Progressive Metastatic Medullary Thyroid Cancer Research Articles

A Randomized, Double-Blind Noninferiority Study to Evaluate the Efficacy of the Cabozantinib Tablet at 60 mg Per Day Compared with the Cabozantinib Capsule at 140 mg Per Day in Patients with Progressive, Metastatic Medullary Thyroid Cancer.

Background:Cabozantinib inhibits pathways involved in medullary thyroid cancer (MTC). Cabozantinib is approved as 140 mg/day in capsules for MTC and 60 mg/day in tablets for other solid tumors. This study compared the two doses in progressive metastatic MTC.Methods:In this Phase 4, randomized, double-blind noninferiority (NI) trial (NCT01896479), patients with progressive metastatic MTC were randomized 1:1 to cabozantinib 60 mg/day tablet or 140 mg/day capsules. The primary end point was progression-free survival (PFS) by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. NI would be concluded if the upper 95% confidence interval [CI] for the PFS hazard ratio (HR) was less than the NI margin, 1.58. The secondary end point was objective response rate (ORR) by BIRC per RECIST v1.1; additional end points included safety and pharmacokinetics.Results:At data cutoff (July 15, 2020), 247 patients were randomized to the 60 mg/day tablet arm (n = 123) and the 140 mg/day capsules arm (n = 124). NI was not met (median PFS 11.0 months vs. 13.9 months in the 60 and 140 mg/day arms [HR 1.24; CI 0.90–1.70; p = 0.19]). The ORR was 33% in both arms. Generally, adverse event (AE) incidence was lower in the 60 mg/day arm (Grade 3/4, 63% vs. 72%), as were dose reductions (69% vs. 81%) and treatment discontinuations due to AEs (23% vs. 36%). Initially, cabozantinib plasma concentrations were higher in the 140 mg/day arm but became similar between arms at later time points.Conclusions:PFS NI of the cabozantinib 60 mg/day tablet vs. 140 mg/day capsules was not met. The 60 mg/day tablet had the same ORR and lower rates of AEs.Clinical Trial Registry:ClinicalTrials.gov NCT01896479.

State of the art and future directions in the systemic treatment of medullary thyroid cancer.

Systemic treatment is the only therapeutic option for patients with progressive, metastatic medullary thyroid cancer (MTC). Since the discovery of the rearranged during transfection (RET) proto-oncogene (100% hereditary, 60-90% sporadic MTC), research has focused on finding effective systemic therapies to target this mutation. This review surveys recent findings. Multikinase inhibitors are systemic agents targeting angiogenesis, inhibiting growth of tumor cells and cells in the tumor environment and healthy endothelium. In the phase III EXAM and ZETA trials, cabozantinib and vandetanib showed progression-free survival benefit, without evidence of prolonged overall survival. Selpercatinib and pralsetinib are kinase inhibitors with high specificity for RET; phase I and II studies showed overall response rates of 73% and 71% in first line, and 69% and 60% in second line treatment, respectively. Although resistance mechanisms to mutation-driven therapy will be a challenge in the future, phase III studies are ongoing and neo-adjuvant therapy with selpercatinib is being studied. The development of selective RET-inhibitors has expanded the therapeutic arsenal to control tumor growth in progressive MTC, with fewer adverse effects than multikinase inhibitors. Future studies should confirm their effectiveness, study neo-adjuvant strategies, and tackle resistance to these inhibitors, ultimately to improve patient outcomes.

Lenvatinib as a salvage therapy for advanced metastatic medullary thyroid cancer.

Patients with advanced progressive metastatic medullary thyroid cancer (MTC), show poor prognosis and few available systemic therapeutic options. After the loss of clinical benefit with other tyrosine kinase inhibitors (TKI), we evaluated the use of lenvatinib as salvage therapy. Ten patients who experienced the loss of clinical benefit after treatment with at least one previous TKI, were treated with lenvatinib. We assessed patient's response immediately before, at the first (first-EV) and last (last-EV) evaluation, after the beginning of treatment. At first-EV, one patient died, while all the remaining 9 showed a stable disease (SD) in the target lesions. At last-EV, SD was still observed in seven patients, while partial response (PR) and progressive disease (PD), in one patient each. Conversely, analyzing all target and non-target lesions, at first-EV, we observed PR in one patient and SD in eight patients. At last-EV, PR was shown in two patients and SD was shown in seven. Bone metastases showed stable disease control at both first-EV and last-EV in only approximately 60% of cases. Tumor markers (CTN and CEA) decreased at first-EV, while they increased at last-EV. Seven patients experienced at least one dose reduction during treatment with lenvatinib. In this real-life clinical experience, lenvatinib showed interesting results as salvage therapy in patients with advanced progressive metastatic MTC patients. Its usefulness could be effective in patients without any other available treatment, because previously used or unsuitable, especially with negative RET status with no access to the new highly selective targeted therapies.

