VEGF Tyrosine Kinase Inhibitors Research Articles

Systemic therapies and primary tumour downsizing in renal cell carcinoma: a real-world comparison of anti-angiogenic and immune checkpoint inhibition regimens.

To investigate responses in the primary tumour to different systemic treatment regimens in patients with metastatic renal cell carcinoma (mRCC). A single-centre retrospective analysis of treatment-naive mRCC patients without prior nephrectomy receiving VEGF tyrosine kinase inhibitors (VEGF only), immune checkpoint inhibitors (IO only), or combinations thereof (IO + VEGF). The primary outcome was the rate of partial response in the primary tumour (primary tumour PR, ≥ 30% diameter reduction). Secondary outcomes were time to best primary tumour diameter change, overall survival (OS) and progression-free survival (PFS) by Kaplan-Meier analysis. Predictors of survival outcomes were explored by Cox proportional hazards regression analysis. The rate of primary tumour PR was 14% for VEGF only (4/28 patients), 22% for IO only (5/23) and 50% for IO + VEGF (7/14), with median best primary tumour diameter change of -8.0%, + 5.1%, and -31.1% respectively, and median time to best primary tumour diameter change of 3.2, 3.0 and 6.9months respectively. Median OS was significantly greater with IO + VEGF compared to VEGF only (HR 0.45, p = 0.04) and non-significantly greater compared to IO only (HR 0.46, p = 0.06). In multivariable analysis, primary tumour PR was the only response variable significantly associated with both OS (adjusted HR 0.32, p = 0.01) and PFS (adjusted HR 0.29, p < 0.01). mRCC patients without prior nephrectomy receiving first-line IO + VEGF regimens showed the greatest primary tumour responses, suggesting further prospective evaluation of this combination in the neoadjuvant and deferred cytoreductive nephrectomy settings.

Idiopathic Pancytopenia Caused By Immune Checkpoint Inhibitor

Immune checkpoint inhibitors (ICI) have demonstrated clinical utility in various cancers, but they also induce immune-related adverse events (irAEs) such as thyroiditis, pneumonitis, or colitis. Immune-related(IR) hematologic toxicities, including anemia, neutropenia, thrombocytopenia, or pancytopenia are rarely reported but can be fatal. However, the underlying immunobiology of IR hematologic toxicities by ICIs has been very poorly investigated. We report a case of IR pancytopenia by ICIs including an in-depth analysis of single-cell RNA sequencing for the bone marrow (BM). A 57-year-old man with metastatic clear cell renal cell carcinoma was treated with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) and showed rapid tumor reduction. After 7 months of ICI treatment, he showed fever and pancytopenia with hemoglobin - 8.3 g/dl, platelet count - 64,000 /㎕, WBC count - 2500 cells/㎕, absolute neutrophil count - 745 cells/㎕, MCH - 25.9pg, MCV - 82.0fl, MCHC - 31.5g/dl, RDW - 18.2% and reticulocyte count - 1.65%. Direct and indirect antiglobulin test was negative. On BM aspiration, the number of erythroid and megakaryocytic series was slightly increased and that of myeloid series was in the normal range. In BM biopsy, cellularity was 70-80% and three hematopoietic series showed mild hyperplasia. There were no abnormal findings in morphology and chromosomal analysis. BM diagnosis was idiopathic cytopenia of undetermined significance. Although he was treated with methylprednisolone (1mg/kg), hematologic improvement was minimal. Cyclosporine demonstrated the hematologic response in the case. After 5 months of immune suppressive therapy (6-month-discontinuation of nivolumab), he maintained anti-tumor responses by ICIs. We cautiously re-challenge nivolumab as maintenance therapy, but the pancytopenia reappeared. ICI was permanently terminated, and therapy was changed to axitinib (VEGF tyrosine kinase inhibitor). To gain comprehensive insights, we performed single-cell analysis on BM aspirate. Our approach aimed to retain the integrity of both mononuclear cells and granulocytes without cryopreservation by analyzing the sample promptly after collection. Following this, we segregated the sample into distinct fractions, namely bone marrow mononuclear cells (BMMC) and whole blood (BM), and subjected both fractions to in-depth single-cell analysis. This method allowed us to explore the cellular composition and heterogeneity within the BM aspirate, contributing valuable insights to our research. The analysis detected 19,227 cells and identified unique cellular subsets, including terminally differentiated CD8+ T cells (CD8 T EF) and T Helper 17 cells (T H17), which are not commonly found in BM. CD8 T EF cells expressed activation and exhaustion markers, HLA-DRA and KLRG1. Additionally, T H17 cells demonstrated elevated expression of typical T H17 markers RORC and CCR6, as well as polyfunctional markers, including KLRB1, TNFRSF4, and TNFRSF18. Interestingly, previous studies on IR-myocarditis have shown an increased presence of CD8 T EF in the peripheral blood. Moreover, the studies have associated aplastic anemia with the T H17 cell population. These findings offer significant insights into the molecular and cellular mechanisms, as well as the BM microenvironment, contributing to the IR hematologic toxicities by ICIs.

