Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition

Background ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. Results Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, b..... READ ARTICLE

Clinical Proteomics DOI:10.1186/s12014-020-9269-6

Authors: Couëtoux du Tertre, M., Marques, M., McNamara, S. et al.

Clinical TrialsKirk SmithFebruary 7, 2020Protein signature, Crizotinib, Liquid biopsy, NSCLC, Prediction of response

The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants

Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib. Conclusions: The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers. READ ARTICLE

Advances in Therapy DOI:10.1007/s12325-019-01198-9

Authors: Joseph Chen, Huiping Xu, Sylvester Pawlak, Leonard P. James, Gerson Peltz, Kimberly Lee, Katherine Ginman, Michelle Bergeron & Yazdi K. Pithavala

Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer

Objectives: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17–0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). Conclusions: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues. READ ARTICLE

Lung Cancer. DOI: 10.1016/j.lungcan.2019.11.025

Authors: Kazuhiko Nakagawa, Toyoaki Hida, Hiroshi Nokihara, Masahiro Morise, Koichi Azuma, Young Hak Kim, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Hiroshige Yoshioka, Toru Kumagai, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Miyako Satouchi, Toshiyuki Kozuki, Ryo Koyama, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Takashi Asakawa, Morihiko Hayashi, Wakako Hasegawa, Tomohide Tamura

Clinical TrialsKirk SmithNovember 28, 2019Alectinib, ALK-positive, Crizotinib, J-ALEX, NSCLC, PFS

Final Overall Survival and Other Efficacy and Safety Results From ASCEND-3: Phase II Study of Ceritinib in ALKi-Naive Patients With ALK-Rearranged NSCLC

Introduction: The phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)–naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results. Conclusions: Ceritinib exhibited prolonged and clinically meaningful OS, PFS, and duration of response in chemotherapy-pretreated (at least three lines), ALKi-naive patients with ALK+ NSCLC. The safety profile was consistent with that reported in previous studies. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.006

Authors: Makoto Nishio, Enriqueta Felip, Sergey Orlov, Keunchil Park, Chong-Jen Yu, Chun-Ming Tsai, Manuel Cobo, Mark McKeage, Wu-Chou Su, Tony Mok, Giorgio V. Scagliotti, David R. Spigel, Kalyanee Viraswami-Appanna, Zhe Chen, Vanessa Q. Passos, Alice T. Shaw

Clinical TrialsKirk SmithNovember 25, 2019Ceritinib, ALK, NSCLC, Phase II, ASCEND-3

$Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial$

Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial

Introduction: We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase–positive NSCLC. Conclusions: Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.004

Authors: Rudolf M. Huber, MD, Karin H. Hansen, Luis Paz-Ares Rodríguez, Howard L. West, Karen L. Reckamp, Natasha B. Leighl, Marcello Tiseo, Egbert F. Smit, Dong-Wan Kim, Scott N. Gettinger, Maximilian J. Hochmair, Sang-We Kim, Corey J. Langer, Myung-Ju Ahn, Edward S. Kim, David Kerstein, Harry J.M. Groen, D. Ross Camidge

Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non–Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study

Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients.In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.10.006

Authors: Enriqueta Felip, Filippo G. de Braud, Michela Maur, Herbert H. Loong, Alice Tsang Shaw, Johan F. Vansteenkiste, Thomas John, PGeoffrey Liu, Martijn P. Lolkema, Giovanni Selvaggi, Vanessa Giannone, Pilar Cazorla, Jason Baum, O. Alejandro Balbin, Luojun (Victor) Wang, Yvonne Y. Lau, Jeffrey W. Scott, Daniel Shao-Weng Tan

Clinical TrialsKirk SmithOctober 18, 2019Ceritinib, Nivolumab, ALK, PD-1, NSCLC

Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial

Background: Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored. Interpretation: Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies. READ ARTICLE

The Lancet Respiratory Medicine DOI:10.1016/S2213-2600(19)30252-8

Authors: Yunpeng Yang, Jianya Zhou, Jianying Zhou, Jifeng Feng, Wu Zhuang, Prof Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Prof Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Prof Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Prof Yunpeng Liu, Zhendong Zheng, Prof Gaofeng Li, Prof Ning Wu, Prof Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Prof Li Mao, Giovanni Selvaggi, Xiaobin Yuan, Yuanqing Fu, Tao Wang, Shanshan Xiao, Li Zhang

Pooled overall survival and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small-cell lung cancer

Objectives: A pooled analysis of two open-label phase II studies of alectinib (NP28673 [NCT01801111] and NP28761 [NCT01871805]) demonstrated clinical activity in patients with advanced, anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) previously treated with crizotinib. Longer-term and final pooled analyses of overall survival (OS) and safety data from the two studies are presented here. Conclusion: Updated results from this pooled analysis further demonstrate that alectinib has robust clinical activity and a manageable safety profile in patients with advanced, ALK+ NSCLC pretreated with crizotinib. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.10.015

