P101-24 Preclinical Proteomic Evaluation of Alternating ALK TKI Therapy Versus Continuous Dosing in ALK NSCLC to Inform the ALKternate Clinical Trial

In many patients the underlying cause of drug resistance is unexplained. ALKternate is a clinical trial recruiting pre-treated patients, testing the hypothesis that with fixed alternating TKI therapy, the emergence of ALK resistant clones can be suppressed through applying variable selection pressure compared to continuous treatment with a TKI. This has been tested pre-clinically with a human cell line to complement the clinical trial in progress, ALKternate In this study, ALK TKI treatment was conducted on resistant ALK-rearranged cell lines (methods in Abstract #2074). Protein profiling was performed using the SWATH-MS 2.0 algorithm, conducted on the Sciex 6600 TripleTOF on cell pellets collected prior to treatment and at cycles (C) 5, 11 and 17 of both alternating lorlatinib with crizotinib (ALT) and continual lorlatinib (CONT) treatment arms.This study represents the first of proteomics used to identify resistance mechanisms to ALK TKIs. Data from this in vitro work will inform th..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.739

Authors: M. Itchins, A. Hudson, R. Harvie, T. Zaw, M. Mckay, S. Clarke, V. Howell, N. Pavlakis, S. Hayes

Conference PaperKirk SmithOctober 1, 2019NSCLC, ALK, proteomic, ALKternate

EP116-32 Percentage of ALK Rearrangement as a Response Predictor in Non-Small Cell Lung Cancer Treatment

Our study aimed to correlate the percentage of ALK rearrangement found as a predictor of response in NSCLC ALK-positive treatment. Designed a retrospective study with NSCLC ALK rearrangement patients in a peripheral Hospital from the last six years. Collected demographic data, histology, disease stage, the percentage of ALK rearrangement detected by FISH, lines of treatment, the response rate (RR) evaluated by RECIST 1.1 criteria, the progression-free survival (PFS) and the overall survival (OS) in patients under ALK inhibitors. Results are presented as medians and range for non-normally distributed continuous variables and as number/total for categorical data. Statistical analysis was performed using U-Mann-Whitney test, considering a significance level of 5%. Besides our negative results with the the percentage of ALK rearrangement, we found in our sample an improvement in the RR, PFS and OS in patients that made in first line, ALK inhibitors rather than platinum-based chemotherapy, ..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2397

Authors: M. Oliveira, R. Natal, J. Costa, R. Gomes, A. Amaral, L. Ferreira

EP116-28 ALK Translocated Patients: Survival in an Unselected Population

A cohort of 34 patients diagnosed of non-small cell lung cancer with ALK translocation were retrospectively analyzed in our center between 2008-2018. Baseline demographics characteristics were described. OS was calculated as the main objective.Patients were followed a median of 47 months (IQR 30-203). Median age was 59 years (IQR 36-83), being 47% male and 53% female. 44% were never smokers and 58% had any comorbidities. At diagnosis, 83% were symptomatic and the most frequent metastases were bone ones (32%). Complete baseline characteristics are shown in Table 1. Median OS was 32 months (IQR 15-78). 1-year, 2-year and 3- year survival was 75%, 69% 49.9% respectively. The ALK translocation and targeted treatments have led to a dramatic improvement in overall survival in clinical trials confirmed in our series. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2393

Authors: B. Núñez-García, R. Gómez-Bravo, J.C. Sánchez, B. Cantos, M. Méndez, A.M. Morito, M. Blanco, V. Calvo, M. Provencio

Conference PaperKirk SmithOctober 1, 2019NSCLC, ALK mutation, OS

EP114-47 Lung Adenocarcinoma with Concurrent KRAS Mutation and ALK Rearrangement Responding to Crizotinib

We reported a rare case of 47-year-old female was diagnosed with lung adenocarcinoma and treated with three cycles of chemotherapy. A biopsy acquired after disease progression revealed concurrent KRAS mutation and ALK translocation by a NGS assay. Based on molecular findings, treatment was initiated with crizotinib in September, 2016. After 2 months of therapy, the patient achieved a partial response. Afterwards, the patient was further administrated with crizotinib for 9 months with a stable disease before tumor progression.A further understanding of the molecular biology with multiple oncogenic drivers will promote the optimal treatment for NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2332

Authors: Y. Zhu, W. Wang, C. Xu, X. Li, W. Zhuang, K. Du, G. Chen, M. Fang, T. Lv, Y. Song

Case StudyKirk SmithOctober 1, 2019lung adenocarcinoma, ALK rearrangement, KRAS mutation