242P Changing the first-line landscape in metastatic renal cell carcinoma with a combination of immunotherapy and VEGF tyrosine kinase inhibitors: A real-world Indian experience

242P Changing the first-line landscape in metastatic renal cell carcinoma with a combination of immunotherapy and VEGF tyrosine kinase inhibitors: A real-world Indian experience

FDA analysis of treatment-free survival in frontline advanced immuno-oncology–VEGF TKI renal cell carcinoma trials.

e13602 Background: Treatment-free survival (TFS) with and without (w/o) toxicity are outcome measures that describe health states where patients are experiencing clinically stable disease while off anti-cancer treatment, a clinically meaningful attribute seen with some immune-oncology (IO) regimens. We sought to characterize TFS with and w/o ongoing toxicity in addition to time on protocol therapy (combination and monotherapy) in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in pts with advanced renal cell carcinoma (aRCC). Methods: We pooled randomized trials submitted to FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months (mos) of median follow-up. OS was partitioned into health states, including TFS, defined as area between Kaplan-Meier curves for 2 time-to-event endpoints originating at randomization: 1) time to all protocol therapy cessation and 2) time to subsequent systemic therapy initiation or death. Health state areas under the curve were estimated by 30-mo restricted mean times. We pooled data by treatment arm. Results: Three trials (KEYNOTE-426, JAVELIN Renal 100, CheckMate 9ER) met criteria for analysis; in total, 1183 pts received IO-TKI vs. 1184 on control arms receiving sunitinib (SUN). IO-TKI and SUN groups spent 9% (2.7 mos [95% confidence interval (CI): 1.8, 3.5]) and 10% (2.9 mos [95% CI: 2.1, 3.8]) of the 30-mo period alive and treatment-free. Mean TFS with grade ≥3 toxicity were 1 and 0.6 mos in the IO-TKI and SUN groups, respectively. Mean TFS w/o grade ≥3 toxicity were 1.7 and 2.3 mos in IO-TKI and SUN groups, respectively. In IO-TKI group, the 30-mo mean time on combination therapy was 13.7 mos (46% of 30-mo period) and 3.9 mos on monotherapy (13% of 30-mo period). Following cessation of one drug in IO-TKI arm, monotherapy duration of TKI was longer than IO: 2.9 and 1 mos, respectively. Conclusions: In this descriptive, exploratory analysis, TFS and TFS w/o toxicity were similar in IO-TKI group compared to SUN group, in contrast to improved TFS in IO-IO vs. SUN seen in published literature. Among pts on IO-TKI, more time was spent on TKI monotherapy than IO monotherapy. These findings may reflect continuation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in 2 trials, and may inform individual pt choice of IO-IO vs. IO-TKI. [Table: see text]

Real world outcomes of patients with non-clear cell renal cell carcinoma: A single Asian centre experience.

632 Background: Non-clear cell RCC (nccRCC) represents a heterogenous group of tumors which is less well studied than clear cell RCC. Clinical data supporting the treatment of nccRCC are still based on phase 2 studies and clinical trials conducted in ccRCC. Little is known about this group of patients in Asia. In this study, we aim to report the real world outcomes of nccRCC patients in a cancer centre in Singapore. Methods: We conducted a retrospective analysis on 81 non-clear cell RCC patients treated at the National Cancer Centre Singapore from 2007-2022. Data on patient demographics, disease characteristics, treatment outcomes and adverse events were collected retrospectively up till March 2022. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method. Responses to treatment were recorded based on RECIST v1.1 and analyzed using logistic regression. Results: 81 patients were included in this analysis, with a median age at diagnosis of 57 years old. Papillary RCC accounted for 32% (n=26) of the cases, chromophobe RCC was 2% (n=2), unclassified RCC was 28% (n=23), and other subtypes was 20% (n=24). Sarcomatoid features were present in 8% (n=10). Median follow-up time was 24 months. Among this cohort, 73 patients (90%) received tyrosine kinase inhibitors (TKI) alone, 8 patients (9%) had immunotherapy with VEGF TKI while 4 patients (4%) underwent dual checkpoint inhibitors. Median OS for the cohort was 19.4 months, while median PFS was 16 months. Overall disease control rate rate (CR/PR/SD) for first-line treatment was 60%. Comparison of outcomes shown below. Conclusions: This real-world Asian study provides important data regarding clinical outcomes in this rare and heterogeneous group of non-clear cell RCC patients. OS in nccRCC remains inferior to ccRCC and is comparable to data reported in Western populations [Table: see text]

