NCT02737501: ALTA-1L

ALTA-1L Study: A Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase Positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC) Participants

Completed Phase 3 Results posted Last updated 20 August 2021

What this trial tests

Phase 3 trial testing Brigatinib in Non-small Cell Lung Cancer in 275 participants. Completed in 29 January 2021.

Timeline

26 May 2016

Primary endpoint
28 July 2020

29 January 2021

Quick facts

Lead sponsor	Ariad Pharmaceuticals
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	275
Start date	26 May 2016
Primary completion	28 July 2020
Estimated completion	29 January 2021
Sites	91 locations across Hong Kong, Italy, Taiwan, South Korea, Denmark, Netherlands, Sweden, United States

Drugs / interventions tested

• Brigatinib (brigatinib) — full drug profile →
• Crizotinib (crizotinib) — full drug profile →

Conditions studied

• Non-small Cell Lung Cancer — all drugs for Non-small Cell Lung Cancer →
• Lung Cancer — all drugs for Lung Cancer →
• Advanced Malignancies — all drugs for Advanced Malignancies →
• Carcinoma — all drugs for Carcinoma →

Sponsor

Ariad Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with Non-small Cell Lung Cancer or Lung Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Progression-free Survival (PFS) Primary · Up to end of study (Up to 56 months)

PFS as assessed by Blinded Independent Review Committee (BIRC), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was defined as the time interval from the date of randomization until the date of the first documented PD event. The data was censored for participants without a PFS event.

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	24.016	18.46 – 43.20
Randomized Phase: Crizotinib 250 mg BID	11.072	9.13 – 13.01
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	16.821	10.12 – 23.85

Confirmed Objective Response Rate (ORR) Secondary · Baseline up to end of treatment (Up to 36 months)

ORR was defined as percentage of participants who achieved Complete response (CR) or Partial responses (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1 criteria. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to less than (\<) 10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in SLD of target lesions, taking as reference baseline

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	74.5	66.30 – 81.52
Randomized Phase: Crizotinib 250 mg BID	62.3	53.68 – 70.42
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	56.9	44.04 – 69.15

Confirmed Intracranial ORR (iORR) Secondary · Baseline up to end of treatment (Up to 36 months)

ORR was defined as percentage of participants who achieved CR or PR in the central nervous system (CNS) in randomized participants with intracranial CNS metastasis at baseline. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	66.0	50.69 – 79.14
Randomized Phase: Crizotinib 250 mg BID	14.3	5.94 – 27.24
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	35.7	21.55 – 51.97

Intracranial Progression Free Survival Secondary · Baseline up to end of study (Up to 56 months)

Intracranial PFS as assessed by BIRC, is defined as the time from randomization until first CNS PD is documented, or death due to any cause. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	23.951	12.91 – 30.78
Randomized Phase: Crizotinib 250 mg BID	5.520	3.71 – 7.52
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	24.542	12.58 – NA

Overall Survival (OS) Secondary · Baseline up to end of study (Up to 56 months)

Overall survival is defined as the time from randomization until death due to any cause.

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	NA	NA – NA
Randomized Phase: Crizotinib 250 mg BID	NA	NA – NA
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	35.023	30.42 – NA

Duration of Response (DOR) Secondary · Baseline up to end of study (Up to 56 months)

Duration of response as assessed by BIRC, is defined as the time interval from the date that the criteria are first met for CR/PR (whichever is first recorded) until the first date that progressive disease (PD) is objectively documented. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30 % decrease in the SLD of target le

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	33.150	1.84 – 50.60
Randomized Phase: Crizotinib 250 mg BID	13.832	1.45 – 49.81
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	19.154	1.97 – 33.15

Time to Response (TTR) Secondary · Baseline up to end of treatment (Up to 36 months)

Time to response as assessed by BIRC, assessment and is defined as the time interval from the date of randomization until the initial observation of CR or PR. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	1.840	1.02 – 29.47
Randomized Phase: Crizotinib 250 mg BID	1.873	0.79 – 7.43
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	1.873	0.20 – 18.33

Disease Control Rate (DCR) Secondary · Baseline up to end of treatment (Up to 36 months)

Disease control as assessed by BIRC, defined as percentage of randomized participants who have achieved CR, PR, or stable disease (SD) after randomization. CR defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR: at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to quali

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	85.4	78.36 – 90.85
Randomized Phase: Crizotinib 250 mg BID	86.2	79.34 – 91.50
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	73.8	61.46 – 83.97

Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Secondary · From first dose up to 30 days after last dose of study drug (Up to approximately 37 months)

An AE is any untoward medical occurrence in a participant. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product whether or not considered related to the medicinal product. Any worsening of a preexisting condition which is temporally associated with the use of the study drug (i.e., occurs after the first dose of study drug) is also an AE. TEAEs are defined as AEs starting/worsening on or after the first dose of study treatment and no later than the earliest of 30 days after the

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	100
Randomized Phase: Crizotinib 250 mg BID	100
Crossover Phase: Brigatinib 90 mg QD/180 mg QD	98.5

Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0) Secondary · Baseline and Month 36

HRQoL: perceived quality of participant's life, includes self-reported multidimensional measures of physical and mental health. Patient-reported symptoms (PROs) and HRQoL will be collected by administering the european organisation for research and treatment of cancer (EORTC) quality of life (QLQ)-C30 questionnaire. EORTC-QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health st

Group	Value	95% CI
Randomized Phase: Brigatinib 90 mg QD/180 QD	4.007	± 25.7563
Randomized Phase: Crizotinib 250 mg BID	-4.088	± 27.4748

