Neoadjuvant chemo-free combination of camrelizumab and apatinib for locally advanced resectable oral squamous cell carcinoma – A pilot study

Novel neoadjuvant therapy regimens are needed to improve the outcomes of patients with locally advanced resectable oral squamous cell carcinoma (OSCC). We conducted a prospective, open-label, single-arm trial (n = 21, NCT04393506) to determine the safety and feasibility of neoadjuvant camrelizumab (an anti-PD-1 antibody) plus apatinib (a VEGFR inhibitor) for locally advanced resectable OSCC. The primary endpoints were safety and major pathological response (MPR). Neoadjuvant camrelizumab plus apatinib was well-tolerated and the MPR rate was 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃ 10 had MPR. Additionally, patients achieving MPR showed more CD4+ T cell infiltration and a higher CD8+/FoxP3+ ratio than those without MPR (p < 0.05), and decreased CD31 and ɑ-SMA expression were observed after neoadjuvant therapy. Our findings demonstrate that neoadjuvant therapy with a chemo-free combination of camrelizumab and apatinib is safe and yields a promising MPR rate, supporting further trials.

Design, Synthesis and Biological Evaluation of HDAC and VEGFR Dual Inhibitors as a Multi-targeted Anticancer Agents

Herein a novel series of HDAC and VEGFR dual inhibitors were designed, synthesized and biologically evaluated based on the previously reported pazopanib-based HDAC and VEGFR dual inhibitors. Most target compounds showed significant HDAC1, HDAC6 and VEGFR2 inhibition, which contributed their potent antiproliferative activities against multiple cancer cells lines and significant antiangiogenic potencies in both HUVECs tube formation assay and rat thoracic aorta rings assay. Further HDAC selectivity evaluation indicated that hydroxamic acids 5 and 9e possessed similar HDAC isoform selectivity profiles to the approved HDAC inhibitor SAHA, while hydrazide 12 presented similar HDAC isoform selectivity profiles to the clinical HDAC inhibitor MS275. The VEGFR inhibition profiles of 5, 9e and 12 were similar to that of the approved VEGFR inhibitor pazopanib. The intracellular target engagements of compounds 5 and 12 were confirmed by western blot analysis. Though the mouse liver microsome metabolic stabilities of 5, 9e and 12 were inferior to than of pazopanib, these HDAC and VEGFR dual inhibitors provided lead compounds for further structural optimization to get polypharmacological anticancer agents.

The Efficacy and Safety of Fruquintinib Plus PD-1 Inhibitor in ≥3 line MSS Metastatic Colorectal Cancer Patients

Purpose: Based on the suggestion of REGONIVO study, we reviewed the data of 26 MSS mCRC patients to elaborate the efficacy and safety of fruquintinib (a VEGFR inhibitor) plus PD-1 inhibitor and explore the potential predictors for survival in 3+ line microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients.Patients and methods: This retrospective study enrolled 26 MSS mCRC patients who progressed after at least 2 lines of systematic chemotherapy but didn’t receive PD-1 inhibitors. Fruquintinib of 3mg was administered once daily with 21 days on/7 days off plus PD-1 inhibitor 200mg every 3 weeks until intolerable toxicity or disease progression. Results: Median overall survival (mOS) was 6.1m (ranged 1.8m-NR 95%CI: 2.60-9.60); median progression free survival (mPFS) was 2.3m (ranged 1.5m-NR 95%CI: 0.93-3.67). There was one complete response (CR) and no partial response (PR). Stable disease was observed in 11 patients (42%) and progression disease (PD) was observed in 14 patients (54%). The object response rate (ORR) was 4% (1/26) and disease control rate (DCR) was 46 %( 12/26). Grade ≥3 AEs were observed in 5 patients (19.2%). Grade 5 AEs (immune related encephalitis and cardiotoxicity) were observed in 2 patients. Additionally, there was a significant correlation between NLR < 3.06 and longer survival (P=0.000) for MSS mCRC patients treated with fruquintinib plus PD-1 inhibitor. Conclusions: Fruquintinib plus PD-1 inhibitor may be a choice for 3+ line MSS mCRC patients，especially with pretreatment NLR<3.06.

Preliminary results of a phase 1b study of fruquintinib plus sintilimab in advanced colorectal cancer.

