VEGFR Inhibitor Research Articles

#3261 SAR131675, A SELECTIVE VEGFR3 INHIBITOR, AMELIORATES RENAL INFLAMMATION AND LYMPHANGIOGENESIS IN THE MURINE LUPUS NEPHRITIS MODEL

Abstract Background and Aims Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune-complex deposits and inflammatory cell infiltrations in multiple organs, and approximately half of lupus patients have nephritis. Lymphangiogenesis is the proliferation of pre-existing lymphatic vessels (LVs), which regulate tissue fluid homeostasis and immune cell trafficking, responding to the tissue environment. In this study, we evaluated the therapeutic effect of SAR131672, a selective VEGFR3 inhibitor, on the murine lupus nephritis model by regulating inflammation and lymphangiogenesis. Method First, we reviewed medical records for the biopsy-proven lupus nephritis and performed an immunohistochemistry study for D2-40. For animal experiments, seven to eight-week-old male BALB/c mice were used. The back area's skin was shaved and treated topically three times per week, with 100 μg of resiquimod in 100 μl of acetone for eight weeks and concomitantly treatment of VEGFR3 inhibitor, SAR 131672 by oral gavage. We evaluated renal histology and immunofluorescent study for inflammatory cells and lymphatic vessels. We also evaluated inflammatory cytokines and chemokines, lymphangiogenic factors by qRT-PCR. Results In a human study, we found that the higher lupus activity index, the more D2-40(+) lymphatic vessels are expressed in the tubulointerstitial areas. In an animal study, eight weeks of topical treatment of resiquimod to Balb/c mice induces lupus-like symptoms such as weight loss, splenomegaly, and glomerular immune complexes deposits such as IgG, IgM, and C3 in immunofluorescent staining. Histologically, glomerular mesangial cell proliferation and increased inflammatory cells in tubulointerstitial areas were noted in the H&E stain. Inhibition of VEGFR3 by oral SAR131672 treatment decreases glomerular and tubulointerstitial inflammation and decreases LYVE-1(+) lymphatic vessels. The pro-inflammatory cytokines and chemokines such as ICAM-1, VCAM-1, MCP-1, CCL19, CCL21, CCR7, CXCL13, and BAFF mRNA levels were increased compared with the vehicle-treated group. Treatment SAR131672 decreases pro-inflammatory cytokines and chemokine. Conclusion Inhibition of VEGFR3 by SAR131672 decreases the resiquimod-induced lupus nephritis model by regulating inflammation and lymphangiogenesis.

Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives.

This study involved the design and synthesis of 21 new nitrogen-containing heterocyclic chalcone derivatives utilizing the active substructure splicing principle, with glycyrrhiza chalcone serving as the lead compound. The targets of these derivatives were VEGFR-2 and P-gp, and their efficacy against cervical cancer was evaluated. Following preliminary conformational analysis, compound 6f ((E)-1-(2-hydroxy-5-((4-hydroxypiperidin-1-yl)methyl)-4-methoxyphenyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)prop-2-en-1-one) exhibited significant antiproliferative activity against human cervical cancer cells (HeLa and SiHa) with IC50 values of 6.52 ± 0.42 and 7.88 ± 0.52 μM, respectively, when compared to other compounds and positive control drugs. Additionally, this compound demonstrated lower toxicity towards human normal cervical epithelial cells (H8). Subsequent investigations have demonstrated that 6f exerts an inhibitory impact on VEGFR-2, as evidenced by its ability to impede the phosphorylation of p-VEGFR-2, p-PI3K, and p-Akt proteins in HeLa cells. This, in turn, results in the suppression of cell proliferation and the induction of both early and late apoptosis in a concentration-dependent manner. Furthermore, 6f significantly curtails the invasion and migration of HeLa cells. In addition, 6f had an IC50 of 7.74 ± 0.36 μM against human cervical cancer cisplatin-resistant HeLa/DDP cells and a resistance index (RI) of 1.19, compared to 7.36 for cisplatin HeLa cells. The combination of 6f and cisplatin resulted in a significant reduction in cisplatin resistance in HeLa/DDP cells. Molecular docking analyses revealed that 6f exhibited binding free energies of -9.074 and -9.823 kcal·mol-1 to VEGFR-2 and P-gp targets, respectively, and formed hydrogen bonding forces. These findings suggest that 6f has potential as an anti-cervical cancer agent and may reverse cisplatin-resistant activity in cervical cancer. The introduction of the 4-hydroxy piperidine and 4-methyl piperidine rings may contribute to its efficacy, and its mechanism of action may involve dual inhibition of VEGFR-2 and P-gp targets.

The effect of graphydine oxide (GDYO) nanosheets on disrupting theF-actin filament of anaplastic thyroid carcinoma (ATC) cells

Anaplastic thyroid carcinoma is deadly cancer with high mortality rates. Previous studies have shown that MART-10, ananalog to vitamin D, effectively prevents cancer’s metastatic potential by downregulating N-cadherin and filamentousactin filaments (F-action filament). In more recent studies around AML (acute myeloid leukemia), a novel materialname graphene oxide nanosheets (GDYO) are effective against AML related to DNA(cytosine-5)methyltransferase3A(DNMT3A)-mutated genes. It has also been found that GDYO nanosheets have been able to disrupt the F-actinfilament of AML cells, inducing cell apoptosis which leads to the destruction of the mutated cells. This paper exploresthe further application of this material in the biomedical field by testing the ability of GDYO nanosheets to inducecell apoptosis in other types of cancer, for example, ATC cells. The study will use an 8505C cell line with negativephosphate-buffered saline (PBS) and positive control Nexavar, a clinically tested drug that treats early ATC cell growth.Nexavar, also known as Sorafenib, inhibits tumor growth by a dual mechanism, acting directly on the tumor (throughinhibition of Raf and Kit signaling) and tumor angiogenesis (through inhibition of VEGFR and PDGFR signaling).The paper investigates whether GDYO can successfully disrupt the F-actin filaments of ATC cells, thereby killing themthrough inducing apoptosis and preventing the metastatic potential of ATC cells.

