Brigatinib versus Crizotinib in ALK-Positive Non–Small-Cell Lung Cancer

A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval , 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501.) READ ARTICLE

The New England Journal of Medicine DOI: 10.1056/NEJMoa1810171

Authors: D. Ross Camidge, Hye Ryun Kim, Myung-Ju Ahn, James Chih-Hsin Yang, Ji-Youn Han, Jong-Seok Lee, Maximilian J. Hochmair, Jacky Yu-Chung Li, Gee-Chen Chang, Ki Hyeong Lee, Cesare Gridelli, Angelo Delmonte, Rosario Garcia Campelo, Dong-Wan Kim, Alessandra Bearz, Frank Griesinger, Alessandro Morabito, Enriqueta Felip, Raffaele Califano, Sharmistha Ghosh, Alexander Spira, Scott N. Gettinger, Marcello Tiseo, Neeraj Gupta, Jeff Haney, David Kerstein, Sanjay Popat

Clinical TrialsKirk SmithNovember 1, 2018brigatinib, ALK, crizotinib, non-small cell lung cancer (NSCLC)

Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study

The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advancedALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. READ ARTICLE

Annals of Oncology DOI:10.1093/annonc/mdy405

Authors: S.Gadgeel, S.Peters, T.Mok, A.T.Shaw, D.W.Kim, S.I.Ou, M.Pérol, A.Wrona, S.Novello, R.Rosell, A.Zeaiter, T.Liu, E.Nüesch, B.Balas, D.R.Camidge

Clinical TrialsKirk SmithNovember 1, 2018alectinib, ALK-positive, CNS, non-small cell lung cancer (NSCLC), ALEX

ADAURA: Phase III, Double-blind, Randomized Study of Osimertinib Versus Placebo in EGFR Mutation-positive Early-stage NSCLC After Complete Surgical Resection

Currently, the role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as adjuvant therapy for early-stage non–small-cell lung cancer after complete surgical tumor resection remains under investigation. We present the rationale and study design for the ADAURA (ClinicalTrials.gov identifier, NCT02511106) trial, a multicenter, double-blind, randomized, placebo-controlled study. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2018.04.004

Authors: Yi-LongWu, Roy S. Herbst, Helen Mann, Yuri Rukazenkov, Marcelo Marotti and MasahiroTsuboi

Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer

During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee–assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib).
As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC READ ARTICLE

the New England Journal of Medicine DOI:10.1056/NEJMoa1704795

Authors: Solange Peters, M.D., Ph.D., D. Ross Camidge, M.D., Ph.D., Alice T. Shaw, M.D., Ph.D., Shirish Gadgeel, M.D., Jin S. Ahn, M.D., Dong-Wan Kim, M.D., Ph.D., Sai-Hong I. Ou, M.D., Ph.D., Maurice Pérol, M.D., Rafal Dziadziuszko, M.D., Rafael Rosell, M.D., Ph.D., Ali Zeaiter, M.D., Emmanuel Mitry, M.D., Ph.D., Sophie Golding, M.Sc., Bogdana Balas, M.D., Johannes Noe, Ph.D., Peter N. Morcos, Pharm.D., and Tony Mok, M.D.

Clinical TrialsKirk SmithAugust 31, 2017Alectinib, Crizotinib, ALEX

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3

These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. READ ARTICLE

Lancet DOI: 10.1016/S0140-6736(17)30565-2

Authors: Toyoaki Hida MD, Hiroshi Nokihara MD, Masashi Kondo MD, Young Hak Kim MD, Koichi Azuma MD, Takashi Seto MD, Yuichi Takiguchi MD, Makoto Nishio MD, Hiroshige Yoshioka MD, Fumio Imamura MD, Katsuyuki Hotta MD, Satoshi Watanabe MD, Koichi Goto MD, Miyako Satouchi MD, Toshiyuki Kozuki MD, Takehito Shukuya MD, Kazuhiko Nakagawa MD, Tetsuya Mitsudomi MD, Nobuyuki Yamamoto MD,Takashi Asakawa PhD, Ryoichi Asabe MS, Tomohiro Tanaka MS, Tomohide Tamura MD

Clinical TrialsKirk SmithJuly 1, 2017ALEX Study, alectinib, crizotinib

Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study.

At J-ALEX IA, Alectinib demonstrated significantly prolonged PFS compared with Crizotinib and was well tolerated with a favorable AE profile. READ ARTICLE

Journal of Clinical Oncology DOI: 10.1200/JCO.2016.34.15_suppl.9008

Authors: Hiroshi Nokihara, Toyoaki Hida, Masashi Kondo, Young Hak Kim, Koichi Azuma, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Hiroshige Yoshioka, Fumio Imamura, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Hiroshi Kuriki, Ryoichi Asabe, Tomohiro Tanaka, Tomohide Tamura

Clinical TrialsKirk SmithMay 25, 2016ALEX Study, Crizotinib, alectinib

Phase 3 study of first-line crizotinib vs pemetrexed−cisplatin/carboplatin (PCC) in East Asian patients (pts) with ALK+ advanced non-squamous non-small cell lung cancer (NSCLC).

These results confirm the findings from PROFILE 1014 and demonstrate that first-line crizotinib significantly improves PFS and ORR vs PCC in an East Asian population with ALK+ advanced NSCLC with an acceptable safety profile. Clinical trial information: NCT01639001. READ ARTICLE

Journal of Clinical Oncology DOI: 10.1200/JCO.2016.34.15_suppl.9058

AUTHORS: Shun Lu, Tony Mok, You Lu, Jianying Zhou, Yuankai Shi, Virote Sriuranpong, James C. M. Ho, Choo Khoon Ong, Chun-Ming Tsai, Chin-Hee Chung, Keith D. Wilner, Yiyun Tang, Elizabeth Masters, Paulina Selaru, Yi-Long Wu

Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG)

Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2. READ ARTICLE

Lancet, Oncology DOI:10.1016/S1470-2045(14)70362-6

Authors: Shirish M Gadgeel, Leena Gandhi, Gregory J Riely, Alberto A Chiappori, Howard L West, Michele C Azada, Peter N Morcos, Ruey-Min Lee, Linta Garcia, Li Yu, Frederic Boisserie, Laura Di Laurenzio, Sophie Golding, Jotaro Sato, Shumpei Yokoyama, Tomohiro Tanaka, Sai-Hong Ignatius Ou

Clinical TrialsKirk SmithSeptember 1, 2014Alectinib

Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066

The MTD of PF is 250 mg BID. The major AEs were fatigue or GI-related, and all AEs were manageable and reversible. There was no evidence of non-linear PK at PF doses >100 QD. Treatment with PF-02341066 resulted in promising clinical activity against tumors carrying activating ALK gene rearrangements. Further study of PF in pts with ALK-dependent tumors is warranted. READ ARTICLE

Journal of Clinical Oncology

Authors: E. L. Kwak, D. R. Camidge, J. Clark, G. I. Shapiro, R. G. Maki, M. J. RatainB. Solomon, Y. Bang, S. Ou, R. Salgia

Clinical TrialsKirk SmithMay 1, 2009PF-02341066, crizotinib, ALK inhibitor