1466P Efficacy of immune checkpoint inhibitors (ICI) in renal cell carcinoma (RCC) venous tumor thrombus (VTT) shrinkage

ICI, either in combination with other ICI or with VEGF tyrosine kinase inhibitors (TKI), is now the standard of care treatment for first line metastatic RCC patients (pts). The presence of renal cell carcinoma with a VTT is associated with a pejorative survival prognosis. Several ICI based neoadjuvant trials are ongoing. However, data regarding the efficacy of ICI in VTT shrinkage are scarce. We performed a French multicenter retrospective study of pts with metastatic RCC with a VTT and treated in first line or beyond with ICI. The main objective was to assess the objective response rate (ORR) of ICI on VTT. Radiological assessment was performed by treating physician according to iRECIST criteria. Twenty-five pts were included, between January 2015 and December 2021, at the participating institutions. Median age at diagnosis was 65 years (range 37-88). IMDC risk group was intermediate (14/25; 56%) and poor for 11 pts (44%). Most frequent metastatic sites were lung (88%; 22/25), lymph nodes (56%; 14/25), bone (40%; 10/25) and liver (36%; 9/25). Seventeen pts (68%) were treated with ICI in first line, 7/25 (28%) in 2ndline and 1 pt (4%) in 3rd line. Fourteen pts were treated with anti-PD-L1 in combination with antiCTLA-4 therapy, 10 pts with ICI monotherapy and 1 with ICI in combination with antiangiogenic TKI. At baseline, median VTT diameter was 20 mm (range 7-85) and VTT extension according to Novick’s classification was I for 9pts, II for 7pts, III for 4pts, IV for 2 and unknown for 3 pts. After a median duration of treatment of 3 months (range 3-89), ORR was 36% including 3 complete responses (CR) and 6 partial responses (PR). Eleven pts presented a stable disease (SD) and 5 progression disease (PD) as best response on VTT. Three patients presented a reduction on VTT extension according to Novick’s classification. These data highlight the efficacy of ICI to shrink VTT even if it seems to have little impact on VTT level of extension. Further studies are needed to assess the role of ICI in neoadjuvant setting.

Abstract 5122: Identification of PD-L1 expression on circulating tumor cells as a prognostic indicator in prospective clinical trial, OMNIVORE

Abstract Despite recent therapeutic advances for patients with renal cell carcinoma (RCC) with immunotherapies, alone or in combination with VEGF tyrosine kinase inhibitors, there are no available biomarkers to predict patient benefit or evaluate mechanisms of resistance. The known heterogeneity of RCC may explain the limited utility of biomarker testing on single-site biopsies. This has led to great interest in liquid biopsy as an accessible source of tumor cells to evaluate mechanisms of response and resistance. Given the growing use of immunotherapy (IO) in patients with RCC, and the promise of their companion diagnostics in other disease settings, we evaluated the ability of liquid biopsy quantification of PD-L1 to predict patient response to IO in the OMNIVORE clinical trial, NCT03203473. Patients on trial were given nivolumab monotherapy, followed by radiographic scans at C3D1, with follow-up scans confirming CR/PR defined as “response.” Responding patients were placed on observation, while non-responders were transitioned to the dual therapy with nivolumab and ipilimumab arm. PD-L1 and HLA I expression was quantified on circulating tumor cells (CTCs) using Exclusion-Based Sample Preparation (ESP). Single-cell protein analysis of PD-L1 and HLA I on CTCs facilitated the generation of summary statistics including average expression of all CTCs, number of CTCs categorized as PD-L1 or HLA I positive, and frequency of CTCs with either positive or negative expression. ROC curves were used to compare diagnostic sensitivity and specificity of different CTC summary statistics for 30 patients with evaluable matched baseline and arm assignment data. Kaplan-Meier curve evaluation was performed on the summary statistic identified as that with the greatest clinical value. ROC curve analysis identified the metric “number of PD-L1+ CTCs” at arm assignment as having the greatest clinical value (AUC 0.8) compared to all other CTC summary statistics evaluated, with a diagnostic sensitivity/specificity of 88/60% at a cutoff of 2.5 PD-L1+ CTCs/7.5 mL. Survival analysis showed that patients with fewer PD-L1+ CTCs had a longer durable response (68 weeks vs. 16 weeks, HR 2.9) to single agent nivolumab. These results suggest that the number of PD-L1+ CTCs is a potential biomarker of treatment response that may have utility for treatment stratification and investigation of novel combination strategies for patients with poor prognostic features. This biomarker is now being tested in multiple prospective clinical trials to further study clinical utility. Citation Format: Rory M. Bade, Jennifer L. Schehr, Matthew C. Mannino, Matthew L. Bootsma, Hamid Emamekhoo, Shuang G. Zhao, Toni K. Choueiri, Sabina Signoretti, Rana R. McKay, Joshua M. Lang. Identification of PD-L1 expression on circulating tumor cells as a prognostic indicator in prospective clinical trial, OMNIVORE [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5122.

