The efficacy and safety of cabozantinib in patients with metastatic or advanced renal cell carcinoma: a systematic review and meta-analysis.

Background: Cabozantinib, a new first-line treatment for advanced renal cell carcinoma (aRCC), targets essential tyrosine kinases and outperforms the established comparator (sunitinib) in various efficacy outcomes. This systematic review and meta-analysis aimed to assess the efficacy and safety of cabozantinib compared to other aRCC treatments. Methods: Following PRISMA and Cochrane guidelines, our protocol was registered in PROSPERO. A systematic search, without date limits, was conducted on PubMed, Cochrane, Web of Science, and EMBASE until October 8, 2023. Data extraction encompassed study details, baseline information, and outcomes. Hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals were employed for each outcome, and a random-effects model was applied to account for expected heterogeneity. Results: Three studies, encompassing 967 patients, were included in our analysis. In terms of efficacy, the pooled rate for overall survival significantly favored cabozantinib. However, in subgroup analyses, cabozantinib was only statistically superior to everolimus. For progression-free survival and tumor objective response rate, cabozantinib outperformed both everolimus and sunitinib. In adverse events, compared to sunitinib, cabozantinib exhibited inferiority in nearly all evaluated aspects, except for nausea and stomatitis, which showed no difference between the two groups. Conversely, it demonstrated a comparable risk profile with everolimus across various side effects. Conclusion: Cabozantinib shows significant efficacy in extending overall survival, progression-free survival, and tumor objective response rate despite a potentially higher risk of adverse events compared to sunitinib. These findings support cabozantinib as a first-line therapy for aRCC, either as an initial treatment or after prior VEGFR-targeted therapies.

Zanzalintinib (XL092): a next-generation tyrosine kinase inhibitor-comprehensive review of early safety & efficacy data.

INTRODUCTION: Zanzalintinib (XL092) is a next-generation anti-VEGFR-related multi-targeted TKI that exhibits immunomodulatory effects. AREAS COVERED: This review explores preclinical and clinical data, along with the future directions associated with zanzalintinib and its combination with immune checkpoint inhibitors (ICIs). EXPERT OPINION: In addition to its anti-VEGFR activity, zanzalintinib demonstrates potential synergistic effects with ICIs through its immunomodulatory impact, attributed to its inhibition of MET and TAM kinases. Recent preclinical studies provide compelling evidence supporting this synergistic potential. Furthermore, a recent phase 1 dose escalation study confirmed the tolerability of the zanzalintinib and anti-PDL1 combination without major safety concerns.Multiple ongoing clinical trials are investigating the combination of zanzalintinib and ICIs across various solid tumor types, including phase 3 studies for renal cell carcinoma, colorectal, and head and neck cancer. These trials aim to elucidate the therapeutic role of this new-generation TKI and ICI combination.However, the identification of reliable predictive biomarkers for the zanzalintinib and ICI combination presents significant challenges. Given the intricate nature of their mechanistic rationale and the difficulties in identifying reliable biomarkers for combined anti-angiogenesis and ICI therapies, addressing this challenge remains a priority for ongoing and future research.

Cabozantinib plus ipilimumab/nivolumab in patients with previously treated advanced differentiated thyroid cancer.

BACKGROUND: This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) (NCT03914300). METHODS: Eligible patients with RAI-refractory DTC who progressed on 1 prior line of VEGFR-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2. RESULTS: Among 11 patients enrolled, the median age was 69 years. Prior VEGFR-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 7.9 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months [95% CI: 3.0, not reached] and median overall survival was 19.2 months [(95% CI: 4.6, not reached]. Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold. CONCLUSION: CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs. CLINICAL TRIAL REGISTRATION: NCT03914300.

Changes in outcome of patients with advanced non-clear cell renal cell carcinoma from the tyrosine kinase inhibitor era to the immuno-oncology era.

BACKGROUND: The therapeutic benefit of immuno-oncology (IO) therapy for patients with advanced non-clear-cell renal cell carcinoma (nccRCC) remains unclear. PATIENTS AND METHODS: We reviewed clinical data from 93 patients with advanced nccRCC who received first-line systemic therapy including IO combination therapy and tyrosine kinase inhibitor (TKI) monotherapy at our affiliated institutions. Patients were divided based on the period when the treatment was implemented as the standard of care into the IO and TKI eras. Survival and tumor response outcomes were compared between the IO and TKI eras. RESULTS: Of the 93 patients, 50 (54%) and 43 (46%) were categorized as IO era and TKI era groups, respectively. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the IO era than in the TKI era (median PFS: 8.97 vs. 4.96 months, p = 0.0152; median OS: 38.4 vs. 13.5 months, p = 0.0001). After the adjustment using other covariates, the treatment era was an independent factor for PFS (hazard ratio: 0.59, p = 0.0235) and OS (hazard ratio: 0.27, p < 0.0001). Objective response and disease control rates was not significantly different between the treatment eras (26% vs. 16.3%, p = 0.268; 62% vs. 62.8%, p = 0.594). CONCLUSION: The implementation of IO therapy was significantly associated with longer survival in the nccRCC population. Further studies are needed to establish a more effective treatment strategy in this population using multiple regimens of IO combination therapy.

