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Alice T Shaw - One of the best experts on this subject based on the ideXlab platform.

  • updated overall survival and final progression free survival data for patients with treatment naive advanced alk positive non small cell lung cancer in the alex study
    Annals of Oncology, 2020
    Co-Authors: Tony Mok, Rafal Dziadziuszko, Shirish M Gadgeel, M Perol, Alice T Shaw, R Rosell, D R Camidge, D W Kim, J S Ahn, Walter Bordogna
    Abstract:

    Background The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus Crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients and methods Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or Crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Results Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32–0.58; median PFS 34.8 versus 10.9 months Crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months Crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with Crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). The 5-year OS rate was 62.5% (95% CI 54.3–70.8) with alectinib and 45.5% (95% CI 33.6–57.4) with Crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34–1.00)] and those without [HR 0.76 (95% CI 0.45–1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Conclusions Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over Crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus Crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus Crizotinib in treatment-naive ALK-positive NSCLC. Clinical trials number NCT02075840.

  • alectinib versus Crizotinib in treatment naive anaplastic lymphoma kinase positive alk non small cell lung cancer cns efficacy results from the alex study
    Annals of Oncology, 2018
    Co-Authors: Shirish M Gadgeel, Solange Peters, Tony Mok, M Perol, Silvia Novello, Alice T Shaw, Dongwan Kim, Anna Wrona, R Rosell, A Zeaiter
    Abstract:

    ABSTRACT Background 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. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or Crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib,n = 64; Crizotinib,n = 58), 43 had measurable lesions (alectinib,n = 21; Crizotinib,n = 22), and 46 had received prior radiotherapy (alectinib,n = 25; Crizotinib,n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80,P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus Crizotinib and comparable between patients with and without baseline CNS metastases (P Conclusion 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. Clinical trial registration ClinicalTrials.gov NCT02075840

  • Crizotinib versus chemotherapy in asian patients with alk positive advanced non small cell lung cancer
    Cancer Research and Treatment, 2017
    Co-Authors: Makoto Nishio, Benjamin Solomon, Alice T Shaw, Dongwan Kim, Kazuhiko Nakagawa, Tiziana Usari, Jolanda Paolini, Satoshi Hashigaki, Emiko Ohki, A Polli
    Abstract:

    Purpose Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of Crizotinib in Asian subpopulations of two global phase III trials. Materials and Methods This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of Crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and "as-treated" populations for efficacy and safety endpoints, respectively. Results In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with Crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with Crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with Crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity. Conclusion These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of Crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.

  • alectinib versus Crizotinib in treatment naive advanced alk positive non small cell lung cancer nsclc primary results of the global phase iii alex study
    Journal of Clinical Oncology, 2017
    Co-Authors: Alice T Shaw, Rafal Dziadziuszko, Solange Peters, Tony Mok, Shirish M Gadgeel, M Perol, Dongwan Kim, R Rosell, J S Ahn, A Zeaiter
    Abstract:

    LBA9008Background: Alectinib, a TKI targeting ALK, has shown robust efficacy in Crizotinib-naive/resistant ALK+ NSCLC. J-ALEX showed superiority of alectinib 300mg BID vs Crizotinib in Japanese pts with Crizotinib-naive ALK+ NSCLC (progression-free survival [PFS] HR 0.34, p<0.0001). We report primary results from the ALEX study of first-line alectinib 600mg BID vs Crizotinib in advanced ALK+ NSCLC (NCT02075840). Methods: This open-label randomized multicenter phase III study enrolled pts with stage IIIB/IV ALK+ NSCLC, determined by central IHC testing. Eligible pts had ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC. Pts with asymptomatic CNS metastases were allowed. Pts (n=303) were randomized 1:1 to receive alectinib 600mg or Crizotinib 250mg BID. Primary endpoint: Investigator (Inv)-assessed PFS (RECIST v1.1), with systematic CNS imaging in all pts. Secondary endpoints included independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression (TTP), objective response r...

