CaboCombo: a prospective, phase IV study of first-line cabozantinib + nivolumab for advanced renal cell carcinoma
Abstract
Cabozantinib plus nivolumab was approved as a first-line (1L) treatment for advanced renal cell carcinoma (aRCC) following the CheckMate 9ER trial. CaboCombo (ClinicalTrials.gov identifier: NCT05361434) is a non-interventional study designed to evaluate the effectiveness and tolerability of cabozantinib plus nivolumab in a real-world setting. Overall, 311 patients with clear-cell aRCC receiving 1L cabozantinib plus nivolumab will be recruited from at least 70 centers in seven countries worldwide. The primary end point is overall survival at 18 months. Secondary end points include progression-free survival, objective response rate, safety, patterns of treatment, subsequent anticancer therapies and quality of life. CaboCombo will provide real-world evidence on the characteristics, treatment sequences, and outcomes of patients with aRCC receiving 1L cabozantinib plus nivolumab.
Plain language summary – CaboCombo: a prospective, phase IV study of first-line cabozantinib + nivolumab for advanced renal cell carcinoma
Renal cell carcinomas (RCC) are cancers that grow in the kidneys. Clear-cell RCC is the most common type reported in almost three quarters of patients. RCC tumors become advanced if they grow and spread to other parts of the body.
In a clinical trial called CheckMate 9ER, a combination of two drugs called cabozantinib and nivolumab improved survival compared with a drug called sunitinib in patients with advanced clear-cell RCC who had not received any previous treatments. In CheckMate 9ER, cabozantinib plus nivolumab also reduced the size and slowed the spread of tumors compared with sunitinib. However, clinical trials only allow certain patients to participate under strict treatment conditions and so do not provide information on how a treatment will work in all patients. Researchers therefore carry out additional studies to gather extra information from real-world clinical practice.
CaboCombo is a study that will look at how well cabozantinib plus nivolumab stops tumors from growing and spreading, the side effects of the drugs, and also how the drugs are used by doctors. It is an observational study, which means that researchers will observe all patients and doctors using the treatment but they will not intervene.
The aim of the study is to gather information that will help doctors make treatment decisions for their patients. This article describes how the CaboCombo study will be carried out and the information it will give the researchers. The results will help physicians make decisions on the best treatment option for patients.
Clinical Trial Registration:NCT05361434 (ClinicalTrials.gov)
Disease area
In 2020, more than 430,000 new cases of kidney cancer were diagnosed worldwide and there were approximately 180,000 deaths [1]. Renal cell carcinoma (RCC) is the most common kidney cancer and comprises a broad spectrum of histopathological entities, but there are three main types: clear cell (accounting for ∼75% of cases), papillary (∼15% of cases) and chromophobe (∼5%) [2,3]. Many patients with RCC have advanced or metastatic disease at the time of diagnosis. This delayed diagnosis is associated with a poor prognosis: among patients diagnosed with stage IV disease, the 5-year survival in the USA is approximately 15% [4]. Although outcomes for patients with advanced or metastatic disease have improved with advances in systemic therapy, prognosis among these patients varies [3]. For instance, median overall survival (OS) in patients with metastatic RCC classified as having International Metastatic Renal-Cell Carcinoma Database Consortium favorable risk was 43.2 months, intermediate risk was 22.5 months and poor risk was 7.8 months [5].
For patients with advanced clear-cell RCC, several treatment options have shown improved patient outcomes and safety in phase III trials and are now recommended first-line treatment options [3,6,7]. These include tyrosine kinase inhibitor plus checkpoint inhibitor combinations [6]. The physician's choice of treatment is based on clinical criteria, including patients' performance status, International Metastatic Renal-Cell Carcinoma Database Consortium risk group, comorbidities, metastatic sites and possible contraindication to immunotherapy [8]. One therapeutic strategy combines cabozantinib with nivolumab (Figure 1; [19,20,21,22,23,24,25,26]). Cabozantinib is an inhibitor of multiple receptor tyrosine kinases targeting VEGFR2, c-MET and AXL, among others, which are implicated in tumor cell proliferation, neovascularization and immune-cell regulation and has immunomodulatory properties that can potentially enhance responses to immune checkpoint inhibition [9,10,11,12]. Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds to PD-1 and blocks its interaction with PD-ligands 1 and 2, thereby potentiating T-cell responses, including anti-tumor responses [13,14]. On the basis of data from the phase III CheckMate 9ER trial (NCT03141177) [15,16], cabozantinib plus nivolumab was approved in Europe and the USA in 2021 for the first-line treatment of patients with advanced RCC (aRCC) [17,18]. To date, no prospective studies have evaluated the effectiveness and tolerability of first-line treatment with cabozantinib plus nivolumab in patients with aRCC in the real-world setting.
