Tyrosine Kinase Inhibitor Of KIT Research Articles

Systemic Mastocytosis: State of the Art.

Since identification of Systemic mastocytosis (SM) as a distinct disease entity by the World Health Organisation (WHO), there has been a wealth of new research in therapeutic targeting of the pathogenic C-KIT D816V mutation. Avapritinib, the first licensed drug in SM capable of disease modification alongside the increasingly potent, oral and highly selective KIT tyrosine kinase inhibitors (TKIs) Bezuclastinib and now Elenestinib have enabled the prospect of long-term remissions. Studies have shown improved survival and symptomatic control in patients with SM. Of great triumph, this has been achieved in an outpatient setting with apparent tolerable and minimal toxicity. The importance of molecular profiling is being demonstrated in administering combination therapies for SM with an associated haematological neoplasm (AHN), allowing more personalised and streamlined treatment regimes. This review focuses on current management strategies of SM, focusing on state-of-the-art directed therapies, the evidence behind their use with presentation of two clinical cases to highlight key messages.

P105 Adult-onset mastocytosis: a retrospective review

Abstract Mastocytosis is characterized by an abnormal proliferation of mast cells in different organs, with the skin being the most frequently affected site. Adult-onset mastocytosis often follows a chronic course and is more likely to have extracutaneous involvement. We undertook a retrospective case note review of adult patients with a diagnosis of mastocytosis in our dermatology department between 2021 and 2022. Fourteen patients were identified with a female-to-male ratio of 1.8 : 1. Median age at disease onset was 46 years (range 25–75). Lesions were described as maculopapular (n = 8), macular (n = 3), telangiectatic (n = 2) and urticated (n = 1). The torso was affected in 12 patients (86%). The most commonly reported symptom was pruritus (n = 9). Other complaints included flushing (n = 3), abdominal pain (n = 2), dizziness (n = 2), weight loss (n = 2), night sweats (n = 2), syncope (n = 1), musculoskeletal pain (n = 1) and symptoms of recurrent anaphylaxis (n = 1). Two patients were asymptomatic. Darier sign was elicited in five patients and negative in two (not documented in seven). Eight patients were assessed for lymphadenopathy and organomegaly, with no detected abnormality. Eleven patients had skin biopsies; 10 (91%) had mastocytosis in the skin confirmed on histology; one patient had a nondiagnostic histological finding, but mastocytosis was diagnosed on the basis of clinical presentation. Seven patients had elevated serum tryptase levels (> 20 ng mL−1) on at least one occasion. Bone densitometry was done in five patients with elevated serum tryptase: two had osteopenia and one had osteoporosis. Eleven patients underwent bone marrow examination. Mast cell infiltration of the bone marrow was detected in four patients; KIT mutations in bone marrow were subsequently identified in three patients. Twelve patients remain under long-term follow-up. Treatments prescribed included antihistamine (n = 10), epinephrine autoinjector (n = 6), topical steroids (n = 5), vitamin D (n = 5), calcium (n = 4), H2 blocker (n = 2), bisphosphonates (n = 2), phototherapy (n = 2), leukotriene antagonists (n = 2), cosmetic camouflage (n = 1), oral sodium cromoglicate (n = 1) and KIT–tyrosine kinase inhibitor (n = 1). Despite treatments, none of the patients had regression (partial or complete) of cutaneous disease, although no fatal outcome was observed. Four (29%) cases had a final diagnosis of indolent systemic mastocytosis (all had elevated serum tryptase levels, two had anaemia). Our findings were consistent with the literature, where serum tryptase levels rather than systemic symptoms were a reliable predictor of systemic mastocytosis. Interestingly, 10 (71%) patients had mastocytosis limited to the skin, which is in contrast to the published literature, where the majority of people with adult-onset mastocytosis have systemic forms of the disease.

Emerging Data on the Safety and Efficacy of Ripretinib for the Treatment of Gastrointestinal Stromal Tumors.

