Growth Factor Tyrosine Kinase Inhibitors Research Articles

Putative mechanisms of primary resistance to EGFR-targeted therapies: A retrospective study

BackgroundsAdvanced lung adenocarcinoma (LUAD) patient with EGFR mutations often experience resistance to first-line epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) therapy. Nonetheless, the mechanism and biomarkers of primary resistance remain unclear. Further exploration of independent prognostic factors will help clinicians identify patients who may not respond to EGFR-TKIs and select appropriate treatment strategies. MethodsA retrospective study involving 124 patients with stage IV LUAD harboring a common sensitizing EGFR mutation (exon 19 deletion or L858R mutation) who received EGFR-TKIs as first-line therapy was performed. All participants were tested by DNA-targeted sequencing in baseline samples, and there were 19 patients with progression-free survival (PFS) ≤ 3 months (cohort 1, C1, primary resistance), 22 patients with 3 < PFS < 8 months (cohort 2, C2, poor response) without known mutations associated with resistance, and 83 patients with PFS ≥ 8 months (cohort 3, C3, normal). ResultsThe most commonly mutated genes at baseline in patients prior to treatment within the entire study population. were TP53 (65 %), MYC (19 %), CDKN2A (12 %), MUC16 (12 %) and RBM10 (12 %). The baseline characteristics, except for the proportions of patients with EGFR L858R mutation and exon 19 deletion in C1 plus C2 compared to C3 (p = 0.036), were not significantly different among the cohorts. The frequencies of PIK3C2G, STK11, EPAS1, RARA and BTG2 variation were significantly higher in C1, the primary resistance group. Multivariate Cox analysis revealed that PIK3C2G (HR 15.70 95 % CI 3.24–76.05, p < 0.001), STK11 (HR 17.04, 95 % CI 3.68–78.92, p < 0.001), EPAS1 (HR 11.99, 95 % CI 2.57–56.03, p = 0.002), and BTG2 amplification (HR 9.53, 95 % CI 1.67–54.28, p = 0.011) were significantly associated with shorter PFS. ConclusionsThe genomic landscape varies significantly among patients with LUAD, which should be considered when making personalized treatment decisions. This information could provide insights into molecular changes and their effects on clinical treatment in diverse patients with LUAD harboring sensitizing EGFR mutations.

FDA Approval Summary: Belzutifan for Patients with Advanced Renal Cell Carcinoma.

On December 14, 2023, the United States Food and Drug Administration (FDA) approved belzutifan (Welireg, Merck & Co., Inc.) for patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 or programmed death-ligand 1 (PD-1/PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). FDA granted traditional approval based on LITESPARK-005 (NCT04195750), an open-label, randomized, head-to-head trial of 746 patients with advanced RCC that progressed following both a PD-1/PD-L1 inhibitor and a VEGF-TKI. Patients were randomized (1:1) to receive belzutifan or everolimus. The primary endpoints were progression-free survival (PFS) assessed by blinded independent central review (BICR) and overall survival (OS). A statistically significant improvement in PFS was demonstrated for belzutifan compared with everolimus [hazard ratio (HR)=0.75 (95% CI: 0.63, 0.90); 1-sided p-value=0.0008]. Kaplan-Meier curves reflected non-proportional hazards with similar median PFS estimates of 5.6 months (95% CI: 3.9, 7.0) in the belzutifan arm and 5.6 months (95% CI: 4.8, 5.8) in the everolimus arm. While not reaching full maturity, OS results appeared to show a favorable trend in the belzutifan arm compared to everolimus [HR=0.88 (95% CI: 0.73, 1.07)]. The confirmed objective response rate by BICR was 22% and 3.6% in belzutifan and everolimus arms, respectively. Observed toxicities differed between treatment arms, but drug discontinuations and interruptions due to treatment-emergent adverse events were lower on the belzutifan arm compared to the everolimus arm, and a descriptive analysis of patient-reported symptom and functional outcomes was suggestive of favorable tolerability for belzutifan compared to everolimus.

Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma

Belzutifan is a first-in-class hypoxia-inducible factor subunit 2α (HIF-2α) inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed cell death protein 1 (PD-1) [or programmed death ligand 1 (PD-L1)] inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether the belzutifan dose could be optimized is unclear. The phase II LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1 : 1 to receive belzutifan 120 or 200 mg once daily. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. The secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 154 patients were enrolled (120 mg: n= 76; 200 mg: n= 78). The median follow-up was 20.1 months (range 14.8-28.4). The ORR was 23.7% versus 23.1% for the 120 mg and 200 mg groups, respectively [P= 0.5312;-0.5%, 95% confidence interval (CI)-14.0% to 12.9%]. The median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS [hazard ratio (HR) 0.94, 95% CI 0.63-1.40] or OS (medians not reached; HR 1.11, 95% CI 0.65-1.90). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group. The efficacy of belzutifan was similar between the 120 mg dose and the 200 mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.

39 Safety profile of belzutifan monotherapy in patients with renal cell carcinoma: A pooled analysis of 4 clinical trials

Abstract Background The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, is indicated in the United States for the treatment of certain patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery and for patients with advanced RCC previously treated with a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. Due to its unique mechanism of action, belzutifan has a distinct safety profile. We characterized the safety profile of belzutifan monotherapy in a post hoc pooled analysis of patients with previously treated advanced clear cell RCC in the phase 1 LITESPARK-001 (NCT02974738), phase 3 LITESPARK-005 (NCT04195750), and phase 2 LITESPARK-013 (NCT04489771) studies and patients with RCC associated with VHL disease in the phase 2 LITESPARK-004 study (NCT03401788). Methods All patients who received ≥1 dose of belzutifan 120 mg orally once daily across the 4 studies were included. Severity of adverse events (AEs) were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 or 5.0, and were descriptively summarized. Results A total of 576 patients were included (n = 58 [including 3 patients with advanced solid tumors other than RCC], LITESPARK-001; n = 381, LITESPARK-005; n = 76, LITESPARK-013; and n = 61, LITESPARK-004). Overall, 572 patients (99.3%) had ≥1 all-cause AE and 355 patients (61.6%) had ≥1 grade 3-5 AE. AEs led to dose modification (reduction, interruption, or discontinuation) in 288 patients (50.0%), although treatment discontinuation for AEs occurred in 37 patients (6.4%). The most common all-grade AEs were anemia (including patients with decreased hemoglobin; n = 485 [84.2%]; grade 3 or 4, n = 166 [28.8%]), fatigue (n = 246 [42.7%]; grade 3, n = 16 [2.8%]), nausea (n = 139 [24.1%]; grade 3, n = 5 [0.9%]), and dyspnea (n = 123 [21.4%]; grade 3 or 4, n = 10 [1.7%]). Hypoxia was reported in 94 patients (16.3%); grade 3 or 4 hypoxia occurred in 57 patients (9.9%). Summary and time to first onset of adverse drug reactions (AEs considered associated with belzutifan), including anemia and hypoxia, are reported in the table. Among 485 patients with anemia or decreased hemoglobin, 111 (22.9%) were treated with erythropoiesis-stimulating agent (ESA) only, 85 (17.5%) were treated with blood transfusions only, and 62 (12.8%) were treated with ESA and blood transfusions. Among 94 patients with hypoxia, 66 (70.2%) were treated with oxygen therapy. Treatment-related AEs occurred in 526 patients (91.3%) and 217 (37.7%) experienced a grade 3-5 treatment-related AE. One grade 5 adverse event (multiple organ dysfunction syndrome) was considered related to treatment. Conclusions To date, this is the largest pooled safety dataset for belzutifan monotherapy in patients with RCC. The results provide an in-depth characterization of the safety profile for belzutifan and the associated AE management strategies.

42 Belzutifan versus everolimus for previously treated advanced clear cell renal cell carcinoma: Subgroup analysis of the phase 3 LITESPARK-005 study

