Antiangiogenic Tyrosine Kinase Inhibitors Research Articles

Real world effectiveness of immunotherapy combined with anti-angiogenic therapy in patients with anthracycline-resistant soft tissue sarcomas.

e23543 Background: Soft tissue sarcomas are a heterogeneous group of malignant tumors of mesenchymal origin with more than 50 histologic subtypes. They have distinct molecular, genetic and clinical features and account for 1% of adult malignancies, the most common being liposarcoma, undifferentiated pleomorphic sarcoma and leiomyosarcoma. Immune checkpoint inhibitors (ICIs) have limited efficacy in sarcomas compared to other solid tumors; however, they have shown some activity in certain subtypes. The use of immunotherapy in sarcoma faces many challenges due to tumor heterogeneity, scarcity of therapeutic antibodies and chimeric antigen receptors to target antigens in sarcoma subtypes. However, combining ICIs with other therapies seems to improve the therapeutic efficacy to some extent. Antiangiogenic targeted therapy has been recommended by major guidelines as the treatment of choice for second-line soft tissue sarcomas. However, there are limited results from large clinical studies on whether immunotherapy combined with antiangiogenic therapy improves the efficacy. Methods: In this real-world single-center retrospective cohort study conducted at the First Affiliated Hospital of Zhejiang University School of Medicine, the efficacy of immunotherapy combined with antivascular therapy was assessed by progression-free survival (PFS) and overall survival (OS). Safety was assessed using the Common Terminology Criteria for Adverse Events version 5.0. Results: In this study, we enrolled a total of 21 eligible patients, of which 6 were liposarcoma, 4 were leiomyosarcoma, 4 were rhabdomyosarcoma, and 7 were other types. The immunotherapy used in all patients was anti-PD-1 antibody, with bevacizumab as the antivascular therapy drug in four of them and antiangiogenic tyrosine kinase inhibitors in the others. 12(57%) patients had received one-line therapy, 9 (43%) had received ≥ second-line therapy. Median progression-free survival (mPFS) was 5.5 months and median overall survival (mOS) 16.1 months in the total population. mPFS was significantly longer in 2nd-line V.S. ≥3rd-line patients (9.6 months V.S. 3.1 months, P = 0.0007), with a tendency to be prolonged mOS in 2nd-line treatment (16.1 months V.S. 9.3 months), but with no statistically significant difference. The most common grade ≥3 adverse events were hypertension, hand-foot syndrome, and abnormal thyroid function. Conclusions: This study confirms that immunotherapy combined with antiangiogenic therapy is effective and tolerable in anthracycline-resistant soft tissue sarcomas in the real world.It is possible that use in the second line may lead to better efficacy than use in multiple lines, and more clinical studies are expected.

Update results of anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

e16017 Background: Recently, PD-1 blockades combined with dual chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might be a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for patients with ESCC in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Preliminary results were presented at the 2024 ASCO-GI Symposium (Abs 340), the consecutively updated results were presented in this report. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m2, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Dec 2023, a total of 27 patients were enrolled, 25 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 1 CR (4.0%), 18 PR (72.0%), 3 SD (12.0%) and 3 NE (12.0%). Therefore, the preliminary ORR was 76.0% (95%CI: 54.9%-90.6%), DCR was 88.0% (95%CI: 68.8%-97.5%). Median PFS of the 25 patients was not yet reached. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 27 patients with the incidence > 20% were anemia (40.7%), peripheral nerve toxicity (37.0) and white blood cell decreased (25.9%). Common grade ≥3 treatment-emergent adverse events were white blood cell decreased (7.4%), diarrhea (3.7%), glutamic-pyruvic transaminase was elevated (3.7%), glutamic oxalacetic transaminase increased (3.7%), hypertension (3.7%) and immune enteritis (3.7%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. And the conclusions needed to be confirmed in subsequent trials.

Anti-PD-L1 antibody TQB2450 combined with tyrosine kinase receptor inhibitor AL2846 for immunotherapy-refractory advanced hepatocellular carcinoma and esophageal squamous cell carcinoma: A prospective phase 1b cohort study.

Effective systemic therapy remains limited for advanced esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC), particularly after prior failed treatment with immune checkpoint inhibitors (ICIs). Theoretically, a combination of tyrosine kinase inhibitors (TKIs) with ICIs may restore immunotherapy sensitivity. In this phase 1b study, patients received AL2846, an antiangiogenic TKI with multiple targets (c-MET, VEGFR1, c-KIT, Axl, RET, KDR, and VEGFR3), in combination with an anti-PD-L1 antibody (TQB2450) until disease progression, intolerable toxicity, death, or discontinuation for any cause. The primary end points included overall response rate (ORR) and safety, with secondary end points encompassing progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response. Between November 2021 and September 2022, 18 patients with ESCC and 15 patients with HCC, whose ORR was 11.1% (95% confidence interval [CI], 3.1%-32.8%) and 0%, respectively, were enrolled. Adverse events (AEs) of any grade and treatment-related AEs were documented in 32 patients (97.0%) and 31 patients (93.9%), respectively. Grade 3 or higher AEs were observed in 10 patients (30.3%), with vomiting (6.1%) and infectious pneumonia (9.1%) being the most prevalent. Median PFS and OS values were 3.22 months (95% CI, 1.35-5.68 months) and 5.98 months (95% CI, 3.71-8.87 months), respectively, in patients with ESCC, and 5.55 months (95% CI, 2.66 months to not evaluable [NE]) and 16.72 months (95% CI, 4.86 months to NE), respectively, in patients with HCC. The DCRs were 66.7% (95% CI, 43.75%-83.72%) in patients with ESCC and 73.3% (95% CI, 48.05%-89.10%) in patients with HCC. Combined TQB2450 and AL2846 therapy exhibited a favorable safety profile in immunotherapy-refractory patients with advanced ESCC and HCC.

Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma.

Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.

Renal carcinoma: what therapeutic options in 2024?

The most important modifiable risk factors of renal cell carcinoma are smoking, obesity and hypertension. A biopsy of the renal tumour is not always necessary. It is important in situations where it can change the therapeutic attitude and should be discussed in particular for tumors < 4 cm in size and in metastatic stage. Treatment of localized and locoregional disease consists mainly of surgical removal of the tumor. Local ablative therapy (radiofrequency, thermoablation) or active surveillance are options for small tumors < 4 cm and frail patients with high surgical risk. Systemic treatment of metastatic disease consists of antiangiogenic tyrosine kinase inhibitors and immunotherapy with checkpoint inhibitors.

A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR)

BackgroundDespite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer.MethodsThis is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS).DiscussionOur prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients.Trial registrationClinicalTrials.gov: NCT06059014.

The Expression of Alamandine Receptor MrgD in Clear Cell Renal Cell Carcinoma Is Associated with a Worse Prognosis and Unfavorable Response to Antiangiogenic Therapy.

Renal cell carcinoma (RCC) ranks among the most prevalent malignancies in Western countries, marked by its notable heterogeneity, which contributes to an unpredictable clinical trajectory. The insufficiency of dependable biomarkers adds complexity to assessing this tumor progression. Imbalances of several components of the intrarenal renin-angiotensin system (iRAS) significantly impact patient prognoses and responses to first-line immunotherapies. In this study, we analyzed the immunohistochemical expression of the Mas-related G-protein-coupled receptor D (MrgD), which recognizes the novel RAS peptide alamandine (ALA), in a series of 87 clear cell renal cell (CCRCCs), 19 papillary (PRCC), 7 chromophobe (ChRCC) renal cell carcinomas, and 11 renal oncocytomas (RO). MrgD was expressed in all the renal tumor subtypes, with a higher mean staining intensity in the PRCCs, ChRCCs, and ROs. A high expression of MrgD at the tumor center and at the infiltrative front of CCRCC tissues was significantly associated with a high histological grade, large tumor diameter, local invasion, and locoregional node and distant metastasis. Patients with worse 5-year cancer-specific survival and a poorer response to antiangiogenic tyrosine-kinase inhibitors (TKIs) showed higher MrgD expression at the center of their primary tumors. These findings suggest a possible role of MrgD in renal carcinogenetic processes. Further studies are necessary to unveil its potential as a novel biomarker for CCRCC prognosis and response to frontline therapies.

Anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

340 Background: Recently, PD-1 blockades combined with dual chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might be a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for patients with ESCC in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m2, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Aug 2023, a total of 23 patients were enrolled, 19 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 14 PR (73.7%), 2 SD (10.5%) and 3 NE (15.8%). Therefore, the preliminary ORR was 73.7% (95%CI: 48.8%-90.9%), DCR was 84.2% (95%CI: 60.4%-96.6%). Median PFS of the 19 patients was not yet reached. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 23 patients with the incidence &gt;20% were leukopenia (30%) and anemia (30%). Common grade ≥3 treatment-emergent adverse events were leukopenia (9%), glutamic-pyruvic transaminase was elevated (4%), glutamic oxaloacetic transaminase increased (4%), hypertension (4%) and diarrhea (4%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. The conclusions needed to be confirmed in subsequent trials.

Preliminary results of ALTER-H006: A phase II study of TQB2450 plus anlotinib as adjuvant therapy in hepatocellular carcinoma (HCC) with high risk of recurrence after radical resection.

494 Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Surgical resection remains as the mainstay of curative treatment option, However, the recurrence rate after surgical resection could be high especially in patients with CNLC stage IIb (tumor number ≥ 4) and IIIa (vascular invasion). Herein we evaluated the efficacy and safety of the anti-angiogenic tyrosine kinase inhibitor, anlotinib, plus TQB2450, a novel programmed death-ligand 1 (PD-L1) inhibitor as an adjuvant treatment for HCC with high risk of recurrence after radical resection. Methods: This prospective, multiple-center, single-arm phase II study (NCT05111366) enrolled histologically confirmed resectable HCC pts for CNLC Stage IIb/IIIa with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b) portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. At 4-8 weeks after R0 resection, adjuvant therapy was started with anlotinib (12 mg, p.o., qd, d1-14, q3w) plus TQB2450 (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year). Primary endpoint was 1-year recurrence-free survival (RFS) rate; secondary endpoints were RFS, 1-year overall survival (OS) rate, and safety. Results: Between January 2022 and August 2023, a total of 22 pts from 4 centers were enrolled, 21 pts included in per-protocol set analysis. The 21 pts were predominantly male (95 %, n = 20), and the median age was 50 years (range: 33–75). Eight pts (38%) had CNLC Stage IIb and 13(62%) had CNLC Stage IIIa HCC. Among them, 19 pts received at least once tumor assessment. According to RECIST 1.1, out of 21 pts, 16 showed no recurrence, 3 relapsed, 1 dropped out and 1 discontinued due to serious adverse events. The 1-year RFS rate was 62.31%（95%CI: 17.15-88.08）, while the median RFS was not mature. Additionally, safety profile exhibited that the regimen was tolerable. 16 of 22 pts (73%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 6 pts (27 %) including hypertension (13.5 %), neutropenia (9 %), and bleeding (4.5 %). Conclusions: The present study indicated that anlotinib plus TQB2450 as adjuvant treatment for HCC with high risk of recurrence after radical resection exhibited potential efficacy and tolerable safety profile. The conclusion should be validated in more participants included subsequently. Clinical trial information: NCT05111366 .

Fruquintinib with PD-1 inhibitors versus fruquintinib monotherapy in late-line mCRC: A retrospective cohort study based on propensity score matching.

139 Background: Immune checkpoint inhibitors (ICIs) are highly effective in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC). However, the population of MSI-H/dMMR only accounts for 5% of mCRC. And most of the remaining microsatellite stable or proficient mismatch repair (MSS/pMMR) mCRC patients appeared not to benefit from mere immunotherapy. Fruquintinib, as the standard third-line regimen for mCRC, is an oral small-molecule anti-angiogenic tyrosine kinase inhibitor. Studies demonstrated that fruquintinib combined with programmed death receptor-1 (PD-1) inhibitors (FP) can reverse the immunosuppression and achieve promising efficacy. However, due to the lack of the research comparing the efficacy between fruquintinib monotherapy (FM) and FP, it remains unclear if FP can bring extra benefit. Methods: This is a retrospective cohort study conducted in the First Affiliated Hospital of Zhengzhou University. Patients (pts) with MSS/pMMR mCRC who had received at least the 2nd line treatment were eligible. Propensity score (PS) would be calculated to balance the baseline characteristics of two cohorts. Progression-Free survival (PFS) was set as the primary endpoint. The Kaplan–Meier method and Cox proportional hazard model was used to evaluate PFS and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: From Apr 2020 to Jan 2023, 83 eligible pts in total were enrolled. According to the treatment received, 47 and 36 pts were respectively allocated into FP cohort and FM cohort. With a global median follow-up of 16.5 mo, the crude PFS was 6.8 (95% CI: 4.3-11.3) mo in FP cohort vs. 3.9 (3.1-4.7) mo in FM cohort. The HR of FP was 0.58 (95% CI: 0.34-0.98, FM as reference). Multivariate Cox regression showed that the adjusted HR was 0.49 (95% CI: 0.26-0.93), which was adjusted with sex, age greater than 65 yr, ECOG-PS, RAS mutation, BRAF mutation, location of lesion (left or right), surgery history, metastases (liver and lung), prior medication (bevacizumab and cetuximab), and current line (3 or later). With PS, we performed three statistical methods, namely inverse probability weighting, PS matching (the sample size was 37 vs. 29 after matching), and additional adjustment for propensity score with multivariate cox regression. The HR of FP were 0.49 (95% CI: 0.26-0.94), 0.40 (95% CI: 0.21-0.77), and 0.46 (95% CI: 0.24-0.90), respectively. Conclusions: Pts in FP cohort showed a significantly greater PFS than those in FM cohort. And with further analysis, FP indicated robustly lower HRs than FM. Our study suggests FP could provide additional benefits to pts with MSS/pMMR mCRC, and warrants further investigations in a large cohort.

Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma.

Renal cell carcinoma (RCC), the most prevalent type of kidney cancer, is a significant cause of cancer morbidity and mortality worldwide. Antiangiogenic tyrosine kinase inhibitors (TKIs), in combination with immune checkpoint inhibitors (ICIs), are among the first-line treatment options for patients with advanced RCC. These therapies target the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase pathway and other kinases crucial to cancer proliferation, survival, and metastasis. TKIs have yielded substantial improvements in progression-free survival (PFS) and overall survival (OS) for patients with advanced RCC. However, nearly all patients eventually progress on these drugs as resistance develops. This review provides an overview of TKI resistance in RCC and explores different mechanisms of resistance, including upregulation of alternative proangiogenic pathways, epithelial-mesenchymal transition (EMT), decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration, alterations in the tumor microenvironment including bone marrow-derived cells (BMDCs) and tumor-associated fibroblasts (TAFs), and genetic factors such as single nucleotide polymorphisms (SNPs). A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKI resistance, thereby improving outcomes for patients with advanced RCC.