In patients with gastrointestinal stromal tumors (GIST), systemic treatment after disease progression on imatinib is challenging. Sunitinib and regorafenib are approved in the second- and third-line setting, respectively, with activity against certain secondary mutations with comparatively much lower response rates and survival increment compared to imatinib. All three of these drugs were serendipitously found to have activity in GIST, starting with imatinib, which was formulated for its ability to inhibit BCR-ABL in chronic myelogenous leukemia. Ripretinib is a drug that was specifically developed as a more potent KIT tyrosine kinase inhibitor (TKI), with broad-spectrum activity against the mutations encountered in GIST. Encouraging responses in early and later lines of treatment in the Phase 1 trial of ripretinib in GIST led to the rapid development of this novel drug. In a Phase 3 randomized clinical trial with cross-over, ripretinib demonstrated superior PFS and overall survival (OS) in 4th-line treatment and beyond compared to placebo. This established 150 mg once daily ripretinib as the standard of care in this setting. Ripretinib is generally well tolerated, with common adverse effects of hair loss, diarrhea, cramps, fatigue and nausea. The favorable safety profile and efficacy of ripretinib prompted its evaluation in a randomized phase 3 trial in the 2nd-line treatment setting. However, it did not result in a longer PFS duration than sunitinib. Although the efficacy of ripretinib in this unselected patient population was not significantly different from that of sunitinib, the tolerability profile was better. This review article aims to review the efficacy and tolerability profile of ripretinib, together with its role in the setting of unresectable or metastatic GIST.

The clinical experience of compassionate use program for avapritinib: implications for drug positioning in the therapeutic scenario of systemic mastocytosis

In systemic mastocytosis, cytoreductive treatment is indicated for advanced systemic mastocytosis (AdvSM) variants. The treatment scenario is rapidly diversifying especially with the introduction of KIT tyrosine kinase inhibitors. Avapritinib is a second-generation potent and selective inhibitor of the mutant KIT D816V that, based on the results of pivotal clinical trials, was approved for the treatment of adults with AdvSM by the regulatory agencies US FDA and EMA. The present article reports the experience of treating SM patients with avapritinib in an Italian compassionate use program. The data from our case series confirm the drug as being active after multiple lines of treatment allowing rapid achievement of profound responses, making it also an effective bridging strategy to allogeneic transplant in eligible patients. However, the anticipated wider use of avapritinib in the near future will require careful monitoring of side effects, especially in heavily pretreated patients.

Effects of CYP3A Inhibition, CYP3A Induction, and Gastric Acid Reduction on the Pharmacokinetics of Ripretinib, a Switch Control KIT Tyrosine Kinase Inhibitor.

Ripretinib is a switch control KIT kinase inhibitor approved for treatment of adults with advanced gastrointestinal stromal tumors who received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are cleared mainly via cytochrome P450 enzyme 3A4/5 (CYP3A4/5), and ripretinib solubility is pH-dependent, thus the drug-drug interaction potentials of ripretinib with itraconazole (strong CYP3A inhibitor), rifampin (strong CYP3A inducer), and pantoprazole (proton pump inhibitor) were each evaluated in open-label, fixed-sequence study designs. Overall, 20 participants received ripretinib 50mg alone and with itraconazole 200mg once daily, 24participants received ripretinib 100mg alone and with rifampin 600mg once daily, and 25 participants received ripretinib 50mg alone and with pantoprazole 40mg once daily. Ripretinib exposure increased with concomitant itraconazole, with geometric least-squares (LS) mean ratios of ripretinib area under the concentration-time curve from 0 to ∞ (AUC0-∞ ) and maximum observed concentration (Cmax ) of 199% and 136%. Ripretinib exposure decreased with concomitant rifampin: geometric LS mean ratios for ripretinib AUC0-∞ and Cmax were 39% and 82%. Pantoprazole coadministration had no effect on ripretinib pharmacokinetics. No unexpected safety signals occurred. No dose adjustment is required for ripretinib coadministered with gastric acid reducers and strong CYP3A inhibitors; patients also receiving strong CYP3A inhibitors should be monitored more frequently for adverse reactions. Concomitant ripretinib use with strong CYP3A inducers should be avoided. Prescribers should refer to approved labeling for specific dose recommendations with concomitant use of strong and moderate CYP3A inducers.