Abstract Background Belzutifan monotherapy is approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) based on the results of the phase 3 LITESPARK-005 study (NCT04195750). In LITESPARK-005, belzutifan improved progression-free survival (PFS; HR 0.75; 95% CI, 0.63-0.90; P &amp;lt; 0.001) and objective response rate (ORR; 21.9% vs 3.5%; P &amp;lt; 0.00001) versus everolimus at first interim analysis (IA1); overall survival (OS) did not reach statistical significance at IA2 (HR 0.88; 95% CI, 0.73-1.07; P = 0.1). We present efficacy outcomes by prespecified subgroups from IA2. Methods Patients with clear cell RCC whose disease progressed after anti–PD-(L)1 and VEGF-targeted therapies and who had 1-3 prior systemic regimens were randomly assigned 1:1 to belzutifan 120 mg by mouth once daily or everolimus 10 mg by mouth once daily until progression or intolerable toxicity. The dual primary end points of PFS by central review per RECIST v1.1 and OS and the key secondary end point of ORR were evaluated by prespecified baseline characteristic subgroups: IMDC risk (favorable vs intermediate/poor), prior VEGF-TKIs (1 vs 2-3), and number of prior lines of therapy (1 vs 2 vs 3). These analyses were not controlled for multiplicity and no formal statistical testing occurred. The database cutoff date was June 13, 2023. Results Overall, 746 patients were assigned to belzutifan (n = 374) or everolimus (n = 372). Baseline characteristics were balanced between groups. Median follow-up was 25.7 months (range, 16.8-39.1). Across analyzed subgroups, PFS and OS results were consistent with the primary analysis (Table). ORR favored belzutifan over everolimus for all subgroups: IMDC favorable risk (22.8% vs 6.0%), IMDC intermediate/poor risk (22.7% vs 2.8%), 1 prior VEGF-TKI (19.7% vs 3.7%), 2 prior VEGF-TKIs (25.7% vs 3.3%), 1 prior line of therapy (28.3% vs 5.8%), 2 prior lines (19.1% vs 2.4%), and 3 prior lines (24.6% vs 3.9%). Conclusions Consistent with the intention-to-treat population of LITESPARK-005, PFS and ORR favored belzutifan over everolimus across prespecified subgroups. These results support belzutifan as a new treatment option for patients with advanced clear cell RCC after prior anti–PD-(L)1 and VEGF-targeted therapies.

Gastrointestinal Cancer Therapy and Cardiotoxicity.

Gastrointestinal cancers are a heterogenous group of cancers that share common risk factors with cardiovascular disease. Therapy for gastrointestinal cancers have improved cancer-specific outcomes at the cost of cardiotoxicity. The most common cardiotoxic therapies utilized in gastrointestinal cancers include conventional chemotherapy (including fluoropyrimidines and anthracyclines), targeted therapies including anti-vascular endothelial growth factor (VEGF) therapy and tyrosine kinase inhibitors (TKI), and immunotherapy. It is important for clinicians managing patients with gastrointestinal cancers to be aware of potential cardiotoxicity associated with these agents.

FDA analysis of immune checkpoint inhibitors in combination with vascular endothelial growth factor tyrosine kinase inhibitors in the second-line treatment of patients with advanced non-small cell lung cancer.

8595 Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 in combination with platinum-based chemotherapy is standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). The majority of these patients progress and there remains a high unmet medical need in the second-line setting given the limited FDA approved available therapies. The ICI plus vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) combination, successful across several tumor types, was studied in NSCLC as a potential treatment option. Methods: The FDA identified 3 randomized trials conducted between June 2019 and August 2023, comparing the combination regimen ICI plus VEGF TKI to docetaxel in patients with advanced NSCLC who had progressed on both platinum-based chemotherapy and an ICI. All 3 trials were publicly reported to have not met their primary endpoint. Topline results for key efficacy and safety outcomes from each of the 3 trials were provided by the commercial sponsors. Results: 1317 total patients across 3 trials (LEAP-008, SAPPHIRE and CONTACT-01) were randomized to receive either an ICI plus VEGF TKI or docetaxel. The results are presented (Table). Efficacy parameters demonstrated similar results across trials between arms. There was no clear signal that the combination is more effective than single agent docetaxel. Safety parameters across trials consistently demonstrated higher rates of toxicity with the combination. Conclusions: ICI plus oral VEGF TKI combinations have not demonstrated an advantage over docetaxel in randomized trials of patients with advanced NSCLC. In 2 of the 3 trials, response rate data did not demonstrate superior efficacy compared to docetaxel. Additionally, any observed PFS benefit was small in magnitude. The relatively low efficacy, in combination with the additive toxicity of the regimen, may curtail a potential OS benefit. There remains a high unmet medical need in this patient population and further analysis is necessary to explore potential NSCLC subgroups which may derive benefit. [Table: see text]

The efficacy and safety of a novel PD-1/CTLA-4 bispecific antibody cadonilimab (AK104) in advanced non-small cell lung cancer: A multicenter retrospective observational study in China.