EP114-07 Efficacy and Safety of ALK Inhibitors in ALK-Rearranged Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

We conducted a systematic review and meta-analysis to assess the efficacy and safety of ALK inhibitors compared to chemotherapy (ALK vs. chemo) and 2nd generation ALK inhibitors compared to 1st generation ALK inhibitors (ALK 2G vs. ALK 1G).The electronic databases PubMed and EMBASE, were searched for relevant randomized trials. Pooled hazard ratios (HR) for overall survival (OS) and progression free survival (PFS), and pooled risk ratios for objective response rates (ORR) and grade 3 or higher toxicity were meta-analyzed using the generic inverse variance and the Mantel-Haenszel methods. To account for between-studies heterogeneity, random-effect models were used. Subgroup analyses compared PFS by gender, smoking status, brain metastases, race and age.This meta-analysis is the first, to our knowledge, to report an OS improvement with the use of ALK vs. chemo. A trend toward a better OS was also seen with ALK 2G vs. ALK 1G and this is likely because of crossover effects and limited OS f..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2292

Authors: D. Breadner, S. Shanmuganatjan, G. Boldt, P. Blanchette, J. Raphael

Conference PaperKirk SmithOctober 1, 2019ALK, Targeted therapy, advanced NSCLC

EP114-02 Comparative Efficacy of First-Line Ceritinib at a Dose of 450mg with Food and Alectinib in Advanced ALK+ NSCLC

Ceritinib and alectinib were both second generation of ALK inhibitors that approved as first-treatment for ALK+ NSCLC. Ceritinib is initially approved at the recommended dose of 750 mg/day fasted (ceritinib 750-mg fasted). Ceritinib at a dose of 450 mg with food (ceritinib 450-mg fed) compared to ceritinib 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity in the Ascend 8 trial. Although a previous cross-study indirect study compared the efficacy of ceritinib 750-mg fasted with alectinib, the efficacy of ceritinib 450-mg fed compared with alectinib is unknown. Progression-free survival of ceritinib 450-mg fed was indirectly compared with that of alectinib using a Bucher anchor-based indirect comparison approach using ceritinib 750-mg fasted as the common anchor. The comparative efficacy of alectinib vs ceritinib 750-mg fasted was obtained from matching-adjusted indirect comparison(MAIC) and the comparative efficacy of ceritinib 450-mg fed vs ceritinib 750-mg fa..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2287

Authors: F. Liang, D. Shen

Conference PaperKirk SmithOctober 1, 2019ALK, Ceritinib, alectinib]

MA1807 Identification of Neuroendocrine Transformation in Anaplastic Lymphoma Kinase Rearranged (ALK+) Tumors After Tyrosine Kinase Inhibitors

We describe results of a program utilizing routine biopsy post-progression in ALK+ patients for clinical and research purposes.Since 2014, ALK+ lung cancer patients treated at the Princess Margaret Cancer Centre have undergone routine biopsies at disease progression time points upon failure of an ALK-tyrosine kinase inhibitor (TKI) for both clinical purposes and research purposes, in particular to obtain tissue for primary derived xenograft (PDX) engraftment. The study found that routine combined clinical and research biopsy of ALK+ patients at time of TKI failure helped to identify these recent cases of neuroendocrine transformation as a possible mode of resistance and provide tissue for model development. This is the first time that ALK+ transformation to large cell neuroendocrine carcinoma is reported in the literature. (PP, AFF, SNMF, LN contributed equally). READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.651

Authors: P. Pal, A. Fares, D. Patel, E. Stewart, N. Perera-Low, A. Grindley, F. Allison, N. Pham, R. Shi, N. Leighl, F. Shepherd, P. Bradbury, A. Sacher, P. Rogalla, K. Yasufuku, M. Cabanero, M. Tsao, G. Liu, S. Martins-Filho, L. Nguyen

Case StudyKirk SmithOctober 1, 2019Neuroendocrine transformation, Anaplastic lymphoma kinase

P201-35 Acquired MET-Aberrance Is a Mechanism of Resistance to ALK Inhibitors in ALK-Positive Advanced Non-Small-Cell Lung Cancer

Totally 136 ALK-positive advanced NSCLC patients were screened for ALK rearrangement detected by tumor tissue or plasma Next-generation sequencing (NGS) at the Guangdong Lung Cancer Institute from January 2016 to December 2018. MET-aberrance was defined as c-Met overexpression performed by immunohistochemical(IHC) staining method with SP44 antibody and MET amplification assessed by tumor tissue or plasma Next-generation sequencing (NGS) or fluorescent in situ hybridization (FISH)The study found acquired MET-aberrance maybe a mechanism of acquired resistance to the second-generation ALK-TKIs for ALK-rearranged advanced NSCLC patients. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1379