Abstract B024: KO-2806, a next-generation farnesyltransferase inhibitor, potentiates the antitumor activity of cabozantinib in clear cell renal cell carcinoma models

Abstract Conventional treatments for advanced clear cell renal cell carcinoma (ccRCC) include tyrosine kinase inhibitors (TKI) that target angiogenesis, a critical element for ccRCC tumor growth and survival. Cabozantinib, a TKI that inhibits VEGFR, AXL, and MET, is an approved therapy in advanced RCC. However, cabozantinib has limited therapeutic benefit; for example, patients with prior VEGFR TKI therapy had an overall response rate of 21% and median progression-free survival of 7.4 months. Thus, there is an urgent need to identify combination drug partners that can improve the depth and/or durability of clinical responses to cabozantinib. Here, we present preclinical evidence that supports combining the farnesyltransferase inhibitor (FTI), KO-2806, with cabozantinib in ccRCC. KO-2806 is a next-generation farnesyltransferase inhibitor with increased potency and improved pharmacokinetic properties relative to earlier FTI drug candidates and is poised to enter a first-in-human clinical trial. We demonstrate that addition of KO-2806 enhanced tumor growth inhibition of cabozantinib in multiple ccRCC cell line- and patient-derived xenograft models, resulting in either tumor stasis or regression. Immunohistochemical analysis of angiogenic markers in 786-O tumors revealed that, consistent with its mechanism of action, cabozantinib significantly reduced angiogenesis, an effect that was deepened by KO-2806. In support of this, cell viability experiments performed in primary human endothelial cells showed that the combination of KO-2806 and cabozantinib was more effective in reducing cell viability than cabozantinib alone. In addition, we investigated the mechanism underlying the improved response of tumors with the KO-2806-cabozantinib combination by analyzing the major growth signaling pathways in 786-O tumors. Cabozantinib alone reduced both MAPK and PI3K/AKT/mTOR signaling, but addition of KO-2806 resulted in enhanced inhibition of mTOR signaling and increased cell cycle arrest compared to either agent alone. We hypothesize that exposure to anti-angiogenic TKIs render ccRCC tumors more hypoxic, and thus more reliant on compensatory, oncogenic mechanisms like mTOR signaling that allow them to adapt to a nutrient- and oxygen-deprived environment. Mechanistically, KO-2806 potently inhibits the farnesylation, and hence the activity, of the farnesylation-dependent protein RHEB, a positive regulator of mTOR, suggesting that the improved anti-tumor efficacy of the combination may arise through RHEB inhibition in this model. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of the effects of the KO-2806-cabozantinib combination and strengthen the therapeutic rationale for the investigation of this approach in the treatment of patients with ccRCC. Citation Format: Jovylyn Gatchalian, Linda Kessler, Hetika Patel, Stacia Chan, Francis Burrows, Shivani Malik. KO-2806, a next-generation farnesyltransferase inhibitor, potentiates the antitumor activity of cabozantinib in clear cell renal cell carcinoma models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B024.

Prognostic significance of annexin A2 and tumor associated macrophages (TAMs) in metastatic renal cell carcinoma and their relation to Sunitinib resistance

ABSTRACT Sunitinib, an antiangiogenic tyrosine kinase inhibitor, is the main treatment for metastatic renal cell carcinoma (mRCC). Development of resistance is a major obstacle against therapy success. The aim of this study was to assess annexin A2 and CD163+ tumor associated macrophages (TAMs) immunohistochemical expression in 50 mRCC cases as regard to patients’ prognosis and Sunitinib response. Also, to assess the correlation between annexin A2 and TAMs expression. High annexin A2 expression and TAMs density were associated with serum calcium level (P = 0.024 and 0.037, respectively), larger tumor size (P < 0.001), high tumor grade (P = 0.014 and <0.001, respectively), and the presence of tumor necrosis (P < 0.001). High annexin A2 and TAMs expressions were related to shorter patients’ overall survival (P = 0.009 and 0.001, respectively) and progression-free survival (P = 0.003 and 0.001, respectively). Annexin A2 was correlated with TAMs density (r = 0.890). Annexin A2 and TAMs are associated with poor prognostic parameters in mRCC patients, including high nuclear grade, increased tumor size, and the presence of tumor necrosis, together with shorter patients’ survivals and poor response to Sunitinib. Annexin A2 expression is correlated with TAMs density suggesting immunomodulatory role of annexin A2.