L2086F Mutant ROS1-Rearranged NSCLC Resistant to Repotrectinib Responds to Cabozantinib: A Case Report.

Repotrectinib, licensed in November 2023, is a novel ROS1 tyrosine kinase inhibitor (TKI) with activity against G2032R, the most common resistance mutation to prior generations of ROS1 TKIs. Here, we report a case of a patient who was heavily pretreated, with advanced L1951R and L2026M mutated ROS1-rearranged NSCLC, who initially responded to repotrectinib but later developed further on-target resistance with the emergence of an L2086F mutation. The disease then responded to cabozantinib, a separate class of ROS1 TKI with preclinical activity against L2086F.

Final Analysis of a Noninterventional Study on Cabozantinib in Patients With Advanced Renal Cell Carcinoma After Prior Checkpoint Inhibitor Therapy of the German Interdisciplinary Working Group on Renal Tumors (IAG-N).

BACKGROUND: Efficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC). OBJECTIVE: To evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies. DESIGN, SETTING AND PARTICIPANTS: Patients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany. INTERVENTIONS: Cabozantinib was administered as a standard of care. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized. RESULTS AND LIMITATIONS: About 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study. CONCLUSIONS: Cabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment.

A fatal case of cabozantinib-induced cardiomyopathy.

Cabozantinib, a multi-kinase receptor inhibitor, is utilized in the treatment of advanced malignancies such as metastatic renal cancers. While rare, cabozantinib-induced cardiotoxicity has emerged as a recognized adverse effect with potentially reversible outcomes. We report the case of a 55-year-old male who developed fatal cardiomyopathy 4 months after initiating cabozantinib therapy. Despite its rarity, cardiomyopathy after initiation of cabozantinib can be lethal if not diagnosed early. This case underscores a significant gap in the surveillance of patients treated with newer agents like cabozantinib. Larger observational studies are needed to assess the prevalence and impact of cardiomyopathy after initiation of cabozantinib therapy, and to determine the cost-effectiveness of early surveillance protocols.

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Comparison of the Efficacy and Safety of Nivolumab Plus Cabozantinib versus Sunitinib in the Treatment of Elderly Patients with Advanced Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Advanced clear cell renal cell carcinoma (ccRCC) seriously affects the life and health of patients, but effective treatment for this disease is still lacking in clinic. This study investigated the efficacy of nivolumab plus cabozantinib versus sunitinib in the treatment of elderly patients with advanced ccRCC. METHODS: The clinical data of 216 elderly patients with advanced ccRCC in our hospital from January 2020 to January 2022 were retrospectively analysed. On the basis of different treatment regimens, patients were divided into the cabozantinib group (n = 111, receiving nivolumab and cabozantinib) and the sunitinib group (n = 105, receiving nivolumab and sunitinib). The overall survival time, disease control rates, health status, incidence of adverse events and identification of prognostic risk were compared between the two groups. RESULTS: The cabozantinib group had higher overall survival time, disease control rate and scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index and EuroQol-Five Dimensions-Three Levels Questionnaire than the sunitinib group. The incidence of adverse events in the cabozantinib group was lower than that in the sunitinib group (p < 0.001). However, no difference existed in the identification of prognostic risk between the two groups (p > 0.05). CONCLUSIONS: The effect of nivolumab plus cabozantinib on the treatment of elderly patients with advanced ccRCC is better than that of nivolumab plus sunitinib, with fewer adverse reactions and higher safety. However, the research results require further clinical studies to confirm and promote.

Pathological concordance rate and outcomes by subtype in advanced papillary renal cell carcinoma.

OBJECTIVE: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. METHODS: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression-free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. RESULTS: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. CONCLUSIONS: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. PATIENT SUMMARY: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial.

Efficacy and safety of multikinase inhibitors for patients with refractory thyroid cancer: Systematic review and network meta-analysis.

