Growth factor signaling predicts therapy resistance mechanisms and defines neuroblastoma subtypes

Neuroblastoma (NB) has a low frequency of recurrent mutations compared to other cancers, which hinders the development of targeted therapies and novel risk stratification strategies. Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the cancer cells’ ability to adapt to these drugs through the employment of alternative signaling pathways. Based on the expression of 48 growth factor-related genes in 1189 NB tumors, we have developed a model for NB patient survival prediction. This model discriminates between stage 4 NB tumors with favorable outcomes (>80% overall survival) and very poor outcomes (<10%) independently from MYCN-amplification status. Using signaling pathway analysis and gene set enrichment methods in 60 NB patients with known therapy response, we identified signaling pathways, including EPO, NGF, and HGF, upregulated in patients with no or partial response. In a therapeutic setting, we showed that among six selected growth factors, EPO, and NGF showed the most pronounced protective effects in vitro against several promising anti-NB multikinase inhibitors: imatinib, dasatinib, crizotinib, cabozantinib, and axitinib. Mechanistically kinase inhibitors potentiated NB cells to stronger ERK activation by EPO and NGF. The protective action of these growth factors strongly correlated with ERK activation and was ERK-dependent. ERK inhibitors combined with anticancer drugs, especially with dasatinib, showed a synergistic effect on NB cell death. Consideration of growth factor signaling activity benefits NB outcome prediction and tailoring therapy regimens to treat NB.

Predictors of Response and Survival to Multikinase Inhibitors in Radioiodine Resistant Differentiated Thyroid Cancer

Sorafenib and lenvatinib are the only multikinase inhibitors (MKIs) approved for the treatment of radioactive iodine refractory differentiated thyroid cancer (RR-DTC). Although they have been demonstrated to improve progression free survival and overall response rate, the risk of toxicities is very high, worsening patients’ quality of life. Therefore, predicting MKI treatment outcomes in the setting of RR-DTC is very challenging for optimizing patients’ management. The current review provides an overview of the predictive factors for the response and survival of sorafenib and lenvatinib in RR-DTC. In this setting, a systemic therapy should be considered after conducting a multidisciplinary discussion aimed at evaluating the risk-benefit ratio of the treatment and taking into account several clinical, biochemical, and molecular factors. Age, performance status, and cancer-related symptoms are the most important clinical markers to be considered prior to starting MKI treatment, together with tumor burden. Some tissue and circulating biomarkers have been investigated, those involved in the angiogenic pathways being the most promising. Finally, prospective clinical trials aimed at evaluating predictive markers for therapeutic response are needed for tailoring patient management and allowing more appropriate treatment choices.

Encorafenib and binimetinib with or without nivolumab in treating patients with metastatic radioiodine refractory BRAF V600 mutant thyroid cancer.

TPS6085 Background: Differentiated thyroid cancer is the most common endocrine malignancy and has a high frequency of actionable molecular aberrations including BRAF V600E mutations (45%), RET fusions (10%), and NTRK fusions ( < 2%). FDA approved systemic therapies for metastatic radioiodine refractory differentiated thyroid cancer (RR-DTC) include multikinase inhibitors (Lenvatinib and sorafenib), NTRK inhibitors (larotrectinib and entrectinib for NTRK fusion+ cancers), and RET inhibitors (selpercatinib and pralsetinib for RET fusion+ cancers). Previous phase II clinical trials showed clinical efficacy with first and second generation BRAF inhibitors in patients with BRAF mutant RR-DTC. BRAF inhibitors have not yet been FDA approved for treatment of BRAF mutant RR-DTC. Effective therapeutic options for patients with BRAF mutant RR-DTC remains an important unmet clinical need. BRAF mutant thyroid cancers often show elevated expression of PD-L1. Additionally, BRAF inhibition results in increased expression of PD-L1 in thyroid cancer. This clinical trial seeks to evaluate the safety and efficacy of encorafenib plus binimetinib with or without nivolumab in patients with BRAF mutant metastatic RR-DTC. Encorafenib and binimetinib are highly selective and potent oral inhibitors of BRAF and MEK, respectively. Nivolumab is a potent inhibitor of the immune co-inhibitory receptor programmed cell death protein 1 (PD-1). Methods: This is a phase II, single institution, open-label, randomized clinical trial evaluating the combinations of (Arm 1) encorafenib 450 mg/day + binimetinib 45 mg twice daily and (Arm 2) encorafenib 450 mg/day + binimetinib 45 mg twice daily + nivolumab 480 mg I.V. every 4 weeks in patients with metastatic BRAF mutant RR-DTC. The trial will enroll 20 patients in each arm and treatment will be given in 28 day cycles for up to 2 years. Eligible patients must have metastatic/unresectable BRAF mutant RR-DTC, an ECOG performance status of 0-1 and adequate bone marrow, liver and kidney function. Patients with CNS metastases are included if the metastases have been treated and remained stable or are asymptomatic and ≤10 mm in diameter. Patients may be systemic therapy naïve or have previously been treated with multikinase inhibitors. Prior therapy with BRAF, MEK or immune checkpoint inhibitors is exclusionary. The primary endpoint is confirmed objective response rate (ORR) determined by RECIST v1.1 with restaging imaging every 12 weeks. Secondary endpoints include progression free survival, overall survival, and safety/tolerability (CTCAE v5.0). Arms 1 and 2 will be evaluated independently and are not powered for direct comparison. The trial design includes continuous toxicity monitoring with a Pocock-type stopping boundary. This clinical trial is in progress and 3 patients have been enrolled. Clinical trial information: NCT04061980.