CTIM-23. SAFETY RUN-IN RESULTS OF A PHASE I/II STUDY TO EVALUATE ATEZOLIZUMAB IN COMBINATION WITH CABOZANTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Immune checkpoint inhibitor therapy has shown limited efficacy in the treatment of glioblastoma (GBM) in both newly diagnosed and recurrent disease which underscores the need for rational combinatorial strategies. Atezolizumab is a humanized monoclonal antibody that targets PD-L1 and has been shown to enhance the magnitude of tumor-specific T cell responses. Combining PD-L1/PD-1 axis inhibition with targeted therapy like cabozantinib which has both anti-tumoral and immunomodulatory properties may result in synergistic effects. Cabozantinib may modulate the myeloid cell population to overcome resistance to anti-PD-1/PD-L1 therapy. METHODS Eligibility criteria were those with recurrent GBM, age &amp;gt;18 yrs with 1st or 2nd recurrence who were naïve to antiangiogenic and receptor tyrosine kinase inhibitor treatment. The primary objective of the phase I run-in was to evaluate the safety of atezolizumab in combination with cabozantinib. RESULTS 1 dose-limiting toxicity (DLT) of a grade 3 ALT elevation was observed in the first 6 DLT evaluable patients treated during the safety run-in phase. Regarding immune related adverse events, 1 of 6 patients developed atezolizumab-related grade 1 hypothyroidism. 1 of 6 patients developed study treatment-related grade 2 diarrhea. 2 patients after completion of 2 cycles of treatment had evidence of a partial radiographic response ( &amp;gt; 50% decrease). 1 patient had a near partial radiographic response (45% decrease). 2 patients had stable disease after completion of 2 cycles of the combinatorial treatment. 1 patient had only completed the first 28-day cycle, DLT period, and had not yet had imaging to reassess disease status. CONCLUSIONS The combination of atezolizumab with cabozantinib was tolerable, and no new safety signals were noted. In this small cohort of recurrent GBM patients, radiographic responses were observed. The phase II component of the trial is recruiting patients (n = 45) to evaluate clinical efficacy. Multi-omic correlative studies and fecal microbiome analyses are planned.

Prior Anti-Angiogenic TKI-Based Treatment as Potential Predisposing Factor to Nivolumab-Mediated Recurrent Thyroid Disorder Adverse Events in mRCC Patients: A Case Series.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) have revolutionized the management of many types of solid tumors, including metastatic renal cell carcinoma (mRCC). Both sequential and combinatorial therapeutic strategies utilizing anti-PD-1 monoclonal antibodies (mAbs) and anti-angiogenic tyrosine kinase inhibitors (TKIs) have demonstrated to improve the survival of patients with mRCC as compared to standard therapies. On the other hand, both ICIs and TKIs are well known to potentially cause thyroid disorder adverse events (TDAEs). However, in the context of sequential therapeutic strategy, it is not clear whether prior anti-angiogenic TKI may increase the risk and/or the severity of ICI-related TDAEs. In this work, by describing and analyzing a case series of mRCC patients treated sequentially with prior TKIs and then with ICIs, we investigated the role of prior anti-angiogenic TKI-based treatment as a potential predisposing factor to anti-PD-1-mediated recurrent TDAEs, as well as its potential impact on the clinical characteristics of nivolumab-mediated recurrent TDAEs. Fifty mRCC patients were included in the analysis. TKI-mediated TDAEs were reported in ten out of fifty patients. TKI-mediated TDAEs were characterized by hypothyroidism in all ten patients. Specifically, 40%, 40% and 20% of patients presented grade 1, 2 and 3 hypothyroidisms, respectively. Following tumor progression and during anti-PD-1 nivolumab treatment, five out of ten patients developed anti-PD-1 nivolumab-mediated recurrent TDAEs. Anti-PD-1 nivolumab-mediated recurrent TDAEs were characterized by an early transient phase of thyrotoxicosis and a late phase of hypothyroidism in all five patients. The TDAEs were grade 1 and 2 in four and one patients, respectively. Prior anti-angiogenic TKI did not modify the clinical characteristics of nivolumab-mediated recurrent TDAEs. However, all five patients required an increased dosage of levothyroxine replacement therapy. In conclusion, our work suggests that prior anti-angiogenic TKI-based treatment significantly increases the risk of ICI-mediated recurrent TDAEs in patients with mRCC without modifying their clinical characteristics. The most relevant effect for these patients is the need to increase the dosage of lifelong levothyroxine replacement therapy.

