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Click here for Xalkori® (crizotinib) Prescribing Information. Adverse event reporting information can be found at the bottom of the page.

PROFILE 1014 : ALK+ NSCLC

XALKORI is an option for the first-line treatment of ALK-positive advanced NSCLC and the treatment of ROS1-positive advanced NSCLC​​​​​​​.1

PROFILE 1014: First-line XALKORI vs chemotherapy in ALK+ advanced NSCLC2​​​​​​​

Study Design and Endpoints2

PROFILE 1014 is the 1st prospective, randomised Phase III trial to demonstrate superiority of first-line XALKORI over chemotherapy for previously untreated ALK+ advanced NSCLC.2

*ALK status determined using standard ALK break-apart FISH assay.
ALK, anaplastic lymphoma kinase; AUC, area under the curve; BID, twice a day; ECOG, Easter Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EQ-5D, EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D); FISH, Fluorescence in situ hybridisation; IC TTP, intracranial time to progression; IRR, Independent Radiology Review; NSCLC, non-small-cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PO, by mouth; RECIST, Response Evaluation Criteria In Solid Tumours.

Progression Free Survival1,2

XALKORI significantly prolonged median PFS to 10.9 months vs. 7.0 months with chemotherapy.1,2

Kaplan-Meier curve estimating PFS1,2

Objective Response Rate1,2

XALKORI® significantly improved objective response rate vs chemotherapy.1,2

1st-line XALKORI offers your patients a RAPID and DURABLE response compared to chemotherapy.1,2 

  • 1.4 (0.6-9.5) months median time to response vs 2.8 (1.2-8.5) months with chemotherapy
  • 11.3 (8.1-13.8) months duration of response vs 5.3 (4.1-5.8) months with chemotherapy

CNS Metastases2,4

First-line XALKORI is an option for your patients with ALK-positive advanced NSCLC, including those with stable brain metastases.2,4

Quality Of Life2

1st-line XALKORI significantly improved ALK+ advanced NSCLC patients global quality of life and 4 out of the 5 functioning domains from baseline vs. chemotherapy (P<0.001).2

Quality-of-life improvements from baseline (QLQ-C30)2

Overall Survival (OS)3,5

Final Overall Survival (OS) Analysis from PROFILE 10145

Background

The first PROFILE 1014 results were published in 2014 after a median follow-up of 17 months. The study met its primary endpoint showing the superiority of XALKORI to pemetrexed-plus-platinum chemotherapy for progression-free survival, as assessed by independent radiologic review. Median overall survival (OS) was not reached in either group at the time of the first report.2 

Study Objectives

To investigate the secondary endpoints of OS and safety in XALKORI versus pemetrexed-plus-platinum chemotherapy over an additional 3 years of follow-up to the initial PROFILE 1014 results.5

Results

Kaplan-Meier curve estimating OS5

Adapted from Soloman et al 2018.5  aEstimated by Cox proportional hazards regression analysis with adjustment for ECOG PS, race, brain metastases;  b2-sided p-value from the log-rank test stratified by ECOG PS, race, brain metastases.​​​​​​​

  • 4-year OS rates were 56.6% for XALKORI and 49.1% for pemetrexed-plus-platinum chemotherapy (HR: 0.760; 95% CI: 0.548, 1.053; p=0.0978). This difference did not reach statistical significance.5

Although statistical significance was not reached, 84.2% of patients in the chemotherapy arm crossed over to XALKORI as their first subsequent follow-up treatment and 19.2% of patients in the XALKORI arm crossed over to platinum-based chemotherapy.5 The rank-preserving structural failure time model (RPSFTM) was used to adjust for the effect of crossover on OS.

Analysis: OS Adjusted for crossover using RPSFTM3,5

RPSFTM applies a parameter to relate the observed OS to its hypothetical OS, i.e. what would have been observed without crossover to other treatments.

  • Due to randomisation, the hypothetical OS without XALKORI treatment was expected to be the same between two arms, taking into account both the XALKORI randomised treatment phase and the crossover phase.

Hence, the observed survival times for patients who crossed over were corrected to the survival time that would have been observed if there was no crossover.

The use of RPFSTM allows an unbiased estimation of treatment effect on OS as if there was no crossover.

Assumptions:

  • The treatment effect of an experimental treatment received by patients who crossover must be the same as the treatment effect in patients initially randomised to that treatment (“Independent of line of treatment”).
  • The effect of other subsequent systemic therapies on OS is the same between the 2 arms.

Final OS adjusted for crossover by RPSFTM5​​​​​​​

Adapted from Soloman et al 2018.5 aCalculated using the stratified Cox proportional hazards regression approach applied to crossover adjusted data by a parameter derived using the stratification log-rank test and its bootstrap CI.

  • After adjusting for crossover using the RPFSTM, OS in the XALKORI arm was longer than in the chemotherapy arm (HR, 0.346 [95% bootstrap CI, 0.081–0.718]).5

Impact of subsequent therapy on OS: ALK TKI vs treatment other than ALK TKI5

Adapted from Soloman et al 2018.2 Patients who did not receive subsequent therapy after XALKORI or chemotherapy, and patients still on XALKORI treatment at the end of the study are not shown.

Patients who received XALKORI followed by another ALK TKI were found to have a longer OS than those receiving XALKORI followed by any follow-up therapy other than an ALK TKI, as well as those patients who received chemotherapy first-line.5

Conclusions

  • The safety profile for XALKORI was consistent with previously reported PROFILE 1014 data. The most frequent adverse events reported for XALKORI were vision disorder (73.1%), diarrhoea (65.5%), nausea (59.1%) and oedema (52.6%).5
  • The difference in OS between the XALKORI and chemotherapy arm (HR= 0.76; two-sided p= 0.978) did not reach statistical significance. However, after adjusting for crossover using the RPFSTM , OS in the XALKORI arm was longer than in the chemotherapy arm (HR, 0.346 [95% bootstrap CI, 0.081–0.718]).5
  • Patients who received XALKORI followed by another ALK TKI were found to have a longer OS than those receiving XALKORI followed by any follow-up therapy other than an ALK TKI, as well as those patients who received chemotherapy first-line.5
  • The magnitude of OS seen in both treatment arms of this trial is noteworthy for patients with advanced, ALK-positive NSCLC.​​​​​​​5

CI, confidence interval; HR, hazard ratio; ITT, intention to treat; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

Safety

See all Xalkori Safety Information.

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References
  1. XALKORI Summary of Product Characteristics
  2. Solomon BJ, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014:371(23):2167-2177.
  3. Robins JM, et al. Correcting for non-compliance in randomized trials using rank preserving structural failure time models. Commun Stat Theory Methods 1991;20(8):2609-31
  4. Solomon BJ et al. Intracranial Efficacy of Crizotinib Versus Chemotherapy in Patients With Advanced ALK-Positive Non-Small-Cell Lung Cancer: Results From PROFILE 1014. J Clin Oncol. 2016 Aug 20;34(24):2858-65.
  5. Solomon BJ et al. Final overall survival analysis from a study comparing first-line crizotinib with chemotherapy: results from PROFILE 1014, J Clin Oncol 2018. JCO2017774794.
PP-XLK-GBR-1166. March 2021

Indication

XALKORI as a monotherapy is indicated for:1

  • The first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)
  • The treatment of adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)
  • The treatment of adults with ROS1-positive advanced non-small cell lung cancer (NSCLC)

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