e20518 Background: Treatment choice for advanced non-small cell lung cancer (NSCLC) after front-line immuno-chemotherapy therapy is limited. As the first approved dual programmed cell death-1(PD-1) / cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) bispecific antibody worldwide, cadonilimab combined with anlotinib, a vascular epidermal growth factor tyrosine kinase inhibitor, showed potential anti-tumor activity in advanced NSCLC patients resistant to anti-PD-1/ programmed cell death ligand-1(PD-L1) antibodies in a phase Ib/II clinical trial. Methods: We retrospectively collectedthe efficacy and safety data in advanced NSCLC patients treated with cadonilimab in later therapy lines. The primary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety results. The secondary endpoints were overall survival (OS). Results: Totally, 41 advanced NSCLC patients who were refractory to previous chemotherapy and anti-PD-1/PD-L1 therapy and treated with later line cadonilimab-based regimens were enrolled. More than half of patients received cadonilimab as a fourth or later line of treatment. Until the data cut-off date (August 29, 2023), the treatment efficacy of 23 patients could be evaluated. One (4.3%) patient had partial response, 8 (34.8%) patients had stable disease, and 14 (60.9%) patients progressed. The ORR and DCR were 4.3% and 39.1%, respectively. The median PFS of all evaluated patients was 108.0 days (95% confidence interval: 62.3-153.7). Due to the short follow-up, median OS has not been reached yet. Treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) occurred in 26(63.4%) and 9(22%) patients, respectively. The most common AEs included gamma-glutamyl transferase elevation (17.1%), coughing (14.6%), and fatigue (12.2%). Five patients (12.2%) experienced grade≥3 AEs. Two patients temporarily paused medication due to Grade 2 rash. One patient and 2 patients permanently discontinued medication due to Grade 3 myocarditis and Grade 2 infusion reactions, respectively. Metabolomics results showed that lipids and lipid-like molecules were rich in stools of patients responsive to cadonilimab treatment. Conclusions: In this heavily treated advanced NSCLC patient cohort, cadonilimab-based regimens only showed moderate anti-tumor efficacy with a generally tolerable and manageable safety profile. More evidence supporting administration of cadonilimab is needed in NSCLC patients refractory to previous anti-PD-1/PD-L1 therapy.

Selection of postoperative adjuvant therapy for patients with stage IB lung adenocarcinoma: analysis of 653 cases

To explore the optimal postoperative adjuvant regimens for patients with stage IB lung adenocarcinoma. We respectively analyzed the data of 653 patients undergoing surgery for stage IB lung adenocarcinoma in our hospital from January, 2013 to December, 2021. The 5-year disease-free survival (DFS) and overall survival (OS) rates were compared among the patients receiving postoperative adjuvant therapy with epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs group, n=111), chemotherapy (CT group, n=108) and clinical observation (CO group, n=434). In TKIs, CT, and CO groups, the 5-year DFS rates were 92.8%, 80.7%, and 81.7%, respectively, significantly higher in TKIs group than in CO group (P < 0.01). The 3-year OS rates of the 3 groups were 96.8%, 97.1%, and 91.7%, respectively. Subgroup analysis showed that in TKIs, CT, and CO groups, the 5-year DFS rates of patients with with T3-4 cmN0M0 were 92.6%, 84.0%, and 81.4%, respectively, significantly higher in TKIs group than in CO group (P < 0.05); the 5-year DFS rates of T2ViscPlN0M0 patients were 95.1%, 71.4%, and 83.5%, respectively. Multivariate COX regression analysis showed that age (P < 0.05; HR=0.631, 95% CI: 0.401-0.993), solid nodules (P < 0.01; HR=7.620, 95% CI: 3.037-19.121), micropapillary or solid component (P < 0.05; HR= 1.776, 95% CI: 1.010-3.122), lymphovascular invasion (P < 0.05; HR=2.981, 95% CI: 1.198-7.419), and adjuvant therapy (P < 0.01) were independent predictors of DFS. The most common adverse effects included rashes, paronychia, and diarrhea for TKIs and hematological suppression and gastrointestinal reactions for chemotherapy, and TKIs were associated with a higher incidence of grade 3 or above adverse effects (44.4% vs 9.0%). Adjuvant therapy with TKIs helps improve DFS in patients with stage IB (T3-4cmN0M0) lung adenocarcinoma but not in patients with T2ViscPlN0M0. Adjuvant chemotherapy does not improve DFS or OS in patients with stage IB lung adenocarcinoma.

Belzutifan (Welireg) for advanced renal cell carcinoma.