INTRIGUE: A phase III, randomized, open-label study to evaluate the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib

359881 Background: Sunitinib is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib, a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor (TKI), is indicated for the treatment of adult patients (pts) with GIST who received prior treatment with 3 or more TKIs, including imatinib. We compared the efficacy and safety of ripretinib vs sunitinib in pts with advanced GIST who progressed on or were intolerant to imatinib. Methods: This multicenter, global, randomized, open-label phase 3 study (NCT03673501) enrolled adult pts with GIST who progressed on or had intolerance to imatinib. Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Randomization was stratified by KIT mutational status and imatinib intolerance. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using modified RECIST version 1.1. Key secondary endpoints were objective response rate (ORR) by IRR and overall survival (OS). Hierarchical testing was performed for primary and key secondary endpoints in a prespecified sequence; testing pts with a KIT exon 11 primary mutation (Ex11 intention-to-treat [ITT] population) preceded the all-patient (AP) ITT population. Data cutoff was 1 Sep 2021; final analyses of PFS and ORR and the first interim analysis of OS were conducted. Results: A total of 453 pts were randomized to ripretinib (n = 226; Ex11 ITT, n = 163) or sunitinib (n = 227; Ex11 ITT, n = 164). Median age was 60 yrs (range 18–88) and most pts were white (66.2%) males (62.0%). PFS was not statistically different between ripretinib and sunitinib in the Ex11 ITT (hazard ratio [HR] 0.88, 95% CI 0.66, 1.16; P = 0.36; median 8.3 vs 7.0 mos) or in the AP populations (HR 1.05, 95% CI 0.82, 1.33; P = 0.72; median 8.0 vs 8.3 mos). ORR was numerically higher for ripretinib vs sunitinib in the Ex11 ITT (23.9% vs 14.6%; difference 9.3%, 95% CI 0.7, 17.8; nominal P = 0.03) and AP ITT populations (21.7% vs 17.6%; difference 4.2%, 95% CI −3.2, 11.5; nominal P = 0.27). OS data was highly immature; median OS was not reached in either arm. Fewer pts in the ripretinib arm experienced Grade 3-4 (G3-4) treatment-emergent adverse events (TEAEs) vs sunitinib (41.3% vs 65.6%). Among G3-4 TEAEs with a difference ≥5% between arms, ripretinib had fewer events vs sunitinib (hypertension [8.5% vs 26.7%], palmar-plantar erythrodysesthesia [1.3% vs 10.0%], neutropenia [0% vs 6.3%], and neutrophil count decreased [0% vs 7.2%]). Conclusions: The PFS in both arms was longer than PFS achieved by sunitinib in its pivotal phase 3 trial. While the PFS for ripretinib did not meet the primary endpoint of superiority vs sunitinib, meaningful clinical activity and fewer G3-4 TEAEs were observed in pts with advanced GIST treated with ripretinib after imatinib failure. Clinical trial information: NCT03673501.

New treatment strategies for advanced-stage gastrointestinal stromal tumours.

When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease. At present, seven drugs are approved by the FDA for the treatment of advanced-stage GIST (imatinib, sunitinib, regorafenib, ripretinib, avapritinib, larotrectinib and entrectinib), all of which are TKIs. Although these agents can be very effective for treating certain GIST subtypes, challenges remain and new therapeutic approaches are needed. In this Review, we discuss the molecular subtypes of GIST and the evolution of current treatments, as well as their therapeutic limitations. We also highlight emerging therapeutic approaches that might overcome clinical challenges through novel strategies predicated on the biological features of the distinct GIST molecular subtypes.

Virtual Screening and Molecular Docking: Discovering Novel c-KIT Inhibitors.