Predictive biomarkers of benefit to axitinib plus avelumab in patients with recurrent/metastatic adenoid cystic carcinoma (R/M ACC).

6096 Background: ACC is a heterogeneous malignancy with no standard treatment for patients (pts) with R/M disease. Two distinct ACC subtypes have been identified proteogenomically, which contribute to ACC’s biological variability. ACC-I is enriched with NOTCH activating mutations and MYC overexpression and has a poor prognosis (median survival [mOS] = 3.4 years). ACC-II has upregulation of TP63 and presents with an indolent disease course (mOS = 23.2 years). In a phase II trial of axitinib (VEGFR inhibitor) plus avelumab (PD-L1 inhibitor) in R/M ACC, clinical benefit was heterogenous. We hypothesized that ACC subtype and gene expression profile are associated with benefit to axitinib plus avelumab. Methods: Cohort of 28 R/M ACC pts with radiological or clinical progression within 6 months (mos) of enrollment in the axitinib plus avelumab trial (NCT03990571). Target transcriptome profile including 19,616 probes was generated using HTG Transcriptome Panel [HTP]. Gene expression was used to identify ACC subtypes (ACC-I vs. ACC-II). Confirmed overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) per RECIST v1.1 was assessed for each ACC subtype. An analysis of genes associated with benefit vs. no benefit from axitinib plus avelumab was conducted for the overall population and per ACC subtype. Benefit was defined as disease control (partial response [PR] or stable disease [SD]) and PFS longer than the median PFS. PFS > 6 mos was not used to define benefit due to the significant differences in PFS between ACC subtypes. Results: Out of 28 pts, 14 (50%) were classified as ACC-I and 14 (50%) were ACC-II. For ACC-I, ORR was 14.3% (2/14; 95%CI: 1.8-42.8%), DCR was 35.7% (2 PR + 3 SD; 95%CI: 12.8-64.9%) and median PFS was 1.86 mos (95%CI: 1.81-8.61 mos). For ACC-II, ORR was 21.4% (3/14; 95%CI: 4.7-50.8%), DCR was 100% (3 PR + 11 SD; 95%CI: 76.8-100%) and median PFS was 10.5 mos (95%CI: 7.40-NA). PFS was significantly longer for ACC-II vs. ACC-I (HR 0.19 [95%CI: 0.08 – 0.49], p = 0.0002). Through the previously defined benefit vs. no benefit cutoff, ACC-I had a 42.9% (6/14) and ACC-II had a 50.0% (7/14) benefit rate. Benefit in all ACC pts, ACC-I and ACC-II was associated with high expression of immune-related genes, especially B and T-lymphocyte function. Angiogenesis-related genes were not significantly upregulated in the benefit group as previously reported in renal cell carcinoma pts treated with the same combination. Conclusions: Clinical outcomes to axitinib plus avelumab were distinct between ACC-I and ACC-II subtypes, with ACC-II pts demonstrating an improved DCR and significantly longer PFS. Gene expression analysis revealed high expression of immune function-related genes in patients who benefited from axitinib plus avelumab in both ACC subtypes, indicating possible biomarkers predictive of benefit from the combination in ACC. Clinical trial information: NCT03990571 .

NeoPlus: A phase II study of neoadjuvant lenvatinib and pembrolizumab in resectable mucosal melanoma.

9514 Background: Combination therapy of anti-PD1 agent with VEGFR inhibitor is a promising therapeutic approach in unresectable or metastatic mucosal melanoma. We conducted this study evaluating neoadjuvant lenvatinib and pembrolizumab in pts with resectable mucosal melanoma. Methods: This was a single-arm, open-label, single-center, ongoing phase 2 study conducted from Sep 2021. Eligible pts were adults (18-75 yr) with histologically confirmed, resectable mucosal melanoma. Pts received lenvatinib 20mg qd and pembrolizumab 200mg q3w for 2 cycles, followed by surgery. Pembrolizumab (200mg q3w) continued post operatively for further 15 cycles. The primary endpoint was complete pathologic response (pCR). Secondary endpoints were Event free survival (EFS), Overall survival (OS) and safety. Results: As of Dec 2022, 19 pts were enrolled with a median follow-up of 49 wks (95%CI, 38 -60). Median age was 57 yrs, 14 were female. Primary sites included: 8 female genital, 6 ano-rectal, 4 head & neck (1 nasal, 3 oral),1 esophageal. 12 pts were localized disease,7(37%) were regional lymphatic disease. KIT or NRAS mutations were presented in 2 and 3 pts, respectively. 15 pts underwent surgery, 2 pts had a pCR (13.3 %), 1 MPR, 3 pPR, with a pathologic response rate of 40%(6/15,95%CI 16-67%). 4 pts did not proceed with planned surgery for pts preference. Median EFS has not been reached. IHC data of the resected tumor showed higher CD8+ T cells density in responders (R=pCR+ MPR + pPR) than non-responders (NR=pNR) (p = 0.04). In 6 pts(one pPR and 5pNR) with paired pre and post treatment samples, CD3+ and CD8+ T cells were significantly increased following treatment (p =0.03). Most common AEs were proteinuria (6, 32%), hypothyroidism (6, 32%), dysphonia (5, 26%). One pt(5%, 1/19) had grade 3 ALT elevation. No grade 4-5 toxicities were observed. Conclusions: The combination of pembrolizumab plus lenvatinib as neoadjuvant therapy in resectable MM is safe. The preliminary data has shown promising pathologic response with increased CD8+ T cell infiltration, supporting further investigation of neoadjuvant treatment in MM. Acknowledgement: Investigational funding and products are granted from Merck Sharp & Dohme LLC. Clinical trial information: NCT04622566 .