Structural Doubling Time Predicts Overall Survival in Patients with Medullary Thyroid Cancer in Patients with Rapidly Progressive Metastatic Medullary Thyroid Cancer Treated with Molecular Targeted Therapies.

Purpose: To evaluate the impact of structural disease progression of metastatic lesions after initial surgery on overall survival (OS) of patients presenting with metastatic medullary thyroid cancer (MTC). We used tumor volume doubling time (TVDT) as a marker of structural disease progression and aimed to correlate the average structural tumor volume doubling time (midDT) with OS in MTC patients after initial surgery. Methods: In this retrospective study, we examined the clinical characteristics; average tumor volume doubling times of neck, lung, and liver metastasis; and disease-specific survival of patients with metastatic MTC. Results: Tumor growth is constant in MTC metastasis, irrespective of location of the metastasis. The median correlation coefficient (r) and the coefficient of determination (r2) were similar in lung metastasis (r = 0.91, r2 = 0.95) and liver metastasis (r = 0.88, r2 = 0.94), and comparable in neck metastasis (r = 0.73, r2 = 0.85). Patients with metastatic MTC with a midDT ≤1 year have a worse prognosis than those with higher midDT (p = 0.002). Those with midDT ≤1 year had a median OS of 11.1 years [confidence interval (CI) 7.4-14.8 years]. In contrast, patients with midDT 1-3 years had a median OS of 16.5 years [CI 10.3-22.6 years]. All patients with midDT ≥3 survived by the end of the follow-up period. Preliminary results suggest that measurement of midDT can predict response to molecular targeted therapies. Conclusions: In conclusion, TVDT is a strong predictor of OS in patients with recurrent or metastatic MTC, can be used as a marker of progression, and potentially can help select patients who may benefit from molecular targeted therapy.

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor.

Cabozantinib is an oral small-molecule multitargeted tyrosine kinase inhibitor (TKI) that may confer an advantage over other TKIs that target a single receptor. It was approved by the U.S. Food and Drug Administration for the treatment of both advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, and it is being investigated for a wide array of other malignancies. Rationale for use, clinical trial data, and current recommendations for cabozantinib in renal cell cancer, thyroid cancer, prostate cancer, hepatocellular cancer, and lung cancer are detailed in this article. Common adverse events are reviewed, and management strategies for select adverse events are discussed. Implications for contemporary practitioners are also provided because use of this novel agent is likely to increase as more studies are completed.

Cabozantinib in the treatment of hepatocellular carcinoma.

Despite clinical studies with different mechanisms of action, no new systemic therapies were approved for hepatocellular carcinoma (HCC) between sorafenib in 2007 and regorafenib in 2017. This is an area of interest to improve outcomes and quality of life. Cabozantinib is oral, small-molecule tyrosine kinase inhibitor that primarily targets MET, VEGFR2, AXL and RET, with additional effect on KIT and FLT3. Cabozantinib is approved for progressive metastatic medullary thyroid cancer and previously treated renal cell carcinoma, and is in development for multiple solid tumors. Given positive results from a Phase II study, cabozantinib is under evaluation in a Phase III randomized controlled trial for patients with advanced HCC previously treated with sorafenib. It has been granted orphan drug status in the USA for this indication. This review summarizes the development of cabozantinib in HCC.

Cabozantinib : modalités d’action, efficacité et indications

Cabozantinib is an oral multiple tyrosine kinase receptor inhibitor (ITK): VEGFR2, c-MET and RET. Inhibition of VEGFR and c-MET decrease resistance of VEGFR inhibitor via c-MET axis. Cabozantinib improve progression-free survival (PFS) in progressive metastatic medullary thyroid cancer (MTC): 4months in the placebo group and 11.2months in the cabozantinib group (P<0.001) in all patient subgroups including those with or without prior ITK and RET mutation status. Cabozantinib increased overall survival (OS) compared with everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR ITK treatment: 21.4months in cabozantinib group and 16.5months in everolimus group (P<0.0003). Cabozantinib obtained the AMM for the treatment of progressive metastatic MTC and advanced renal cell carcinoma. Cabozantinib is a new option in the treatment of MTC by inclusion in therapeutic trials (no payment in this indication) and advanced renal cell carcinoma (hospital delivery). Its tolerance is similar to anti-angiogenic therapies and justifies an optimal management of the secondary effect.

Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib.

Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq®) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC). Four identified inactive metabolites constitute >65 % of total cabozantinib-related AUC following a single 140-mg free base equivalent dose. Cabozantinib AUC was increased by 63-81 % or 7-30 % in subjects with mild/moderate hepatic or renal impairment, respectively; by 34-38 % with concomitant cytochrome P450 3A4 inhibitor ketoconazole; and by 57 % following a high-fat meal. Cabozantinib AUC was decreased by 76-77 % with concomitant cytochrome P450 3A4 inducer rifampin, and was unaffected following administration of proton pump inhibitor esomeprazole. Cabozantinib is a potent in vitro inhibitor of P-glycoprotein, and multidrug and toxin extrusion transporter 1 and 2-K, and is a substrate for multidrug resistance protein 2. No clinically significant covariates affecting cabozantinib pharmacokinetics were identified in a population pharmacokinetic analysis. Patients with medullary thyroid cancer with low model-predicted apparent clearance were more likely to dose hold/reduce cabozantinib early, and had a lower average dose through day 85. However, longitudinal tumor modeling suggests that cabozantinib dose reductions from 140 to 60 mg/day did not markedly reduce tumor growth inhibition in medullary thyroid cancer patients.

The safety of vandetanib for the treatment of thyroid cancer

ABSTRACTIntroduction: The tyrosine kinase inhibitor vandetanib was approved for use in 2012 for aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease. As the first effective systemic therapy for MTC, vandetanib is a major step forward and the phase III study suggests an important role for this agent. Trials have also been performed for its use in differentiated thyroid cancer (DTC) though it is not yet approved for use for this indication.Areas covered: The efficacy and safety of vandetanib is discussed. Studies suggest improvement in progression-free survival (PFS) without clear overall survival benefit but with manageable low grade toxicities and improved quality of life on therapy.Expert opinion: Vandetanib has an important role in the management of patients with progressive metastatic MTC. The use in patients with stable or asymptomatic disease has no proven benefit. The side effects can usually be managed with dose reduction, interruption, and/or specific symptomatic therapy.

Population pharmacokinetic/pharmacodynamic modeling of tumor growth kinetics in medullary thyroid cancer patients receiving cabozantinib.

Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from healthy-volunteer studies. Semi-mechanistic models predict well for tumors with static, increasing, or decreasing growth over time, but they were not considered adequate for predicting tumor sizes in medullary thyroid cancer patients, among whom an early reduction in tumor size was followed by a late stabilization phase in those receiving cabozantinib. A semi-empirical tumor model adequately predicted tumor profiles that were assumed to have a net growth rate constant that was piecewise continuous in the regions of 0-110 and 110-280 days. Emax models relating average concentration to average change in tumor size predicted that an average concentration of 79 and 58 ng/ml, respectively, would yield 50% of the maximum possible tumor reduction during the first 110 days of dosing and during the subsequent 110-280 days of dosing. Simulations of tumor responses showed that daily doses of 60 mg or greater are expected to provide a similar tumor reduction. Both model evaluation of observed data and simulation results suggested that the two protocol-defined cabozantinib dose reductions from 140 to 100 mg/day and from 100 to 60 mg/day are not projected to result in a marked reduction in target lesion regrowth.

Sorafenib for the Treatment of Progressive Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis

Treatment of advanced medullary thyroid carcinoma (MTC) was recently improved with the approval of vandetanib and cabozantinib. However, there is still a need to explore sequential therapy with more than one tyrosine kinase inhibitor (TKI) and to explore alternative therapies when vandetanib and cabozantinib are not available. This study reports the authors' experience with sorafenib as a treatment for advanced MTC. This is a retrospective longitudinal study of 13 patients with progressive metastatic MTC treated with sorafenib 400 mg twice daily between December 2011 and January 2015. The primary endpoints were to evaluate response and progression-free survival (PFS) in patients treated with sorafenib outside a clinical trial. The secondary endpoint was an assessment of the toxicity profile. One patient was excluded because of a serious allergic skin rash one week after starting sorafenib. The analysis included 12 patients with metastatic MTC (median age 48 years), 10 with sporadic and 2 with hereditary disease. The median duration of treatment was 11 months, and the median follow-up was 15.5 months. At data cutoff, 2/12 (16%) patients were still on treatment for 16 and 34 months. According to Response Evaluation Criteria in Solid Tumors analysis, 10 (83.3%) patients showed stable disease, and two (16.6%) had progression of disease; no partial response was observed. The median PFS was nine months. However, three patients with extensive and rapidly progressive disease died within three months of sorafenib treatment. The median PFS excluding these three patients was 12 months. Adverse events (AE) occurred in nine (75%) patients. The main AEs were skin toxicity, weight loss, and fatigue. Five (41.6%) patients needed dose reduction, and one patient discontinued treatment because of toxicity. Treatment with sorafenib in progressive metastatic MTC is well tolerated and resulted in disease control and durable clinical benefit in 75% of patients. Sorafenib treatment could be considered when vandetanib and cabozantinib are not available or after failing these drugs.

Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer

Cabozantinib (XL-184) is a potent inhibitor of MET, VEGFR 2/KDR, RET and other receptor tyrosine kinases, such as KIT, AXL and FLT3. Its efficacy against MTC has been demonstrated in a prospective, randomized, placebo-controlled study (EXAM). Cabozantinib comparing to placebo significantly prolonged progression free survival both in hereditary and sporadic MTC, 11.2 vs 4.0 months, respectively. Final analysis showed no global differences in overall survival (OS) between cabozantinib and placebo. However, in a subgroup with RET M918T mutation the difference in OS was significant: 44.3 vs 18.9 months, respectively. Among the most frequent cabozantinib-related adverse events (AEs), observed in >30% of patients were diarrhea, palmar-plantar erythrodysesthesia, decreased weight, decreased appetite, nausea, fatigue, dysgeusia, hair color changes and hypertension. Expert Commentary: Cabozantinib constitutes an effective treatment option with acceptable toxicity in MTC patients showing either germinal or sporadic tumor RET M918T mutation as the drug prolonged OS in these subjects.

Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients

Medullary thyroid cancer (MTC) occurs sporadically in 75% of all cases. In patients with local disease prognosis is excellent. In metastatic disease 10-year survival is significantly decreased. For the therapy of progressive metastatic MTC patients two tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available.

Cabozantinib for progressive metastatic medullary thyroid cancer: a review.

Medullary thyroid cancer is uncommon and patients typically present with advanced disease. Treatment options for patients with progressive, metastatic medullary thyroid cancer had been limited until recently. Tyrosine kinase inhibitors have garnered increasing interest in this subset of patients. The US Food and Drug Administration recently approved cabozantinib, a tyrosine kinase inhibitor, after promising results were shown in a large Phase III clinical trial. This review summarizes the clinical pharmacology, clinical trials, and safety data for cabozantinib and concludes with a discussion of possible future directions for the treatment of medullary thyroid cancer.

Development of cabozantinib for the treatment of prostate cancer

Cabozantinib (XL184) is a multitargeted receptor tyrosine kinase with predominantly MET and vascular endothelial growth factor inhibition properties. It is currently approved by the US Food and Drug Administration for the treatment of progressive metastatic medullary thyroid cancer. The agent has a convenient once-daily oral dosing schedule and has demonstrated encouraging activity in metastatic castrate-resistant prostate cancer (CRPC). A Phase I/II trial demonstrated responses in soft tissue, visceral disease, and bone metastases in CRPC. An objective response rate of 5%, a stable disease rate of 75%, and a median progression-free survival of 6 months was observed. As compared with the 140 mg daily dose used in thyroid cancer, a lower dose of 60 mg daily is currently being utilized in prostate cancer studies due to the fact that toxicity could be reduced without compromising efficacy. Randomized trials are ongoing in comparison with prednisone or with mitoxantrone and prednisone in pretreated metastatic CRPC. Cabozantinib has demonstrated a unique mechanism of action and preliminary efficacy in the crowded therapeutic field of prostate cancer. Since multiple therapies have recently demonstrated overall survival benefit in metastatic CRPC, cabozantinib will likely face some challenges in clinical application. At present, in this rapidly evolving field, it is unclear what proportion of patients with prostate cancer will be eligible to receive this therapy. The cost of cabozantinib is likely to be another deterrent, especially if it remains more expensive than other oral therapies, such as abiraterone and enzalutamide. Defining the role of MET overexpression and RET mutations as biomarkers in prostate cancer may help to guide patient selection, and enrich and enhance the future applications of this targeted novel agent.