BRCA1-Associated Protein 1 (BAP-1) as a Prognostic and Predictive Biomarker in Clear Cell Renal Cell Carcinoma: A Systematic Review

BACKGROUND: The gene that encodes BRCA1-associated protein 1 (BAP1) has been reported to be dysregulated in several human cancers such as uveal melanoma, malignant pleural mesothelioma, hepatocellular carcinoma, thymic epithelial tumors, and clear-cell renal cell carcinoma (ccRCC). The gene is located on the human chromosome 3p21.3, encoding a deubiquitinase and acts as a classic two-hit tumor suppressor gene. BAP1 predominantly resides in the nucleus, where it interacts with several chromatin-associated factors, as well as regulates calcium signaling in the cytoplasm. As newer therapies continue to evolve for the management of RCC, it is important to understand the role of BAP1 mutation as a prognostic and predictive biomarker. OBJECTIVE: We aimed to systematically evaluate the role of BAP1 mutations in patients with RCC in terms of its impact on prognosis and its role as a predictive biomarker. METHODS: Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through March 2021. Titles and abstracts were screened to identify articles for full-text and then a descriptive review was performed. RESULTS: A total of 490 articles were initially identified. Ultimately 71 articles that met our inclusion criteria published between 2012–2021 were included in the analysis. Data were extracted and organized to reflect the role of BAP1 alterations as a marker of prognosis as well as a marker of response to treatments, such as mTOR inhibitors, VEGF tyrosine kinase inhibitors, and immune checkpoint inhibitors. CONCLUSIONS: Alterations in BAP1 appear to be uniformly associated with poor prognosis in patients with RCC. Knowledge gaps remain with regard to the predictive relevance of BAP1 alterations, especially in the context of immunotherapy. Prospective studies are required to more precisely ascertain the predictive value of BAP1 alterations in RCC.

Nemvaleukin alfa combination therapy for gastrointestinal (GI) cancers: Preclinical evidence and clinical data from the ARTISTRY-1 trial.

659 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells, with minimal expansion of regulatory T cells. Inherently active, nemvaleukin neither requires metabolic/proteolytic conversion nor degrades into native IL-2. Preclinical characterization confirmed receptor selectivity and antitumor activity of nemvaleukin alone and with checkpoint inhibitors (CPIs) and informed dose selection for the first-in-human study ARTISTRY-1; other combination regimens are ongoing evaluation. In ARTISTRY-1, responses with nemvaleukin in combination with pembrolizumab were observed in a variety of tumors, including GI. In addition to the clinical outcomes of these patients (pts), we describe preclinical evaluation of nemvaleukin with tyrosine kinase inhibitors (TKIs)—a drug class indicated for some GI cancers. Methods: Pts with GI cancers who had progressed on prior therapy were enrolled into cohorts of mixed tumor types in ARTISTRY-1 (NCT02799095) and received IV nemvaleukin (3 µg/kg) and pembrolizumab (200 mg). Outcomes presented include antitumor activity and safety as of August 2021. Combinations of nemvaleukin with TKIs were evaluated in mouse tumor models, including colorectal adenocarcinoma (MC38). Results: Clinically, 26 pts with GI cancer (colon/colorectal, n = 14; esophageal, n = 5; hepatocellular, n = 3; pancreatic, n = 3; gastric, n = 1) received nemvaleukin + pembrolizumab (median 3 cycles [range: 1-24]). Median age was 55 y (range: 26-82), ECOG performance status was 0 (n = 6) or 1 (n = 20), and median prior lines of therapy was 3 (range: 1-6). Four pts had a partial response, 2 with esophageal, 1 with MSI-H colorectal, and 1 with pancreatic cancer, with target lesion decreases of 37% to 63%. Six pts had stable disease. Two responders remain on treatment (&gt; 36 and &gt; 80 wks for colorectal and esophageal cancer, respectively). Frequent (&gt; 25%) nemvaleukin-related adverse events (AEs) among all pts receiving nemvaleukin combination (n = 156) were chills (58%), pyrexia (53%), nausea (29%), and fatigue (29%). Grade ≥3 nemvaleukin-related AEs (≥8%) were reported in 48%, including anemia (12%), neutrophil count decreased (10%), and neutropenia (8%). In mice, the combination of the mouse ortholog of nemvaleukin with VEGF TKIs showed improved antitumor activity and survival, along with increased immune activation and angiogenesis blockade in the tumor microenvironment compared with any compound alone. Conclusions: Emerging clinical data show responses in GI tumors may be achieved with nemvaleukin/pembrolizumab with manageable safety. Preclinical evidence of antitumor activity of nemvaleukin with CPIs or TKIs warrants further exploration of nemvaleukin in new combinations for pts with GI cancers. Clinical trial information: NCT02799095.