Gastrointestinal stromal tumors (GISTs) are unusual cancers, which are developed in specialized cells in the gastrointestinal tract wall. Various strategies involving single-agents, combinations, and rapid complementary inhibitor cycling are now being used to control such tumors. Based on promising early clinical trial experience, certain novel KIT and PDGFRA tyrosine kinase inhibitors have shown advanced clinical development. Resistance to tyrosine kinase inhibitors has brought immense difficulties, with patients now requiring additional therapeutic options. This review describes and discusses the last five years (2016-2020) in developing novel c-KIT kinase inhibitors using virtual screening and docking approaches. Computational techniques can be used to complement experimental studies to identify new candidate molecules for therapeutic use. Molecular modeling strategies allow the analysis of the required characteristics that compounds must have to effectively bind c-KIT. Through such analyses, it is possible to both discover and design novel inhibitors against cancer-related proteins that play a critical role in tumor development (including mutant strains). Docking showed potential in the detection of the key residues responsible for ligand recognition and is very helpful to understand the interactions in the active site that can be used to develop new compounds/classes of anticancer drugs and help millions of cancer patients.

P-107 Dermatopathological review of cutaneous squamous cell carcinoma events in patients with gastrointestinal stromal tumors treated with ripretinib

Ripretinib, a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor (TKI), is indicated for patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib also inhibits BRAF in vitro. The incidence of all-grade cutaneous squamous cell carcinoma (cuSCC) with BRAF inhibitors, vemurafenib and dabrafenib, was 12.5% in a meta-analysis of 6,445 patients from 21 studies. cuSCC occurred in 7% of 351 patients with advanced GIST enrolled in either the phase 1 (NCT02571036) or phase 3 INVICTUS study (NCT03353753) receiving at least 1 dose of ripretinib.

Avapritinib in the treatment of PDGFRA exon 18 mutated gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST) can be molecularly classified based on different subtypes including mutations in KIT and PDGFRA. Patients with PDGFRA mutations are an important subgroup that commonly arise in the stomach and are associated with a more indolent disease course. Importantly, the most common PDGFRA molecular subtype, the D842V mutation in exon 18 of the gene which alters the activation loop, is imatinib insensitive in in vitro studies. Poor responses to imatinib have been seen clinically compared with PDGFRA exon 18 non-D842V-mutated GIST. Avapritinib (BLU-285) is a potent KIT and PDGFRA-specific tyrosine kinase inhibitor which has shown >90% response rates in patients with PDGFRA exon 18 D842V-mutated GIST. Results from the Phase I trial of avapritinib have indicated that this drug should be the standard of care for patients with PDGFRA exon 18 D842V-mutated GIST.

Safety of Imatinib Mesylate in a Multicenter Expanded Access Program in Adult Patients with Gastrointestinal Stromal Tumors in the Adjuvant Setting

Background: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors most often caused by activating mutations of the KIT gene. KIT tyrosine kinase inhibitors provide targeted therapy for the underlying genetic mutation, and adjuvant therapy is indicated for patients who are at significant risk of relapse following GIST resection. This is a report of the safety of imatinib in patients with GIST in the adjuvant setting in an expanded access program. Methods: In this multicenter, open-label, single-arm trial, safety was assessed based on the frequency of adverse events (AEs). Results: Three hundred patients were treated and analyzed; 40 patients discontinued treatment. Median overall exposure during the program was 181 days (range 9–420); most patients (260/300 treated) completed the study. Six patients had disease recurrence, 4 of whom discontinued. In line with previously published reports, the most frequent AEs were nausea, diarrhea, and periorbital edema. The AEs were mild to moderate in most cases (76%). Conclusions: These findings are in agreement with the known safety profile of imatinib and confirm the safety of imatinib at 400 mg/day in the adjuvant setting. The incidence of severe AEs was low.

ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KIT.

KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17-mutant KIT. Because secondary kinase domain mutations are a common mechanism of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for these emerging therapeutics. Midostaurin and avapritinib displayed different vulnerabilities to secondary kinase domain substitutions, with the T670I gatekeeper mutation being selectively problematic for avapritinib. Although gatekeeper mutations often directly disrupt inhibitor binding, we provide evidence that T670I confers avapritinib resistance indirectly by inducing distant conformational changes in the phosphate-binding loop. These findings suggest combining midostaurin and avapritinib may forestall acquired resistance mediated by secondary kinase domain mutations. SIGNIFICANCE: This study identifies potential problematic kinase domain mutations for next-generation KIT inhibitors midostaurin and avapritinib.

Nuclear KIT induces a NFKBIB-RELA-KIT autoregulatory loop in imatinib-resistant gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inhibitor. However, acquired resistance is an increasing clinical issue in GIST patients receiving front-line imatinib therapy. Our previous studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowing the role of nuclear KIT in GIST tumorigenesis. In this article, we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, which was accompanied with enhanced NFKBIB protein expression in GIST cells. Clinically, high NCCN risk GISTs had significantly higher mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or low/very low-risk GISTs. Conversely, downregulation of NFKBIB by siRNA led to RELA nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST cells. These findings were further confirmed by either RELA overexpression or NFKB/RELA inducer, valproic acid, treatment to result in reduced KIT expression and relative cell viability of imatinib-resistant GIST cells. Combining valproic acid with imatinib showed significantly better growth inhibitory effects on imatinib-resistant GIST48 and GIST430 cells in vitro, and in the GIST430 animal xenograft model. Taken together, these results demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are potential targets for developing combination therapy to overcome imatinib-resistant of KIT-expressing GISTs.

New Mechanisms of mTOR Pathway Activation in KIT-mutant Malignant GISTs

A great majority of gastrointestinal stromal tumors (GISTs) are primarily driven by gain-of-function KIT receptor tyrosine kinase mutations that subsequently lead to activation of phosphatidiylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway, a downstream effector of KIT signaling. KIT tyrosine kinase inhibitor, imatinib mesylate, has been successfully used for the treatment of primary, advanced, and disseminated GISTs. Recently, activation of mTOR pathway independent of KIT signaling was demonstrated in imatinib mesylate naïve malignant GISTs and treatment-resistant metastatic tumors. This activation was attributed to oncogenic mutations in PIK3CA encoding PI3K 110α subunit, or to the inactivation of PTEN tumor suppressor, a potent mTOR negative regulator. In this study, mTOR pathway genes were evaluated in 14 imatinib mesylate naïve, KIT-mutant, malignant small intestinal GISTs using next-generation sequencing. Mutations were detected in 3 (21%) of 14 analyzed tumors: (1) c.3200A>T substitution in PIK3CB encoding PI3K 110β subunit, (2) c.1040A>G substitution in tuberous sclerosis complex (TSC2) encoding tuberin, mTOR down-regulator (3) c.6625C>G substitution in mTOR. At the protein level, these changes were predicted to cause, respectively, PIK3CB p.D1067V, TSC2 p.K347R, and mTOR p.L2209V mutations. Previously reported "in vitro" experiments with mouse 3T3 fibroblasts demonstrated oncogenic potential of PIK3CB p.D1067V and mTOR p.L2209V mutants; whereas, PolyPhen-2 software analysis predicted TSC2 p.K347R mutation to likely have a damaging impact on tuberin function. The results of this and previous studies indicate diversity of genetic changes leading to activation of PI3K-AKT-TSC-mTOR pathway in malignant GISTs. Extensive genotyping of the genes involved in mTOR pathway demonstrates common alterations that need to be considered in targeted treatment.

