5 mg/kg intravenously (iv.) every 2 weeks (Q2W), olaparib 300 mg PO BID or 5-FU 2400 mg/m2 iv. Q2W plus bevacizumab 5 mg/kg iv. over 46–48 h Q2W (Figure 1). Randomization will be stratified by response to prior FOLFOX plus bevacizumab (stable disease vs partial response/complete response), mutation status (BRAFmut and/or RASmut vs BRAFWT and RASWT), and the number of cycles of FOLFOX plus bevacizumab previously received (6–8 cycles vs >8 cycles). Patients will continue to receive treatment until documented disease progression, unacceptable toxicity or patient or physician decision to withdraw.
Eligibility criteria
Eligible patients must be ≥18 years of age and have histologically confirmed metastatic or unresectable (stage IV) CRC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients with any BRAF mutation are eligible. Patients must have received a first-line induction course of ≥6 cycles of FOLFOX (folinic acid, 5-FU, oxaliplatin) plus bevacizumab and their cancer must not have progressed after this induction therapy. Patients must also have experienced toxicity with oxaliplatin that, in the opinion of the treating physician, warranted treatment discontinuation. Patients who have previously received a PARP inhibitor will be excluded from the study. Patients who received systemic therapy other than FOLFOX plus bevacizumab within 28 days of randomization, or radiotherapy within 14 days of start of study treatment, will also be excluded. Additional eligibility criteria are listed in Table 2.
| Inclusion | Exclusion |
|---|---|
| • Adult male or female patient • ≥18 years of age • Histologically confirmed metastatic or unresectable (stage IV as per AJCC 8th edition) colorectal adenocarcinoma • Has not had disease progression after a first-line induction course of ≥6 cycles of FOLFOX + bevacizumab as first-line therapy† • Has experienced unacceptable toxicity to oxaliplatin that required the discontinuation of oxaliplatin‡ • Has provided ≥1 set of radiographic images taken during the FOLFOX + bevacizumab induction period and ≥42 days prior to imaging performed during screening • ECOG PS of 0 or 1 within 10 days of randomization • Has the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption • Adequate organ function • Has provided a tumor tissue sample for biomarker analysis | • Known hypersensitivity to the components and/or excipients in bevacizumab, 5-FU, or olaparib • Known active CNS metastases and/or carcinomatous meningitis ○ Previously treated brain metastases were allowed if radiologically stable (i.e., without progression for ≥28 days), clinically stable, and had not required steroid intervention for ≥14 days prior to the first dose of study drug • Active infection requiring systemic therapy • Known history of HIV, HBV (HBsAg reactive), or HCV (HCV RNA detected) infection • MDS/AML or features suggestive of MDS/AML • Hemoptysis, hematemesis, or clinically significant bleeding within 28 days prior to randomization • Evidence of bleeding diathesis or significant coagulopathy • Clinically significant bleeding within 28 days prior to randomization • ≥1 condition making the patient ineligible for treatment with bevacizumab • Has received prior treatment with the following: ○ Systemic anticancer therapy (other than FOLFOX + bevacizumab induction) within 28 days of randomization ○ Olaparib or any other PARP inhibitor ○ Radiotherapy within 2 weeks of start of study intervention • Clinically significant cardiovascular disease • Has known DPD deficiency • Is currently receiving strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study |
Study procedures
Tumor response will be assessed using computed tomography or contrast-enhanced magnetic resonance imaging. Imaging will be performed at baseline, then every 8 weeks through year 1, followed by every 12 weeks thereafter until verified disease progression. The investigator will use baseline imaging to confirm that the patient does not have disease progression prior to randomization.
Safety will be assessed throughout the study and for 30 days after discontinuation of study drug or 90 days for serious adverse events. Adverse events will be assessed and graded based on National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Patient-reported outcomes will be assessed, and blood sampling for pharmacokinetic and biomarker analysis will also be performed.
Objectives
The primary objective is to compare PFS with olaparib alone or olaparib plus bevacizumab versus bevacizumab plus 5-FU in patients with unresectable or metastatic CRC that has not progressed on first-line FOLFOX plus bevacizumab. The study will meet its primary objective if either olaparib alone or olaparib plus bevacizumab provides longer PFS compared with bevacizumab plus 5-FU. PFS will be assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review. A key secondary objective is to compare OS between treatment arms in this patient population. Additional secondary objectives include the evaluation of objective response rate (ORR) and duration of response (DOR) as per RECIST v1.1 by blinded independent central review and safety of olaparib alone and olaparib plus bevacizumab. Exploratory objectives include the evaluation of time from randomization to second documented disease progression or death due to any cause, whichever occurs first (PFS2), by investigator assessment; health-related quality of life using the EORTC QLQ-C30, EORTC QLQ-C29 and EQ-5D-5L instruments; molecular biomarkers; and pharmacokinetics (Cmax and Ctrough) of olaparib and olaparib plus bevacizumab.
Statistics
Efficacy will be assessed in all patients randomly assigned to treatment, and safety will be assessed in all patients who receive ≥1 dose of study drug. The Kaplan–Meier method will be used to estimate PFS and OS. Treatment differences will be assessed by the stratified log-rank test and a Cox proportional hazard model with the Efron method of tie handling will be used to calculate the hazard ratio and corresponding 95% CI. A stratified Miettinen and Nurminen method will be used to compare ORR between the treatment arms. If the sample size permits, DOR will be summarized descriptively using the Kaplan–Meier method. Health-related quality of life will be assessed in patients who have ≥1 patient-reported outcome assessment available and who received ≥1 dose of study drug. Target enrollment is 525 patients in 123 centers.