Authors: Sai-Hong Ignatius Ou, Shirish M. Gadgeel, Fabrice Barlesi, James Chih-Hsin Yang, Luigi De Petris, Dong-Wan Kim, Ramaswamy Govindan, Anne-Marie Dingemans, Lucio Crino, Hervé Léna, Sanjay Popat, Jin Seok Ahn, Eric Dansin, Emmanuel Mitry, Barbara Müller, Walter Bordogna, Bogdana Balas, Peter N. Morcos, Alice T. Shaw

Clinical TrialsKirk SmithOctober 14, 2019Alectinib, ALK+, NSCLC, Overall survival, Pooled analysis, Safety

Patient-reported outcomes from the randomized phase III ALEX study of alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer

Objectives: Alectinib demonstrated superior efficacy and a safety profile that compared favorably with crizotinib in treatment-naïve ALK+ non-small-cell lung cancer (NSCLC) in the phase III ALEX study. We present patient-reported outcomes (PROs) from ALEX to assess disease burden, treatment-related symptom tolerability, and health-related quality of life (HRQoL) with alectinib versus crizotinib. Conclusion: PRO data support the superior efficacy and tolerability of alectinib relative to crizotinib demonstrated in the ALEX study.

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Lung Cancer DOI: 10.1016/j.lungcan.2019.10.002

AUTHORS: Maurice Pérol, Nick Pavlakis, Evgeny Levchenko, Marco Platania, Julio Oliveira, Silvia Novello, Rita Chiari, Teresa Moran, Emmanuel Mitry, Eveline Nüesch, Ting Liu, Bogdana Balas, Krzysztof Konopa, Solange Peters

Clinical TrialsKirk SmithOctober 11, 2019Alectinib, ALK-positive, Crizotinib, NSCLC, Patient-reported outcomes, ALEX

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

LBA81_PR - Phase II/III blood first assay screening trial (BFAST) in patients (pts) with treatment-naïve NSCLC: Initial results from the ALK+ cohort

Background: Tissue-based assessment of actionable mutations in pts with NSCLC is limited by invasive biopsies and adequacy of biopsied tumour material. Blood-based testing may overcome such limitations, allowing multiplex profiling in a single test. BFAST (NCT03178552) is an ongoing multicentre, open-label, multi-cohort study evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations in cell-free DNA, and the activity of targeted therapies and immunotherapy in pts with treatment-naïve advanced NSCLC. We present first results from the ALK+ cohort. Conclusions: Blood-based detection of ALK fusions results in high ORR and clinical benefit in pts receiving alectinib. These data validate the clinical utility of blood-based NGS as an additional method to inform clinical decision-making in ALK+ NSCLC. READ ARTICLE

Annals of Oncology DOI:10.1093/annonc/mdz394.079

Authors: S. M. Gadgeel, T. S. K. Mok, S. Peters, J. A. A. Alexander, N. B. Leighl, V. Sriuranpong, M. Perol, G. De Castro Jr., E. Nadal, F. De Marinis, J.-Y. Han, M. Yan, T. Riehl, E. Schleifman, S. M. Paul, S. Mocci, D. Shames, M. S. Mathisen, R. Dziadziuszko

OA0207 Phase 3 ALUR Study of Alectinib in Pretreated ALK+ NSCLC: Final Efficacy, Safety and Targeted Genomic Sequencing Analyses

The ALUR (NCT02604342) primary analysis (cut-off January 2017) demonstrated improved efficacy and safety with alectinib versus chemotherapy in patients with ALK+ NSCLC previously treated with chemotherapy and crizotinib. These patients can develop crizotinib resistance through ALK secondary mutations, but limited data exist regarding alectinib’s efficacy in patients with different post-crizotinib genetic profiles. We report final data from ALUR including treatment outcomes according to genetic profile. Overall, 119 patients with locally determined ALK+ NSCLC were randomised 2:1 to receive alectinib 600mg bid or chemotherapy (pemetrexed 500mg/m2 or docetaxel 75mg/m2 q3w). The primary endpoint was PFS by investigator. Targeted genomic sequencing (FoundationONE® [tissue; 315 genes] and FoundationACT® [plasma; 62 genes]) was performed retrospectively using tumour tissue (n=33) and baseline plasma (n=59). Final data from ALUR confirm the primary analysis, demonstrating improved efficacy and..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.416

Authors: J. Wolf, Å. Helland, I. Oh, M.R. Migliorino, R. Dziadziuszko, J. De Castro Carpeno, J. Mazieres, F. Griesinger, M. Chlistalla, A. Cardona, T. Ruf, K. Trunzer, V. Smoljanovic, S. Novello