CONTEXT: Multikinase inhibitors (MKIs) improve the treatment of refractory thyroid cancer, included radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and advanced medullary thyroid carcinoma (aMTC). OBJECTIVE: This study aims to compare the efficacy of MKIs in improving survival outcomes and safety. DATA SOURCES: Comprehensive database searches of MEDLINE via PubMed, EMBASE and Cochrane performed from inception to December 2023. STUDY SELECTION: Three independent authors selected these studies. Randomised-controlled trials that compared the use of a MKI to other MKIs or placebo were included. DATA EXTRACTION AND SYNTHESIS: This review followed PRISMA guidelines. Risk of bias was analyzed using the Cochrane RoB 2 tool. Bayesian network meta-analysis was performed. Treatments were grouped into common nodes based on the type of MKI. MAIN OUTCOMES AND MEASURES: Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate, disease control rate, clinical benefit rate, and adverse events. RESULTS: Cabozantinib 60 mg/d (CAB60) was associated with the highest prolonged PFS in RAIR-DTC patients, followed by lentivatinib 18 or 24 mg/d (LEN18 or LEN24), and apatinib. PFS was also improved in in aMTC patients received CAB 140 mg/d (CAB140), CAB60, or anlotinib. A significantly greater improvement on the performance of OS was seen in CAB60, LEN24, anlotinib, and sorafenib in RAIR-DTC patients, but which in aMTC patients were lack of statistical differences. Compared with the low-dose of MKIs, high-dose of MKIs such as CAB, LEN, and vandetanib increased the incidence of adverse events. CONCLUSION: CAB60, LEN, and apatinib are promising topical MKIs with statistically significant primary outcomes in RAIR-DTC patients, while CAB and anlotinib are effective in prolonging PFS in aMTC patients.

Small molecule tyrosine kinase inhibitors approved for systemic therapy of advanced hepatocellular carcinoma: recent advances and future perspectives.

Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC.

Prognostic Impact of the Administration of Antibiotics and Proton Pump Inhibitors in Immune Checkpoint Inhibitor Combination Therapy for Advanced Renal Cell Carcinoma.

Background/Aim: The prognostic impact of the administration of antibiotics and proton pump inhibitors (PPIs) in immune checkpoint inhibitor (ICI) therapy for advanced cancer has recently been documented. However, how these drugs affect the outcomes of first-line ICI combination therapy for advanced renal cell carcinoma (RCC) remains unclear. Patients and Methods: We retrospectively evaluated the data of 128 patients with RCC who received first-line ICI combination therapy. The patients were grouped according to their history of antibiotics and PPIs use one month before the initiation of ICI combination therapy. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) after ICI combination therapy were compared between patients treated with and without antibiotics or PPIs. Results: Of the 128 patients, 30 (23%) and 44 (34%) received antibiotics and PPIs, respectively. Patients treated with antibiotics exhibited shorter PFS and OS compared to those who did not receive antibiotics (median PFS: 4.9 vs. 16.1 months, p<0.0001; OS: 20.8 vs. 49.0 months, p=0.0034). Multivariate analyses showed that antibiotic administration was an independent predictor of shorter PFS (hazard ratio: 2.54: p=0.0002) and OS (hazard ratio: 2.56: p=0.0067) after adjusting for other covariates. In contrast, there were no significant differences in either PFS or OS between patients who received PPIs and those who did not. (PFS: p=0.828; OS: p=0.105). Conclusion: Antibiotics administration before ICI combination therapy was negatively associated with outcomes of first-line ICI combination therapy for advanced RCC. Therefore, careful monitoring is required for potentially high-risk patients undergoing ICI combination therapy.

Management of metastatic pheochromocytomas and paragangliomas: when and what.

Recently, the treatment landscape for metastatic pheochromocytomas and paragangliomas (MPPGL) has seen both progress and setbacks. We provide an up-to-date review of the multimodality management of MPPGL and discuss novel opportunities and current challenges in the treatment landscape. Given the unique clinical presentation of MPPGL, we discuss the management of hormone-related clinical sequelae and traditional modalities of therapy. Advances in the understanding of the molecular biology of these diverse tumors have enabled novel strategies such as augmenting DNA damage by targeted delivery of radionuclides such as 131I and 177Lu, abrogating tumor angiogenesis, hypoxia resistance, and DNA damage repair. Despite progress, we address the significant challenges still faced by patients and researchers engaged in efforts to improve outcomes in these rare cancers.

APG-1252 combined with Cabozantinib inhibits hepatocellular carcinoma by suppressing MEK/ERK and CREB/Bcl-xl pathways.

BACKGROUND AND PURPOSE: Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied. EXPERIMENTAL: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo. KEY RESULTS: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib. CONCLUSION AND IMPLICATIONS: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.