Mechanisms of the resistance of gastrointestinal stromal tumors to imatinib

The review describes the modern concepts of the primary and secondary (acquired) resistance of gastrointestinal stromal tumors to the targeted drug imatinib. Gastrointestinal stromal tumors are the mesenchymal tumors of gastrointestinal tract that originate from interstitial cells of Cajal or their stem cell precursors. Up to 85 % of gastrointestinal stromal tumors have the mutations of KIT gene that lead to ligand-independent activation of this tyrosine kinase. Imatinib is an inhibitor of KIT tyrosine kinase which is hyperexpressed in 70-85 % of cases on the cell membrane of gastrointestinal stromal tumors. Despite the high effectiveness of imatinib in gastrointestinal stromal tumors, up to 15 % of patients do not respond to this therapy, and over 50 % of patients acquire the resistance to this drug 2 years after initiation of target therapy with imatinib. The mechanisms of primary resistance include basically the mutational status of KIT, PDGFRA and, rarely, mutations of SDH, NF1, BRAF, PI3K3CA, CBL, and KRAS. The mechanisms of secondary resistance of tumor cells to imatinib are not restricted to the secondary mutations of KIT and PDGFRA, but also might be due to the loss of KIT expression associated by overexpression of the alternative receptor- and non-receptor tyrosine kinases, such as MET, AXL, FGFR2α, FAK, etc. Alternative mechanisms of acquired resistance might be due to the mutations of BRAF gene.

LMTK3 is essential for oncogenic KIT expression in KIT-mutant GIST and melanoma.

Certain cancers, including gastrointestinal stromal tumor (GIST) and subsets of melanoma, are caused by somatic KIT mutations that result in KIT receptor tyrosine kinase constitutive activity, which drives proliferation. The treatment of KIT-mutant GIST has been revolutionized with the advent of KIT-directed cancer therapies. KIT tyrosine kinase inhibitors (TKI) are superior to conventional chemotherapy in their ability to control advanced KIT-mutant disease. However, these therapies have a limited duration of activity due to drug-resistant secondary KIT mutations that arise (or that are selected for) during KIT TKI treatment. To overcome the problem of KIT TKI resistance, we sought to identify novel therapeutic targets in KIT-mutant GIST and melanoma cells using a human tyrosine kinome siRNA screen. From this screen, we identified lemur tyrosine kinase 3 (LMTK3) and herein describe its role as a novel KIT regulator in KIT-mutant GIST and melanoma cells. We find that LMTK3 regulated the translation rate of KIT, such that loss of LMTK3 reduced total KIT, and thus KIT downstream signaling in cancer cells. Silencing of LMTK3 decreased cell viability and increased cell death in KIT-dependent, but not KIT-independent GIST and melanoma cell lines. Notably, LMTK3 silencing reduced viability of all KIT-mutant cell lines tested, even those with drug-resistant KIT secondary mutations. Furthermore, targeting of LMTK3 with siRNA delayed KIT-dependent GIST growth in a xenograft model. Our data suggest the potential of LMTK3 as a target for treatment of patients with KIT-mutant cancer, particularly after failure of KIT TKIs.

NFM-01. NF105: A PHASE II PROSPECTIVE STUDY OF CABOZANTINIB (XL184) FOR PLEXIFORM NEUROFIBROMAS IN SUBJECTS WITH NEUROFIBROMATOSIS TYPE 1: A NEUROFIBROMATOSIS CLINICAL TRIAL CONSORTIUM (NFCTC) STUDY

BACKGROUND Plexiform neurofibromas (PNs) are histologically complex peripheral nerve sheath tumors composed of Schwann cells and fibrocytes. Pre-clinical models have demonstrated that altering the microenvironment with molecular targeting therapy may lead to the shrinkage of PN. Here we test the activity of Cabozantinib, a tyrosine kinase inhibitor of KIT, MET, VEGF, and AXL, in adolescents and adults with NF1-associated PN.

Subgroup analyses of a phase 1/2 study of lenvatinib (E7080), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC).