Fruquintinib plus oxaliplatin combined with S-1 (SOX) as neoadjuvant therapy for locally advanced gastric adenocarcinoma (FRUTINEOGA): A multicenter, phase II study.

e16063 Background: Neoadjuvant chemotherapy (NCT) has become the standard treatment for patients (pts) with locally advanced GC, and SOX is the most common neoadjuvant regimen in China. Fruquintinib is a VEGFR inhibitor that blocks new blood vessel growth associated with tumor proliferation. It is a potent, highly selective small-molecule inhibitor of VEGFR-1,-2, and -3. The generally good tolerability in pts and fruquintinib’s low potential for drug-drug interaction suggest that it may be highly suitable for combinations with other antineoplastic therapies. We aimed to investigate the efficacy and toxicity of fruquintinib plus SOX as neoadjuvant treatment for locally advanced GC. Methods: It was a prospective, multicenter, phase II study in pts with stage III (cT3/4aN+M0) GC. Pts received 2 to 4 cycles of fruquintinib (5mg qd D1-14, Q3W) plus SOX (oxaliplatin 130mg/m2 D1, S-1 40-60mg bid D1-14 depending on body surface area (BSA), Q3W). Pts underwent D2 gastrectomy after neoadjuvant treatment. The primary endpoint was pathological response rate (pRR), and the secondary endpoints were disease-free survival (DFS), overall survival (OS), objective response rate (ORR), major pathological response rate (MPR), and R0 resection rate. Results: Up to February 3, 2023, 19 pts were eligible for the study. Median age was 62 years (29-73), 68.4% were male, and 21.1% were ECOG 1. Seven pts dropped out of clinical trial for AEs (2 pts), violation of treatment protocol (1 pt), staging error (2 pts), and refusal of surgery (2 pts). Twelve pts underwent surgery, 1 patient was found with peritoneal implantation, 11 patients underwent gastrectomy. Among the 11 pts, 9 pts achieved pRR (81.8%) and 3 pts achieved MPR (27.3%). The pathologic CR rate was 27.3% (3 of 11 pts). Moreover, 11 pts had curative intended operations and R0 resection rate was 90.9%. Among all the 19 pts, 16 pts received at least one dose of the combination treatment. A total of 2 pts had target lesions, 1 patient had complete response and 1 had partial response. Among the other 14 pts without target lesions, 1 (7.1%) had progressive disease with peritoneal implantation metastasis, and none had complete response. Furthermore, the most common TEAEs of grade ≥ 3 occurred in 19 pts were decreased appetite (21.1%), hypertension (21.1%), nausea (15.8%), vomiting (10.5%), oral mucositis (10.5%), fatigue (5.3%), diarrhea (5.3%) and respiratory infections (5.3%). There were neither new safety signals nor AEs inducing treatment deaths. Conclusions: The combination of fruquintinib and SOX as neoadjuvant treatment in patients with locally advanced GC is safe. The combination demonstrates promising evidence of anti-tumor efficacy in terms of pathological response. Clinical trial information: NCT05122091 .

A phase II study of lenvatinib plus pembrolizumab in patients with progressive, recurrent/metastatic adenoid cystic carcinoma.

6048 Background: Recurrent/metastatic adenoid cystic carcinoma (R/M ACC) is a rare salivary gland cancer (SGC) without standard treatments. The multitargeted, antiangiogenic kinase inhibitor lenvatinib (len) has activity in R/M ACC, but immune checkpoint inhibitor (ICI) therapies lack efficacy. Hypothesizing that VEGFR inhibition can enhance ICI-induced responses, we conducted a phase II trial evaluating len plus the programmed death-1 (PD-1) inhibitor pembrolizumab (pem) in two R/M SGC cohorts: ACC and non-ACC. Here we report results from the completed ACC cohort. Methods: Patients (Pts) with R/M ACC were enrolled. RECIST v1.1 measurable disease and evidence of progression on imaging performed within 6 months of enrollment were required; any number of prior therapies was allowed. Pts were treated with len 20 mg orally daily and pem 200 mg intravenously every 3 weeks (21-day cycles). The primary objective was to evaluate best overall response rate (ORR), seeking an ORR improvement with len+pem from 15% (previously reported with len alone) to 35%. In the first stage, > 3 confirmed complete and partial responses (cCRs+ cPRs) were required among 17 pts to continue to the second stage; > 8 responses among 32 total pts would have been considered positive (1-sided alpha 0.1, power 0.9). Secondary objectives included evaluating progression-free survival (PFS) and safety/tolerability per CTCAE v5.0 criteria. Results: 17 R/M ACC pts were enrolled and evaluable for the primary objective. One pt had a cPR for an ORR of 6%, failing to meet the rule for progression to the second stage. Thirteen (76%) pts had stable disease and 2 (12%) progression of disease as best response; 1 pt did not have response assessed. Thirteen (76%) pts experienced some degree of regression in RECIST target lesions (TLs; -1.9% to –42.8%), including 5 (29%) with > -20% regression. Eleven (65%) pts were progression-free for > 24 weeks. Twelve (71%) pts experienced at least one > Grade 3 adverse event related to study treatment. Sixteen pts had at least one treatment interruption or len dose reduction; 2 pts received only 1 cycle of therapy. Five pts were treated beyond first progression without observation of subsequent response. Quality of life data and correlative tissue studies are ongoing. Conclusions: The trial failed to demonstrate that len+pem produces a greater ORR in patients with R/M ACC than what was previously reported with len alone. Further investigation into the biology mediating ICI-resistance and development of novel approaches to augment the efficacy of immune-based therapies in ACC are needed. (Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA provided lenvatinib and pembrolizumab for the study.) Clinical trial information: NCT04209660 .

MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001).

