Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient\'s bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp.

OBJECTIVE: Atezolizumab plus beva-cizumab (AteBev) are an integral part of first-line therapy for unresectable hepatocellular carcinoma (uHCC), whereas no second-line regimen has been developed for these patients. This study evaluated the efficacy of second-line therapy for uHCC following AteBev treatment.
METHODS: Sixty uHCC patients who were administered AteBev therapy were included in the study. Dynamic computed tomography was conducted after 6, 9, and 12 weeks, and blood tests were performed at baseline and after three weeks.
RESULTS: After six weeks of AteBev therapy, 19 patients experienced partial response (PR), 12 had stable disease (SD), and 29 exhibited progressive disease (PD), with an overall response rate (ORR) of 31.7%. Of the 21 patients treated with lenvatinib as second-line treatment, one dropped out, nine experienced a compete response (CR) or PR, and 11 had SD or PD, resulting in an ORR of 45.0%. Serum levels of fibroblast growth factors (FGF)-19 increased substantially following lenvatinib therapy in the CR+PR group, although the levels decreased significantly in the SD+PD group. Soluble FGF-R4 levels did not differ significantly between the CR+PR group and the SD+PD group when assessed before and after lenvatinib treatment.
CONCLUSIONS: Lenvatinib is useful as second-line treatment after Ate/Bev for uHCC patients who do not response to Ate/Bev treatment. Changes in serum FGF-19 levels after three weeks of AteBev therapy may serve as a biomarker for selecting lenvatinib as second-line therapy.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

BACKGROUND: The therapeutic benefit of immuno-oncology (IO) therapy for patients with advanced non-clear-cell renal cell carcinoma (nccRCC) remains unclear.
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).
CONCLUSIONS: 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.

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.
CONCLUSIONS: CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs.
BACKGROUND: NCT03914300.

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.
[Box: see text].

UNASSIGNED: Zanzalintinib (XL092) is a next-generation anti-VEGFR-related multi-targeted TKI that exhibits immunomodulatory effects.
UNASSIGNED: This review explores preclinical and clinical data, along with the future directions associated with zanzalintinib and its combination with immune checkpoint inhibitors (ICIs).
UNASSIGNED: 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.

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.
METHODS: Patients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany.
METHODS: Cabozantinib was administered as a standard of care.
METHODS: 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.
CONCLUSIONS: 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.

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.

OBJECTIVE: 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.
CONCLUSIONS: 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.