  • Crizotinib resistance implications for therapeutic strategies
    Annals of Oncology, 2016
    Co-Authors: Ibiayi Dagogojack, Alice T Shaw
    Abstract:

    In 2007, a chromosomal rearrangement resulting in a gene fusion leading to expression of a constitutively active anaplastic lymphoma kinase (ALK) fusion protein was identified as an oncogenic driver in non-small-cell lung cancer (NSCLC). ALK rearrangements are detected in 3%-7% of patients with NSCLC and are particularly enriched in younger patients with adenocarcinoma and a never or light smoking history. Fortuitously, Crizotinib, a small molecule tyrosine kinase inhibitor initially developed to target cMET, was able to be repurposed for ALK-rearranged (ALK+) NSCLC. Despite dramatic and durable initial responses to Crizotinib; however, the vast majority of patients will develop resistance within a few years. Diverse molecular mechanisms underlie resistance to Crizotinib. This review will describe the clinical activity of Crizotinib, review identified mechanisms of Crizotinib resistance, and end with a survey of emerging therapeutic strategies aimed at overcoming Crizotinib resistance.

Dongwan Kim - One of the best experts on this subject based on the ideXlab platform.

  • alectinib versus Crizotinib in treatment naive anaplastic lymphoma kinase positive alk non small cell lung cancer cns efficacy results from the alex study
    Annals of Oncology, 2018
    Co-Authors: Shirish M Gadgeel, Solange Peters, Tony Mok, M Perol, Silvia Novello, Alice T Shaw, Dongwan Kim, Anna Wrona, R Rosell, A Zeaiter
    Abstract:

    ABSTRACT Background 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. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or Crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib,n = 64; Crizotinib,n = 58), 43 had measurable lesions (alectinib,n = 21; Crizotinib,n = 22), and 46 had received prior radiotherapy (alectinib,n = 25; Crizotinib,n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80,P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus Crizotinib and comparable between patients with and without baseline CNS metastases (P Conclusion 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. Clinical trial registration ClinicalTrials.gov NCT02075840

  • final overall survival analysis from a study comparing first line Crizotinib versus chemotherapy in alk mutation positive non small cell lung cancer
    Journal of Clinical Oncology, 2018
    Co-Authors: Benjamin Solomon, Dongwan Kim, Kazuhiko Nakagawa, Tiziana Usari, Tarek Mekhail, Enriqueta Felip, Federico Cappuzzo, Jolanda Paolini, Yiyun Tang, Keith D Wilner
    Abstract:

    Purpose The phase III PROFILE 1014 trial compared Crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) -positive advanced nonsquamous non-small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients and Methods Patients were randomly assigned to receive oral Crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin (area under the concentration-time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to Crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Results Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received Crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Median OS was not reached (NR) with Crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with Crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored Crizotinib (hazard ratio, 0.346; 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in Crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. Conclusion The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non-small-cell lung cancer and highlights the benefit of Crizotinib for prolonging survival in this patient population.

  • Crizotinib versus chemotherapy in asian patients with alk positive advanced non small cell lung cancer
    Cancer Research and Treatment, 2017
    Co-Authors: Makoto Nishio, Benjamin Solomon, Alice T Shaw, Dongwan Kim, Kazuhiko Nakagawa, Tiziana Usari, Jolanda Paolini, Satoshi Hashigaki, Emiko Ohki, A Polli
    Abstract:

    Purpose Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of Crizotinib in Asian subpopulations of two global phase III trials. Materials and Methods This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of Crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and "as-treated" populations for efficacy and safety endpoints, respectively. Results In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with Crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with Crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with Crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity. Conclusion These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of Crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.