Clinical TrialsKirk SmithOctober 1, 2019ALUR, alectinib, chemotherapy, ALK+ NSCLC, crizotinib

A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas

Background: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers. Conclusions: At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued. READ ARTICLE

British Journal of Cancer DOI:10.1038/s41416-019-0503-9

Authors: Chia-Chi Lin, Hendrik-Tobias Arkenau, Sharon Lu, Jasgit Sachdev, Javier de Castro Carpeño, Monica Mita, Rafal Dziadziuszko, Wu-Chou Su, Dmitri Bobilev, Lorraine Hughes, Jian Chan, Zhi-Yi Zhang, Glen J. Weiss

ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer

Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients.
Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non–small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation–focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status.
We concluded that in patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.18.02236

Authors: Alice T. Shaw, Benjamin J. Solomon, Benjamin Besse, Todd M. Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou, Jill S. Clancy, Sherry Li, Antonello Abbattista, Holger Thurm, Miyako Satouchi, D. Ross Camidge, Steven Kao, Rita Chiari, Shirish M. Gadgeel, Enriqueta Felip, Jean-François Martini

Clinical TrialsKirk SmithMarch 20, 2019ALK, Resistance Mutations, Lorlatinib, Phase 2

Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non–Small Cell Lung Cancer in the Global Phase III ALEX Study

Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant. READ HERE

Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2019.03.007

Authors: D. Ross Camidge, Rafal Dziadziuszko, Solange Peters, Tony Mok,Johannes Noe, Malgorzata Nowicka, Shirish M. Gadgeel, Parneet Cheema, MD, Nick Pavlakis, Filippo de Marinis, Byoung Chul Cho, Li Zhang, Denis Moro-Sibilot, Ting Liu, Walter Bordogna, Bogdana Balas, Barbara Müller,Alice T. Shaw

Clinical TrialsKirk SmithMarch 1, 2019ALEX Study, alectinib, ALK variants

Renal Effects of Crizotinib in Patients With ALK-Positive Advanced NSCLC

Introduction: We retrospectively analyzed the effects of crizotinib on serum creatinine and creatinine-based estimated glomerular filtration rate (eGFR) in patients with anaplastic lymphoma kinase–positive advanced NSCLC across four trials (NCT00585195, NCT00932451, NCT00932893, and NCT01154140). Conclusions: Crizotinib resulted in a decline in creatinine-based estimates of renal function mostly over the first 2 weeks of treatment. However, there was minimal evidence of cumulative effects with prolonged treatment and these changes were largely reversible following treatment discontinuation, consistent with previous reports suggesting this may be predominantly an effect on creatinine secretion as opposed to true nephrotoxicity. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.02.015

Authors: D. Ross Camidge, Elizabeth E. Kim, Tiziana Usari, Anna Polli,Iona Lewis and Keith D. Wilner

Safety and effectiveness of alectinib in a real-world surveillance study in patients with ALK-positive non–small-cell lung cancer in Japan

We conducted a large-scale surveillance study as a post–marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non–small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (al..... READ ARTICLE

Cancer Science
DOI:10.1111/cas.13977

Authors: Noriyuki Masuda,Yuichiro Ohe,Akihiko Gemma,Masahiko Kusumoto,Ikuyo Yamada,Tadashi Ishii,Nobuyuki Yamamoto

Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non–Small Cell Lung Cancer and Brain Metastases in Two Clinical Trials

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor–naive ALK-positive non–small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events). Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.20.00505

Authors: D. Ross Camidge, Dong-Wan Kim, Marcello Tiseo, Corey J. Langer, Myung-Ju Ahn,
Alice T. Shaw, Rudolf M. Huber, Maximilian J. Hochmair, Dae Ho Lee,
Lyudmila A. Bazhenova, Kathryn A. Gold, Sai-Hong Ignatius Ou, Howard L. West,
William Reichmann, Jeff Haney, Tim Clackson, David Kerstein, and Scott N. Gettinger

Clinical TrialsKirk SmithDecember 1, 2018crizotinib, brigatinib, ALTA-1L

Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study

Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. In this phase 2 study, we aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.
Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. READ ARTICLE

The Lancet Oncology DOI:10.1016/S1470-2045(18)30649-1

Authors: Benjamin J Solomon, Benjamin Besse, Todd M Bauer, Enriqueta Felip, Ross A Soo, D Ross Camidge, Rita Chiari, Alessandra Bearz, Chia-Chi Lin, Shirish M Gadgeel, Gregory J Riely, Eng Huat Tan, Takashi Seto, Leonard P James, Jill S Clancy, Antonello Abbattista, Jean-François Martini, Joseph Chen, Gerson Peltz, Holger Thurm, Sai-Hong Ignatius Ou, Alice T Shaw

Clinical TrialsKirk SmithDecember 1, 2018ALK, lorlatinib, CNS