Belzutifan (Welireg – Merck), a first-in-class hypoxia-inducible factor inhibitor, has been approved by the FDA for treatment of advanced renal cell carcinoma (RCC) in adults who received prior treatment with a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Belzutifan was previously approved for use in patients with von Hippel-Lindau disease.

Effects of neoadjuvant VEGF‑TKI treatment on surgery for renal cell carcinoma: A systematic review and meta‑analysis.

To evaluate the effects of neoadjuvant vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) treatment on surgery in patients with renal cell carcinoma (RCC), sources from Embase, PubMed and the Cochrane Library databases collected from inception to December, 2022 were used for analysis in the present study, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data regarding surgical outcomes were collected. The pooled effect sizes were calculated in terms of the risk ratio (RR)/standard mean difference (SMD) with 95% confidence intervals (CIs) using the random-effects model. Subgroup and sensitivity analyses were used to explore the source of heterogeneity within the data. In total, 9 identified articles involving 829 patients (336 in the neoadjuvant + surgery group; 493 in the surgery group) were included in the present study, according to the criteria. The results demonstrated that there were no significant differences in blood loss (SMD=-0.11; 95% CI, -0.63-0.41; P=0.68), postoperative length of hospital stay or total length of hospital stay (SMD=0.23; 95% CI, -0.55-1.01; P=0.57) or complications (RR=1.16; 95% CI, 0.80-1.67; P=0.44) between the two groups. However, neoadjuvant therapy reduced the operation time (SMD=-0.67; 95% CI, -1.25- -0.09; P=0.02) and resulted in a greater proportion of patients choosing partial nephrectomy (RR=1.84; 95% CI, 1.47-2.31; P<0.00001). In the subgroup analysis, the blood loss was significantly lower in patients with RCC with inferior vena cava tumor thrombus in the neoadjuvant group (SMD=-1.10; 95% CI, -1.82- -0.38; P=0.003). In conclusion, the results of the present study indicated that neoadjuvant VEGF-TKI treatment in patients with RCC shortened operation time, decreased blood loss and did not cause an increase in perioperative complications. In addition, this treatment modality may encourage patients to opt for partial nephrectomy to preserve renal function.

The feasibility of an educational and monitoring smartphone application for patients with advanced renal cell carcinoma undergoing combination immunotherapy.

413 Background: Renal Cell Carcinoma (RCC) is a global public health burden with over 400,000 new cases and over 175,000 deaths annually. Immune checkpoint inhibitors (ICI) in combination with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKI) has become an integral part of the management of patients with advanced RCC which requires adaptation of healthcare systems to provide information and optimize the management of drug-related adverse events. This study aims to improve the education on therapy-related symptoms and the quality of life of patients with RCC treated with these drugs. Methods: We created a smartphone application (mHealth) that combines educational data, patient-reported outcomes, and peer-to-peer interactions. We aim to assess the feasibility of expansion of this pilot study. We prospectively enrolled stage IV RCC patients (n=20) undergoing treatment with combination ICI and VEGF-TKI. Therapy-related symptom education, knowledge PRO questionnaires, and peer-to-peer support were provided at baseline and at different time points throughout this study duration (Table 1). Time-course data of PROs were visualized using line plots and then compared with paired t-tests. The study's primary endpoint was to assess acceptability and feasibility of mHealth, defined as acceptable if 50% of patients offered participation agree to be enrolled and feasible if 50% of enrolled patients complete the intervention with 70% of these completing at least 50% of survey instruments. Results: Eighty percent of patients were male, 80% were white, 75% had at least some college education, 70% were married, and the mean age of the cohort was 66 years.A total of 22 patients were approached for the study with an acceptance rate of 90%. Sixty percent of patients completed every questionnaire and knowledge assessment at every timepoint of the intervention and 75% of those completed at least 50% of instruments. PROs data showed no significant difference compared to baseline in global health status, functional scales, and symptom scales across the 24 weeks. We noticed an improvement in the patients' knowledge assessment on symptom management after completion of the mHealth knowledge component. Conclusions: Our pilot study was considered acceptable and feasible, showing preliminary evidence of improvement in patient knowledge with mHealth. Our future direction will be to assess, in a larger randomized study, the efficacy of mHealth in improving the quality of life of patients with advanced RCC treated with ICI and VEGF-TKI. Clinical trial information: NCT05579847 . [Table: see text]

Infusion-related reactions with immune checkpoint inhibitors in genitourinary cancers: A systematic review and meta-analysis.

