On August 21, 2018 AstraZeneca reported that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved Tagrisso (osimertinib) for the 1st-line treatment of patients with inoperable or recurrent epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), following priority review (Press release, AstraZeneca, AUG 21, 2018, View Source [SID1234529010]). The approval is based on results from the global Phase III FLAURA trial which included Japanese patients and which were published in the New England Journal of Medicine.

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Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit, said: "Tagrisso is already approved in Japan for the treatment of patients with EGFR T790M mutation-positive inoperable or recurrent NSCLC that is resistant to existing 1st-line EGFR-inhibitor medicines. Today’s approval moves the use of Tagrisso to the 1st-line setting, replacing older medicines which, given the high prevalence of the EGFR mutation in Japan, offers an important new treatment option for these patients."

The FLAURA trial compared Tagrisso to current 1st-line EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib in previously-untreated patients with locally-advanced or metastatic EGFR-mutated (EGFRm) NSCLC. In the trial, Tagrisso demonstrated superior progression-free survival (PFS) of 18.9 months compared with 10.2 months for the comparator arm (see table below), and this benefit was consistent across all subgroups including in patients with or without central nervous system (CNS) metastases, an important benefit for lung cancer patients.

FLAURA trial efficacy results according to investigator assessment

Safety data for Tagrisso in the FLAURA trial were in line with those observed in prior clinical trials. Tagrisso was generally well tolerated, with Grade 3 or higher adverse events (AEs) occurring in 34% of patients taking Tagrisso and 45% in the comparator arm. The most common adverse reactions in patients treated with Tagrisso were rash/acne (54.5%), diarrhoea (49.5%), dry skin/eczema (33.3%) and nail disorder including paronychia (32.6%) (at the time of supplementary approval).

Tagrisso has now received approval in 40 countries for the 1st-line treatment of patients with metastatic EGFRm NSCLC, including the US, Japan and in Europe. Other global health authority reviews and submissions are ongoing.

About EGFRm NSCLC

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths, more than breast, prostate and colorectal cancers combined. Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC), with 80-85% classified as NSCLC. Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC. These patients are particularly sensitive to treatment with EGFR-TKIs which block the cell-signalling pathways that drive the growth of tumour cells. Approximately 25% of patients with EGFRm NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than 8 months.

About Tagrisso

Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR T790M-resistance mutations, with clinical activity against CNS metastases. Tagrisso 40mg and 80mg once-daily oral tablets have now received approval in 40 countries, including the US, Japan and in Europe, for 1st-line EGFRm advanced NSCLC, and more than 75 countries, including the US, Japan, China and in Europe, for 2nd-line use in patients with EGFR T790M mutation-positive advanced NSCLC. Tagrisso is also being developed in the adjuvant setting (ADAURA), in the locally-advanced unresectable setting (LAURA), and in combination with other treatments.

About the FLAURA trial

The FLAURA trial assessed the efficacy and safety of Tagrisso 80mg orally once daily vs. standard-of-care EGFR-TKIs (either erlotinib [150mg orally, once daily] or gefitinib [250mg orally, once daily]) in previously-untreated patients with locally-advanced or metastatic EGFRm NSCLC. The trial was double-blinded and randomised, with 556 patients across 29 countries.

On August 21, 2018 Kyowa Hakko Kirin Co., Ltd. (Tokyo: 4151 President and COO: Masashi Miyamoto; "Kyowa Hakko Kirin") reported that it has obtained the partial change approval for POTELIGEO* (code name: KW-0761; generic name: mogamulizumab) from the Ministry of Health, Labor and Welfare in Japan (Press release, Kyowa Hakko Kirin, AUG 21, 2018, View Source [SID1234529005]). The approved partial change includes removing the requirement for pre-treatment diagnostic testing, and changing the dosage and administration in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL)*

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The approval is based on data from the MAVORIC (Mogamulizumab anti-CCR4 Antibody Versus ComparatOR In CTCL) study, the largest global randomized clinical trial of systemic therapy in CTCL. In the MAVORIC study, identification of CCR4 positive cells in patients before enrollment into the study was not required and the enrolled patients were treated with mogamulizumab 1.0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles. With the partial change approval, the requirement for diagnostic testing for CCR4 expression will be unnecessary and the dosage schedule will be changed for CTCL in Japan.