  • alectinib versus Crizotinib in treatment naive advanced alk positive non small cell lung cancer nsclc primary results of the global phase iii alex study
    Journal of Clinical Oncology, 2017
    Co-Authors: Alice T Shaw, Rafal Dziadziuszko, Solange Peters, Tony Mok, Shirish M Gadgeel, M Perol, Dongwan Kim, R Rosell, J S Ahn, A Zeaiter
    Abstract:

    LBA9008Background: Alectinib, a TKI targeting ALK, has shown robust efficacy in Crizotinib-naive/resistant ALK+ NSCLC. J-ALEX showed superiority of alectinib 300mg BID vs Crizotinib in Japanese pts with Crizotinib-naive ALK+ NSCLC (progression-free survival [PFS] HR 0.34, p<0.0001). We report primary results from the ALEX study of first-line alectinib 600mg BID vs Crizotinib in advanced ALK+ NSCLC (NCT02075840). Methods: This open-label randomized multicenter phase III study enrolled pts with stage IIIB/IV ALK+ NSCLC, determined by central IHC testing. Eligible pts had ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC. Pts with asymptomatic CNS metastases were allowed. Pts (n=303) were randomized 1:1 to receive alectinib 600mg or Crizotinib 250mg BID. Primary endpoint: Investigator (Inv)-assessed PFS (RECIST v1.1), with systematic CNS imaging in all pts. Secondary endpoints included independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression (TTP), objective response r...

  • first line Crizotinib versus chemotherapy in alk positive lung cancer
    The New England Journal of Medicine, 2014
    Co-Authors: Benjamin Solomon, Tony Mok, Dongwan Kim, Kazuhiko Nakagawa, Tiziana Usari, Tarek Mekhail, Enriqueta Felip, Federico Cappuzzo, Jolanda Paolini, Shrividya Iyer
    Abstract:

    BACKGROUND: The efficacy of the ALK inhibitor Crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS: We conducted an open-label, phase 3 trial comparing Crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral Crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to Crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS: Progression-free survival was significantly longer with Crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with Crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with Crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with Crizotinib and 79% with chemotherapy. The most common adverse events with Crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, Crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS: Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).

Shirish M Gadgeel - One of the best experts on this subject based on the ideXlab platform.

  • updated overall survival and final progression free survival data for patients with treatment naive advanced alk positive non small cell lung cancer in the alex study
    Annals of Oncology, 2020
    Co-Authors: Tony Mok, Rafal Dziadziuszko, Shirish M Gadgeel, M Perol, Alice T Shaw, R Rosell, D R Camidge, D W Kim, J S Ahn, Walter Bordogna
    Abstract:

    Background The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus Crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients and methods Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or Crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Results Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32–0.58; median PFS 34.8 versus 10.9 months Crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months Crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with Crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). The 5-year OS rate was 62.5% (95% CI 54.3–70.8) with alectinib and 45.5% (95% CI 33.6–57.4) with Crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34–1.00)] and those without [HR 0.76 (95% CI 0.45–1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Conclusions Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over Crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus Crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus Crizotinib in treatment-naive ALK-positive NSCLC. Clinical trials number NCT02075840.

  • 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
    Journal of Thoracic Oncology, 2019
    Co-Authors: Ross D Camidge, Rafal Dziadziuszko, Solange Peters, Tony Mok, Johannes Noe, Malgorzata Nowicka, Shirish M Gadgeel, P Cheema, Nick Pavlakis, Filippo De Marinis
    Abstract:

    Abstract Introduction At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus Crizotinib in untreated, anaplastic lymphoma kinase ( ALK )-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34–0.65, p EML4 -ALK ) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017). Methods Patients were randomized to receive twice-daily alectinib, 600 mg, or Crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant. Results Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32–0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with Crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for Crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of Crizotinib), the safety of alectinib compared favorably with that of Crizotinib. Conclusion Alectinib continues to demonstrate superior investigator-assessed PFS versus Crizotinib in untreated ALK -positive NSCLC, irrespective of EML4-ALK variant.