604 Background: Immune checkpoint inhibitors (ICIs) are widely used to treat genitourinary cancers, particularly urothelial carcinoma (UC) and renal cell carcinoma (RCC). Infusion-related reactions (IRRs) have been reported in up to 20% of all patients treated with ICIs. However, the risk of IRRs varies with the type of ICI and the accurate incidence in genitourinary cancers remains unclear. We undertook a systematic review and meta-analysis to determine the incidence of IRRs in patients with genitourinary cancers treated with ICIs. Methods: We performed a systematic search of PubMed/MEDLINE, Embase, and Web of Science to identify phase 3 randomized clinical trials (RCTs) evaluating ICIs (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], programmed cell death protein 1 [PD-1], and programmed death-ligand 1 [PD-L1] inhibitors) in patients with UC and RCC. The odds ratio [OR] of grade 1-5 and grade 3-5 IRRs was calculated and pooled by the random-effect model meta-analysis. Meta-analysis was performed based on study types as follows: 1) Studies with a design “ICI plus treatment A (including placebo/observation) vs. treatment A”, 2) Studies evaluating ICI monotherapy vs. chemotherapy in patients with UC, and 3) Studies assessing ICI plus vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) vs. sunitinib in patients with RCC. When IRRs were reported in studies evaluating oral VEGF-TKIs, IRRs were referred to as hypersensitivity or anaphylactic reactions, defined in each RCT. Results: We identified 12 RCTs with 10,001 participants for the meta-analysis, out of which one evaluated a CTLA-4 inhibitor while the others evaluated PD-1 or PD-L1 inhibitors. The addition of ICIs to other systemic therapies was associated with significantly higher rates of grade 1-5 IRRs (OR=2.90, 95% confidence interval [CI]: 1.16-7.29, p = 0.02) but not of grade 3-5 IRRs (OR=2.98, 95% CI: 0.64-13.74, p = 0.16). When compared to chemotherapy, PD-1 or PD-L1 inhibitor monotherapy was not associated with an increase in either grade 1-5 (OR=0.86, 95% CI: 0.25-2.95, p = 0.81) or grade 3-5 IRRs (OR=1.13, 95% CI: 0.07-18.19, p = 0.93) in patients with UC. When compared to sunitinib in patients with RCC, the combination of ICI plus VEGF-TKIs was not associated with an increase in either grade 1-5 (OR=5.43, 95% CI: 0.62-46.07, p = 0.13) or grade 3-5 IRRs (OR=3.49, 95% CI: 0.64-19.04, p = 0.15). Sensitivity analysis performed by removing studies evaluating avelumab did not alter the overall results (data will be presented). Conclusions: Compared to the previous standard of care without ICIs, therapies with ICIs were not associated with increased IRRs in genitourinary cancers. However, the addition of ICIs to other systemic therapies was associated with an increased incidence of IRRs. The latter merits further prospective evaluation and careful consideration while designing clinical trials.

IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma.

Vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been the standard of care for advanced and metastatic clear cell renal cell carcinoma (ccRCC). However, the therapeutic effect of TKI monotherapy remains unsatisfactory given the high rates of acquired resistance to TKI therapy despite favorable initial tumor response. To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset. Sunitinib-resistant RCC cell lines were established and used to test their malignant behaviors of TKI resistance through in vitro and in vivo studies. Immunohistochemistry was conducted to compare expression between the tumor and normal kidney and verify expression of pathway-related proteins. Integrated differential gene expression analysis revealed increased interferon-induced transmembrane protein 3 (IFITM3) expression in post-TKI samples. IFITM3 expression was increased in ccRCC compared with the normal kidney. TKI-resistant RCC cells showed high expression of IFITM3 compared with TKI-sensitive cells and displayed aggressive biologic features such as higher proliferative ability, clonogenic survival, migration, and invasion while being treated with sunitinib. These aggressive features were suppressed by the inhibition of IFITM3 expression and promoted by IFITM3 overexpression, and these findings were confirmed in a xenograft model. IFITM3-mediated TKI resistance was associated with the activation of TRAF6 and MAPK/AP-1 pathways. These results demonstrate IFITM3-mediated activation of the TRAF6/MAPK/AP-1 pathways as a mechanism of acquired TKI resistance, and suggest IFITM3 as a new target for TKI-resistant ccRCC.

The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassified, and other rare histologies. Due to variations in pathogenesis and therapeutic response, therapy should be tailored to specific variant histologies. For patients with localized nccRCC, surgical resection remains the gold standard. In the metastatic setting, the standard of care has yet to be clearly defined, and most guidelines recommend clinical trial participation. General therapeutic options include immunotherapy, either as monotherapy or in combination, targeted therapies such as vascular endothelial growth factor tyrosine kinase inhibitors and MET inhibitors, and chemotherapy in certain subtypes. Here we present a review of the incidence and pathogenesis of the various subtypes, as well as available clinical data to support therapeutic recommendations for these subtypes. We also highlight currently available clinical trials in nccRCC and future directions in investigating novel treatment modalities tailored to patients with variant histology.

Emerging Antibody-Drug Conjugate Therapies and Targets for Metastatic Renal Cell Carcinoma

Background: Approximately 30% of renal cell carcinoma (RCC) cases present with de novo metastatic disease, while 20% to 30% of those with localized disease will develop metastases following surgical resection. Various drug classes have been investigated to treat RCC, including cytokine-based therapies, small molecule Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibitors (TKIs) and antibody-based therapies. Up to 58% of patients fail to respond to primary immune checkpoint inhibitor (ICI) therapy, and nearly all initial responders experience disease progression due to the development of secondary resistance. Consequently, novel treatment options are being investigated. Objective: Review the rapidly evolving ADC therapeutic landscape in metastatic RCC including recent trials, emerging ADCs targets, and future directions for ADCs in the treatment of advanced RCC. Methods: Literature review using the MEDLINE database on important trials and presentations from the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO) conferences. Key words used included “renal cell carcinoma,” “RCC,” “metastatic RCC,” “advanced RCC,” “antibody-based therapies,” “immunotherapy,” “clinical trials,” and “emerging drugs.” Specifically for review of ADCs in RCC, the following search string was used with additional review of bibliographies from retrieved papers: “((antibody drug conjugate) OR (antibody-dependent cellular cytotoxicity) OR (chimeric antigen receptor)) AND ((kidney cancer) OR (renal cell carcinoma))”. Results: Several promising targets including MMP14, EGFR, MCT4, CA9, MET, CDH13, B7-H3, and PSMA were identified with relevant preclinical and clinical studies reviewed. Conclusions: While ADCs therapeutics have not shown benefit to date for renal cell carcinoma, there are ample promising candidates and targets for future research.

Nephrotoxicity Associated with Contemporary Renal Cell Carcinoma Regimens: A Systematic Review and Meta-Analysis

Background: The nephrotoxicity profile of contemporary first-line regimens for treatment of metastatic renal cell carcinoma (mRCC) has not been systematically studied in published clinical trials. Objective: To assess the rates of nephrotoxic events of contemporary first-line regimens for treatment of mRCC in comparison to vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) mono-therapy. Methods: We performed a systematic search of the literature looking for randomized clinical trials that contemplated National Comprehensive Cancer Network (NCCN) recommended first-line regimens for treating mRCC in which the control arm was a VEGF-TKI. Selected trials could either include an experimental arm of immune checkpoint inhibitor (ICI) plus VEGF-TKI combination or ICI-ICI combination. Nephrotoxic events were defined as proteinuria, hypertension, blood creatinine increase, acute kidney failure or nephritis, which were all described separately. Results: Five studies satisfied our inclusion criteria. Combination of ICI with VEGF-TKI showed a statistically significant higher degree of proteinuria compared to VEGF-TKI alone. There was no statistically significant difference in rates of hypertension between ICI-TKI and VEGF-TKI alone, but VEGF-TKI alone was statistically significantly more associated with hypertension than immunotherapy alone. Other renal toxicities, such as an increase in creatinine, acute kidney injury (AKI) and nephritis, were uncommon and not consistently reported in each trial. Conclusions: Contemporary regimens for first-line treatment of mRCC are associated with a higher grade of proteinuria than VEGF-TKI alone, while VEGF-TKI is more associated with hypertension than an ICI-ICI combination. Description of many renal toxicities across the studies reported have been diverse and a standardized definition across clinical trials would be helpful to reliably interpret the data regarding nephrotoxicity in the setting of treatment of renal cell carcinoma.