Adverse events — posted to ClinicalTrials.gov

Time frame: All-Cause Mortality - Up to 56 months; Serious and other adverse events - From first dose up to 30 days after last dose of study drug (Up to approximately 37 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Randomized Phase: Brigatinib 90 mg QD/180 QD

Serious: 56/136 (41%)

Deaths: 41/137

Randomized Phase: Crizotinib 250 mg BID

Serious: 53/137 (39%)

Deaths: 29/138

Crossover Phase: Brigatinib 90 mg QD/180 mg QD

Serious: 24/65 (37%)

Deaths: 22/65

Serious adverse events (144 terms)

Reaction	System	Randomized Phase: Brigatin…	Randomized Phase: Crizotin…	Crossover Phase: Brigatini…
Pneumonia	Infections and infestations	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Neoplasm Progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Pulmonary Embolism	Respiratory, thoracic and mediastinal disorders	—	—	—
Pyrexia	General disorders	—	—	—
Urinary Tract Infection	Infections and infestations	—	—	—
Respiratory Tract Infection	Infections and infestations	—	—	—
Pleural Effusion	Respiratory, thoracic and mediastinal disorders	—	—	—
Interstitial Lung Disease	Respiratory, thoracic and mediastinal disorders	—	—	—
Non-Cardiac Chest Pain	General disorders	—	—	—
Lower Respiratory Tract Infection	Infections and infestations	—	—	—
Cellulitis	Infections and infestations	—	—	—
Metastases To Meninges	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Confusional State	Psychiatric disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Syncope	Nervous system disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Seizure	Nervous system disorders	—	—	—
Ischaemic Stroke	Nervous system disorders	—	—	—
Atrial Fibrillation	Cardiac disorders	—	—	—
Pericardial Effusion	Cardiac disorders	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—

Other adverse events (87 terms — click to expand)

Reaction	System	Randomized Phase: Brigatin…	Randomized Phase: Crizotin…	Crossover Phase: Brigatini…
Nausea	Gastrointestinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Blood Creatine Phosphokinase Increased	Investigations	—	—	—
Oedema Peripheral	General disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Alanine Aminotransferase Increased	Investigations	—	—	—
Hypertension	Vascular disorders	—	—	—
Aspartate Aminotransferase Increased	Investigations	—	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Fatigue	General disorders	—	—	—
Lipase Increased	Investigations	—	—	—
Dizziness	Nervous system disorders	—	—	—
Photopsia	Eye disorders	—	—	—
Decreased Appetite	Metabolism and nutrition disorders	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Abdominal Pain Upper	Gastrointestinal disorders	—	—	—
Asthenia	General disorders	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Amylase Increased	Investigations	—	—	—
Visual Impairment	Eye disorders	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—
Bradycardia	Cardiac disorders	—	—	—
Pyrexia	General disorders	—	—	—
Dysgeusia	Nervous system disorders	—	—	—
Abdominal Pain	Gastrointestinal disorders	—	—	—
Muscle Spasms	Musculoskeletal and connective tissue disorders	—	—	—
Blood Creatinine Increased	Investigations	—	—	—
Pain In Extremity	Musculoskeletal and connective tissue disorders	—	—	—
Upper Respiratory Tract Infection	Infections and infestations	—	—	—
Blood Alkaline Phosphatase Increased	Investigations	—	—	—
Gastrooesophageal Reflux Disease	Gastrointestinal disorders	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—
Musculoskeletal Pain	Musculoskeletal and connective tissue disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Vision Blurred	Eye disorders	—	—	—

Most-reported serious reactions: Pneumonia, Dyspnoea, Neoplasm Progression, Pulmonary Embolism, Pyrexia, Urinary Tract Infection, Respiratory Tract Infection, Pleural Effusion.

Data from ClinicalTrials.gov NCT02737501 adverse events section.

Sponsor's own description

The purpose of the study is to compare the efficacy of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic non-small cell lung cancer (NSCLC) participants naive to ALK inhibitors, as evidenced by progression-free survival (PFS).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer.
   Camidge DR, Kim HR, Ahn MJ, Yang JC, et al · · 2018 · cited 728× · PMID 30280657 · DOI 10.1056/nejmoa1810171
2. Targeting ALK: Precision Medicine Takes on Drug Resistance.
   Lin JJ, Riely GJ, Shaw AT. · · 2017 · cited 411× · PMID 28122866 · DOI 10.1158/2159-8290.cd-16-1123
3. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications.
   Zhu C, Wei Y, Wei X. · · 2019 · cited 398× · PMID 31684958 · DOI 10.1186/s12943-019-1090-3
4. EGFR-TKIs resistance via EGFR-independent signaling pathways.
   Liu Q, Yu S, Zhao W, Qin S, et al · · 2018 · cited 283× · PMID 29455669 · DOI 10.1186/s12943-018-0793-1
5. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial.
   Camidge DR, Kim HR, Ahn MJ, Yang JCH, et al · · 2020 · cited 239× · PMID 32780660 · DOI 10.1200/jco.20.00505
6. Management of Brain Metastases in Non-Small-Cell Lung Cancer.
   Ernani V, Stinchcombe TE. · · 2019 · cited 151× · PMID 31715122 · DOI 10.1200/jop.19.00357
7. Clinical development of targeted and immune based anti-cancer therapies.
   Seebacher NA, Stacy AE, Porter GM, Merlot AM. · · 2019 · cited 147× · PMID 30975211 · DOI 10.1186/s13046-019-1094-2
8. Crizotinib resistance: implications for therapeutic strategies.
   Dagogo-Jack I, Shaw AT. · · 2016 · cited 116× · PMID 27573756 · DOI 10.1093/annonc/mdw305