Cabozantinib in Progressive Medullary Thyroid Cancer

Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients. Cabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

A phase II study of cabozantinib (XL184) in patients with advanced/metastatic urothelial carcinoma.

TPS4589 Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. Activated MET can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in urothelial carcinoma pathogenesis. Cabozantinib inhibits primarily VEGFR2 and MET pathways. Cabozantinib has been approved by the FDA for the treatment of progressive metastatic medullary thyroid cancer, is in Phase 3 trials for metastatic castration-resistant prostate cancer and has demonstrated clinical activity in multiple solid tumors. We previously reported that shed MET levels in serum and urine of patients with urothelial carcinoma correlate with stage, presence of visceral metastases and urinary source and that cabozantinib is effective in reversing HGF-driven urothelial carcinoma cell growth and invasion. These data support the evaluation of cabozantinib in patients with metastatic urothelial carcinoma. Methods: This is a phase II study of oral cabozantinib 60mg daily given continuously in 28-day cycles. There are three study cohorts: [1] metastatic urothelial carcinoma [2] bone only metastatic urothelial carcinoma [3] metastatic non-urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. A maximum of 55 subjects will be enrolled. Up to 45 patients will be accrued to cohort 1.The remainder will be enrolled on exploratory cohorts 2 &amp; 3. A two-stage single-arm phase II design will be employed. The primary objective is to determine the objective response rate in patients with metastatic urothelial carcinoma who have progressed on prior chemotherapy. Secondary objectives include progression free survival, safety and toxicity, and overall survival. Exploratory objectives include tumor tissue Met expression, shed MET levels in serum and urine, immune subsets, genetic biomarkers, molecular markers of angiogenesis and circulating tumor cells, correlation with clinical response parameters. Finally we will explore treatment evaluation with FDG and NaF PET/CT compared to standard imaging. This study is supported by the Cancer Therapy Evaluation Program (CTEP). NCT01688999 Clinical trial information: NCT01688999.

Panobinostat, a novel histone deacetylase inhibitor, in advanced medullary and iodine-refractory differentiated thyroid cancer: A Wisconsin Oncology Network trial.

e17025 Background: Histone deacetylase (HDAC) inhibitors suppress tumor cell proliferation in medullary thyroid cancer (MTC) and differentiated thyroid cancer (DTC) in vivo. We conducted a multicenter single arm phase II trial of panobinostat, a potent inhibitor of Class I, II, and IV HDAC enzymes, in MTC and radioactive iodine (RAI)-refractory DTC. Methods: We enrolled 13 patients (pts) with progressive metastatic MTC or RAI-refractory DTC. Panobinostat was given at 20 mg orally TIW until disease progression or intolerable toxicities. The primary objective was anti-tumor response rate; secondary objectives included overall survival (OS), progression-free survival (PFS), tolerability, and changes in serum thyroglobulin (Tg) concentration. Results: Mean age was 61±13 yrs; 7 pts were female. 11 pts had DTC; 2 had MTC. Median study follow-up was 11.8 months (mos). 9 pts required dose holds/reductions due to thrombocytopenia (n=7), hypocalcemia (n=3), neutropenia (n=2), diarrhea (n=1), bone pain (n=1), or asthenia (n=1). Due to protocol specified rules, 2 pts were withdrawn from therapy with thrombocytopenia or neutropenia, both asymptomatic. Of the 3 pts with ≥ grade 3 thrombocytopenia, 2 had no bleeding. The third pt continued to bleed from her chronically erosive tumor without exacerbation. Median duration of treatment was 2.1 mos (range, 0.8-11.8). Stable disease (SD) was seen in 7 pts, with a median duration of 5.8 mos (range,1.8-13.8). All 7 SD pts are currently alive, including 2 with SD 4.9 mo and 11.8 mo on treatment. Progressive disease (PD) occurred, and was the cause of death, in 6 pts.No anti-tumor responses were observed. Median PFS for the 13 pts was 3.6 mos (95% CI, 1.8-5.8), with 2 pts having a PFS longer than 6 mos.Median OS for the 13 pts was 18.4 mos (95% CI, 5.8-not estimable). 5 of 11 pts had reductions of their serum Tg on study; however, changes in serial Tg values did not distinguish PD from SD pts. Conclusions: 20 mg TIW was not tolerated by most pts. However, dose modified treatment yielded SD in half of our previously progressing pts. This promising disease stabilization warrants further evaluation, possibly in combination with a VEGFR TKI. Clinical trial information: NCT01013597.