TPS4609 Background: First-line platinum-based chemotherapy followed by maintenance avelumab (Av) is the current preferred standard of care in patients (pts) with mUC who do not progress after platinum-based chemotherapy. There is an unmet need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitors. We hypothesize that CABO-Av combination will be synergistic in pts with mUC with an acceptable safety profile and will improve upon the benefit seen with Av maintenance in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for locally advanced/mUC pts (including N3 only disease) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adult pts will be randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or combination of Av and CABO 40 mg orally daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of immunotherapy (exception of BCG), no central nervous system metastases, no major surgery within 4 wk, no uncontrolled hypertension or cardiovascular disorders. Pts will be stratified based on 1) best response to 1L therapy: complete response vs partial response vs stable disease and 2) presence or absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of one-sided alpha of 0.025, power of 80%, median OS of 21 months (mo) on Av arm and hazard ratio (HR) of 0.75, thus hypothesizing a median OS of 28 mo on CABO-Av combination arm. Key secondary endpoints include progression-free survival, safety, tolerability, and activity of CABO-Av compared to Av alone based on RECIST 1.1 and iRECIST criteria and PD-L1 status of pts’ tumors. Quality of life (QOL) will be assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-avelumab vs avelumab alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test correlation of established and new radiomic signatures with OS, adverse events and QOL and incorporate both radiologic and biologic features to predict outcomes. This trial would be the first to systematically address whether adding a multitargeted TKI, CABO to Av leads to improved clinical outcomes compared to Av alone. Clinical trial information: NCT05092958 .

KC1036, a novel oral multi-kinase inhibitor, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC): Results from a multicenter, single-arm phase II trial.

e16011 Background: Therapeutic options for patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) are limited. KC1036, a novel oral multi-kinase inhibitor of AXL, VEGFR2 and FLT3, has shown promising antitumor activity in preclinical and phase I studies. Here we report the preliminary outcomes from a phase II study, including the safety of KC1036 in patients with advanced gastrointestinal cancers, and the efficacy of KC1036 as second-line or later treatment in patients with advanced ESCC. Methods: In this multicenter, open label, single-arm phase II study, patients with advanced gastrointestinal cancers refractory to standard treatment were enrolled. For patients with advanced ESCC, those who had received standard first-line PD-1 blockade plus chemotherapy were eligible. KC1036 was administered orally at 60 mg QD, every 21 days as a cycle, until disease progression, death or intolerable toxicities. Primary endpoint was objective response rate (ORR) assessed by investigators per RECIST 1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and safety. Results: Between June 8, 2022 and December 30, 2022, 58 patients were enrolled and received at least 1 dose of KC1036. The most common tumor type was ESCC (55.2%%, 32/58), followed by gastric cancer (13.8%, 8/58) and colorectal cancer (13.8%, 8/58). The median age was 63.5 (range 55.0-67.0) years. 29 patients (50.0%) had received prior treatment with PD-1 inhibitors and 46 patients (79.3%) had received platinum-containing chemotherapy. Lung metastasis and liver metastasis were observed at baseline in 39.7% (23/58) and 48.3% (28/58) of the patients, respectively. As of the data cut-off date (December 30, 2022), treatment-related adverse events (TRAEs) of any grade occurred in 50 (86.2%, 50/58) patients. 12 patients (20.7%, 12/58) reported grade 3 TRAEs, and the most common grade 3 TRAE was hypertension (5.2%, 3/58). Grade 4-5 TRAEs were reported in 2 patients, including one case of grade 4 esophagomediastinal fistula, and one case of death from unknown cause. 24 out of the 32 patients with advanced ESCC had at least one tumor response evaluation at data cut-off. Among them, 7 had partial response (PR), 13 had stable disease (SD), and 4 had progressive disease (PD) as best response. The ORR for ESCC patients was 29.2% (95% CI: 12.6%, 51.1%), and the DCR was 83.3% (95% CI: 62.6%, 95.3%). The median PFS was 4.2 months (95% CI, 2.20, 5.75), while the median DoR had not been reached. At data cut-off, 11 patients with ESCC were still receiving KC1036 treatment. Conclusions: KC1036 showed a manageable safety profile and promising anti-tumor activity in patients with previously treated advanced ESCC. This study is ongoing with further investigation of KC1036 in ESCC patients. Clinical trial information: NCT05260385 .

A multicenter, single-arm phase 2 study of surufatinib plus toripalimab for patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer.

6089 Background: For patients (pts) with radioactive iodine–refractory differentiated thyroid cancer (RAIR-DTC), there presents a considerable therapeutic challenge with poor long-term outcomes. The open-label, multi-cohort, single-arm phase 2 study was performed to evaluate surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) in combination with toripalimab (an anti-PD-1 antibody) in pts with RAIR-DTC. Methods: Eligible pts were with locally advanced or metastatic RAIR-DTC who were not amenable for surgery or external beam radiotherapy, with a radiologically confirmed disease progression within 12 months before treatment, and with ≥6 months since last radioiodine treatment. Enrolled pts received surufatinib 250 mg orally, QD, plus toripalimab 240 mg IV, Q3W, until disease progression or reaching the maximum treatment duration with toripalimab of 24 months, or other protocol-specified criteria. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From March 2020 to November 2021, 15 pts were enrolled and received a median duration of 11.1 months of the combination treatment, with a median age of 61 years (range: 37-74). 9 (60%) pts were male, and 12 (80%) had papillary thyroid cancer. Of the 13 pts with PD-L1 immunochemical results, 6 pts had PD-L1 CPS ≥1%. As of 28 Dec 2022, the median follow-up duration was 22.11 months. Of the 15 pts with at least one post-baseline tumor assessment, the confirmed ORR was 33.3% (5 PRs) and DCR was 93.3%. mDoR was 8.34 months. mPFS (95%CI) was 10.91 months (4.01, NA). mOS was not reached, and 12-month OS rate was 100%. 14 (93.3%) pts had treatment-emergent adverse events (TEAEs), and 10 (66.7%) pts reported grade ≥3 TEAEs, most commonly (≥10% pts) with hypocalcemia (20%), diarrhea (20%) and hypertension (13%). There was no death due to TEAE in the study. Conclusions: Surufatinib plus toripalimab showed encouraging antitumor activity and tolerable safety profile in pts with locally advanced or metastatic RAIR-DTC. Clinical trial information: NCT04169672 .

