Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models.

Purpose:MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661-72. ©2017 AACR.

Clinical outcomes following image-guided stereotactic body radiation for pulmonary oligometastases.

ACKNOWLEDGEMENT AND FUNDING: This work was made possible by funding from NIH grant T32 RR023254; Salary support for Dr M.M. Fuster was provided by the Department of Veterans Affairs (BLR&D CDTA Career Development Award). KEYWORDS: Pulmonary metastases; oligometastases; stereotactic body radiotherapy (SBRT); frameless SBRT. BACKGROUND: Lung is a common site of extracranial metastases. Frameless Stereotactic Body Radiation Therapy (SBRT) is a promising new therapy for unresectable neoplastic lung lesions used at our institution. METHODS: A retrospective study of 21 patients and 33 lesions treated with SBRT was done. Local control (LC), distant control (DC), progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Potential prognostic factors were analyzed using the log-rank test and Cox regression. Toxicities were also reported. RESULTS: Actuarial local control rates by lesions were 88% (95% confidence interval [CI], 77-99%) and 76% (95% CI, 59-92%) at 12-and 24-months, respectively. Actuarial local control rates by patients was 80% (95% CI, 62-98%) and 71% (95% CI, 43-100%) for 12- and 24-months, respectively. DC rates were 52% (95% CI 31-74%) and 38% (95% CI, 15-61%), at 12- and 24-months respectively. PFS rates were 52% (95% CI 31-74%) and 32% (95% CI 9-55%) at 12- and 24-months, respectively. Overall survival rates were 90% (95% CI 77-100%) and 78% (95% CI 59-97%) at 12- and 24-months, respectively. Single metastasis was associated with better PFS (p=0.023). No toxicities greater than CTCAE grade 3 were observed. CONCLUSIONS: Frameless SBRT achieves acceptable control in pulmonary metastatic lesions with an excellent toxicity profile.

Clinical outcomes following image-guided stereotactic body radiation for pulmonary oligometastases.

BACKGROUND: The lung is a common site of extracranial metastases. Frameless Stereotactic Body Radiation Therapy (SBRT) is a promising new therapy for non surgically resectable neoplastic lung lesions used at our institution. METHODS: A retrospective study of 21 patients and 33 lesions treated with SBRT was done. Local control (LC), distant control (DC), progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Potential prognostic factors were analyzed using the log-rank test and Cox regression. Toxicities were also reported. RESULTS: Actuarial local control rates by lesions were 88% (95% confidence interval [CI], 77-99%) and 76% (95% CI, 59-92%) at 12-and 24-months, respectively. Actuarial local control rates by patients was 80% (95% CI, 62-98%) and 71% (95% CI, 43-100%) for 12- and 24-months, respectively. DC rates were 52% (95% CI 31-74%) and 38% (95% CI, 15-61%), at 12- and 24-months respectively. PFS rates were 52% (95% CI 31-74%) and 32% (95% CI 9-55%) at 12- and 24-months, respectively. Overall survival rates were 90% (95% CI 77-100%) and 78% (95% CI 59-97%) at 12- and 24-months, respectively. Single metastasis was associated with better PFS (p=0.023). No toxicities greater than CTCAE grade 3 were observed. CONCLUSIONS: Frameless SBRT achieves acceptable control in pulmonary metastatic lesions with an excellent toxicity profile.

Frameless image-guided stereotactic body radiation therapy for lung tumors with 4-dimensional computed tomography or 4-dimensional positron emission tomography/ computed tomography.

BACKGROUND/PURPOSE: To augment the accuracy of stereotactic body radiation therapy (SBRT), a variety of image guidance systems are used for patient positioning and target localization. Clinical outcomes evaluating these systems, especially frameless image-guided systems, are still limited. This article aims to describe and evaluate our frameless image-guided SBRT technique for lung tumors. METHODS: Between 2007 and 2009, 85 pulmonary tumors (50 primaries and 35 metastases) were treated with SBRT using daily image guidance for patient positioning and target localization in lieu of a body frame. Four-dimensional computed tomography (4DCT) or an in-house protocol for integrated 4D positron emission computed tomography (4DPET/CT) was used for planning simulation. RESULTS: Median follow-up was 17 months (range, 4-42). Median overall survival (OS) was 31 months (95% CI, 26-34), and median local failure-free survival was 30 months (95% CI, 18-32). At last follow-up, 9 of 83 evaluable lesions failed locally. Actuarial local control at 24 months was 87% (95% CI, 75-98) and was significantly worse for metastatic lesions (95% vs. 74%; P = .045; log-rank test). No acute or late toxicities (grade ≥ 4) were observed. CONCLUSIONS: Frameless image-guided SBRT is a feasible, safe, and effective treatment for lung tumors.

Definitive radiation therapy for stage I non-small-cell lung carcinoma: institutional experience with contemporary conformal planning.

PURPOSE: Surgical resection for stage I non-small-cell lung cancer (NSCLC) is not always feasible because of the high likelihood of medical comorbidity in this patient population. We report our experience using conventional and hypofractionated radiation therapy schedules with a conformal approach. PATIENTS AND METHODS: Between 1991 and 2006, 102 patients with medically or otherwise inoperable stage T1/T2 N0 NSCLC were treated with curative radiation therapy alone at our institution. Patients received a median total dose of 6600 cGy, with median daily dose fractions of 250 cGy. The following outcomes were analyzed: local failure-free survival (LFFS; time to local failure or death from any cause), time to local or distal failure or death as first event, and overall survival (OS). Local failure was defined as an increase in size on imaging studies. Toxicities were evaluated using Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Median follow-up was 20.9 months (range, 4.0-138.9 months). Median LFFS was 21.2 months (95% CI, 17.3-27.2 months), and median OS was 21.3 months (95% CI, 17.9-28.8 months). Analysis of competing risks showed that at 5 years, the probability of local failure as the first detected event was 15.1% (95% CI, 8.5%-23.4%), the probability of distal failure as the first detected event was 18% (95% CI, 10.9%-26.5%), and the probability of death without recording a failure was 51.6% (95% CI, 40.6%-61.5%). No patients experienced grade >or= 4 toxicity, and only 4 patients experienced grade 3 toxicity. CONCLUSION: Conformal radiation therapy is an effective and safe alternative to surgery for selected patients with stage I NSCLC.