  • 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
    Journal of Thoracic Oncology, 2019
    Co-Authors: Ross D Camidge, Rafal Dziadziuszko, Solange Peters, Tony Mok, Johannes Noe, Malgorzata Nowicka, Shirish M Gadgeel, P Cheema, Nick Pavlakis, Filippo De Marinis
    Abstract:

    Abstract Introduction At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus Crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34–0.65, p Methods Patients were randomized to receive twice-daily alectinib, 600 mg, or Crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant. Results Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32–0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with Crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for Crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of Crizotinib), the safety of alectinib compared favorably with that of Crizotinib. Conclusion Alectinib continues to demonstrate superior investigator-assessed PFS versus Crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.

  • alectinib versus Crizotinib in treatment naive anaplastic lymphoma kinase positive alk non small cell lung cancer cns efficacy results from the alex study
    Annals of Oncology, 2018
    Co-Authors: Shirish M Gadgeel, Solange Peters, Tony Mok, M Perol, Silvia Novello, Alice T Shaw, Dongwan Kim, Anna Wrona, R Rosell, A Zeaiter
    Abstract:

    ABSTRACT Background 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. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or Crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib,n = 64; Crizotinib,n = 58), 43 had measurable lesions (alectinib,n = 21; Crizotinib,n = 22), and 46 had received prior radiotherapy (alectinib,n = 25; Crizotinib,n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80,P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus Crizotinib and comparable between patients with and without baseline CNS metastases (P Conclusion 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. Clinical trial registration ClinicalTrials.gov NCT02075840

  • alectinib versus Crizotinib in treatment naive advanced alk positive non small cell lung cancer nsclc primary results of the global phase iii alex study
    Journal of Clinical Oncology, 2017
    Co-Authors: Alice T Shaw, Rafal Dziadziuszko, Solange Peters, Tony Mok, Shirish M Gadgeel, M Perol, Dongwan Kim, R Rosell, J S Ahn, A Zeaiter
    Abstract:

    LBA9008Background: Alectinib, a TKI targeting ALK, has shown robust efficacy in Crizotinib-naive/resistant ALK+ NSCLC. J-ALEX showed superiority of alectinib 300mg BID vs Crizotinib in Japanese pts with Crizotinib-naive ALK+ NSCLC (progression-free survival [PFS] HR 0.34, p<0.0001). We report primary results from the ALEX study of first-line alectinib 600mg BID vs Crizotinib in advanced ALK+ NSCLC (NCT02075840). Methods: This open-label randomized multicenter phase III study enrolled pts with stage IIIB/IV ALK+ NSCLC, determined by central IHC testing. Eligible pts had ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC. Pts with asymptomatic CNS metastases were allowed. Pts (n=303) were randomized 1:1 to receive alectinib 600mg or Crizotinib 250mg BID. Primary endpoint: Investigator (Inv)-assessed PFS (RECIST v1.1), with systematic CNS imaging in all pts. Secondary endpoints included independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression (TTP), objective response r...

Tony Mok - One of the best experts on this subject based on the ideXlab platform.

  • updated overall survival and final progression free survival data for patients with treatment naive advanced alk positive non small cell lung cancer in the alex study
    Annals of Oncology, 2020
    Co-Authors: Tony Mok, Rafal Dziadziuszko, Shirish M Gadgeel, M Perol, Alice T Shaw, R Rosell, D R Camidge, D W Kim, J S Ahn, Walter Bordogna
    Abstract:

    Background The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus Crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients and methods Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or Crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Results Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32–0.58; median PFS 34.8 versus 10.9 months Crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months Crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with Crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). The 5-year OS rate was 62.5% (95% CI 54.3–70.8) with alectinib and 45.5% (95% CI 33.6–57.4) with Crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34–1.00)] and those without [HR 0.76 (95% CI 0.45–1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Conclusions Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over Crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus Crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus Crizotinib in treatment-naive ALK-positive NSCLC. Clinical trials number NCT02075840.