TAM: TYRO3, AXL, MER; VEGFR: VEGF receptors 1, 2 and 3.
CaboCombo trial
CaboCombo (ClinicalTrials.gov identifier: NCT05361434) is a prospective non-interventional study that will evaluate the effectiveness and tolerability of cabozantinib plus nivolumab as first-line treatment for aRCC. Adults diagnosed with aRCC with a clear-cell component in routine clinical practice will be recruited from at least 70 centers worldwide. Funded by Ipsen, this trial recruited its first patient in September 2022 and has a planned recruitment duration of 24 months.
Background & rationale
In the phase III randomized controlled CheckMate 9ER trial, 651 adults with previously untreated clear-cell aRCC were randomized 1:1 to receive cabozantinib 40 mg once daily plus nivolumab 240 mg every 2 weeks or sunitinib 50 mg once daily (for 4 weeks of a 6-week cycle) [15]. In a long-term follow-up (median 32.9 months), the median OS was 37.7 months with cabozantinib plus nivolumab and 34.3 months with sunitinib (hazard ratio [HR]: 0.70; 95% CI: 0.55–0.90; p < 0.01) [16]. Median progression-free survival (PFS) in patients receiving cabozantinib plus nivolumab was 16.6 months compared with 8.3 months for those receiving sunitinib (HR: 0.56; 95% CI: 0.46–0.68; p < 0.0001). The objective response rate (ORR) was higher in the cabozantinib plus nivolumab group (56%; 12% complete response by blinded independent central review) than in the sunitinib group (28%; 5% complete response). Overall, 65.0% of patients who received cabozantinib plus nivolumab and 53.8% of those who received sunitinib experienced grade ≥3 adverse events (AE). Treatment-related AEs of any grade leading to discontinuation of either drug occurred in 27% of patients in the cabozantinib plus nivolumab group and 10% of those in the sunitinib group. In a more recent 3-year follow-up analysis of CheckMate-9ER, these benefits were maintained [27].
Patient-reported outcomes were analyzed as exploratory end points in CheckMate 9ER, and were maintained or improved with cabozantinib plus nivolumab versus sunitinib [28]. Health-related quality of life was evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19). After an initial decline from baseline in most scores across treatment groups, cabozantinib plus nivolumab was associated with stable (FKSI-19 total score, FKSI-19 functional wellbeing) or improved (FKSI-19 disease-related symptoms version 1 and FKSI-19 disease-related symptoms physical scale) scores over time, whereas sunitinib was associated with a decline from baseline (i.e., deterioration in health status) across all instruments [28]. Cabozantinib plus nivolumab was also associated with a decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib [28].
The benefits of cabozantinib plus nivolumab compared with sunitinib were demonstrated in CheckMate 9ER; however, phase III trials are typically conducted in highly selected patient populations and use tightly controlled treatment and monitoring protocols. For aRCC clinical trials, it has been reported that eligible patients represent approximately 30% of all patients with aRCC [29,30]. Patients with aRCC who are elderly, have brain metastases, renal impairment, poor performance status or who have comorbidities such as cardiac or autoimmune disease are often excluded from clinical trials [16,30,31]. Thus, it is important also to assess clinical outcomes, effectiveness and tolerability of newly approved treatments in real-world patients treated in routine clinical practice. Real-world evidence can complement data from randomized controlled trials, not only by providing external validation, but also by providing insight into unusual presentations of RCC, treatment patterns and factors that drive clinical decisions. Recently, a real-world retrospective study of a patient cohort in Germany supported the use of cabozantinib plus nivolumab as a first-line treatment for aRCC [31]. Here we describe CaboCombo, the first prospective real-world study of first-line cabozantinib plus nivolumab combination therapy and will provide data on effectiveness, tolerability, dosing and treatment sequences in patients with aRCC in routine practice.