Authors: Q. Deng, J. Kang, H. Wang, J. Yang, H. Yan, Z. Wang

P2.01-31 Preliminary Results of Second Generation ALK Inhibitor PLB1003: A Phase La Study

Crizotinib is initially effective in the treatment of ALK-rearranged NSCLC, but the disease eventually progresses. PLB1003, a high-efficiency second generation ALK inhibitor, was developed due to the increased resistance of EML4-ALK fusion genes. Preclinical data show that PLB1003 is safe and effective in cell-based assays and Crizotinib-resistant animal models. This is the ongoing phase Ia study of PLB1003. An open-label, multicenter phase I clinical trial was conducted in patients with locally advanced or metastatic NSCLC who had previously failed or were intolerable to Crizotinib or chemotherapy. The study result shows PLB1003 is safe, tolerable and has potential clinical benefit to locally advanced or metastatic NSCLC patients with ALK rearrangement mutation and had disease progression or were intolerable to previously treatment of Crizotinib or chemtherapy. (ClinicalTrials.gov number, NCT03130881) READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1375

Authors: B. Han, T. Chu, J. Qian, B. Yan, Y. Zhang, Q. Chang

P118-04 Neoadjuvant Ceritinib for Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement: SAKULA Tria

We conducted a multicenter single-arm phase II study to assess the efficacy and safety of neoadjuvant therapy with ceritinib followed by surgery in patients with ALK-positive resectable locally advanced (LA) NSCLC.Three cycles of ceritinib were administered as induction therapy. The drug was administered orally at the dose 750 mg once daily for 28 days per cycle. The primary endpoint was the major pathological response rate (mpRR). This study required 19 patients, with mpRR of 15% considered non-promising and 45% promising (one-side alpha = 0.025; beta = 0.2). Biomarker analyses using pre- and post-ceritinib through next-generation sequencing (NGS) of plasma and tissue is also planned. (Trial Identifier, UMIN000017906). Our results showed that neoadjuvant ceritinib is safe and effective, with a high rate of pathologic response, in patients with ALK-positive resectable LA-NSCLC, although the limitation of the data interpretation due to small sample size. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/J.JTHO.2019.08.1320

Authors: Y. Zenke, K. Yoh, J. Sakakibara-Konishi, H. Daga, Y. Hosomi, N. Nogami, I. Okamoto, S. Matsumoto, S. Kuroda, M. Wakabayashi, S. Nomura, G. Ishii, A. Sato, M. Tsuboi, K. Goto

P116-46 Genetic Testing Patterns, Treatment Characteristics, and Overall Survival in ALK-Positive Metastatic NSCLC Patients Treated with Ceritinib

This study therefore sought to assess ALK testing patterns, treatment characteristics, and overall survival (OS) in patients with mNSCLC treated with ceritinib in routine practice.87 patients were selected (median age: 53 years). Nearly 56% of patients had been tested for ALK mutation before initiating the first-line therapy (1L); 72% were tested before 2L and 77% before 3L. The most common regimens were cisplatin/pemetrexed (25%) in 1L, crizotinib (28%) in 2L, and ceritinib (35%) in 3L. Over two-thirds (68%) received treatment with at least 2 ALKis. The most commonly observed ALKi sequences were crizotinib followed by ceritinib (52%), ceritinib only (23%), and crizotinib followed by ceritinib followed by alectinib (12%). Median OS (95% CI) from mNSCLC diagnosis was 39 (33.1-50.1) months. Median OS (95% CI) from treatment initiation was 36 (28.2-48.9) months for 1L, 29 (22.1-42.8) months for 2L, and 23 (14.0-40.5) months for 3L. Only slightly more than half of patients with ALK-positi..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1272

Authors: J. Mazieres, M. Ahn, C. Chouaid, A. Kron, J. Wolf, R. Goyal, K. Davis, M. Perrinjaquet, T. Pham, S. Knoll

Conference PaperKirk SmithOctober 1, 2019ALK, metastatic NSCLC, Ceritinib

P116-30 Impact of Patient TKI Copayments on Insurance Expenditure in Advanced EGFR or ALK Positive Non-Small Cell Lung Cancer (NSCLC)

To influence treatment choice and control expenditures, insurance plans impose cost sharing policies for expensive oral tyrosine kinase inhibitors (TKIs). We evaluated the effect of patient TKI copayments on insurance expenditures among patients with EGFR and ALK positive advanced NSCLC receiving TKIs. The results show that higher TKI copayments were not associated with lower insurance expenditures. Eliminating TKI copayments would reduce patient financial burden and not adversely impact insurer spending. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1256

Authors: B. Haddock Lobo Goulart, S. Chennupati, K. Egan, C. Fedorenko, S. Ramsey

Conference PaperKirk SmithOctober 1, 2019Copayment, Insurance, Cost

The Humanistic Burden of ALK+ NSCLC: Findings from the ALKConnect Patient Insight Network and Research Platform

The ALKConnect Patient Insight Network (www.alkconnect.com) is a patient-centered online registry that provides support to and collects information from patients living with Anaplastic Lymphoma Kinase-Positive (ALK+) Non-Small Cell Lung Cancer (NSCLC). The objectives of this study were to: (1) describe the characteristics of patients in ALKConnect; (2) quantify patients’ preferences, ALK+ NSCLC symptom burden, and health-related quality of life (HRQoL); and (3) determine whether disease treatment and employment status were associated with HRQoL.ALKConnect gathered humanistic burden data directly from patients with ALK+ NSCLC. Participants reported that the most burdensome symptoms were fatigue, sleep disturbance, and drowsiness, and that symptoms interfered most with work and general activity. A 3-month delay in cancer progression and HRQoL were important treatment attributes. Patients’ HRQoL was positively associated with ALK TKI treatment and the ability to maintain employment status, suggesting that these aspects may be important for ALK+ NSCLC patients’ well-being. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1254

Authors: H. Lin, X. Pan, A. Biller, K. Covey, H. Huang, V. Rangel Miller, M. Smith, H. West

$P114-57 Post-Ensartinib Outcomes in Refractory Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer (NSCLC)$

P114-57 Post-Ensartinib Outcomes in Refractory Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer (NSCLC)

With the advent of novel ALK inhibitors utilized in sequence, the survival of patients with ALK-rearranged tumors has improved dramatically. This case series serves to compare tumor response rates and long-term survival outcomes among four patients treated with ensartinib over the course of four years at our institution.We found that ensartinib is well tolerated and has clinical activity in advanced ALK-rearranged NSCLC patients with brain metastases, despite previously progressing on crizotinib, with durable post-ensartinib survival on subsequent next-generation ALK inhibitors such as brigatinib and lorlatinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.5455/jpma.3142. PMID: 32296229.

Authors: H. Kim, P. Vu, K. Harrow, C. Liang, G. Selvaggi, E. Weihe, W. Mitchell, L. Bazhenova, S. Patel

Conference PaperKirk SmithOctober 1, 2019NSCLC, ALK, ensartinib

Safety and efficacy of WX-0593 in ALK-positive or ROS1-positive non-small cell lung cancer

WX-0593 is a potent ALK inhibitor against ALK and ROS1 rearrangement and a series of crizotinib (CRZ)-resistant mutants. We explored the safety and efficacy of WX-0593 in patients (pts) diagnosed with ALK+ or ROS-1+ malignancies, including non-small cell lung cancer (NSCLC). READ ARTICLE

Annals of Oncology DOI:https://doi.org/10.1093/annonc/mdz260.007

Authors: Y-K Shi, J. Fang, S. Zhang, Y. Liu, L. Wang, M. Si, M. Ge and H Geng

Conference PaperKirk SmithOctober 1, 2019WX-0593, ALK+, ROS1, clinical trial

P114-53 Co-Occurring CDKN2A/2B Alteration Is Associated with Poorer Survival in ALK-Positive Lung Cancer

We analyzed whether variants or co-occurring mutations influence the outcome of AKL TKI treatment in ALK+ non-small-cell lung cancer (NSCLC). Between March 2017 and October 2018, 489 NSCLC tumor specimens were examined with OncoPanel AMC version3 which is a NGS based assay for the detection of single-nucleotide variants, insertions, deletions, copy number alterations and structural variants across 382 genes. 43 patients were identified as having ALK rearrangement. And 37 patients received ALK TKI treatment. Progression free survival (PFS) and overall survival (OS) were analyzed respectively according to ALK variants and other co-occuring mutations. We found that in ALK+ NSCLC, having co-occurring CDKN2A/2B alteration was associated with a poorer OS when treated with an anti-ALK agent. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1204

Authors: J.Y. Ha, S. Yoon, D.H. Lee, J. Choi, S. Kim

Conference PaperKirk SmithOctober 1, 2019ALK, CDKN2A/2B, TKI

P114-43 A Novel Patient Derived Synchronous Cell Pair with Different Mutations in an ALK-Rearranged Lung Adenocarcinoma Underlines Tumor Heterogeneity

ALK targeted therapy can provide prolonged clinical response rates in ALK-rearranged lung adenocarcinoma (ADC) patients. However, most tumors relapse within a few years of treatment pressure due to a variety of resistance mechanisms, including intratumoral heterogeneity. Understanding these mechanisms is of utmost importance to more precisely tailor future targeted therapies.This study is the first evidence of the synchronous establishment of two highly distinct patient-derived ALK translocated lung ADC cell lines carrying different resistant mutations. This concept supports the paramount significance of spatiotemporal intratumoral heterogeneity under targeted therapy. Furthermore, our findings showed that HDAC inhibition could enhance sensitivity of resistant tumor cells to ALK targeted therapy in vitro. Altogether, our findings provide strong evidence for the synchronous emergence of multiple resistance mechanisms and emphasize the importance of multiple site re-biopsies to better identify acquired resistance mechanisms under targeted therapy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1194

Authors: P. Stockhammer, C.S.L. Ho, A. Bankfalvi T. Plönes, L. Hegedus, M. Schuler, C. Aigner, A. Schramm, B. Hegedus

P114-39 Acquired ALK Rearrangement in EGFR-Mutant Lung Adenocarcinoma Treated with EGFR TKIs

Few studies have been reported on acquired anaplastic lymphoma kinase (ALK) rearrangement in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients with EGFR tyrosine kinase inhibitors (TKIs).EGFR-mutant lung adenocarcinoma patients were screened after resistance to EGFR TKIs from September 2017 to December 2018 at the Guangdong Lung Cancer Institute. Both EGFR mutation and ALK rearrangement were tested by next-generation sequencing (NGS). Acquired ALK rearrangement was defined as positive ALK rearrangement after resistance to EGFR TKIs, but negative result detected by NGS at the baseline of EGFR TKI treatments.The frequency of acquired ALK rearrangement is similar in EGFR-mutant lung adenocarcinomas after resistance to the first-, second-, or third-generation EGFR TKIs. The majority of acquired ALK-fusion partners are non-EML4. Combination of EGFR TKIs and ALK inhibitors might be a strategy to overcome such resistance. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1190

Authors: Q. Wang, R. Chen, J. Kang, H. Chen, B. Wang, Z. Wang, Q. Zhou, Y. Wu, J. Yang

Conference PaperKirk SmithOctober 1, 2019lung adenocarcinoma, ALK rearrangement, EGFR

P114-35 Epithelial-To-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status

ALK rearrangement, most commonly EML4-ALK, is detected in approximately 3%–5% of NSCLC. ALK tyrosine kinase inhibitor (TKI), shows dramatic clinical efficacy, however, almost all patients acquire resistance over time. The most defined mechanism of crizotinib resistance is secondary ALK mutations. A recent study reported that epithelial-to-mesenchymal transition (EMT) and ALK resistance mutation were simultaneously detected in a single tumor lesion in patients with ALK-rearranged lung cancer who were resistant to ALK-TKIs. However, it is still unknown whether ALK-TKI resistant tumor cells combine mesenchymal phenotype with ALK resistance mutation, or each of the mesenchymal type tumor cells and ALK resistance mutation–positive cells coexist in a single lesion. In any of these cases, no therapy for EMT-associated targeted drug resistance has yet been established. Specimens from a patient with ALK-rearranged lung adenocarcinoma who acquired resistance to crizotinib were stained with IHC, ..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1186

Authors: K. Fukuda, S. Takeuchi, S. Arai, S. Nanjo, R. Katayama, K. Takeuchi, M. Nishio, S. Yano

P114-32 Rash and Efficacy in Anaplastic Lymphoma Kinase Positive (ALK+) Non-Small Cell Lung Cancer Patients Treated with Ensartinib

In a phase 1/2 study, ensartinib was generally well tolerated and demonstrated good clinical activity in pts with ALK+ non-small cell lung cancer (NSCLC). This post hoc analysis sought to determine the relationship between ensartinib-related rash and clinical benefit. The study found that ensartinib was associated with mild to moderate rash that was easily managed. Preliminary findings suggest that rash is potentially associated with better clinical benefit with ensartinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1183

Authors: H. Wakelee, K. Reckamp, T. Leal, A. Chiappori, S. Waqar, K. Zeman, J. Neal, C. Liang, K. Harrow, A. Holzhausen, J. Zhou, G. Selvaggi, L. Horn

Conference PaperKirk SmithOctober 1, 2019ALK, rash, clinical benefit, ensartinib