  • 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
    Journal of Thoracic Oncology, 2019
    Co-Authors: Ross D Camidge, Rafal Dziadziuszko, Solange Peters, Tony Mok, Johannes Noe, Malgorzata Nowicka, Shirish M Gadgeel, P Cheema, Nick Pavlakis, Filippo De Marinis
    Abstract:

    Abstract Introduction At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus Crizotinib in untreated, anaplastic lymphoma kinase ( ALK )-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34–0.65, p EML4 -ALK ) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017). Methods Patients were randomized to receive twice-daily alectinib, 600 mg, or Crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant. Results Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32–0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with Crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for Crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of Crizotinib), the safety of alectinib compared favorably with that of Crizotinib. Conclusion Alectinib continues to demonstrate superior investigator-assessed PFS versus Crizotinib in untreated ALK -positive NSCLC, irrespective of EML4-ALK variant.

  • 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
    Journal of Thoracic Oncology, 2019
    Co-Authors: Ross D Camidge, Rafal Dziadziuszko, Solange Peters, Tony Mok, Johannes Noe, Malgorzata Nowicka, Shirish M Gadgeel, P Cheema, Nick Pavlakis, Filippo De Marinis
    Abstract:

    Abstract Introduction At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus Crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34–0.65, p Methods Patients were randomized to receive twice-daily alectinib, 600 mg, or Crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant. Results Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32–0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with Crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for Crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of Crizotinib), the safety of alectinib compared favorably with that of Crizotinib. Conclusion Alectinib continues to demonstrate superior investigator-assessed PFS versus Crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.

  • alectinib versus Crizotinib in treatment naive anaplastic lymphoma kinase positive alk non small cell lung cancer cns efficacy results from the alex study
    Annals of Oncology, 2018
    Co-Authors: Shirish M Gadgeel, Solange Peters, Tony Mok, M Perol, Silvia Novello, Alice T Shaw, Dongwan Kim, Anna Wrona, R Rosell, A Zeaiter
    Abstract:

    ABSTRACT Background 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. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or Crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib,n = 64; Crizotinib,n = 58), 43 had measurable lesions (alectinib,n = 21; Crizotinib,n = 22), and 46 had received prior radiotherapy (alectinib,n = 25; Crizotinib,n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80,P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus Crizotinib and comparable between patients with and without baseline CNS metastases (P Conclusion 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. Clinical trial registration ClinicalTrials.gov NCT02075840

  • alectinib versus Crizotinib in treatment naive advanced alk positive non small cell lung cancer nsclc primary results of the global phase iii alex study
    Journal of Clinical Oncology, 2017
    Co-Authors: Alice T Shaw, Rafal Dziadziuszko, Solange Peters, Tony Mok, Shirish M Gadgeel, M Perol, Dongwan Kim, R Rosell, J S Ahn, A Zeaiter
    Abstract:

    LBA9008Background: Alectinib, a TKI targeting ALK, has shown robust efficacy in Crizotinib-naive/resistant ALK+ NSCLC. J-ALEX showed superiority of alectinib 300mg BID vs Crizotinib in Japanese pts with Crizotinib-naive ALK+ NSCLC (progression-free survival [PFS] HR 0.34, p<0.0001). We report primary results from the ALEX study of first-line alectinib 600mg BID vs Crizotinib in advanced ALK+ NSCLC (NCT02075840). Methods: This open-label randomized multicenter phase III study enrolled pts with stage IIIB/IV ALK+ NSCLC, determined by central IHC testing. Eligible pts had ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC. Pts with asymptomatic CNS metastases were allowed. Pts (n=303) were randomized 1:1 to receive alectinib 600mg or Crizotinib 250mg BID. Primary endpoint: Investigator (Inv)-assessed PFS (RECIST v1.1), with systematic CNS imaging in all pts. Secondary endpoints included independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression (TTP), objective response r...

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  • final overall survival analysis from a study comparing first line Crizotinib versus chemotherapy in alk mutation positive non small cell lung cancer
    Journal of Clinical Oncology, 2018
    Co-Authors: Benjamin Solomon, Dongwan Kim, Kazuhiko Nakagawa, Tiziana Usari, Tarek Mekhail, Enriqueta Felip, Federico Cappuzzo, Jolanda Paolini, Yiyun Tang, Keith D Wilner
    Abstract:

    Purpose The phase III PROFILE 1014 trial compared Crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) -positive advanced nonsquamous non-small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients and Methods Patients were randomly assigned to receive oral Crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin (area under the concentration-time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to Crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Results Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received Crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Median OS was not reached (NR) with Crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with Crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored Crizotinib (hazard ratio, 0.346; 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in Crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. Conclusion The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non-small-cell lung cancer and highlights the benefit of Crizotinib for prolonging survival in this patient population.