309 Background: Lenvatinib is an oral tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT. A phase 1/2 trial in pts (n = 46) with advanced HCC and Child-Pugh score A treated with lenvatinib 12 mg once daily showed a median overall survival (OS) of 18.7 months, and a median time to progression (TTP) of 12.8 months by investigator review and 7.4 months by independent radiologic review (IRR). Objective response rate was 37.0% as assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Based on these results, a phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib is ongoing. Here, we report subgroup analyses of the phase 2 part of this study. Methods: Subgroups were retrospectively analyzed by Barcelona clinic liver cancer (BCLC) staging, disease etiology, prior therapy for advanced HCC (including sorafenib), and baseline Alpha-fetoprotein (AFP) levels. Efficacy endpoints including OS and TTP by IRR were assessed for each subgroup. TTP based on mRECIST and OS were assessed from the date of study registration to progressive disease and to death, respectively. Results: Median TTP and OS for each of the relevant subgroups of baseline characteristics are shown in the table. Conclusions: Pts with advanced HCC treated with lenvatinib showed similar TTP regardless of subgroup. Although the number of patients was limited, lenvatinib treatment shows promising efficacy even in patients with hepatitis B virus. Clinical trial information: NCT00946153. [Table: see text]

A Phase I Study of the Multi-Targeted Tyrosine Kinase Inhibitor Cabozantinib in Patients with Acute Myeloid Leukemia

Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) of FLT3, MET, AXL, VEGFR, and KIT, all of which are implicated in the pathogenesis of acute myeloid leukemia (AML). Cabozantinib has been studied in clinical trials of solid tumors, and is FDA approved for use in medullary thyroid and renal cell carcinoma. Despite multiple relevant targets, cabozantinib has not been previously studied in AML. Given up-regulation of these key enzymes and related pathways in AML, we sought to assess the safety and tolerability of cabozantinib in this population.The primary objective of this phase I, 3+3 cohort dose-escalation study was to define the maximum tolerated dose (MTD) of cabozantinib in patients with AML. Eligibility included adults ≥ age 18, with relapsed or refractory (R/R) AML, or those aged ≥ 70, with new diagnosed AML but ineligible for or declining conventional therapy. Study treatment required a white blood cell count (WBC) of < 30,000/mm3, but concurrent treatment with hydroxyurea was allowed to control WBC during the first 15 days of cycle 1. The first dose level was 40MG by mouth daily (QD), a dose previously demonstrated to be well-tolerated in solid tumor malignancies. Cabozantinib was administered in 28 day cycles, and dose escalation occurred via 3 cohorts (40MG QD, 60MG QD, 80MG QD). Escalation to each successive dose level was guided by incidence of dose limiting toxicity (DLT) during cycle 1 of study treatment. Pharmacodynamic evaluation of serial plasma samples obtained from patients, by use of a plasma inhibitory assay (PIA), was used to assess FLT3 inhibitory activity in FLT3-ITDcell lines. Response was determined by bone marrow biopsy after the first cycle of treatment, and those achieving complete or partial remission, or with stable disease and clinical benefit, could continue on study until disease progression, intolerable toxicity, or upon receipt of 12 cycles.18 patients were enrolled on study. The median age was 68 (range 27-85); 12 (67%) were male, and 14 (78%) were Caucasian. FLT3-ITD mutations were detected in 5 (23%) patients, and NPM1 mutations in none. 16 patients (89%) had R/R AML, and 2 patients (11%) had newly diagnosed disease. The majority (75%) of those with R/R AML had been treated with two or more lines of prior treatment. 3 patients were enrolled at the first dose level (40MG QD), of whom one experienced >G3 transaminitis, thought unrelated to cabozantinib, but could not be dosed for this reason and was therefore replaced. No DLTs were detected at the first dose level among the 4 studied patients. However, two of the three patients enrolled at the second dose level (60MG QD) experienced DLT, one with grade 3 pancreatitis and the other with grade 3 transaminitis. Three patients were then enrolled at the next lower level, dose level 1 (40MG QD), of whom two could not complete the DLT period, one because of disease progression and the other due to an infected aortic ulceration unrelated to study treatment. These two patients were replaced, and no additional DLTs were noted. 40MG daily was therefore determined to be the MTD, and 6 patients were subsequently treated in an expansion cohort at this dose. Additional ≥ grade 2 toxicities, possibly or probably related to cabozantinib, each affected 3 or less patients, and included fatigue, nausea, anorexia, constipation, oral mucositis, palmar-plantar erythrodysesthesia, transaminitis, and electrolyte imbalance. Fifteen patients could be assessed for response on study. No patients had a marrow response per formal criteria. Four patients had a reduction in peripheral blasts during treatment, of whom 2 transiently cleared their circulating blasts (one with FLT3-ITD). One patient experienced a reduction in marrow blasts, and one had stable marrow disease. FLT3 inhibitory activity of serially collected patient plasma samples, as determined by the ex vivo PIA, consistently revealed potent and sustained inhibition of FLT3 auto-phosphorylation in FLT3-ITDmutant cell lines by day 8 of cycle 1.Cabozantinib, a multi-targeted TKI, is well-tolerated in patients with AML at the MTD of 40 MG daily. In this molecularly heterogeneous, heavily pre-treated population of AML patients, clinical response to cabozantinib monotherapy was limited. However, we found that cabozantinib inhibits FLT3-ITD tyrosine kinase in a potent and sustained fashion. Additional clinical study of cabozantinib among patients with FLT3 mutant AML is therefore warranted. DisclosuresFathi:Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation. Levis:Millennium: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding. Avigan:Astex: Research Funding; DCPrime: Research Funding. Hobbs:Constellation: Other: Advisory Board participation; Incyte: Other: Advisory Board participation.