A Phase 1/2 Study to Evaluate the Safety and Activity of Nivolumab in Combination With Vorolanib, a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor, in Patients With Refractory Thoracic Tumors

IntroductionTargeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies. MethodsThis single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance). The primary objective of phase 1 was to determine the maximum tolerated dose, and the primary end point for each dose-expansion cohort was the objective response rate. ResultsA total of 88 patients were enrolled in phase 1 (n = 11) and dose expansion (n = 77) cohorts. Transaminitis was dose-limiting and expansion proceeded with oral vorolanib 200 mg daily combined with intravenous nivolumab 240 mg every 2 weeks. The objective response rate per cohort were as follows: NSCLC naive 33% (five of 15, 95% confidence interval [CI]: 13%–60%), NSCLC primary refractory 5.9% (one of 17, 95% CI: 0%–17.6%), NSCLC acquired resistance 11.1% (two of 18, 95% CI: 0%–27.8%); SCLC 0% (zero of 18), and thymic carcinoma 11% (one of nine, 95% CI: 0%–33%). Disease control rate ranged from 11.1% in SCLC (two of 18, 0%–27.8%) to 66.7 % in thymic carcinoma (six of nine, 95% CI: 33.3%–100%). The most common adverse events were fatigue (32%), aspartate transaminase (27%) and alanine transaminase elevation (25%), and diarrhea (19%). Transaminitis was more common in patients with thymic carcinoma than other tumors. ConclusionsVorolanib plus nivolumab had a manageable safety profile and may have clinical benefits in various thoracic malignancies. The disease control rate in thymic malignancies warrants further assessment.

Critical review of the current and future prospects of VEGF-TKIs in the management of squamous cell carcinoma of head and neck.

As the prognosis for squamous cell carcinoma of the head and neck remains unsatisfactory when compared to other malignancies, novel therapies targeting specific biomarkers are a critical emerging area of great promise. One particular class of drugs that has been developed to impede tumor angiogenesis is vascular endothelial growth factor-tyrosine kinase inhibitors. As current data is primarily limited to preclinical and phase I/II trials, this review summarizes the current and future prospects of these agents in squamous cell carcinoma of the head and neck. In particular, the combination of these agents with immunotherapy is an exciting area that may be a promising option for patients with recurrent or metastatic disease, evidenced in recent trials such as the combination immune checkpoint inhibitors with lenvatinib and cabozantinib. In addition, the use of such combination therapy preoperatively in locally advanced disease is another area of interest.

Major adverse cardiovascular events of vascular endothelial growth factor tyrosine kinase inhibitors among patients with different malignancy: A systemic review and network meta-analysis.

Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a common cancer treatment. However, the pharmacologic characteristics of VEGF-TKIs may influence cardiovascular risks. The relative risks of major adverse cardiovascular events (MACEs) associated with VEGF-TKIs are poorly understood. We searched PubMed, Embase, and ClinicalTrials.gov from inception until August 31, 2021, for phase II/III randomized controlled trials of 11 VEGF-TKIs (axitinib, cabozantinib, lenvatinib, pazopanib, ponatinib, ripretinib, regorafenib, sorafenib, sunitinib, tivozanib, and vandetanib). The endpoints were heart failure, thromboembolism, and cardiovascular death. The Mantel-Haenszel method was used to calculate the risk of VEGF-TKI among users by comparing it to nonusers. Pairwise meta-analyses with a random-effects model were used to estimate the risks of the various VEGF-TKIs. We estimated ranked probability with a P-score and assessed credibility using the Confidence in Network Meta-Analysis framework. We identified 69 trials involving 30 180 patients with cancer. The highest risk of MACEs was associated with high-potency tivazonib (odds ratio [OR]: 3.34), lenvatinib (OR: 3.26), and axitinib (OR: 2.04), followed by low-potency pazopanib (OR: 1.79), sorafenib (OR: 1.77), and sunitinib (OR: 1.66). The risk of heart failure significantly increased in association with less-selective sorafenib (OR: 3.53), pazopanib (OR: 3.10), and sunitinib (OR: 2.65). The risk of thromboembolism significantly increased in association with nonselective lenvatinib (OR: 3.12), sorafenib (OR: 1.54), and sunitinib (OR: 1.53). Higher potency (tivozanib, axitinib) and lower selectivity (sorafenib, vandetanib, pazopanib, sunitinib) were associated with a higher probability of heart failure. Low selectivity (lenvatinib, cabozantinib, sorafenib, sunitinib) was associated with a higher probability of thromboembolism. Higher-potency and lower-selectivity VEGF-TKIs may influence the risks of MACEs, heart failure, and thromboembolism. These findings may facilitate evidence-based decision-making in clinical practice.