Design
Study design
CaboCombo is an international prospective non-interventional study of first-line cabozantinib plus nivolumab in patients with clear-cell aRCC in the real-world setting. Eligible patients will be recruited from at least 70 centers in France, Greece, Italy, Kingdom of Saudi Arabia, Northern Ireland (UK), South Korea and Spain, which have marketing authorization and reimbursement for cabozantinib plus nivolumab. To reduce selection bias, eligible patients will be enrolled consecutively over a period of 24 months. The primary objective is to describe the real-world effectiveness of cabozantinib plus nivolumab in patients with aRCC.
Eligibility criteria
Eligible patients will be at least 18 years of age with a diagnosis of aRCC with a clear-cell component. The physician-initiated decision to treat with cabozantinib plus nivolumab must have occurred prior to inclusion in the study, according to approved local labels. Patients who have received prior systemic treatment for aRCC with a clear-cell component will be excluded. Eligibility criteria are shown in Table 1.
| Inclusion criteria | Exclusion criteria |
|---|---|
| • Diagnosis of aRCC with a clear-cell component • No prior systemic treatment for aRCC • Physician-initiated decision prior to study enrollment to treat with cabozantinib and nivolumab in combination, according to approved local labels • Signed informed consent to participate in this observational study before starting the combination of cabozantinib and nivolumab • Aged ≥18 years on the day of signed informed consent | • Current participation in an investigational program with any intervention that could possibly interfere with the treatment and impact this study • History of allergy or hypersensitivity to components of the study drugs |
Planned study period
The expected duration of the study is 42 months, and patients will be followed until the end of the study or until death, whichever comes first (Figure 2). Recruitment started in September 2022 and is expected to last for 24 months; maximum study participation will vary from 18 months for the last recruited patient, to 42 months for the first recruited patient. Eligibility will be assessed at the treatment initiation visit. During the treatment period, effectiveness and safety assessments as per routine practice at the participating center will be performed approximately every month until month 4, and then every 3 months (±15 days) until discontinuation of both cabozantinib and nivolumab, disease progression, unacceptable toxicity or withdrawal of consent. During the post-treatment follow-up period (from 30 days after discontinuation of cabozantinib plus nivolumab until the end of the study), patients will receive a phone call every 3 months (±15 days) to assess survival status and collect information about subsequent anticancer therapies.
†Treatment will be in accordance with approved local labels for each drug.
aRCC: Advanced renal cell carcinoma; iv.: Intravenous; Q2W: Every 2 weeks; Q4W: Every 4 weeks; QD: Once daily.
Study procedures
Cabozantinib plus nivolumab will each be prescribed in accordance with local Summaries of Product Characteristics. The decision to prescribe cabozantinib plus nivolumab will be made prior to, and independently from, the decision to enroll the patient in this noninterventional study. Participants will receive treatment in line with routine practice at the participating center until disease progression, unacceptable toxicity, or withdrawal of consent. Data will be collected in line with usual procedures at the participating center using an electronic case report form. If some assessments are not routinely performed by the individual investigator, data will be reported as missing. Following treatment discontinuation, participants will enter the post-treatment follow-up period, allowing data to be collected on survival status, use of subsequent therapies, and new adverse events related to cabozantinib and/or nivolumab.