Cabozantinib use in second or subsequent line of treatment in renal cell carcinoma: an analysis of Italian administrative databases.

Background: Cabozantinib use in everyday clinical practice for advanced or metastatic renal cell carcinoma (RCC) is relatively recent, and real-world data on treatment persistence, adherence and sequencing are still limited. Methods: We conducted an analysis based on an integrated administrative database, covering around 6.9 million health-assisted Italian individuals, to explore the use of cabozantinib for RCC. Patients with at least one prescription for cabozantinib during 2017-2020 were searched. These were characterized during all available period (i.e. from 2010 onwards) before the index date and were observed after inclusion. Results: A total of 113 patients treated with cabozantinib in second or subsequent line were included, and their demographic, clinical and treatment characteristics were described. About half of these RCC patients were aged >65 years (47.8%). Sixty patients (53.1%) were highly adherent to cabozantinib therapy, and the median cabozantinib treatment duration of use was 8.7 months (95% confidence interval: 5.8-11.1). During the first year of follow-up, the average total cost per patient was €32,508. Conclusions: We described second or subsequent line cabozantinib treatment for RCC in a real-world setting and the economic burden of disease in Italy, taking advantage of large, integrated administrative databases.

Challenges in treating radioiodine-refractory thyroid cancer: a global perspective with a focus on developing nations in Latin America.

PURPOSE: This article aims to comprehensively analyze the unique challenges in managing patients with metastatic Differentiated Thyroid Cancer (DTC) that develop radioiodine-refractory disease, especially in developing countries in Latin America. We discuss key contentious aspects of their treatment, such as the optimal timing for initiating systemic therapy, the choice of first-line medications, the appropriate timing for requesting molecular interrogation, and the challenges associated with accessing these drugs and molecular panels. METHODS: To illustrate these challenges and enhance understanding, we present five real clinical cases from the authors' experiences. RESULTS: Patients with Differentiated Thyroid Cancer (DTC) generally have an excellent prognosis, with an overall 10-year survival rate exceeding 97%. However, approximately 5% of DTC patients, especially those with distant metastases, may develop radioiodine-refractory disease, reducing survival rates. Access to medications remains difficult and time-consuming, particularly for patients within the public healthcare system. Urgent discussions on drug pricing involving all stakeholders are imperative. To break free from complacency, stakeholders must prioritize patient well-being by advocating for evidence-based drug pricing, increased participation in clinical trials, and streamlined regulatory processes. CONCLUSION: Beyond the recognized need for prospective randomized clinical trials to determine the optimal first-line drug and the timing of molecular testing, this type of manuscript plays a pivotal role in stimulating discussions and disseminating comprehensive knowledge about the challenges associated with treating and monitoring patients with radioiodine-refractory thyroid carcinoma, especially in developing countries.

Cabozantinib in combination with immune checkpoint inhibitors for renal cell carcinoma: a systematic review and meta-analysis.

Context: Cabozantinib combined with immune checkpoint inhibitors (ICIs) has brought a new therapeutic effect for the medical treatment of renal cell carcinoma (RCC). Objectives: We performed a meta-analysis of randomized controlled trials and single-arm trials to evaluate the efficacy and safety of cabozantinib plus ICIs in RCC. Methods: We extracted data from PubMed, Cochrane, Medline and Embase databases, and rated literature quality through Cochrane risk of bias tool and MINORS. RevMan5.3 software was used to analyze the results of randomized controlled trials and single-arm trials. Results: A total of 7 studies were included. Treatment with cabozantinib plus ICIs improved PFS [HR 0.75, (95%CI: 0.52, 1.08), p = 0.12] and the OS [HR 0.80, (95%CI: 0.60, 1.07), p = 0.13] in randomized controlled trials. Meanwhile, the result of the ORR in randomized controlled trials was [risk ratio (RR) 1.37, (95%CI: 1.21, 1.54), p < 0.00001] and in single-arm trials was [risk difference (RD) 0.49, (95%CI: 0.26, 0.71), p < 0.0001]. Conclusion: Cabozantinib plus ICIs prolonged the PFS and OS, and improved ORR in patients with RCC. Our recommendation is to use cabozantinib plus ICIs to treat advanced RCC, and to continuous monitor and manage the drug-related adverse events. Systematic Review Registration: identifier CRD42023455878.

A phase 1 study of concurrent cabozantinib and cetuximab in recurrent or metastatic head and neck squamous cell cancer.

