Pooja Ghatalia

QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors

Background:Multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are known to cause cardiac toxicity, but the relative risk (RR) of QTc interval prolongation and serious arrhythmias associated with them are not reported.Methods:We conducted a trial-level meta-analysis of randomised phase II and III trials comparing arms with and without a US Food and Drug Administration-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib and regorafenib). A total of 6548 patients from 18 trials were selected. Statistical analyses were conducted to calculate the summary incidence, RR and 95% CIs.Results:The RR for all-grade and high-grade QTc prolongation for the TKI vs no TKI arms was 8.66 (95% CI 4.92–15.2, P<0.001) and 2.69 (95% CI 1.33–5.44, P=0.006), respectively, with most of the events being asymptomatic QTc prolongation. Respectively, 4.4% and 0.83% of patients exposed to VEGFR TKI had all-grade and high-grade QTc prolongation. On subgroup analysis, only sunitinib and vandetanib were associated with a statistically significant risk of QTc prolongation, with higher doses of vandetanib associated with a greater risk. The rate of serious arrhythmias including torsades de pointes did not seem to be higher with high-grade QTc prolongation. The risk of QTc prolongation was independent of the duration of therapy.Conclusions:In the largest study to date, we show that VEGFR TKI can be associated with QTc prolongation. Although most cases were of low clinical significance, it is unclear whether the same applies to patients treated off clinical trials.

Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors

A systematic review and meta-analysis was conducted to determine the relative risk (RR) of congestive heart failure (CHF) associated with approved multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). Eligible studies included randomized trials comparing arms with and without an FDA-approved VEGFR TKI. Statistical analyses calculated the relative risk (RR) and 95% confidence intervals (CI). A total of 10,647 patients from 16 phase III trials and 5 phase II trials were selected. All grade CHF occurred in 138 of 5752 (2.39%) patients receiving VEGFR TKIs and 37 of 4895 (0.75%) patients in the non-TKI group. High-grade CHF occurred in 17 of 1426 (1.19%) patients receiving VEGFR TKIs and 8 of 1232 (0.65%) patients in the non-TKI group. The RR of all grade and high-grade CHF for the TKI vs. no TKI arms was 2.69 (p<0.001; 95% CI: 1.86 to 3.87) and 1.65 (p=0.227, 95% CI: 0.73 to 3.70), respectively. The RR of relatively specific TKIs (axitinib) was similar to relatively non-specific TKIs (sunitinib, sorafenib, vandetanib, pazopanib).

Pancreatitis with vascular endothelial growth factor receptor tyrosine kinase inhibitors

A trial-level meta-analysis was conducted to determine the relative risk (RR) of pancreatitis associated with multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). Eligible studies included randomized phase 2 and 3 trials comparing arms with and without an FDA-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib, regorafenib). Statistical analyses calculated the RR and 95% confidence intervals (CI). A total of 10,578 patients from 16 phase III trials and 6 phase II trials were selected. The RR for all grade and high-grade pancreatitis for the TKI vs. no TKI- arms was 1.95 (p=0.042, 95% CI: 1.02 to 3.70) and 1.89 (p=0.069, 95% CI: 0.95 to 373), respectively. No differential impact of malignancy type or specific TKI agent was seen on RR of all grade of high grade pancreatitis. Better patient selection and monitoring may mitigate the risk of severe pancreatitis.

High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes.

Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM’s and MAPKAPK’s in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.

Hepatotoxicity with vascular endothelial growth factor receptor tyrosine kinase inhibitors: A meta-analysis of randomized clinical trials

A meta-analysis of randomized controlled trials (RCT) was conducted to determine the relative risk (RR) of hepatotoxicity with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). Citations from PubMed/Medline, abstracts from major conferences, clinicaltrials.gov and package inserts were reviewed to include RCTs comparing arms with or without a VEGFR TKI. The RRs of all-grade ALT, AST, ALP and bilirubin elevation in 18,282 patients from 52 trials were 1.57 (95% CI 1.38-1.79, p<0.001), 1.57 (95% CI 1.36-1.81, p<0.001), 1.20 (95% CI 1.09-1.83, p<0.001) and 1.55 (95% CI 1.21-1.97, p<0.001) respectively, and high-grade elevations were 1.66 (95% CI 1.25-2.20, p=0.001), 1.61 (95% CI 1.21-2.14, p=0.001), 1.02 (95% CI 0.70-1.47, p=0.932) and 1.34 (95% CI 1.0-1.81, p=0.054) respectively compared to those in the non-TKI group. The incidence of hepatic failure with VEGFR TKIs was 0.8%.

