Abstract C188: A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers

Abstract Background: RXDX-105 is a potent RET, BRAF and EGFR tyrosine kinase inhibitor (TKI) that exhibits high target affinity at low nanomolar concentrations. The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signaling molecules. RET gain of function alterations are associated with the development of various types of human cancer, including non-small cell lung cancer (NSCLC). BRAF plays a key role in regulating the MEK/ERK signaling pathway, which affects cell division and differentiation. Acquired BRAF mutations can result in constitutive activation of this pathway, thereby fueling cancer growth. RXDX-105 is being developed as an oral therapy for patients with solid tumors that harbor RET or BRAF mutations or gene rearrangements. Methods: Adult pts with advanced solid tumors were enrolled in a Ph 1 single agent dose escalation study with a standard 3 + 3 design to determine the recommended Ph 2 dose. Oral RXDX-105 was given as a fixed dose on a continuous daily schedule. Tumor response was assessed at baseline and every 8 wks (RECIST v1.1). Treatment-emergent adverse events (AEs) were recorded according to NCI CTC v4.03. Pharmacokinetic (PK) assessment was also a study objective. Results: To date, 35 pts (17 M and 18 F) received RXDX-105 across 7 dose levels (20 to 275 mg QD). Median age was 60.5 years (range 27-81). The most frequent tumors (pts) were metastatic CRC (13), ovarian cancer (3), NSCLC (3), cholangiocarcinoma (3), and pancreatic cancer (3). Median number of cycles was 2 (range 1 to 23). 34 pts experienced AEs; 6 pts experienced treatment-related G3 AEs, including anemia, hypophosphatemia, fatigue, diarrhea, abdominal pain, rash and muscle weakness. 22 SAEs were reported from 9 pts, with none considered treatment-related. No treatment-related deaths occurred. The most common AEs were: fatigue (17 pts), vomiting (13 pts), abdominal pain (12 pts), nausea (11 pts), decreased appetite (10 pts), and rash (10 pts). At the time of this report, 3 pts have had DLTs; 1 pt at 200 mg with G2 hand and foot syndrome, 1 pt at 275 mg with G3 fatigue, and 1 pt at 275 mg with G3 asymptomatic hypophosphatemia. The protocol was amended to exclude hypophosphatemia as a DLT since it has been observed with approved TKIs and can be managed by supplementation. The PK data to date have demonstrated that RXDX-105 is absorbed with a median Tmax between 2 and 6 hrs at steady state. RXDX-105 plasma concentrations declined slowly after reaching Cmax with an average terminal half-life of 28 to 42 hrs across dose levels. There was a loss of dose proportionality at doses above 150 mg, possibly due to pH-dependent drug dissolution in the stomach. The impact of the fed state on exposure is being explored. 11 pts have been on treatment for ≥ 12 weeks. No objective responses have been observed; however, 1 pt with BRAF V600E-positive papillary thyroid cancer, previously treated with RAI, EBRT and multiple surgical resections, has been on study with stable disease for almost 2 years (23 cycles). Additionally, 2 heavily pre-treated pts with squamous NSCLC achieved clinical benefit with SD for &amp;gt; 6 months; 1 patient continues. Conclusions: To date, treatment with RXDX-105 demonstrates an acceptable safety profile. Improvements in bioavailability are being investigated. Dose escalation continues. Citation Format: Ding Wang, Manish Patel, Marwan Fakih, A. Craig Lockhart, Anthony J. Olszanski, Rupal Patel, Peter D. Brown, Jennifer W. Oliver, Pratik S. Multani. A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C188.</jats:p

Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies

Mixed lymphohematopoietic chimerism can be induced in mice with bone marrow transplantation (BMT) after a nonmyeloablative preparative regimen that includes cyclophosphamide, anti-T-cell antibody therapy, and thymic irradiation. These mixed chimeras are resistant to the induction of graft-versus-host disease (GVHD) after delayed donor leukocyte infusions (DLIs), despite a potent lymphohematopoietic graft-versus-host reaction that converts the mixed chimeric state to a full donor one. Based on this animal model, we initiated a trial of nonmyeloablative therapy with HLA-matched or -mismatched donor BMT and DLI for refractory hematologic malignancies. Twenty-one of 36 patients enrolled in this trial received a genotypically (n = 20) or phenotypically (n = 1) HLA-matched donor transplant; results reported here are for those patients only. Preparative therapy consisted of cyclophosphamide in doses of 150 to 200 mg/kg; peritransplant antithymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal radiation therapy); and cyclosporine. Eighteen of 20 evaluable patients developed persistent mixed lymphohematopoietic chimerism as defined by >1% donor peripheral white blood cells until at least day 35 posttransplantation. Ten patients received prophylactic DLI beginning 5 to 6 weeks after BMT for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-leukemia effect. Fourteen of 20 evaluable patients (70%) achieved an antitumor response; 8 of these responses were complete, and 6 were partial. Of the 8 evaluable patients who received prophylactic DLI, 6 showed conversion to full donor chimerism. Five of the 9 evaluable patients (56%) who received prophylactic DLI achieved a complete response, compared with 3 of 11 patients (27%) who did not receive prophylactic DLI. Currently 11 patients are alive, and 7 of these are free of disease progression at a median follow-up time of 445 days (range, 105-548 days) posttransplantation. Transplantation-related complications included cyclophosphamide-induced cardiac toxicity in 3 of 21 patients (14%) and grade II or greater GVHD in 6 patients (29%). One patient (5%) died from a complication of BMT, and 1 patient (5%) died from GVHD after 2 prophylactic DLIs were given for conversion of chimerism. In summary, mixed lymphohematopoietic chimerism was reproducibly induced after a novel nonmyeloablative preparative regimen incorporating chemotherapy, peritransplant antithymocyte globulin, and thymic irradiation, allowing for early administration of DLI in 10 of 21 patients. After treatment, striking antitumor responses were observed in the majority of patients with chemotherapy-refractory hematologic malignancies. Biol Blood Marrow Transplant 2000;6(3A):309-20

Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer

IntroductionChromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib.MethodsWe screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment.ResultsWe identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3–4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR.ConclusionsEntrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases

A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105

RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P \u3c 0.001, Fisher exact test): 0% (95% CI, 0%-17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI, 30%-93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RETfusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-KIF5B-RET-containing cancers. Novel approaches to targeting KIF5B-RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed