Santosh Sutradhar

Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial

SUMMARY Background ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALKi) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALKi than crizotinib in vitro, crosses the blood-brain barrier in vivo and shows clinical responses in crizotinib-resistant disease. Here, we assessed whole-body and intracranial activity of ceritinib in both ALK-pretreated and ALKi-naïve patients with ALK-rearranged NSCLC. Methods The primary objective (to determine the maximum tolerated dose of ceritinib) of this first-in-human, phase I, open-label ASCEND-1 trial has been reported previously. In the analysis reported here, antitumour efficacy of ceritinib was evaluated in all patients with ALK-rearranged NSCLC (n=246) treated with ceritinib at the recommended dose of 750 mg/day. Additionally, as patients with untreated or locally treated neurologically stable brain metastases at baseline were permitted in this study, intracranial efficacy was retrospectively confirmed by independent neuroradiologists for 94 patients with baseline brain metastases and at least one post-baseline MRI/CT tumour assessment. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516. Findings Median follow-up at the time of this report was 11 1 months (interquartile range 6·7–15·2). Patients were mainly heavily pretreated (105/246 [42·7%] at least three prior regimens). The overall response rate was 72·3% (60/83; 95% confidence interval [CI] 61·4–81·6) for ALKi-naïve (n=83) and 56·4% (92/163; 95% CI 48·5–64·2) for ALKi-pretreated (n=163) patients. Median progression-free survival in ALKi-naïve and ALKi-pretreated patients was 18·4 (95% CI 11·1-non-estimable) and 6·9 (95% CI 5·6–8·7) months, respectively. Brain metastases by investigator assessment were reported at study entry in 124 patients. Of these, 94 (n=19 ALKi-naïve and n=75 ALKi-pretreated) were included in the retrospective analysis; intracranial disease control rate was 78·9% (15/19; 95% CI 54·4– 93·9) in ALKi-naïve patients and 65·3% (49/75; 95% CI 53·5–76·0) in ALKi-pretreated patients. Of the 94 patients included in the retrospective analysis, 11 had measurable brain lesions and no prior radiotherapy to the brain: 6 of these achieved a partial intracranial response. Safety was evaluated for all 246 patients with ALK-rearranged NSCLC. Serious adverse events were recorded for 117 (47·6%) patients. The most common grade 3/4 laboratory abnormalities were increased alanine aminotransferase and increased aspartate aminotransferase, occurring in 73 (29·7%) and 25 (10·2%) patients, respectively. The most common grade 3/4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6.1%) patients. Two on-treatment deaths in the study were considered to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multi-organ failure that occurred in the context of infection and ischaemic hepatitis. Interpretation This study demonstrated clinically meaningful and durable responses in mainly heavily pretreated patients with ALK-rearranged NSCLC (ALKi-naïve and ALKi-pretreated) receiving ceritinib 750 mg/day. Treatment with ceritinib also achieved both whole-body and intracranial efficacy in patients with brain metastases at baseline, a common site of disease progression in patients with NSCLC. The durable whole-body responses reported, together with the intracranial efficacy, support a clinical benefit for treatment with ceritinib in patients post-crizotinib, or as an alternative to crizotinib in patients with ALK-rearranged NSCLC. Funding Sponsored by Novartis Pharmaceuticals Corporation.BACKGROUND ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood-brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC. METHODS ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK-rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516. FINDINGS Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11·1 months (IQR 6·7-15·2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% [95% CI 61-82]) of 83 ALK inhibitor-naive patients and 92 (56% [49-64]) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17·0 months (95% CI 11·3-non-estimable [NE]) in ALK inhibitor-naive patients and 8·3 months (6·8-9·7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18·4 months (95% CI 11·1-NE) in ALK inhibitor-naive patients and 6·9 months (5·6-8·7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% [95% CI 54-94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54-76]) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). The most common grade 3-4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis. INTERPRETATION The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metastases. FUNDING Novartis Pharmaceuticals Corporation.