Outcome measures/end points
The primary end point will be OS (death from any cause) at 18 months after cabozantinib plus nivolumab treatment initiation, presented as the proportion of patients alive at 18 months. Secondary end points will include investigator-assessed clinical and radiographic median PFS, investigator-assessed ORR, duration of response (DOR), disease control rate (DCR) and time to response (TTR). Where data are routinely available, changes in disease-related symptoms and pain during the treatment period (assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index Disease Related Symptoms [FKSI-DRS] [32] and the Numerical Pain Rating Scale [NPRS] [33]), patterns of use of cabozantinib and nivolumab, and subsequent anticancer therapies will also be evaluated. Participating centers will be asked to conduct FKSI-DRS at their discretion. A full list of secondary end points is provided in Table 2.
| Primary study end point • OS (death from any cause) at 18-month follow-up from the start of cabozantinib plus nivolumab |
| Secondary effectiveness end points • Investigator-assessed clinical and radiographic median PFS†, defined as the time between the start date of cabozantinib plus nivolumab and the date of progression or death of any cause • Investigator-assessed ORR, DOR, DCR and TTR, defined as: ○ ORR: proportion of participants who achieve partial or complete response† ○ DOR: interval from the date of first response (complete or partial) to treatment with cabozantinib plus nivolumab to progressive disease or death† ○ DCR: proportion of participants who achieve complete response, partial response or stable disease† ○ TTR: time between the start date of cabozantinib plus nivolumab and the date of first response (complete or partial)† • Patterns of use of cabozantinib in real-world practice conditions ○ Starting dose, dose reductions and reasons for reduction ○ Duration of treatment ○ Treatment interruptions and reasons ○ Treatment discontinuations and reasons • Patterns of use of nivolumab in real-world practice conditions ○ Dose and date of infusion ○ Whether infusions are performed on time or with a delay‡ ○ Duration of treatment ○ Reasons for delay or discontinuation of treatment • Changes in disease-related symptoms and pain during the treatment period, assessed using the FKSI-DRS questionnaire and the NPRS§ • Subsequent anticancer therapies following cabozantinib plus nivolumab discontinuation ○ Sequences of treatments ○ Drug names and duration of treatment ○ Reason for end of treatment line |
| Safety end points • Incidence of treatment-emergent AEs and SAEs during the treatment period (from baseline until 30 days after discontinuation of cabozantinib plus nivolumab); and any new AEs and SAEs assessed as related to cabozantinib and/or nivolumab that start during the post-treatment follow-up period |
Planned sample size
The sample size for the study was calculated based on the primary end point. In the phase III CheckMate 9ER trial, the OS at 18 months was 79% for cabozantinib plus nivolumab [15]. However, because a lower OS may be anticipated in a real-world study than in a randomized controlled trial, the sample size calculations were based on an OS at 18 months of 75%. A sample of 289 participants would be required to estimate a two-sided 95% CI for an OS at 18 months of 75% with a precision of ± 5%; therefore, assuming that 7% of participants will be non-evaluable for the primary end point (e.g., owing to early withdrawal), a total of 311 participants will be included in the study.
Statistics
Given that this is a non-interventional study, no formal statistical testing will be performed; all analyses will be descriptive in nature. When appropriate, two-sided 95% CIs will be provided. If p-values are presented, they will be for exploratory purposes only.
The primary end point of OS at 18 months will be estimated in the full analysis set (all included participants who receive at least one dose of cabozantinib plus nivolumab) and presented with its 95% CI. OS from the first dose of cabozantinib plus nivolumab until the patient's death will be analyzed using standard survival analysis methods including the Kaplan–Meier product-limit survival curve. The Kaplan–Meier method will also be used to estimate median PFS, median TTR and median DOR, which will each be presented with associated 95% CIs. Estimates of ORR and DCR will be presented with associated 95% CIs, calculated using the Clopper–Pearson exact method.
Concomitant therapies and subsequent anticancer treatments will be coded using the World Health Organization Drug Dictionary and summarized descriptively by drug class and name. Patterns of cabozantinib and nivolumab use will be summarized individually and analyzed descriptively, including data on treatment duration, starting dose and dose reductions, interruptions, or discontinuation with the associated reasons.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Quality-of-life analyses will be conducted using the FKSI-DRS questionnaire and NPRS. Descriptive statistics will be provided for scores at each time point and for change from baseline; comparisons between baseline and post-baseline scores will be performed using paired Student's t-tests.