  • final overall survival analysis from a study comparing first line Crizotinib versus chemotherapy in alk mutation positive non small cell lung cancer
    Journal of Clinical Oncology, 2018
    Co-Authors: Benjamin Solomon, Kazuhiko Nakagawa, Tiziana Usari, Tarek Mekhail, Enriqueta Felip, Federico Cappuzzo, Jolanda Paolini, Yiyun Tang, Yilong Wu, Keith D Wilner
    Abstract:

    PurposeThe phase III PROFILE 1014 trial compared Crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) –positive advanced nonsquamous non–small-cell lung cancer. Here, we report the final overall survival (OS) results.Patients and MethodsPatients were randomly assigned to receive oral Crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin (area under the concentration–time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to Crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover.ResultsMedian follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received Crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Medi...

  • Crizotinib versus chemotherapy in asian patients with alk positive advanced non small cell lung cancer
    Cancer Research and Treatment, 2017
    Co-Authors: Makoto Nishio, Benjamin Solomon, Alice T Shaw, Dongwan Kim, Kazuhiko Nakagawa, Tiziana Usari, Jolanda Paolini, Satoshi Hashigaki, Emiko Ohki, A Polli
    Abstract:

    Purpose Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of Crizotinib in Asian subpopulations of two global phase III trials. Materials and Methods This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of Crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and "as-treated" populations for efficacy and safety endpoints, respectively. Results In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with Crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with Crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with Crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity. Conclusion These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of Crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.

  • progression free and overall survival in alk positive nsclc patients treated with sequential Crizotinib and ceritinib
    Clinical Cancer Research, 2015
    Co-Authors: Justin F Gainor, Filippo De Marinis, Daniel Shaoweng Tan, Tomasso De Pas, Benjamin Solomon, Aziah Ahmad, Chiara Lazzari, Gianluca Spitaleri, Katherine Schultz, Luc Friboulet
    Abstract:

    Purpose: Anaplastic lymphoma kinase ( ALK ) rearrangements are important therapeutic targets in non–small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors Crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents. Experimental Design: We identified 73 ALK-positive NSCLC patients treated with Crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on Crizotinib and ceritinib. Results: Among 73 ALK-positive patients, the median PFS (mPFS) on Crizotinib was 8.2 months [95% confidence interval (CI), 7.4–10.6]. The median interval from Crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1–694). The mPFS on ceritinib was 7.8 months (6.5–9.1). Among 53 patients with no interval therapies between Crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4–9.8). The median combined PFS for sequential treatment with Crizotinib and ceritinib was 17.4 months (15.5–19.4). Among 23 patients who underwent post-Crizotinib/pre-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5–63.1). Conclusions: Ceritinib has significant antitumor activity in ALK-positive NSCLC—even when Crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib. Clin Cancer Res; 1–8. ©2015 AACR.

  • first line Crizotinib versus chemotherapy in alk positive lung cancer
    The New England Journal of Medicine, 2014
    Co-Authors: Benjamin Solomon, Tony Mok, Dongwan Kim, Kazuhiko Nakagawa, Tiziana Usari, Tarek Mekhail, Enriqueta Felip, Federico Cappuzzo, Jolanda Paolini, Shrividya Iyer
    Abstract:

    BACKGROUND: The efficacy of the ALK inhibitor Crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS: We conducted an open-label, phase 3 trial comparing Crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral Crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to Crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS: Progression-free survival was significantly longer with Crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with Crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with Crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with Crizotinib and 79% with chemotherapy. The most common adverse events with Crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, Crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS: Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).