"With this approval, I believe POTELIGEO is more helpful for patients with relapsed or refractory cutaneous T-cell lymphoma and healthcare professionals in Japan," said Mitsuo Satoh Ph.D., Executive Officer, Vice President Head of R&D Division of Kyowa Hakko Kirin, "Kyowa Hakko Kirin is dedicated to using advanced science and research methodologies to contribute to patients with unmet medical needs."

On August 8, POTELIGEO was approved for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy by the U.S. Food and Drug Administration (FDA). The marketing authorization application for mogamulizumab is currently under review by the European Medicines Agency (EMA) in Europe. The Kyowa Hakko Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

About CTCL (Cutaneous T-cell Lymphoma)
CTCL is a rare type of non-Hodgkin’s T-cell lymphoma. The two most common types of CTCL are mycosis fungoides (MF) and Sézary syndrome (SS), and depending on the stage, the disease may involve skin, blood, lymph nodes, and viscera. In advanced stage CTCL is associated with significant morbidity and mortality.

About POTELIGEO (KW-0761)
News Release
POTELIGEO is a humanized monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4), which is frequently expressed on leukemic cells of certain hematologic malignancies including CTCL (cutaneous T-cell lymphoma). POTELIGEO was produced using Kyowa Hakko Kirin’s proprietary POTELLIGENT platform, which is associated with enhanced antibody-dependent cellular cytotoxicity (ADCC). It was approved first in japan for treatment of relapsed or refractory CCR4 positive adult T cell lymphoma (ATL) in March 2012 (brand name: POTELIGEO). In addition, mogamulizumab received approvals in Japan for an additional indication for relapsed or refractory CCR4-positive peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) in March 2014 and for chemotherapy-naïve CCR4-positive adult T-cell leukemia-lymphoma (ATL) in December 2014.

About MAVORIC
MAVORIC is a Phase 3 open-label, multi-centre, randomized study of mogamulizumab versus Vorinostat, active comparator in patients with CTCL who have failed at least one prior systemic treatment. The study was the largest comparative trial in patients with CTCL conducted in the US, Europe, Japan and Australia, and randomized 372 patients.

On August 20, 2018 Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapies against cancers and infectious diseases, reported the completion of the transactions signed with Tasly Biopharmaceuticals. Co. Ltd. ("Tasly Biopharmaceuticals") on July 10, 2018 (Press release, Transgene, AUG 20, 2018, View Source [SID1234621825]). These agreements demonstrate the significant potential of the novel oncolytic virus TG6002 and the chronic hepatitis B therapeutic vaccine TG1050, on which the regional products T6011 and T1011 are based. T601 and T101 are now being developed by Tasly Biopharmaceuticals for patients in Greater China2.

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All closing conditions including completion of the administrative transfer of the assets contributed by Transgene to Tasly Biopharmaceuticals have been completed and 27.4 million newly-issued shares of Tasly Biopharmaceuticals valued at $48 million have been delivered to Transgene.

As a result of the transactions, Transgene holds approximately 2.53% of the outstanding capital of Tasly Biopharmaceuticals, which announced its intention to float on the Hong Kong Stock Exchange. Tasly Biopharmaceuticals controls all research, development and commercial rights to T601 and T101 in Greater China.

Transgene continues to develop TG6002 and TG1050 outside of Greater China.

The details of the transactions are described in the press release distributed on July 10, 2018.

On August 20, 2018 Cellectar Biosciences (Nasdaq: CLRB), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported that data from Cohort 5 of the company’s ongoing Phase 1b clinical trial evaluating CLR 131 for the treatment of relapsed/refractory (R/R) multiple myeloma (MM) (Press release, Cellectar Biosciences, AUG 20, 2018, View Source [SID1234529088]).

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Unlike prior cohorts that used single doses of CLR 131, Cohort 5 utilized a fractionated two-dose regimen of 15.625 mCi/m2 given approximately one week apart. This dosing schedule provides higher average drug exposure but lower peak serum levels than non-fractionated dosing potentially reducing adverse events and improving efficacy. The independent Data Monitoring Committee (DMC) determined the fractionated dose used in Cohort 5 to be safe and well tolerated and recommended advancement to a higher dose cohort.