A phase Ib/II study (IMMCO-1) of atezolizumab plus tivozanib in immunologically cold pancreatic, gallbladder, and biliary cancers.

TPS491 Background: Checkpoint inhibition (CPI) represents a significant advance in cancer care however it is not effective in the treatment of several immunologically cold tumors including pancreatic, gallbladder, and biliary cancers where checkpoint inhibitors have produced objective response rates of &lt;5%. VEGF is thought to play a key role in modulating the anti-tumor immune response. Secreted by tumors, it leads to endothelial cell proliferation, vascular permeability, and vasodilation that together leads to the development of an abnormal vasculature with excessive permeability and poor blood flow, thus limiting immune surveillance. In addition, VEGF inhibits dendritic cell differentiation, limiting the presentation of tumor antigens to CD4 and CD8 T cells. Through the inhibition of VEGF, it may be possible to potentiate the effect of immune checkpoint blockade. Combined use of a VEGF tyrosine kinase inhibitor (TKI) and checkpoint inhibitor is already standard of care in advanced kidney, cervical and endometrial cancers. There has been suggestion that such a combination may have clinical activity in some microsatellite stable (MSS) GI malignancies. This signal seeking study aims to build upon those observations by incorporating a pan-VEGF axis inhibitor (tivozanib) with CPI. Methods: This is an open-label non-randomized phase Ib/II signal seeking basket study in multiple immunologically cold tumors. The co-primary endpoints are safety and efficacy of the combination of the VEGF-TKI tivozanib and CPI atezolizumab. Key eligibility criteria includes patients with MSS pancreatic, biliary (cholangiocarcinoma and gallbladder), well-differentiated grade 2 and 3 neuroendocrine tumors, ovarian and vulvar cancer, soft tissue sarcoma, castrate resistant prostate cancer, and HER2 positive hormone receptor negative breast cancer, that is metastatic and progressed on at least one line of therapy. Key exclusion criteria will include patients with known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. The phase Ib portion will assess the safety profile of the combination of tivozanib and atezolizumab with a potential dose de-escalation of tivozanib using a 3+3 study design. Starting doses include tivozanib 1.34 mg per day for 21 days of each 28-day cycle and atezolizumab 1680 mg on day 1 of every 28-day cycle. The phase II portion will enroll up to 26 additional patients using the dose of tivozanib found to be safe in the Ib portion. Disease response assessments are every 12 weeks with CT Chest, Abdomen, and Pelvis via RECIST 1.1. Treatment will continue until progression or intolerance. This signal seeking study is looking to confirm the best objective response rate for evaluable patients increasing from &lt;7% (null hypothesis) to 25% (one-sided alpha = 0.05; 80% power). Active enrollment continues. Clinical trial information: NCT05000294.

Precision medicine in aggressive thyroid cancer: Moving beyond multitargeted tyrosine kinase inhibitors

Precision medicine in aggressive thyroid cancer: Moving beyond multitargeted tyrosine kinase inhibitors

1659P Immune checkpoint inhibitors plus VEGF tyrosine kinase inhibitors as second-line or later therapy for patients with extensive stage small cell lung cancer

Immune checkpoint inhibitors (ICIs) have greatly changed the current treatment status of extensive-stage small-cell lung cancer (ES-SCLC) and are approved to be used in the first-line setting of ES-SCLC. However. treatment choices in second line or above in ES-SCLC setting remains limited. Hence, the present retrospective study aimed to evaluate the efficacy of ICIs plus anti-VEGF/VEGFR agents in ES-SCLC patients in the second line or later setting, and preliminarily explore the predictive value of neutrophil-to-lymphocyte ratio (NLR) in ES-SCLC.

Retrospective Study of Bleeding Risk with Concomitant Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor and Anticoagulation.