MINI01.01: Whole Body and Intracranial Efficacy of Ceritinib in ALK-inhibitor Naïve Patients with ALK+ NSCLC and Brain Metastases: Results of ASCEND 1 and 3: Topic: Medical Oncology

MINI ORAL SESSIONS SATURDAY, SEPTEMBER 24, 2016 MINI01.01 Whole Body and Intracranial Efficacy of Ceritinib in ALK-inhibitor Naïve Patients with ALK+ NSCLC and Brain Metastases: Results of ASCEND 1 and 3 Topic: Medical Oncology Alice T. Shaw, David R. Spigel, Daniel S.-W. Tan, Dong-Wan Kim, Ranee Mehra, Sergey Orlov, Keunchil Park, Chong-Jen Yu, Tony Mok, Makoto Nishio, Giorgio Scagliotti, Santosh Sutradhar, Dajana Cesic, Enriqueta Felip Massachusetts General Hospital, Boston/United States of America, Sarah Cannon Research Institute, Nashville, TN/United States of America, National Cancer Centre Singapore, Singapore/Singapore, Seoul National University Hospital, Seoul/Korea, Republic of, Fox Chase Cancer Center, Philadelphia, PA/United States of America, St. Petersburg State Medical University, St. Petersburg/Russian Federation, Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul/ Korea, Republic of, National Taiwan University Hospital, Taipei City/Taiwan, Chinese University of Hong Kong, Sha Tin/China, Japanese Foundation for Cancer Research, Tokyo/Japan, University of Torino, Torino/ Italy, Novartis Pharmaceuticals Corporation, East Hanover, NJ/United States of America, Vall d’Hebron University, Barcelona/Spain Background: Here we present efficacy outcomes in ALKrearranged (ALK+) NSCLC patients with baseline (BL) brain metastases (BM) treated with the selective oral ALKi ceritinib in the ASCEND-1 (phase 1; NCT01283516) and ASCEND-3 (phase 2; NCT01685138) trials. Methods: ALKi-naive patients with ALK+ NSCLC and stable BL BM received ceritinib 750 mg/day. Efficacy analyses (by blinded independent review committee [BIRC]) assessed whole body responses for ASCEND-1 and -3 according to RECIST 1.0 and 1.1 criteria, respectively. Pooled intracranial responses were evaluated by BIRC (ASCEND-1, retrospectively; ASCEND-3, prospectively) in patients with measureable BL BM (RECIST 1.1). Results: Of 26 and 50 ALKi-naïve patients with BL BM enrolled in ASCEND-1 and -3, respectively, 88.5% and Journal of Thoracic Oncology Vol. 11 No. 11S: S256-S269 100% had prior chemotherapy and 57.7% and 54.0% had prior brain radiotherapy (RT); median times from prior RT to first ceritinib dose were 4.6 and 2.7 months. Ceritinib showed whole body and intracranial efficacy (Table). The most common AEs (ASCEND-1; ASCEND-3) were nausea (84.6%; 78.0%), diarrhea (92.3%; 76.0%) and vomiting (76.9%; 72.0%); 46 patients (ASCEND-1: 19; ASCEND-3: 27) had dose reductions and 4 patients (ASCEND-1: 3; ASCEND-3: 1) discontinued due to AEs. Conclusion: Clinically meaningful whole body and intracranial activity with an acceptable tolerability profile were observed in ALKi-naïve patients with ALK+ NSCLC and BL BM treated with ceritinib. MINI01.02 Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (pts) with ALK+ NSCLC Topic: Medical Oncology Leora Horn, Heather Wakelee, Karen L. Reckamp, George Blumenschein Jr., Jeffrey R. Infante, Corey A. Carter, Saiama N. Waqar, Joel W. Neal, Kimberly Harrow, Jon P. Gockerman, Gary Dukart, Chris Liang, James L. Gibbons, Jennifer Hernandez, Tera Newman-Eerkes, Lee Lim, Christine M. Lovly Vanderbilt University Medical Center, Nashville, TN/United States of America, Stanford Cancer Institute, Stanford, CA/United States of America, City of Hope Comprehensive Cancer Center, Duarte/United States of America, Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX/United States of America, Sarah Cannon Research Institute, Nashville, TN/United States of America, Walter Reed National Military Medical Center, Germantown, MD/