A Young Man with an Abnormal Chest X-ray

Gastrointestinal stromal tumors(GIST) are an uncommon neoplasms of the GI tract. We present a rare case of esophageal GIST in a previously healthy young male. A 30 year old male presented to the ED after waking up ith cough, eigastric pain, nausea and vomiting. A chest x- ray showed upper mediastinal widening. Contrast enhanced CT scan incshowed a posterior mediastinal mass. Transbronchial needle aspiration and biopsy of a subcarinal mass was performed which revealed necrotic tissuecand was not diagnostic. Repeat biopsy with right video assisted thoracic surgery was performed. Immunohistochemistry was positive for CD117. A repeat chest x-ray 3 months later revealed resolution of previously described mass. He remained well until 10 months after initial presentation when he presented with chest pain, back pain and dry cough. A chest CT revealed a recurrent 5 cm subcarinal density. Right thoracotomy and resection of the mass was performed. Pathology results showed GIST with high mitotic rate. Patient was started on Imatinib. Endoscopic ultrasound two months later showed a residual mass. Fine needle aspiration and biopsy was positive for GIST. He underwent esophagectomy. Histologic evaluation revealed high grade epithelioid GIST. Patient has been asymptomatic without recurrence since.Figure 1Figure 2Figure 3GISTs affect mainly older individuals. It occurs mainly in stomach and express KIT or cell surface marker cd117 in 85-90% of cases, which is a tyrosine kinase receptor. Initial patient evaluation is usually with CT scan. Radical surgery is the treatment of choice in primary resectable GISTs. Almost all are associated with a risk of recurrence with rate of 40-50%. Imatinib Mesylate, inhibitor of KIT Tyrosine Kinase is used as an adjuvant therapy to decrease the risk of post operative recurrence. High risk tumors have a risk of 66% recurrence, making it obvious that surgery alone is not sufficient to provide long term survival. It is also used as neoadjuvant in cases that complete surgical resection is impossible and also for reducing tumor size. Since patients with high risk GIST relapse within 2 years, the follow up should be adopted to tumor criteria. CTS in the technique of choice for follow up. Our patient is particularly unique because of the age of presentation and location of tumor. Immunohistochemistry for CD117 has a high value of specificity for GIST. Treatment is complete resection. Recurrence is mainly dependent on mitotic activity. Imatinib is a useful adjuvant.