THU535 Anti-angiogenic Multi-kinase Inhibitor In NUTM1 Rearranged Carcinoma Of Thyroid

Abstract Disclosure: S. Tella: None. J.C. Morris: None. M. Rivera: None. S. Gupta: None. M.M. Ryder: None. Introduction: NUT carcinoma is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT-fusion oncoproteins with a very dismal prognosis. Recent data showed that NUTM1 rearranged carcinoma of the thyroid can mimic other thyroid primaries but NSD3-NUTM1 fusions aid in the diagnosis. Other than systemic chemotherapy with ifosfamide-based therapies and bromodomain inhibitors, therapeutic options for metastatic NUTM1 rearranged carcinoma of thyroid are limited. Herein, we describe a case of NUTM1 carcinoma of thyroid that had an impressive response to lenvatinib. Clinical case: We describe a case of a 41-year-old Caucasian male who presented to urgent care with acute onset aphonia and was eventually diagnosed with poorly differentiated thyroid carcinoma of size 4 x 4 cms extending into the internal jugular vein. He was managed with partial resection of the mass, internal jugular vein ligation, and a right select neck dissection. He had R2 resection due to possible vascular or airway invasion. As such, he received external beam radiation 70 Gy with 35 fractions with concurrent cisplatin followed by 200 mci radio-iodine therapy. The radiation therapy was complicated by the formation of a tracheo-esophageal fistula. A follow-up FDG-avid PET scan demonstrated residual thyroid bed disease and oligometastatic disease in bones. He received a couple of Stereotactic Body Radiation Therapy twice for bone lesions. Unfortunately, he had rapid disease progression with large pleural-based nodules and histology showed poorly differentiated thyroid carcinoma. NUT1 IHC stain was negative. We simultaneously obtained next-generation sequencing (NGS) and started him on lenvatinib 20 mg. Interestingly, NGS showed NSD3-NUTM1 fusions favoring the diagnosis of NUTM1 rearranged carcinoma of thyroid. He had an impressive partial response to lenvatinib within 4 weeks of initiation of lenvatinib and the response is sustained on 8-month follow-up. He tolerated lenvatinib reasonably without any unexpected complications. In an event of progression, we intend to consider a clinical trial, chemotherapy in combination with bromodomain inhibitors, or another anti-angiogenic tyrosine kinase inhibitor therapy. Conclusions: We noticed an impressive and sustained partial response in NUTM1 rearranged carcinoma of thyroid with anti-angiogenic multi-kinase inhibitor, lenvatinib opening new avenues of targeted therapy in the therapeutic landscape of NUT1 carcinomas. Importantly, NUT1 stain could be negative and NGS is the gold standard for accurate diagnosis. Although our study is limited by one case report, we hope that by highlighting the spectrum of this disease that more cases will be recognized, facilitating risk stratification and improved treatment, and further enabling future studies to explore the clinical management and biology of NUTM1 rearranged carcinoma of thyroid. Presentation: Thursday, June 15, 2023

PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors.

Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI). HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC. VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group. By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.

Abstract B028: Tipifarnib synergizes with axitinib in renal cell carcinoma models

Abstract Clear cell renal cell carcinoma (ccRCC) is a highly vascularized tumor type, primarily due to loss of the Von Hippel-Lindau (VHL) gene that stabilizes hypoxia-inducible factor alpha proteins (HIF1α and HIF2a), primary drivers of the angiogenic response in this cell type. This includes production of angiogenic factors, such as VEGFA, which promotes the formation of blood vessels that provide tumors oxygen, nutrients, and growth factors. Anti-angiogenic tyrosine kinase inhibitors (TKIs) such as the VEGFR1/2/3 inhibitor axitinib have demonstrated therapeutic benefit in RCC patients by exploiting the critical dependency of RCC tumors on their vasculature. However, resistance to TKIs is commonly observed, leading to clinical relapse. Here, we report that the farnesyltransferase inhibitor (FTI), tipifarnib synergizes with axitinib, resulting in tumor regressions in the VHL-mutant RCC cell line-derived xenograft (CDX) models, 786-O and A498, and stasis in VHL-wild type Caki1 CDX and KI-9310 PDX models, despite the modest antitumor activity of either drug as monotherapy. To investigate the mechanism underlying this synergism, we performed immunohistochemical analysis of angiogenic markers in 786-O tumors treated with tipifarnib, axitinib, or the combination. Consistent with its mechanism of action, axitinib alone decreased angiogenesis compared to vehicle, which was evident as reduced expression of endothelial cell (EC) markers in the tumors. The combination of tipifarnib and axitinib, however, led to a further two-fold reduction in EC staining, suggesting that tipifarnib is enhancing the anti-angiogenic effect of axitinib. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of the axitinib-tipifarnib effects in RCC. Citation Format: Jovylyn Gatchalian, Linda Kessler, Hetika Vora Patel, Stacia Chan, Francis Burrows, Shivani Malik. Tipifarnib synergizes with axitinib in renal cell carcinoma models [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B028.

SEOM SOGUG clinical guideline for treatment of kidney cancer (2022).

Renal cancer is the seventh most common cancer in men and the tenth in women. The aim of this article is to review the diagnosis, treatment, and follow-up of renal carcinoma accompanied by recommendations with new evidence and treatment algorithms. A new pathologic classification of RCC by the World Health Organization (WHO) was published in 2022 and this classification would be considered a "bridge" to a future molecular classification. For patients with localized disease, surgery is the treatment of choice with nephron-sparing surgery recommended when feasible. Adjuvant treatment with pembrolizumab is an option for intermediate-or high-risk cases, as well as patients after complete resection of metastatic disease. More data are needed in the future, including positive overall survival data. Clinical prognostic classification, preferably IMDC, should be used for treatment decision making in mRCC. Cytoreductive nephrectomy should not be deemed mandatory in individuals with intermediate-poor IMDC/MSKCC risk who require systemic therapy. Metastasectomy can be contemplated in selected subjects with a limited number of metastases or long metachronous disease-free interval. For the population of patients with metastatic ccRCC as a whole, the combination of pembrolizumab-axitinib, nivolumab-cabozantinib, or pembrolizumab-lenvatinib can be considered as the first option based on the benefit obtained in OS versus sunitinib. In cases that have an intermediate IMDC and poor prognosis, the combination of ipilimumab and nivolumab has demonstrated superior OS compared to sunitinib. As for individuals with advanced RCC previously treated with one or two antiangiogenic tyrosine-kinase inhibitors, nivolumab and cabozantinib are the options of choice. When there is progression following initial immunotherapy-based treatment, we recommend treatment with an antiangiogenic tyrosine-kinase inhibitor. While no clear sequence can be advocated, medical oncologists and patients should be aware of the recent advances and new strategies that improve survival and quality of life in the setting of metastatic RC.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study

Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.