Pooled Efficacy and Safety Analysis of the Phase III Studies of Alectinib vs. Crizotinib in Untreated ALK-Positive Non-Small Cell Lung Cancer

Lead Investigator: Marco Tagliamento, IRCCS Ospedale Policlinico San Martino
Title of Proposal Research: Pooled Efficacy and Safety Analysis of the Phase III Studies of Alectinib vs. Crizotinib in Untreated ALK-Positive Non-Small Cell Lung Cancer
Vivli Data Request: 7842
Funding Source: None
Potential Conflicts of Interest: Dr. Tagliamento reports: I report travel grants from Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly and Honoraria as medical writer from Novartis, Amgen. These disclosures refer to more that 2 years ago, and have no connection with the submitted research project.
Dr. Besse reports: Sponsored Research at Gustave Roussy Cancer Center: Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. None related to the current project.
Dr. Hendriks reports: research funding: Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda (all institution, Beigene under negotiation); advisory board: BMS, Eli Lilly, Roche Genentech, Pfizer, Takeda, MSD, Merck, Novartis, Boehringer Ingelheim, Amgen, Janssen (all institution, Roche one time self); speaker: MSD, Lilly, AstraZeneca (institution); travel/conference reimbursement: Roche Genentech (self); mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars/podcast: Benecke, Medtalks, VJOncology (self), high5oncology, Takeda (institution); interview sessions funded by Roche Genentech, Bayer, Lilly (institution); local PI of clinical trials: AstraZeneca, Novartis, BMS, MSD /Merck, GSK, Takeda, Blueprint Medicines, Roche Genentech, Mirati, Abbvie.
These COI are not related to the current project, and anyway will be declared in future publications.
Dr. Lambertini reports: Matteo Lambertini acted as adviser for Roche, AstraZeneca, Eli Lilly, and Novartis; and received honoraria from Takeda, Roche, AstraZeneca, Eli Lilly, Pfizer, Novartis, and Sandoz. None of these conflicts of interest is related to the current project.

Summary of the Proposed Research:
ALK (anaplastic lymphoma kinase) gene gives instructions for coding a protein called ALK tyrosine kinase receptor, that is a cell membrane receptor involved in the regulation of cell growth. Alterations (i.e. rearrangements) of this gene may result in increased growth of the tumor cells. Altered forms of the ALK gene have been found in some types of cancer, including 3-5% of cases of non-small cell lung cancer (NSCLC), and in some anaplastic large cell lymphoma. Patients with tumors harboring such alterations of the ALK gene and protein are highly sensitive to a class of drugs called ALK inhibitors (i.e. ALK tyrosine kinase inhibitors [TKI]). To date, three generations of ALK inhibitors have revolutionized the treatment and the natural history of this disease. Crizotinib, a first-generation ALK TKI, was the first among these drugs to demonstrate to prolong the survival as compared with chemotherapy in patients with pretreated and treatment-naïve ALK-positive metastatic NSCLC. It represented the standard of care, until the development of further-generation ALK inhibitors, like Alectinib, Brigatinib and Ceritinib. These latter became new treatment options, at first as a sequential therapy after disease progression to Crizotinib. Nonetheless, to date Alectinib, Brigatinib and Lorlatinib are available as first line therapy options, after having been compared to Crizotinib in phase 3 studies. They led to increased objective response rate (ORR), intracranial disease control and progression-free survival (PFS) as compared to the first-generation agent. Finally, the third-generation TKI Lorlatinib, first approved at disease progression to second-generation TKIs, has been investigated as first line treatment within the CROWN phase III trial, with impressive results.
In many countries, Alectinib represents the first line standard of care for patients with ALK-positive disease, based on strong efficacy and safety results. To date, no data of comparison between further-generation ALK TKIs are available. Three randomized controlled trials compared Alectininb to Crizotinib: the ALEX trial (NCT02075840), the ALESIA trial (NCT02838420, conducted in Asian population) and the J-ALEX trial (JapicCTI-132316, conducted in Japanese population). To date, an analysis describing efficacy and safety of Alectinib as first line therapy by pooling together the population enrolled in each single trial has not been conducted. In this complex scenario, providing patient-level data about a worldwide used drug, to investigate predictors of activity, would be of great importance when treating a patient with a newly diagnosed ALK-positive metastatic NSCLC.

Requested Studies:
Randomized, Multicenter, Phase III, Open-Label Study of Alectinib Versus Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02075840
Sponsor ID: BO28984

Randomized Phase III Open-Label Study Comparing the Efficacy and Safety of Crizotinib and CH5424802 in ALK-Positive Advanced or Recurrent Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: JO28928
Sponsor ID: JO28928