Patients with cancer are at higher risk for venous thromboembolism (VTE) and bleeding, in turn complicating anticoagulant therapy. An added complexity is the toxicity profile of agents used to treat certain cancers, namely the vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), which are associated with both thromboembolism and hemorrhages. The purpose of this study was to evaluate whether patients taking concurrent VEGF TKI and therapeutic anticoagulant were at higher risk for bleeding compared with patients taking VEGF TKI alone. This was a single-center, retrospective chart review of patients who underwent treatment with a VEGF TKI with or without anticoagulant. The primary outcome included comparison of major bleeding rates between groups. Secondary outcomes included comparison of composite major and minor bleed rates and assessment of VTE incidence and recurrence among patients treated with a VEGF TKI and VEGF TKI plus anticoagulant, respectively. A total of 184 and 74 patients were included in the VEGF TKI alone and VEGF TKI + anticoagulant groups, respectively. Major bleeding events occurred in 6 of 184 patients (3.3%) and 6 of 74 patients (8.1%), respectively (p = .095). Composite major and minor bleeding events occurred in 22 of 184 (13.6%) and 17 of 74 (23%), respectively (p = .026). A total of 26 of 258 patients (10.1%) experienced a VTE event while taking a VEGF TKI, and 1 of 26 (3.8%) experienced a recurrent VTE event while taking a VEGF TKI plus anticoagulant. Patients who received concomitant VEGF TKI plus anticoagulant had increased incidence of bleeding, although prospective studies are needed to further explore this association. The current study showed that use of concomitant vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGF TKI) and therapeutic anticoagulation was associated with an increased risk of composite bleeding events, although at comparable rates between patients treated with VEGF TKI plus direct oral anticoagulant (DOAC) versus VEGF TKI plus non-DOAC anticoagulant. This suggests that when anticoagulation is indicated in a patient receiving a VEGF TKI, the novel DOACs may be a safe alternative to historical anticoagulants (warfarin and enoxaparin). These results fill a gap in the literature and will help guide treatment decisions for patients requiring concurrent VEGF TKI and anticoagulation.

A Combined Phytochemistry and Network Pharmacology Approach to Reveal Potential Anti-NSCLC Effective Substances and Mechanisms in Marsdenia tenacissima (Roxb.) Moon (Stem).

Marsdeniae tenacissimae Caulis is a traditional Chinese medicine, named Tongguanteng (TGT), that is often used for the adjuvant treatment of cancer. In our previous study, we reported that an ethyl acetate extract of TGT had inhibitory effects against adenocarcinoma A549 cells growth. To identify the components of TGT with anti-tumor activity and to elucidate their underlying mechanisms of action, we developed a technique for isolating compounds, which was then followed by cytotoxicity screening, network pharmacology analysis, and cellular and molecular experiments. We isolated a total of 19 compounds from a TGT ethyl acetate extract. Two novel steroidal saponins were assessed using an ultra-performance liquid chromatography-photodiode array coupled with quadrupole time-of-flight mass (UPLC-ESI-Q/TOF-MS). Then, we screened these constituents for anti-cancer activity against non-small cell lung cancer (NSCLC) in vitro and obtained six target compounds. Furthermore, a compound-target-pathway network of these six bioactive ingredients was constructed to elucidate the potential pathways that controlled anticancer effects. Approximately 205 putative targets that were associated with TGT, as well as 270 putative targets that were related to NSCLC, were obtained from online databases and target prediction software. Protein–protein interaction networks for drugs as well as disease putative targets were generated, and 18 candidate targets were detected based on topological features. In addition, pathway enrichment analysis was performed to identify related pathways, including PI3K/AKT, VEGF, and EGFR tyrosine kinase inhibitor resistance, which are all related to metabolic processes and intrinsic apoptotic pathways involving reactive oxygen species (ROS). Then, various cellular experiments were conducted to validate drug-target mechanisms that had been predicted using network pharmacology analysis. The experimental results showed the four C21 steroidal saponins could upregulate Bax and downregulate Bcl-2 expression, thereby changing the mitochondrial membrane potential, producing ROS, and releasing cytochrome C, which finally activated caspase-3, caspase-9, and caspase-8, all of which induced apoptosis in A549 cells. In addition, these components also downregulated the expression of MMP-2 and MMP-9 proteins, further weakening their degradation of extracellular matrix components and type IV collagen, and inhibiting the migration and invasion of A549 cells. Our study elucidated the chemical composition and underlying anti-tumor mechanism of TGT, which may be utilized in the treatment of lung cancer.