OBJECTIVES: Epidermal growth factor receptor (EGFR) inhibition with cetuximab is a standard treatment for head and neck squamous cell carcinoma (HNSCC). Activation of the receptor tyrosine kinases AXL, MET and VEGFR can mediate resistance to cetuximab. Cabozantinib, a multikinase inhibitor (MKI) targeting AXL/MET/VEGFR, has demonstrated antitumor activity in preclinical models of HNSCC. This investigator- initiated phase I trial evaluated the safety and efficacy of cetuximab plus cabozantinib in patients with recurrent/metastatic (R/M) HNSCC. MATERIALS AND METHODS: Patients received cetuximab concurrently with cabozantinib daily on a 28-day cycle. Using a 3 + 3 dose-escalation design, the primary endpoint was to determine the maximally tolerated dose (MTD) of cabozantinib. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) RESULTS: Among the 20 patients enrolled, most had prior disease progression on immune checkpoint inhibitors (95 %), platinum-based chemotherapy (95 %), and cetuximab (80 %). No dose-limiting toxicities were recorded and the MTD for cabozantinib was established to be 60 mg. Grade ≥ 3 adverse events occurred in 65 % of patients (n = 13). ORR was 20 %, with 4 partial responses (PRs). Two PRs were observed in cetuximab-naïve patients (n = 4), with an ORR of 50 % in this subgroup. In the overall population, DCR was 75 %, median PFS was 3.4 months and median OS was 8.1 months. CONCLUSION: Cetuximab plus cabozantinib demonstrated a manageable toxicity profile and preliminary efficacy in patients with heavily treated R/M HNSCC. The combination of cetuximab with MKIs targeting the AXL/MET/VEGFR axis warrants further investigation, including in cetuximab-naïve patients.

Cabozantinib Plus Nivolumab in Patients with Non-Clear Cell Renal Cell Carcinoma: Updated Results from a Phase 2 Trial.

Treatment options are limited for patients with non-clear cell renal cell carcinoma (nccRCC). Patients with nccRCC experienced a favorable objective response rate (ORR) in a phase 2 trial of cabozantinib plus nivolumab. We now report updated efficacy and safety results at median follow-up of 34 mo for patients with papillary, unclassified, or translocation-associated RCC. Cabozantinib and nivolumab were administered at standard doses to patients with metastatic nccRCC that had progressed on zero or one line of systemic therapy. The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Forty patients were treated. At median follow-up of 34 mo for survivors, the ORR was 48% (95% confidence interval [CI] 31.5-63.9%). Median PFS was 13 mo (95% CI 7-16); the 12-mo and 24-mo PFS rates were 51% (95% CI 34-65%) and 23% (95% CI 11-37%), respectively. Median OS was 28 mo (95% CI 23-43); the 18-mo and 36-mo OS rates were 70% (95% CI 53-82%) and 44% (95% CI 28-60%), respectively. No new safety signals were seen with cabozantinib and nivolumab. This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic nccRCC.

First-line immunotherapy of metastatic renal cell carcinoma: an updated network meta-analysis including triplet therapy.

OBJECTIVE: To compare the differential efficacy of first-line immune checkpoint inhibitor (ICI)-based combined therapies among patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), as recently, the efficacy of triplet therapy comprising nivolumab plus ipilimumab plus cabozantinib has been published. PATIENTS AND METHODS: Three databases were searched in December 2022 for randomised controlled trials (RCTs) analysing oncological outcomes in patients with mRCC treated with first-line ICI-based combined therapies. We performed network meta-analysis (NMA) to compare the outcomes, including progression-free survival (PFS) and objective response rates (ORRs), in patients with intermediate- and poor-risk mRCC; we also assessed treatment-related adverse events. RESULTS: Overall, seven RCTs were included in the meta-analyses and NMAs. Treatment ranking analysis revealed that pembrolizumab + lenvatinib (99%) had the highest likelihood of improved PFS, followed by nivolumab + cabozantinib (79%), and nivolumab + ipilimumab + cabozantinib (77%). Notably, compared to nivolumab + cabozantinib, adding ipilimumab to nivolumab + cabozantinib did not improve PFS (hazard ratio 1.02, 95% confidence interval 0.72-1.43). Regarding ORRs, treatment ranking analysis also revealed that pembrolizumab + lenvatinib had the highest likelihood of providing better ORRs (99.7%). The likelihoods of improved PFS and ORRs of pembrolizumab + lenvatinib were true in both International Metastatic RCC Database Consortium (IMDC) risk groups. CONCLUSIONS: Our analyses confirmed the robust efficacy of pembrolizumab + lenvatinib as first-line treatment for patients with intermediate or poor IMDC risk mRCC. Triplet therapy did not result in superior efficacy. Considering both toxicity and the lack of mature overall survival data, triplet therapy should only be considered in selected patients.