Results from Cohort 5 indicate enhanced tolerability and safety in comparison to Cohort 4 despite an 18% increase in total average dose from 55.29 mCi to 65.15 mCi of CLR 131. Patients in Cohort 5 required less supportive care such as transfusions of platelets or packed red blood cells than seen in previous cohorts. Based on the results and DMC recommendation, the company plans to initiate a sixth cohort using a fractionated dose regimen of two doses of 18.75 mCi/m2 administered one week apart and to modify the dosing regimen of its ongoing Phase 2 trial of R/R hematologic malignancies to use fractionated dosing.

In addition to the improved safety profile demonstrated in Cohort 5, the company also monitored signals of efficacy. Despite Cohort 5 patients averaging 5 lines of prior systemic therapies, all patients experienced clinical benefit with two patients achieving minimal responses and two stable disease. Furthermore, looking at surrogate markers, patients in Cohort 5 monitored by M-protein showed a nearly 50% further reduction in M-protein than seen in Cohort 4.

"We are encouraged with the potential for improving the CLR 131 profile with the fractionated dose regimen. These results point to the promise of this dosing strategy to increase efficacy and improve clinical outcomes," said James Caruso, president and chief executive officer of Cellectar Biosciences. "In the fight against cancer, dose-limiting toxicities are a critical challenge to achieving therapeutic efficacy. We believe the fractionated dose regimen and our targeted drug delivery may overcome this challenge and we plan to incorporate it into current and future trial designs."

About Phospholipid Drug Conjugates

Cellectar’s product candidates are built upon a patented delivery and retention platform that utilizes optimized phospholipid ether-drug conjugates (PDCs) to target cancer cells. The PDC platform selectively delivers diverse oncologic payloads to cancerous cells and cancer stem cells, including hematologic cancers and solid tumors. This selective delivery allows the payloads’ therapeutic window to be modified, which may maintain or enhance drug potency while reducing the number and severity of adverse events. This platform takes advantage of a metabolic pathway utilized by all tumor cell types in all cell cycle stages. Compared with other targeted delivery platforms, the PDC platform’s mechanism of entry does not rely upon specific cell surface epitopes or antigens. In addition, PDCs can be conjugated to molecules in numerous ways, thereby increasing the types of molecules selectively delivered. Cellectar believes the PDC platform holds potential for the discovery and development of the next generation of cancer-targeting agents.

About CLR 131

CLR 131 is Cellectar’s investigational radioiodinated PDC therapy that exploits the tumor-targeting properties of the company’s proprietary phospholipid ether (PLE) and PLE analogs to selectively deliver radiation to malignant tumor cells, thus minimizing radiation exposure to normal tissues. CLR 131 is in a Phase 2 clinical study in R/R MM and a range of B-cell malignancies and a Phase 1b clinical study in patients with R/R MM exploring fractionated dosing. The objective of the multicenter, open-label, Phase 1b dose-escalation study is the characterization of safety and tolerability of CLR 131 in patients with R/R MM. Patients in Cohorts 1-4 received single doses of CLR 131 ranging from 12.5 mCi/m2 to 31.25 mCi/m2. All study doses have been deemed safe and well tolerated by an independent Data Monitoring Committee. The company is currently initiating a Phase 1 study with CLR 131 in pediatric solid tumors and lymphoma, and is planning a second Phase 1 study in combination with external beam radiation for head and neck cancer.

On August 20, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the China National Drug Administration (CNDA) has granted marketing authorisation for Alecensa (alectinib) as a monotherapy treatment for patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC) (Press release, Hoffmann-La Roche, AUG 20, 2018, View Source [SID1234529063]). The approval follows priority review of Alecensa in China and has been granted just eight and nine months after European Medicines Agency (EMA) and US Food and Drug Administration (FDA) approvals, respectively.

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"Today’s approval marks a new era for ALK-positive lung cancer patients in China, who now have a treatment option that offers a meaningful, sustained benefit compared with the previous standard of care," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "It also represents a significant regulatory shift, with the approval received under unprecedented timelines. We are proud to be at the forefront of healthcare innovation in China by helping to bring Alecensa to patients as quickly as possible."

The approval is based on primary analyses from the pivotal global phase III ALEX study, assessing Alecensa versus crizotinib in the first-line treatment of people with ALK-positive metastatic (advanced) NSCLC, the pharmacokinetics results in Asian patients from the phase III ALESIA study, also investigating Alecensa compared to crizotinib in the first-line setting, and two phase II studies assessing Alecensa in patients who have progressed on or are intolerant to crizotinib.