Phase III study evaluating efficacy and safety of MK-6482 + lenvatinib versus cabozantinib for second- or third-line therapy in patients with advanced renal cell carcinoma (RCC) who progressed after prior anti-PD-1/L1 therapy.

TPS372 Background: There is an unmet need for treatment options in the second-line or later setting following anti–PD-1/L1 or VEGF tyrosine kinase inhibitor (TKI) therapy in patients with advanced RCC. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). Promising antitumor activity has been reported for the first-in-class small molecular HIF-2α inhibitor, MK-6482, in heavily pretreated patients with ccRCC and patients with VHL disease–associated RCC. HIF-2α also regulates VEGF gene expression and plays a role in resistance to anti-VEGF therapy. Therefore, combining MK-6842 with a VEGF receptor TKI, such as lenvatinib, is an attractive treatment option in the advanced RCC setting. Methods: This is a randomized, open-label, active-controlled, multicenter phase III trial evaluating the efficacy and safety of MK-6482 + lenvatinib compared with cabozantinib in patients with advanced ccRCC who have progressed on prior anti–PD-1/L1 therapy (NCT04586231). Eligibility criteria include age ≥18 years; histologically confirmed, unresectable, locally advanced or metastatic ccRCC; disease progression on or after first- or second-line systemic treatment with an anti–PD-1/L1 therapy (monotherapy or in combination with other agent[s]) for locally advanced or metastatic disease, the immediately preceding line of treatment must be an anti–PD-1/L1 therapy; no more than 2 prior systemic regimens, with only 1 prior anti–PD-1/L1 therapy; measurable disease per RECIST v1.1; and Karnofsky performance status ≥70%. Patients must provide tissue for biomarker analysis. Approximately 708 patients will be randomly assigned in a 1:1 ratio to receive MK-6482 120 mg orally once daily (QD) + lenvatinib 20 mg orally QD or cabozantinib 60 mg orally QD. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are International mRCC Database Consortium prognostic scores (0, 1-2, or 3-6), number of prior lines of therapy (1 or 2), and geographic region (North America, Western Europe, or rest of the world). Imaging will be assessed by CT or MRI every 8 weeks through week 80, then every 12 weeks thereafter. The dual primary end points are progression-free survival per RECIST v1.1 as assessed by blinded independent central review (BICR) and overall survival. Secondary end points are objective response rate and duration of response per RECIST v1.1 as assessed by BICR, and safety. Safety and tolerability will be evaluated using a tiered approach. Clinical trial information: NCT04586231 .

Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality and has an increasing incidence worldwide. Locoregional therapies, defined as imaging-guided liver tumour-directed procedures, play a leading part in the management of 50-60% of HCCs. Radiofrequency is the mainstay for local ablation at early stages and transarterial chemoembolization (TACE) remains the standard treatment for intermediate-stage HCC. Other local ablative techniques (microwave ablation, cryoablation and irreversible electroporation) or locoregional therapies (for example, radioembolization and sterotactic body radiation therapy) have been explored, but have not yet modified the standard therapies established decades ago. This understanding is currently changing, and several drugs have been approved for the management of advanced HCC. Molecular therapies dominate the adjuvant trials after curative therapies and combination strategies with TACE for intermediate stages. The rationale for these combinations is sound. Local therapies induce antigen and proinflammatory cytokine release, whereas VEGF inhibitors and tyrosine kinase inhibitors boost immunity and prime tumours for checkpoint inhibition. In this Review, we analyse data from randomized and uncontrolled studies reported with ablative and locoregional techniques and examine the expected effects of combinations with systemic treatments. We also discuss trial design and benchmarks to be used as a reference for future investigations in the dawn of a promising new era for HCC treatment.

Sorafenib as a second-line treatment in metastatic renal cell carcinoma in Mexico: a prospective cohort study

BackgroundSequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a second-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI).MethodsA prospective observational cohort in Mexico (2012–2019). We included 132 subjects with metastatic RCC and who had progression despite treatment with sunitinib. The primary end-point was time to disease progression as evaluated every 12–16 weeks.ResultsThe mean age of the cohort was 59 years (interquartile range [IQR] 50–72), 96 (73%) were men, and 48 (36%) had a favorable prognosis according to the IMDC (International Metastatic RCC Database Consortium) prognostic model. The median progression-free survival (PFS) and overall-survival after the introduction of sorafenib treatment was 8.6 months (95% confidence interval [CI]: 6.7–10.5) and 40 months (95% CI: 34.5–45.4) respectively. The median overall survival from RCC diagnosis to death was 71 months (95% CI: 58.2–83.8). On multivariable analyses, age > 65 years was associated with a longer PFS (HR 0.51; 95% CI: 0.31–0.86; p = 0.018). The median PFS in subjects aged > 65 years was longer compared to subjects ≤65 years (14.0 [95% CI: 9.2–18.8] vs. 7.2 months [95% CI: 5.3–9.1]; p = 0.012). Adverse events grade ≥ 3 associated with sorafenib occurred in 38 (29%) patients.ConclusionSequential inhibition of VEGF with sorafenib as a second-line treatment may benefit patients with metastatic RCC, especially in subjects > 65 years old.