A multicenter, single-arm, phase 2 study of surufatinib plus toripalimab for patients with advanced endometrial cancer.

5609 Background: Several immunotherapy monotherapies, or combined with antiangiogenic inhibitors, have shown antitumor efficacy in endometrial cancer (EMC) and been approved by FDA. However, therapeutic options for EMC after failure of first-line treatment remain scarce in China. The open-label, multi-cohort, single-arm phase 2 study was performed to evaluate the efficacy and safety of the combination of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) with toripalimab (an anti-PD-1 antibody) for Chinese patients (pts) with EMC after failure of one or more prior lines of systemic treatment. Methods: Pts with EMC who progressed or were intolerable after at least one prior line of systemic antitumor therapy were eligible and enrolled. They received 21-day cycles of surufatinib 250 mg orally, QD, plus toripalimab 240 mg IV, Q3W, until disease progression or reaching the maximum treatment duration with toripalimab of 24 months, or other protocol-specified criteria. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From August 2020 to March 2022, 28 pts were enrolled and received the combination treatment (median duration: 4.6 months). Median age was 58 years (range: 50-71), and 22 (78.6%) pts were endometrioid adenocarcinoma at diagnosis. 9 (32.1%) pts had received ≥2 prior lines of therapy. As of 28 Dec 2022, the median follow-up duration was 16.8 months. Microsatellite status was available in 25 pts. 20 with mismatch repair-proficient (pMMR) and 5 with mismatch repair-deficient (dMMR) were determined. All 28 pts were evaluable with at least one post-baseline tumor assessment. Efficacy results were: confirmed ORR, 28.6% (8 partial response [PRs]); DCR, 82.1%; mDoR, 5.7 months; mPFS (95%CI), 5.4 months (2.7, 8.3); 12-month OS rate, 71.0%. Among pts with pMMR, the confirmed ORR was 25.0%; DCR was 85.0%; mDoR was 4.2 months; mPFS (95%CI) was 4.0 months (2.7, 8.3); 12-month OS rate was 75.4%. All pts experienced at least one treatment-emergent adverse event (TEAE), and 19 (67.9%) of them reported grade ≥3 TEAEs. The most common (≥5% pts) grade ≥3 TEAEs were hypertension (28.6%), aspartate aminotransferase increased (14.3%), alanine aminotransferase increased (10.7%), proteinuria (7.1%), Gamma-glutamyltransferase increased (7.1%) and malignant neoplasm progression (7.1%). No new safety signals were observed. Conclusions: Surufatinib plus toripalimab had a promising antitumor activity and a manageable safety profile in pts with EMC after failure of one or more prior lines of systemic therapy. Clinical trial information: NCT04169672 .

Neoadjuvant immunochemotherapy for esophageal squamous cell carcinoma with camrelizumab, albumin-paclitaxel, carboplatin and apatinib (GASTO-1093): A single-arm, open-label, phase 2 trial.

e16068 Background: Camrelizumab combined with chemotherapy has shown antitumor efficacy in the neoadjuvant therapy of esophageal squamous cell carcinoma (ESCC). Apatinib, a selective inhibitor of VEGFR2, showed a synergistic effect when combined with camrelizumab and chemotherapy in advanced ESCC. We aim to assess the efficacy and safety of using the combination of camrelizumab with apatinib and chemotherapy (albumin-paclitaxel plus carboplatin) as the neoadjuvant therapy for ESCC. Methods: Patients with untreated, resectable (stage II or III) ESCC were enrolled. Each patient received two 21-day cycles of neoadjuvant treatment with intravenous camrelizumab (200mg), albumin-paclitaxel (260mg/m2), carboplatin (area under the curve = 5) on day 1, and oral apatinib 250 mg/day on days 1-14, followed by the third cycle without apatinib. The patients underwent surgical resections about 9 weeks after Day 1 of Cycle 1. The primary end point was pathological complete response (PCR). Secondary endpoints included safety, objective response rate (ORR) and disease control rate (DCR). This analysis was approved by the study's Data and Safety Monitoring Committee. Results: Between February 2022 and January 2023, 38 eligible patients were enrolled. Two patients withdrew and eight recent patients have not completed two treatment cycles yet; therefore, 28 patients who have completed the full three-cycle treatment were included in this analysis. The ORR and DCR were 92.9% and 100%, respectively. 26 (92.9%) patients underwent surgery, and R0 resection was achieved in all cases. PCR (ypT0N0) was identified in 11 (42.3%) patients, and 2 (7.7%) patients had complete response of the primary tumor but residual disease in lymph nodes alone (ypT0N+). The most common grade 1 or 2 treatment-related adverse events (trAEs) were pruritus (85.7%), asthenia (75%), and peripheral sensory neuropathy (60.7%). Grade 3 or 4 trAEs included neutropenia (53.6%), leukopenia (53.6%), thrombocytopenia (25%), hepatitis (10.7%), febrile neutropenia (10.7%), hypertension (7.1%), and rash (3.6%). Immune-related AEs included rash (21.4%), hepatitis (10.7%), reactive capillary hemangiomas (10.7%) and hyperthyroidism (3.6%). Of note, treatment-related hepatitis led to the discontinuation of treatment and surgical delay in 1 patient (3.6%). There was no treatment-related, in-hospital, postoperative 30-day, and postoperative 90-day mortality. Conclusions: Neoadjuvant camrelizumab combined with apatinib and chemotherapy in patients with resectable ESCC had manageable trAEs and a high PCR rate (42.3%). Larger cohorts are needed to examine whether this PCR rate is significantly higher than the PCR rate (25%) of a different trial using camrelizumab combined with chemotherapy ( ChiCTR2000028900 ). Clinical trial information: ChiCTR2100051763 .