2514 Background: To explore the safety and synergistic anti-tumor effect of fruquintinib (a VEGFR inhibitor) in combination with sintilimab (an anti-PD-1 Ab) in patients (pts) with advanced colorectal cancer (CRC) and other solid tumors. Methods: This is an ongoing phase Ib/II, multicenter, two-stage study. Pts with variety cancer types, including CRC, were enrolled and is continuously enrolling in the study. For this interim analysis, all pts were analyzed for safety whereas only CRC pts were analyzed for efficacy. MMR status were analyzed for all enrolled CRC pts. Stage 1 was classical “3+3” dose escalation with pts assigned to one of the following 4 cohorts, fruquintinib taken orally at 3mg (Cohort A, 3 weeks on/ 1 week off), 4mg (Cohort B, 3 weeks on/ 1 week off), 5mg-intermittent (Cohort C, 2 weeks on/ 1 week off) or 3mg-continuous (Cohort E, once daily), while sintilimab was given at 200mg intravenously with Q4W in Cohort A and Cohort B whereas Q3W in Cohort C and Cohort E. DLT was observed for 28 days. Stage 2 was dose expansion with pts receiving 5mg-intermittent or 3mg-continuous fruquintinib plus sintilimab (200mg, Q3W). The primary endpoints were safety and tolerability and secondary endpoint was objective response rate (ORR). Results: As of Jan 5, 2021, 44 CRC pts which failed to at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan were enrolled. They received either 5mg-intermittent or 3mg-continous dosage (n = 22, each), the ORR was 22.7% (10/44, 95% CI: 11.5-37.8%) with 27.3% (6/22, 95% CI: 10.7-50.2%) in 5mg-intermittent group and 18.2% (4/22, 95% CI: 5.2-40.3%) in 3mg-continuous group. With a median follow-up time of 8.3 (range: 0-9.6) months, the K-M estimated median PFS was 6.8 (95% CI:5.6-NA) months and 4.3 (95% CI:3.5-NA) months for 5mg-intermittent group and 3mg-continuous group, respectively. Overall, 60 pts were enrolled for safety analysis, including 23 in stage1 and 37 (only CRC) in stage 2. In stage 1, all pts experienced TEAEs, 52.2% of which were ≥ grade 3. The most frequently reported TEAEs were TSH increasing (73.9%), fecal occult blood positive (56.5%), and Palmar-plantar erythrodysaesthesia syndrome (PPES) (56.5%). SAEs occurred in 8 (34.8%) pts and no treatment-related death was reported. One patient in Cohort B reported manageable DLT. In stage 2, all pts experienced TEAEs, 18 (48.6%) pts experienced ≥ grade 3 TEAEs with 6 (31.6%) in 5mg-intermittent group and 12 (66.7%) in 3mg-continuous group. The most common TEAEs were proteinuria (45.9%) and TSH increasing (37.8%). TEAEs leading to either fruquintinib or sintilimab discontinuation occurred in 3 (5%) pts each. Conclusions: Fruquintinib plus sintilimab showed promising efficacy and favorable safety profile in advanced CRC. Clinical trial information: NCT03903705.

EXPRESS: SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

Introduction: SU5416 plus chronic hypoxia causes pulmonary arterial hypertension (PAH) in rats and is assumed to occur through VEGFR2 inhibition. Cabozantinib is a far more potent VEGFR2 inhibitor than SU5416. Therefore, we hypothesized that cabozantinib plus hypoxia would induce severe PAH in rats. Methods: Cell proliferation and pharmacokinetic studies were performed. Rats were given SU5416 or cabozantinib SC or via osmotic pump and kept hypoxic for 3 weeks. Right ventricular systolic pressure (RVSP) and hypertrophy (RVH) were evaluated at day 14 and 28 following removal from hypoxia. RV fibrosis was evaluated with Picro-Sirius Red staining. Kinome inhibition profiles of SU5416 and cabozantinib were performed. Inhibitor binding constants of SU5416 and cabozantinib for BMPR2 were determined and Nanostring analyses of lung mRNA were performed. Results: Cabozantinib was a more potent VEGFR inhibitor than SU5416 and had a longer half-life in rats. Cabozantinib SC plus hypoxia did not induce severe PAH. RVSP at 14 and 28d post-hypoxia was 36.8 ± 2.3 mmHg and 36.2 ± 3.4 mmHg, respectively, versus 27.5 ± 1.5 mmHg in normal controls. For cabozantinib given by osmotic pump during hypoxia, RVSP was 40.0 ± 3.1 mmHg at 14d and 27.9 ± 1.9 mmHg at 28d post-hypoxia. SU5416 plus hypoxia induced severe PAH (RVSP 61.9 ± 6.1 mmHg and 64.9 ± 8.4 mmHg at 14d and 28d post-hypoxia, respectively). Cabozantinib induced less RVH (RV/(LV+IVS) at 14d post-hypoxia compared to SU5416. RV fibrosis was more extensive in the SU5416 groups compared to the Cabozantinib groups. SU5416 (but not cabozantinib) inhibited BMPR2. Nanostring analyses showed effects on pulmonary gene expression of BMP10 and VEGFR1 in the SU5416 28 day post hypoxia group. Conclusion: Selective VEGFR2 inhibition using cabozantinib plus hypoxia did not induce severe PAH. Severe PAH due to SU5416 plus hypoxia may be due to combined VEGFR2 and BMPR2 inhibition.

An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model

In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.