Advanced Thyroid Carcinoma: Evolving Systemic Therapy Options

Although multikinase inhibitors are established therapies in advanced thyroid cancers, treatment-related adverse events can lead to dose reductions and discontinuations, thereby limiting the effectiveness of these treatments. Gene‐specific treatments have emerged as new standard-of-care therapies, and continue to demonstrate efficacy and improved tolerability, although genotyping is needed to identify patients that would benefit from these therapies and more education is needed in regard to the optimal use of these novel agents. Additionally, the emergence of acquired resistance has become a new problem in the field.

Efficacy of First Line Systemic Chemotherapy and Multikinase Inhibitors in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis

BackgroundHepatocellular carcinoma (HCC) is the third most fatal cancer, with a 5-year survival rate of 18%. Standard frontline-therapy is multikinase inhibitors (MKIs), but accessibility is still limited, particularly in developing countries. This network meta-analysis (NMA) aimed to compare the efficacy of usual chemotherapy vs MKIs.MethodRandomised-controlled trials (RCTs) comparing any among chemotherapy vs MKIs in treatment-naïve patients with advanced HCCs were identified from MEDLINE and SCOPUS databases. Overall survival (OS) and progression-free survival (PFS) probabilities and times were extracted from Kaplan-Meier curves using Digitizer, and then converted to individual patient time-to-event data. A one-stage mixed-effect survival model was applied to estimate median OS and PFS. A two-stage NMA was applied for the overall response rate and adverse events (AEs) outcome.ResultsA total of 20 RCTs were eligible for NMA. Lenvatinib was the best treatment among single MKIs, with median OS and PFS of 9 and 6.3 months, without significant differences in AEs relative to other MKIs. Median OS and PFS were 0.70 (-0.42, 1.83) and 2.17 (1.41, 2.93) months longer with Lenvatinib than Sorafenib. Among chemotherapy agents, FOLFOX4 had the longest median OS and PFS at 7.9 and 4.3 months, respectively, without significant AEs compared to other chemotherapies. The combination of Sorafenib+Doxorubicin prolonged median OS and PFS to 12.7 and 6.3 months, respectively.ConclusionUse of the MKIs Lenvatinib or Sorafenib as first line systemic treatment for advanced HCC could be beneficial. However, FOLFOX4 might be the optimal choice in a developing country where the health-care budget is limited.

Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: A multinational, multicenter retrospective study.

272 Background: Atezolizumab-bevacizumab is the new standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, the optimal sequence of therapy after disease progression on atezolizumab-bevacizumab is unclear. Methods: This multinational, multicenter, retrospective study assessed clinical outcomes of patients with advanced HCC who received subsequent systemic therapy after progression on atezolizumab-bevacizumab in Korea, Hong Kong and Singapore between July 2016 and April 2019. Results: A total of 49 patients were included; the median age was 60 years (range, 3780) and 73.5% were male. All patients were classified as Child-Pugh A and Barcelona-Clinic Liver Cancer stage C. Multikinase inhibitors (MKIs), including sorafenib (n = 29), lenvatinib (n = 19), and cabozantinib (n = 1), were used as second-line therapy for all patients. The objective response rate (ORR) and disease control rate (DCR) were 6.1% and 63.3%, respectively, in all patients. With a median follow-up duration of 11.0 months, median progression-free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI] 1.84.9) and 14.7 months (95% CI 8.121.2) in all patients. Median PFS with lenvatinib was significantly longer than that with sorafenib (6.1 months vs. 2.5 months; P= 0.004), although there was no significant difference in median OS (16.6 months vs. 11.2 months; P= 0.347). Treatment-related adverse events (TRAEs) of any grade and grade 3 occurred in 42 (85.7%) and 8 (16.3%) of patients. Common TRAEs included hand-foot syndrome (HFS) (n = 26, 53.1%), fatigue (n = 14, 28.6%), hypertension (n = 14, 28.6%), and diarrhea (n = 12, 24.5%). Conclusions: Second-line treatment with MKIs, mostly sorafenib and lenvatinib, showed comparable efficacy and manageable toxicities in patients with advanced HCC after disease progression on atezolizumab-bevacizumab.

Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.