Activity of cabozantinib (CABO) plus durvalumab (DURVA) in patients (pts) with advanced urothelial carcinoma (UC) or non-UC variant histologies (VH) after platinum chemotherapy: Interim results from the phase 2 ARCADIA trial.

4578 Background: Combining multitargeted receptor tyrosine kinase inhibitor (TKI) with checkpoint inhibitors has shown synergistic effect in pts with UC due to the immunomodulatory propriety of VEGFR inhibitors. We investigated if the combination of CABO and DURVA in pts with advanced UC and non-UC histology (VHs) in a phase II study (NCT03824691). Herein the preliminary results of the interim analysis. Methods: Patients affected by UC and VHs recurred or progressed after failure of at least one line of platinum-based chemotherapy for metastatic disease have been treated with CABO 40 mg daily, orally, and are administered DURVA 1500 mg IV, q28 days, until disease progression (PD, by RECIST 1.1) or onset of unacceptable toxicity. Key inclusion criteria were ECOG-PS 0-1 and adequate organ function. Response was evaluated by RECIST criteria v.1.1 every 8 wks. The primary endpoint of the study was OS. Secondary endpoints included safety (CTCAE v.4.03), objective response-rate (ORR), duration of response (DoR), progression-free survival (PFS). The assumption was to detect an improvement in the median OS from ≤6 months (H0) to ≥9 months (H1). Results: Between September 2019 and February 10, 2023, the ARCADIA study enrolled 63 pts: this interim analysis was performed after obtaining at least one post-baseline tumor assessment data from 58 pts. The median follow-up was 23.5 mos (interquartile [IQ] range: 7.7-27.7mos): 27% were female, the median age was 64 yrs (range: 42-81), 20 pts (34%) had a pure/predominant non-UC VH: 9 (45%) a squamous differentiation/sarcomatoid tumor, 5 (25%) an adenocarcinoma, 4 (20%) a small-cell neuroendocrine tumor, 1 (5%) a clear-cell tumor, and 1 a nested VH (5%). Eleven pts (19%) had received ≥2 prior systemic anticancer therapies. In 58 response-evaluable pts, 12 (20%) complete responses (CR) and 11 partial responses (PR) were obtained, the ORR being 39.7% (95%CI: 27.1-53.4) and disease control rate was 69% (95%CI: 55.5-80.5). In the cohort of pts with VH, the ORR was 45% (95%CI: 23.1-68.5). Median PFS was 7.6 mos (95%CI: 4.6-13-6 mos) and median OS was 11.6 (95% CI 6.8-20.3 months). Median exposure of treatment was 4.8 mos; 35 pts (55.5%) of 63 pts had all-grade treatment-related adverse events (AE) and 4 pts (6.3%) reported grade 3 (treatment related) AE with no grade 3-5 events. Dose-reductions of CABO were needed in 25 pts (39%). No treatment-related deaths were reported. Conclusions: CABO in combination with DURVA showed promising preliminary activity with a manageable safety profile in pts with advanced UC and in non-UC VH after previous chemotherapy exposure, deserving further evaluation of the combination that is ongoing with ARCADIA and other clinical trials. More mature results with longer follow-up will be presented. Clinical trial information: NCT03824691 .

Fruquintinib plus sintilimab in patients with either treatment-naive or previously first line treated metastatic clear-cell renal cell carcinoma (ccRCC): Results from a multicenter, single-arm phase 2 study.

e16514 Background: Antiangiogenic therapy combined with immunotherapy significantly improved the progression-free survival (PFS) and preliminary survival benefit for advanced clear-cell renal cell carcinoma (ccRCC). However, no combined immune therapies are currently approved for ccRCC in China. Fruquintinib (F, a highly selective VEGFR inhibitor) combined with sintilimab (S, an anti-PD-1 monoclonal antibody) showed encouraging antitumor activity in multiple solid tumors. Here, we reported the results of F plus S in metastatic ccRCC cohort from an open-label, single-arm phase 2 study (NCT03903705). Methods: Patients (pts) with pathologically confirmed metastatic ccRCC who were treatment-naive or had failed previously first-line treatment were eligible. They received F (5 mg, 2 weeks on/1 week off, orally, QD) plus S (200 mg, IV, Q3W) in 21-day cycles until disease progression or unacceptable toxicity; treatment of S was allowed for up to 24 months. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: As of cutoff (November 30, 2022), a total of 42 pts (22 treatment-naïve pts, and 20 previously first-line treated pts) were enrolled and received the combination treatment. Median (range) age was 59.0 (34.2-72.4) years; 34 (81.0%) pts were male. Among previously treated pts, 19 (19/20, 95.0%) pts had received VEGFR therapy as prior first-line treatment, including sunitinib (3/20, 15.0%), pazopanib (7/20, 35.0%), axitinib (2/20, 10.0%) and others (7/20, 35.0%). International Metastatic RCC Database Consortium (IMDC) risk included: favorable in 15 (35.7%) pts, intermediate in 22 (52.4%) pts, and poor in 5 (11.9%) pts. The median follow-up duration was 14.8 months (m) and 23.3 m for treatment-naive and previously treated pts, respectively. All pts had at least 1 post-baseline tumor assessment. Confirmed ORR was 68.2% and 60.0%, median duration of response was not reached (NR) and 13.9 m, and disease control rate was 95.5% and 85.0% for treatment-naive and previously treated pts, respectively. Median PFS (mPFS) was NR and 12m-PFS rate was 64.8% in treatment-naive pts; mPFS was 15.9 m in previously treated pts. The median treatment duration of F and S was both 14.7 m. All pts experienced at least 1 treatment-emergent adverse event (TEAE). Common (≥5%) grade ≥3 TEAEs were hypertension (21.4%), hypertriglyceridaemia (9.5%), amylase increased (7.1%), cerebral infarction (7.1%) and proteinuria (7.1%). No new safety signals were observed. Conclusions: F plus S demonstrated a favorable efficacy with manageable toxicity for treatment-naive and previously first-line treated metastatic ccRCC. A phase 2/3 study is being conducted to confirm this combination efficacy in the second-line treatment of ccRCC (NCT05522231). Clinical trial information: NCT03903705 .

Efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in metastatic colorectal cancer: A multicenter, single-arm phase 2 trial.

3582 Background: Emerging evidence suggested that chemotherapy in combination with anti-angiogenic targeted agents can achieve higher response in multiple solid tumors. Fruquintinib is a highly selective small-molecule VEGFR inhibitor that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, we assessed the efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in pretreated advanced mCRC patients. Methods: In this prospective, open-label, multicenter, single-arm phase 2 trial (ChiCTR2200059280), patients with mCRC progressed after first-line prior systemic treatment were administered fruquintinib (5~3mg, D1-21, Q4w) and investigator's choice of chemotherapy (fluorouracil ± irinotecan ± oxaliplatin, Q3w) for up to 8 cycles. Patients without disease progression (PD) were followed by fruquintinib maintenance until PD or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety. Results: As the data cutoff on February 10, 2023, 37 patients have been enrolled and treated, with 31 evaluable for efficacy. Median age was 63 years (range, 44-76) and 22 (59.5%) were male. The left colon cancer involved in 28 patients (75.7%). All patients were microsatellite-stable phenotype and 11 (29.7%) had mutations in KRAS gene. 16 (43.2%) patients received prior anti-VEGF therapy. 20 (54.1%) and 11 (29.7%) patients had liver and lung metastases respectively. At a median follow-up of 8.4 months, 28 patients are still on treatment. The ORR is 48.4%, with 15 partial response. The DCR is 90.3%. At data cutoff, median PFS has not yet reached. 23 patients (74.2%) remained progression free at 6 months. In terms of safety, the regimen was well tolerated, mainly grade 1/2 adverse events (AEs). Grade 3/4 AEs were neutropenia (21.6%), leukopenia (10.8%), thrombocytopenia (5.4%), proteinuria, diarrhea, hand-foot syndrome and hypertension accounted for 2.7% respectively. 5 pts received reduced doses of fruquintinib. No treatment-related deaths occurred. Conclusions: Fruquintinib combined with chemotherapy followed by fruquintinib maintenance shows promising efficacy and manageable safety profile for mCRC patients in second-line setting. Updated follow up data will be presented in the future. Clinical trial information: ChiCTR2200059280 .

A retrospective cohort study examining the effects of anti–PD-1 antibody in combination with apatinib in patients previously treated for HER2-negative advanced gastric/gastroesophageal junction cancer.

e16048 Background: Combining immune checkpoint inhibitors with vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) inhibitors are effective in treating a number of solid tumors; however, evidence in advanced gastric/gastroesophageal junction (G/GEJ) cancer is limited. Methods: This retrospective study included consecutive patients who received a programmed cell death protein 1 (PD-1) inhibitor plus the VEGFR-2 inhibitor apatinib, second-line or later to treat unresectable advanced or metastatic, histologically-proven, human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer in a single center between November 1, 2018 and March 31, 2021. Treatment was continued until the disease progressed or the toxicity became intolerable. Results: Data from 52 patients (median age 64 years; 38 men) were analyzed. The primary tumor site was the stomach in 29 patients (56%) and the GEJ in 23 patients (44%). The number of previous line(s) of therapy was one in 22 patients (42%) and two or more in 30 patients (58%). Liver metastasis was present in 22 patients (42%) and 33 patients (63%) had two or more metastatic sites. PD-1 inhibitors taken included camrelizumab (n=28), sintilimab (n=18), pembrolizumab (n=3) and tislelizumab (n=1), all given 200 mg every 3 weeks (Q3W), and toripalimab (240 mg Q3W) and nivolumab (200 mg every 2 weeks) in 1 patient each. The objective response rate was 15.4% (95% confidence interval [CI] 6.9–28.1), the disease control rate was 61.5% (95% CI 47.0–74.7). After a median follow-up of 14.8 months (range 11.8–23.5), median progression-free survival was 4.2 months (95% CI 2.6–4.8), overall survival was 9.3 months (95% CI 7.9–12.9). Grade 3–4 treatment-related adverse events occurred in 12 patients (23.1%). There was no unexpected toxicity or death. Conclusions: Combination therapy with an anti-PD-1 antibody and apatinib was effective in patients with previously treated, unresectable advanced or metastatic G/GEJ cancer, with a manageable safety profile.

Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least one prior systemic therapy: A single-arm phase II trial.