In updated analyses of the phase III ALEX study presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, the primary endpoint of investigator assessed progression-free survival (PFS) was more than tripled in people who received Alecensa compared to those who received crizotinib (34.8 months [95% CI: 17.7 months-NE) versus 10.9 months [95% CI 9.1-12.9 months]) as assessed by the investigator.1

Further supporting the use of Alecensa in this setting, the phase III ALESIA study, which met its primary endpoint and showed that Alecensa as an initial (first-line) treatment significantly reduced the risk of disease worsening or death (PFS) compared to crizotinib in Asian patients with ALK-positive NSCLC, will be submitted to the CNDA to complete a post-approval agreement.2 This is the third phase III study to show that Alecensa was superior as an initial treatment compared to crizotinib in this type of lung cancer.2 Full results from the ALESIA study will be presented at an upcoming medical meeting.
Unlike in western countries, lung cancer incidence rates have continued to rise in China, and the disease is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths.3NSCLC is the most common form of lung cancer, with ALK-positive NSCLC, a distinct form, commonly affecting younger people (median age 52), and those with a light or non-smoking history.3,4 Approximately 5% of NSCLC cancer cases are ALK-positive, with around 75,000 people diagnosed with ALK-positive NSCLC every year.5-7

Alecensa is now approved in over 57 countries around the world as an initial (first-line) treatment for ALK-positive advanced NSCLC, including the US, Europe and Japan. It was approved by the FDA and the EMA in November and December 2017, respectively.

About the ALEX study8
ALEX (NCT02075840/B028984) is a randomised, multicentre, open-label, phase III study evaluating the efficacy and safety of Alecensa versus crizotinib in treatment-naïve people with ALK-positive NSCLC whose tumours were characterised as ALK-positive by the VENTANA ALK (D5F3) CDx Assay, a companion immunohistochemistry (IHC) test developed by Roche Tissue Diagnostics. People were randomised (1:1) to receive either Alecensa or crizotinib. The primary endpoint of the ALEX study was PFS as assessed by the investigator, and secondary endpoints included: Independent Review Committee (IRC)-assessed PFS, time to CNS progression, objective response rate (ORR), duration of response (DOR) and overall survival (OS). The multicentre study was conducted in 303 people across 161 sites in 31 countries. OS data are currently considered immature with only about a third of events being reported.

Primary data from the ALEX study were presented at the 2017 ASCO (Free ASCO Whitepaper) Annual Meeting, and were published in the New England Journal of Medicine, with key results showing: 9,10

Alecensa reduced the risk of disease worsening or death (PFS) by 53% compared to crizotinib (HR=0.47, 95% CI: 0.34‒0.65, p<0.0001).
Investigator-reported median PFS (the primary endpoint) was not yet reached in the Alecensa arm (95% CI: 17.7‒not reached) versus 11.1 months (95% CI: 9.1‒13.1 months) in the crizotinib arm.
IRC-reported median PFS (a secondary endpoint) was 25.7 months (95% CI: 19.9‒not reached) in the Alecensa arm versus 10.4 months (95% CI: 7.7‒14.6 months) in the crizotinib arm (HR=0.50, 95% CI: 0.36‒0.70; p<0.0001).
Alecensa reduced the risk of progression in the CNS by 84% (HR=0.16, 95% CI: 0.10‒0.28; p<0.0001).
The 12-month cumulative rate of CNS progression for people with or without existing CNS metastases at baseline was 9.4% (95% CI: 5.4‒14.7%) for people treated with Alecensa and 41.4% (95% CI: 33.2‒49.4%) for people treated with crizotinib.
Overall survival (OS) data were considered immature with only about a quarter of events being reported.
Grade 3‒5 adverse events (AEs) were less frequent in the Alecensa arm (41%) compared to the crizotinib arm (50%). In the Alecensa arm, the most common Grade 3‒5 AEs (≥5%) were increased liver enzymes (alanine transferase and aspartate transferase; 5%) and decreased red blood cells (anaemia; 5%). AEs leading to discontinuation (11% vs. 13%), dose reduction (16% vs. 21%) and dose interruption (19% vs. 25%) were all lower in the Alecensa arm compared to the crizotinib arm.
Follow-up results from the ALEX study analysis were presented at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting, and showed:1