Checkpoint Inhibitors for the Treatment of Renal Cell Carcinoma

Opinion statementThe advent of checkpoint inhibitors has revolutionized systemic therapy for many malignancies, including renal cell carcinoma (RCC) where multiple PD-1, PD-L1, and CTLA-4 inhibitors have demonstrated responses and improved survival for patients in clinical trials. Durable benefit with manageable toxicity can be achieved with these agents—but unfortunately for only a minority of individuals. Efforts are ongoing to understand mechanisms driving the response and resistance to checkpoint inhibitors in order to personalize therapy and extend benefit to more patients. In particular, combination immunotherapy is an area of active study with multiple ongoing trials in RCC. Novel immunotherapeutic agents are being explored as well. Clinically, there are nuances related to the use of immunotherapy that are important to understand in order to provide optimal care to patients. Potential autoimmune toxicities are important to identify early so they can be best mitigated with immunosuppression, and careful review of imaging with clinical correlation is important to ensure responding patients are not taken off treatment prematurely due to “pseudo-progression.” Lastly, although immunotherapy is an important new tool, it exists among other active agents in the treatment of RCC, and further study is needed to understand where it best fits in the treatment paradigm. In this article, we review the most recent data for immune checkpoint inhibitors in metastatic renal cell carcinoma and more broadly discuss the rapidly evolving landscape of immunotherapy in RCC, including combination immunotherapies.

Checkpoint inhibitors for renal cell carcinoma: current landscape and future directions

Immunotherapy with checkpoint inhibitors has arrived and begun to change the landscape of clinical oncology, including for patients with renal cell carcinoma. Specifically, drugs targeting the programmed death 1 and cytotoxic T-lymphocyte associated antigen pathways have demonstrated remarkable responses for patients in clinical trials. In this article, we review the most recent available data for immune checkpoint inhibitors for patients with renal cell carcinoma. We discuss potential strategies for rational combination therapies in these patients, some of which are currently being studied, and address important future considerations for use of these novel agents in the years to come.

Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA

Biomarker‐guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell‐free circulating DNA (cfDNA) next‐generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC).

Meta-analysis of regression of advanced solid tumors in patients receiving placebo or no anti-cancer therapy in prospective trials

BACKGROUND A meta-analysis of prospective trials systematically investigated regression of advanced solid tumors in patients receiving placebo or no anticancer therapy to inform on spontaneous regressions. PATIENT AND METHODS Arms of randomized controlled trials (RCTs) of metastatic solid tumors receiving placebo or no anti-cancer therapy were used. Statistical analyses were conducted to calculate the overall response rate (ORR) and to detect differentials based on histology, progression at baseline and prior therapies. RESULTS A total of 7676 patients were evaluable from 61 RCTs evaluating 18 solid tumors. The ORR was 1.95% (95% CI: 1.52-2.48%). There was no significant effect of histology (p=0.110), baseline progressive disease (p>0.20) or the line of therapy (p>0.20) on ORR. CONCLUSIONS Spontaneous regressions are seen across all advanced solid tumors. Some malignancies demonstrated higher rates of spontaneous regressions and may be relatively immunotherapy responsive.

Fatigue with vascular endothelial growth factor receptor tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors in patients with renal cell carcinoma (RCC) and other malignancies: A meta-analysis of randomized clinical trials

A trial-level meta-analysis of randomized phase II/III controlled trials in renal cell carcinoma (RCC) and other malignancies was conducted to systematically determine the relative risk (RR) of fatigue, a common side effect associated with single agent therapy with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) and mammalian target of rapamycin inhibitors (mTORi). The RR of all grade fatigue and high grade fatigue in 7304 patients from 19 trials was 1.35 (95% CI 1.22-1.49, p<0.001) and 1.33 (95% CI 0.97-1.82, p=0.08), respectively in patients receiving VEGFR TKIs or mTORi. The summary incidence of all grade and high grade fatigue in the drug arm was 38.2% (95% CI 31.8-45.1) and 4.0% (95% CI 2.8-5.7), respectively. The type of drug (VEGFR TKI vs. mTORi), line of therapy, age, type of tumor (RCC vs. others) and median duration of therapy did not affect the risk of all-grade fatigue.