5516 Background: The first stage results of a Simon’s two-stage single-arm phase II trial showed promising antitumor activity and manageable safety of camrelizumab (a humanized anti-PD-1 monoclonal antibody) plus apatinib (a highly selective VEGFR2 inhibitor) in patients with advanced or recurrent endometrial cancer after failure of prior systemic therapy. Here, we report the primary results of this trial. Methods: This open-label, single-arm, phase II trial used a minimax Simon’s two-stage design. Patients with advanced or recurrent endometrial cancer that had progressed after at least one prior systemic therapy were treated with camrelizumab (200 mg, intravenously, every two weeks) and apatinib (250 mg, orally, daily) on a four-week cycle until disease progression or intolerable toxicity. The primary endpoint was the objective response rate per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Other assessed endpoints were disease control rate, time to response, duration of response, time to treatment failure, progression-free survival, overall survival, and treatment-related adverse events. Results: Between January 20, 2020 and October 14, 2022, 36 patients (median age: 60 [range: 29, 76] years; 17 [47.2%] had Eastern Cooperative Oncology Group [ECOG] performance status 1; 15 [41.7%] had received at least two prior systemic therapies) were enrolled. At the date of data cutoff (December 31, 2022), the median follow-up time was 13.9 (interquartile range: 5.8-23.2) months. All 36 patients were evaluable for efficacy, the confirmed objective response rate was 44.4% (95% CI: 27.9%, 61.9%) and the conformed disease control rate was 88.9% (95% CI: 73.9%, 96.9%), with two complete response, 14 partial response, and 16 stable disease. The median progression-free survival was 6.4 (95% CI: 5.2, 13.0) months. The treatment-related adverse events of grade 3 or greater occurred in 19 (52.8%) patients, with increased gamma-glutamyltransferase (8 [22.2%]), hyperglycemia (4 [11.1%]), hypertension (4 [11.1%]) and increased direct bilirubin (4 [11.1%]) being most common. Reactive cutaneous capillary endothelial proliferation occurred in 6 (16.7%) patients and all were grade 1 or 2. No treatment-related death occurred. Conclusions: Camrelizumab plus apatinib show promising antitumor activity and manageable toxicity in patients with advanced or recurrent endometrial cancer after failure of prior systemic therapy and warrant further investigation. Clinical trial information: ChiCTR2000031932 .

E7050 Suppresses the Growth of Multidrug-Resistant Human Uterine Sarcoma by Inhibiting Angiogenesis via Targeting of VEGFR2-Mediated Signaling Pathways.

E7050 is an inhibitor of VEGFR2 with anti-tumor activity; however, its therapeutic mechanism remains incompletely understood. In the present study, we aim to evaluate the anti-angiogenic activity of E7050 in vitro and in vivo and define the underlying molecular mechanism. It was observed that treatment with E7050 markedly inhibited proliferation, migration, and capillary-like tube formation in cultured human umbilical vein endothelial cells (HUVECs). E7050 exposure in the chick embryo chorioallantoic membrane (CAM) also reduced the amount of neovessel formation in chick embryos. To understand the molecular basis, E7050 was found to suppress the phosphorylation of VEGFR2 and its downstream signaling pathway components, including PLCγ1, FAK, Src, Akt, JNK, and p38 MAPK in VEGF-stimulated HUVECs. Moreover, E7050 suppressed the phosphorylation of VEGFR2, FAK, Src, Akt, JNK, and p38 MAPK in HUVECs exposed to MES-SA/Dx5 cells-derived conditioned medium (CM). The multidrug-resistant human uterine sarcoma xenograft study revealed that E7050 significantly attenuated the growth of MES-SA/Dx5 tumor xenografts, which was associated with inhibition of tumor angiogenesis. E7050 treatment also decreased the expression of CD31 and p-VEGFR2 in MES-SA/Dx5 tumor tissue sections in comparison with the vehicle control. Collectively, E7050 may serve as a potential agent for the treatment of cancer and angiogenesis-related disorders.

Semi-synthesized anticancer theobromine derivatives targeting VEGFR-2: in silico and in vitro evaluations

Vascular endothelial cell proliferation and angiogenesis are all crucially impacted by Endothelial Growth Factor Receptor-2 (VEGFR-2). Its expression is significantly boosted throughout pathologic angiogenesis causing the development of tumors. Sothat, inhibition of VEGFR-2 has crucial role in cancer treatment. In this study, novel semisynthetic theobromine derivatives were rationally designed as VEGFR-2 inhibitors and subjected to in vitro testing for their ability to block VEGFR-2 activation. Furthermore, the antiproliferative effects of these derivatives were evaluated. Compound 7 g exhibited the most potent anti-VEGFR-2 activity, with an IC50 value of 0.072 µM, and demonstrated excellent dose-dependent inhibitory activity against both MCF-7 and HepG2 cancer cells with IC50 values of 19.35 and 27.89 µM, respectively. Notably, compound 7 g exhibited high selectivity indices of 2.6 and 1.8 against MCF-7 and HepG2 cells, respectively. Compound 7 g induced G2/M phase cell cycle arrest, promoted apoptosis, and boosted immunomodulation by downregulating TNF-α expression and upregulating IL-2 levels in MCF-7 cells. The molecular docking analysis revealed that compound 7 g could bind effectively to the active site of VEGFR-2, and molecular dynamic simulations confirmed the stability of the VEGFR-2/compound 7 g complex. Furthermore, ADME and toxicity profiling indicated the potential suitability of these compounds as drug candidates. In summary, compound 7 g hold promise as a VEGFR-2 inhibitor. Communicated by Ramaswamy H. Sarma

A novel EGFR inhibitor acts as potent tool for hypoxia-activated prodrug systems and exerts strong synergistic activity with VEGFR inhibition in vitro and in vivo

Small-molecule EGFR inhibitors have distinctly improved the overall survival especially in EGFR-mutated lung cancer. However, their use is often limited by severe adverse effects and rapid resistance development. To overcome these limitations, a hypoxia-activatable Co(III)-based prodrug (KP2334) was recently synthesized releasing the new EGFR inhibitor KP2187 in a highly tumor-specific manner only in hypoxic areas of the tumor. However, the chemical modifications in KP2187 necessary for cobalt chelation could potentially interfere with its EGFR-binding ability. Consequently, in this study, the biological activity and EGFR inhibition potential of KP2187 was compared to clinically approved EGFR inhibitors. In general, the activity as well as EGFR binding (shown in docking studies) was very similar to erlotinib and gefitinib (while other EGFR-inhibitory drugs behaved different) indicating no interference of the chelating moiety with the EGFR binding. Moreover, KP2187 significantly inhibited cancer cell proliferation as well as EGFR pathway activation in vitro and in vivo. Finally, KP2187 proved to be highly synergistic with VEGFR inhibitors such as sunitinib. This indicates that KP2187-releasing hypoxia-activated prodrug systems are promising candidates to overcome the clinically observed enhanced toxicity of EGFR-VEGFR inhibitor combination therapies.