Tivozanib, a highly potent and selective inhibitor of VEGF receptor tyrosine kinases, for the treatment of metastatic renal cell carcinoma.

The VHL mutation-HIF upregulation-VEGF transcription sequence is the principal pathway in the development of renal cell carcinoma. Tyrosine kinase inhibitors target the VEGF receptors to inhibit further growth of renal cell carcinoma tumors. Tivozanib, originally named AV-951 and KRN-951, is a novel, orally bioavailable VEGF tyrosine kinase inhibitor that is selective for VEGF receptors 1, 2 and 3. Further, only picomolar concentrations of tivozanib are required to target these VEGF receptors and prevent phosphorylation; this potency prevents the debilitating side effects that occur with treatments whose mechanisms of action involve broad-spectrum tyrosine kinase inhibition. This review summarizes the growing body of evidence supporting tivozanib's efficacy and safety in the treatment of advanced renal cell carcinoma.

Sorafenib as second-line treatment in metastatic renal cell carcinoma: A prospective cohort.

e17077 Background: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with advanced or metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a 2nd-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI). Methods: Prospective observational cohort in Mexico City (July 2012 to July 2019). We included 148 subjects with metastatic RCC, treated by nephrectomy and who had RCC progression despite treatment with sunitinib (n = 144) or pazopanib (n = 4). All patients received sorafenib 400 mg orally twice a day on a continuous dosing schedule until disease progression or intolerable toxicity. The primary endpoint was time to progression evaluated every 12-16 weeks. Risk factors were classified according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC-RF) prognostic model. Results: Mean age of cohort was 58±10 years, 104 (70%) were male, 51 (35%) had none of IMDC-risk factors, and the most common sites of metastasis before sorafenib treatment were lung (n = 79, 53%) and bone (n = 30, 20%). The median progression-free survival and survival after the introduction of sorafenib treatment was 8.5 months (95% IC 6.8-10.2) and 40.1 months (95% IC 35.2-45.0) respectively. Median overall survival from RCC diagnosis to death was 71 months (95% CI 63.9-79.4). Median progression-free survival was longer in advanced RCC with none IMDC-RF compared with subjects with ≥2 IMDC-RF (10.3 [95%CI 6.1-14.6] vs 7.9 [95%CI 5.8-9.9] mo. respectively, p = 0.035). Age &gt; 65 decreased risk of progression after sorafenib therapy (OR 0.33, 95% CI 0.14-0.77, p = 0.010). Median progression-free survival in subjects &gt; 65 yrs old was longer (14 months, 95% CI 9.2-17.9) compared to subjects ≤65 yrs (7.2 months, 95% CI 5.5-8.9, p = 0.018). Adverse events associated to sorafenib occurred in 118 (80%) subjects: hand-foot syndrome (n = 118, 80%), diarrhea (n = 113, 76%), hypothyroidism (41, 28%), and mucositis (84, 57%). Any adverse events corresponding to a grade &gt; 2 occurred in 48 (32%) patients. Conclusions: Sequential inhibition of VEGF with sorafenib as a 2nd-line treatment may benefit patients with metastatic RCC, especially in subjects &gt; 65 yrs old. Further clinical trials are needed.

Targeting PD-1 or PD-L1 in Metastatic Kidney Cancer: Combination Therapy in the First-Line Setting.

Recent FDA approvals of regimens targeting programmed death 1 (PD-1) in combination with anti-CTLA-4 or with VEGF tyrosine kinase inhibitors are reshaping front-line therapy for metastatic kidney cancer. In parallel, therapeutics specific for programmed death ligand 1 (PD-L1), one of the two major ligands for PD-1, are under continued investigation. Surprisingly, not all PD-1 and PD-L1 agents lead to similar clinical outcomes, potentially due to biological differences in the cellular expression and regulation of these targets. Here, we review current clinical data on combination immune checkpoint inhibitor therapy in metastatic kidney cancer and discuss the relevant biology of PD-1 and PD-L1. The design of future rational combination therapy trials in metastatic renal cell carcinoma will rely upon an understanding of this biology, along with an evolving understanding of immune cell populations and their functional states in the tumor microenvironment.