After a further 10 months of follow-up, Alecensa reduced the risk of disease progression or death (PFS) by 57% compared to crizotinib (HR=0.43, 95% CI: 0.32‒0.58). Median follow-up was 27.8 months versus 22.8 months for Alecensa-treated patients and crizotinib-treated patients, respectively.
Investigator-reported median PFS (the primary endpoint) was 34.8 months in the Alecensa arm (95% CI: 17.7‒NE) versus 10.9 months (95% CI: 9.1‒12.9 months) in the crizotinib arm.
ORR for people treated with Alecensa was 82.9% (95% CI: 75.95-88.51) compared to 75.5% (95% CI: 67.84‒82.12) for people treated with crizotinib, as assessed by the investigator.
Alecensa demonstrated superior efficacy compared to crizotinib regardless of the presence or absence of CNS metastases at baseline. Investigator-assessed median PFS for people without CNS metastases at baseline was 34.8 months with Alecensa (95% CI: 22.4‒NE) versus 14.7 months (95% CI: 10.8‒20.3) with crizotinib (HR=0.47, 95% CI: 0.32‒0.71). Investigator-reported median PFS for people with CNS metastases at baseline was 27.7 months in the Alecensa arm (95% CI: 9.2‒NE) versus 7.4 months (95% CI: 6.6‒9.6) in the crizotinib arm (HR=0.35, 95% CI: 0.22‒0.56).
Improvements were observed in the time between first response to treatment and disease worsening (DOR): 33.3 months with Alecensa versus 11.1 months with crizotinib.
Grade 3-5 AEs were less frequent in the Alecensa arm (44.7%) compared to the crizotinib arm (51.0%). The most common Grade 3-4 AEs were increased liver enzymes (aspartate transaminase; 5.5%, and alanine transaminase; 4.6%) and increased muscle enzymes (creatine phosphokinase; 3.3%). Serious adverse reactions reported in ≥ 2% of people treated with Alecensa were acute kidney injury (2.6%) and decreased red blood cells (anaemia; 2.0%).
AEs leading to dose reduction (16.4% vs. 20.5%) and dose interruption (22.4% vs. 25.2%) were lower in the Alecensa arm compared with the crizotinib arm. AEs leading to discontinuation were equal in both arms (13.2%).
About the ALESIA study11
ALESIA (NCT02838420) is a randomised, multicentre, open-label phase III study evaluating the efficacy and safety of Alecensa versus crizotinib, and the pharmacokinetics of Alecensa in Asian patients with treatment-naive ALK-positive advanced NSCLC. Patients were randomised (2:1) to receive either Alecensa or crizotinib. The primary endpoint of the ALESIA study is PFS as assessed by the investigator using the RECIST v1.1 criteria. Secondary endpoints include: IRC-assessed PFS, ORR, DOR, time to CNS progression, OS, health-related quality of life (HRQoL) and safety. The multicentre study was conducted in 187 patients across 27 sites in three countries.

About Alecensa
Alecensa (RG7853/AF-802/RO5424802/CH5424802) is a highly selective, CNS active, oral medicine created at Chugai Kamakura Research Laboratories and is being developed for people with NSCLC whose tumours are identified as ALK-positive. ALK-positive NSCLC is often found in younger people who have a light or non-smoking history.4 It is almost always found in people with a specific type of NSCLC called adenocarcinoma.4 Alecensa is now approved in over 57 countries as an initial (first-line) treatment for ALK-positive, metastatic NSCLC, including in the United States, Europe, Japan, China, Turkey, Cuba, Peru, Thailand, Australia, the Dominican Republic, India, Israel, Paraguay, Switzerland, Bolivia, Serbia, South Korea, Singapore and Argentina. In addition, Alecensa is approved in the US, Europe, Japan, Kuwait, Israel, Hong Kong, Canada, South Korea, Switzerland, India, Bolivia, Australia, Singapore, Taiwan, Thailand, Liechtenstein, Argentina, United Arab Emirates, Saudi Arabia, Peru, New Zealand, Cuba, the Dominican Republic, Qatar, Oman, Serbia, Paraguay, Turkey and China for the treatment of people with advanced (metastatic) ALK-positive NSCLC whose disease has worsened after, or who could not tolerate treatment with, crizotinib.