Two interim analyses will be undertaken during the study: the first when at least 50% of participants (n = 155) have been included (a description of baseline characteristics only) and the second when at least 50% of included participants (n = 155) have completed at least 12 months of follow-up. Results of these interim analyses are for communication purposes and will not affect study design or conduct.
Ethics
The study will be performed in compliance with the recommendations of the Declaration of Helsinki, and the International Ethical Guidelines for Epidemiological Studies from the Council for International Organizations of Medical Sciences [34], as well as any applicable local regulatory requirements.
Conclusion
CaboCombo is an international prospective non-interventional study that will assess the real-world effectiveness and tolerability of first-line cabozantinib plus nivolumab in 311 adults with clear-cell aRCC. Results will provide insight into the characteristics, treatment sequences and outcomes of patients with aRCC receiving first-line cabozantinib plus nivolumab.
Cabozantinib plus nivolumab was approved in Europe and the USA in 2021 for the first-line treatment of patients with advanced renal cell carcinoma (aRCC) based on data from the phase III CheckMate 9ER trial (NCT03141177).
Background & rationale
Given that phase III trials are typically conducted in highly selected patient populations, using tightly controlled treatment and monitoring protocols, it is important to also assess clinical outcomes, effectiveness and tolerability of newly approved treatments in real-world patients managed in routine clinical practice.
CaboCombo trial
Here we describe CaboCombo, a prospective observational study that will evaluate the real-world effectiveness and tolerability of first-line cabozantinib plus nivolumab in adults with aRCC with a clear-cell component in at least 70 centers worldwide.
End points
The primary outcome will be overall survival at 18 months after cabozantinib plus nivolumab treatment initiation.
Secondary end points will include median progression-free survival, objective response rate, duration of response, disease control rate, time to response, pattern of use of cabozantinib and nivolumab and treatment-emergent adverse events, as well as changes in disease-related symptoms and pain during the treatment period and subsequent anticancer therapies following cabozantinib plus nivolumab discontinuation.
Consecutive recruitment of eligible patients was initiated in September 2022 and will continue for 24 months. The planned duration of the study is 42 months.
Conclusion
Data from this real-world study will provide insight into the factors that drive clinical decision-making in patients with aRCC in routine practice.
Author contributions
All named authors have made substantial contributions to the conception and design of the study and have contributed towards drafting this article or revising it critically for important intellectual content. All authors have provided final approval of the publication and have given their approval of this version for publication. They have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Acknowledgments
The authors thank all patients who will be involved in this study, as well as their caregivers and care teams, and the investigators and research staff of the participating institutions.
Financial disclosure
This study, manuscript development and open-access fee were funded by Ipsen. P Barthe´ le´my has received advisory board fees from Amgen, AstraZeneca, BristolMyers Squibb, Ipsen, Janssen-Cilag, Merck, MSD Oncology, and Pfizer, travel grants from Astellas Pharma, Bristol Myers Squibb, Ipsen, Janssen-Cilag, MSD, and Pfizer, honoraria from Astellas Pharma, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Merck KGaA, MSD, Novartis, Pfizer, and Seattle Genetics.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.
Competing interests disclosure
P Dutailly, B Qvick, and V Perrot are employees of Ipsen. E Verzoni has received advisory board and speaker's bureau fees from Ipsen, Janssen, Merck, and MSD. 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.
Writing disclosure
The authors thank L Sloan and E Bolton of Oxford PharmaGenesis, Oxford, UK for providing medical writing support, which was sponsored by Ipsen in accordance with Good Publication Practice guidelines (GPP 2022).
Ethical conduct of research
This noninterventional study involving human participants will be performed in compliance with the recommendations of the Declaration of Helsinki and the International Ethical Guidelines for Epidemiological Studies from the Council for International Organizations of Medical Sciences, as well as any local regulatory requirements applicable.
Previous presentations
Presented at: American Society of Oncology (ASCO) Genitourinary Cancers Symposium, February 16-18 2023, San Fransisco, CA, USA [35]
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
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