Abstract LB-353: Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of cabozantinib.

Abstract Introduction: Cabozantinib is an oral, small-molecule inhibitor of MET, VEGFR2, and RET, and it also inhibits AXL, KIT and TIE-2. These targets are known to play important roles in tumor cell proliferation and/or angiogenesis. Cabozantinib is FDA-approved for the treatment of patients with progressive metastatic medullary thyroid cancer. Methods: Cabozantinib was tested against the PPTP's in vitro cell line panel at concentrations ranging from 1.0 nM to 10.0 μM using the PPTP's standard 96 hour exposure period. It was tested against the PPTP solid tumor xenografts using a dose of 30 mg/kg administered by the oral route daily for 3 or 4 weeks with a total treatment/observation period of 6 weeks. Results: The median relative IC50 value for the PPTP cell lines was 8.1μM, with a range from 0.034 μM to greater than 10.0 μM and with only 3 cell lines showing IC50 values less than 1 μM. The most sensitive cell line, Kasumi-1, is an AML cell line that is known to have an activating KIT mutation. Cabozantinib was generally well tolerated in vivo, with only a 1.8% toxicity rate in treated animals. Thirty-four of 34 tested xenograft models were considered evaluable for efficacy. Cabozantinib induced significant differences in EFS distribution compared to control in 31 of 34 (91%) of the evaluable solid tumor xenografts. Cabozantinib induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C greater than 2) in 22 of 31 (71%) evaluable solid tumor xenografts. Intermediate activity for the EFS T/C metric was observed across all tumor panels evaluated. Partial responses were observed for two of the solid tumor xenografts, the rhabdoid tumor xenograft BT-29 and the slow-growing ependymoma xenograft BT-41. Tumor growth control was most pronounced for the alveolar rhabdomyosarcoma xenografts (ARMS), with 4 of 5 ARMS lines showing less than 20% increase in tumor volume during the 21 days of treatment. Two of 3 Wilms tumor lines (KT-11 and KT-13) also showed complete tumor growth control at Day 21, as did the medulloblastoma xenograft (BT-28) that was studied. Conclusions: The in vitro and in vivo pattern of activity observed for cabozantinib against the PPTP preclinical models is similar to that of agents previously studied by the PPTP that inhibit angiogenesis (e.g., sunitinib, cediranib, and sorafenib). The absence of in vitro activity for most solid tumor cell lines at concentrations associated with specific kinase inhibition together with widespread in vivo tumor growth inhibition and infrequent tumor regression suggest that for most pediatric cancers the in vivo effects of cabozantinib will primarily result from indirect effects on tumor growth (e.g., inhibition of VEGFR2-mediated angiogenesis). Exceptions would be those pediatric cancers with activating genomic alterations in kinases specifically inhibited by cabozantinib (e.g., medullary thyroid cancer with RET mutations). (Supported by NO1-CM-42216 from the NCI). Citation Format: Malcolm Smith, Min Kang, Patrick Reynolds, Richard Gorlick, Anders Kolb, John Maris, Stephen Keir, Catherine Billups, Raushan Kurmasheva, Peter Houghton. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of cabozantinib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-353. doi:10.1158/1538-7445.AM2013-LB-353

Everolimus is an active agent in medullary thyroid cancer: a clinical and in vitro study

Everolimus, an mTOR inhibitor, which has been demonstrated to induce anti-tumour effects in different types of neuroendocrine tumours, has never been evaluated in patients with medullary thyroid cancer (MTC). The aim of this study was to evaluate the in vitro and in vivo effects of everolimus in combination with octreotide in MTC. Two patients with progressive metastatic MTC and high calcitonin levels were treated with everolimus 5–10 mg/day. Both patients were under treatment with octreotide LAR at the study entry. An in vitro study was also performed to assess everolimus effects on MTC cell lines (TT and MZ-CRC-1 cells). A tumour response was observed in both patients. Serum calcitonin decreased by 86% in patient 1 and by 42% in patient 2. In TT and MZ-CRC-1 cells, everolimus induced a significant dose-dependent inhibition in cell proliferation. This effect seems to be related to a cell cycle arrest in G0/G1 phase in both cell lines and to the induction of cellular senescence in TT cells. Everolimus in combination with octreotide may be active as anti-tumour therapy in patients with progressive metastatic MTC, suggesting to further evaluate this agent in MTC patients in a large prospective study.