Discussion & future perspective
The LYNK-003 trial is the first Phase III study investigating the efficacy and safety of olaparib with or without bevacizumab in patients with unresectable or metastatic CRC that has not progressed on first-line FOLFOX plus bevacizumab. Enrollment began in August 2020. The estimated completion date for collection of primary data is January 2027. The study results, in conjunction with the existing data, will help determine whether maintenance therapy with a less intensive regimen can provide continuing benefit with reduced toxicity in patients with advanced CRC who have responded to induction with an oxaliplatin-containing regimen. The results will also help determine whether olaparib, alone or in combination with bevacizumab, is an effective treatment option in the maintenance setting. The current trial may help optimize OS outcomes of patients with metastatic CRC treated with first-line induction therapy.
Conclusion
The LYNK-003 trial will evaluate whether olaparib alone, or in combination with bevacizumab, as maintenance therapy after induction with FOLFOX plus bevacizumab, will prolong PFS compared with 5-FU plus bevacizumab maintenance in patients with unresectable or metastatic CRC. The findings of this study will help define the role of olaparib as monotherapy and in combination with bevacizumab in CRC and may lead to the availability of alternative treatment options with improved safety profiles for patients with advanced CRC.
Background
Platinum-based chemotherapy with or without targeted agents is currently the standard of care for advanced colorectal cancer (CRC); however, long-term exposure to agents such as oxaliplatin is associated with significant cumulative toxicity.
One strategy being investigated to reduce the toxicity associated with these therapies is to administer less intensive maintenance treatment after an induction course of platinum-based combination therapy.
PARP inhibitors have been shown to be effective in platinum-sensitive cancers and provide benefit when used in combination with other targeted therapies.
Olaparib
Olaparib (Lynparza®) is a first-in-class oral PARP inhibitor that is approved by the US Food and Drug Administration for the treatment of ovarian, breast, pancreatic, and prostate cancer tumor types.
Olaparib has been used successfully as maintenance therapy alone in platinum-sensitive, relapsed, high-grade serous ovarian cancer and platinum-sensitive, relapsed, high-grade, germline BRCA1/2-mutated ovarian cancer; and in combination with the vascular endothelial growth factor inhibitor bevacizumab in newly diagnosed, advanced, high-grade ovarian cancer in patients who had a response to platinum-based chemotherapy plus bevacizumab. Olaparib has also been shown to be effective as maintenance therapy alone in germline BRCA1/2-mutated metastatic pancreatic cancer in patients who have not progressed on platinum-based chemotherapy.
LYNK-003 trial
LYNK-003 is a Phase III trial investigating olaparib with or without bevacizumab versus 5-fluourouracil plus bevacizumab in patients with unresectable or metastatic CRC that has not progressed on first-line FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) plus bevacizumab.
Eligible patients have metastatic or unresectable CRC that has not progressed on ≥6 cycles of FOLFOX plus bevacizumab as first-line therapy and have experienced unacceptable toxicity with oxaliplatin.
Patients will be randomly allocated in a 1:1:1 ratio to receive olaparib monotherapy, olaparib plus bevacizumab, or 5-FU plus bevacizumab.
The primary end point is progression-free survival; secondary end points include overall survival, objective response rate, duration of response and safety.
Results of the trial will help define the role of olaparib or olaparib plus bevacizumab as chemotherapy-free options versus 5-fluourouracil plus bevacizumab as maintenance therapies in CRC.
Supplementary data
An infographic accompanies this paper and is included at the end of the references section in the PDF version. To view or download this infographic in your browser please click here: www.futuremedicine.com/doi/suppl/10.2217/fon-2021-0899
Author contributions
TW Kim, J Taieb, EB Gurary, N Lerman and T Yoshino were responsible for the conception and design or planning of the study; TW Kim was responsible for drafting the manuscript; and TW Kim, J Taieb, EB Gurary, N Lerman, K Cui and T Yoshino were responsible for critically reviewing or revising the manuscript for important intellectual content.
Acknowledgments
The authors thank the patients and their families for participating in these trials, all investigators and site personnel, and Chenxiang Li of Merck & Co., Inc., Kenilworth, NJ, USA, for statistical support.
Financial & competing interests disclosure
This study is funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA, and AstraZeneca. TW Kim reports receiving grants to their institution from Sanofi-Aventis, Merck Serono, and AstraZeneca. J Taieb reports receiving consulting fees from Amgen, BMS, AstraZeneca, MSD, Merck, Pierre Fabre, Roche, Sanofi and Servier; and receiving payments or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or education events from Amgen, BMS, AstraZeneca, MSD, Merck, Pierre Fabre, Roche, Sanofi and Servier. EB Gurary reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. N Lerman reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. K Cui has no conflicts to disclose. T Yoshino reports receiving grants to their institution from Taiho Pharmaceutical, Sumitomo Dainippon, Ono Pharmaceutical, Chugai Pharmaceutical, Amgen, Parexel International, MSD, Daiichi Sankyo, and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Medical writing and editorial assistance was provided by J Walker and D Mitra of ApotheCom (PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA and AstraZeneca.
Ethical conduct of research
The study protocol and all amendments will be approved by the relevant Institutional Review Board or ethics committee at each study site. The study will be conducted in accordance with the protocol, the Declaration of Helsinki, and standards of Good Clinical Practice. All patients will provide written informed consent to participate in the clinical trial.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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