Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
NSCLC, alectinib, ALK positive,adjuvant treatment, platinum based chemotherapy, complete resection, Stage IB-IIIA.
Brief summary
This randomized, active-controlled, multicenter, open-label, Phase III study is designed to investigate the efficacy and safety of alectinib compared with platinum-based in the adjuvant setting. Participants in the experimental arm will receive alectinib at 600 mg orally twice daily (BID) taken with food for 24 months. Participants in the control arm will receive one of the protocol specified platinum based chemotherapy regimens for 4 cycles. Following treatment completion, participants will be followed up for their disease until disease recurrence. At the time of disease recurrence, participants will enter a survival follow-up until death, withdrawal of consent or study closure, whichever occurs earlier.
Interventions
DRUGAlectnib
Participants will receive alectinib 600 mg orally BID until completion of treatment period (24 months) or recurrence of disease , unacceptable toxicity, withdrawal of consent or death, whichever occurs first.
DRUGCisplatin
Participants will receive Cisplatin 75 milligrams per square meter (mg/m\^2) on Day 1 every 21 days IV intravenously (IV) until completion of treatment period (4 cycles), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first."
DRUGVinorelbine
Participants will receive Vinorelbine 25 mg/m\^2 IV on Days 1 and 8 Q21D until completion of treatment period (4 cycles), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
DRUGGemcitabine
Participants will receive Gemcitabine 1250 mg/m\^2 on Days 1 and 8 Q21D IV until completion of treatment period (4 cycles), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
DRUGPemetrexed
Participants will receive 500 mg/m\^2 Day 1 Q21D until completion of treatment period (4 cycles), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first."
DRUGCarboplatin
For participants who experience unacceptable toxicity with cisplatin, carboplatin can be used.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria * Age ≥18 years * Complete resection of histologically confirmed Stage IB (tumor ≥ 4 cm) to Stage IIIA (T2-3 N0, T1-3 N1, T1-3 N2, T4 N0-1) NSCLC as per Union Internationale Contre le Cancer / American Joint Committee on Cancer, 7th edition, with negative margins, at 4-12 weeks before enrollment * If mediastinoscopy was not performed preoperatively, it is expected that, at a minimum, mediastinal lymph node systematic sampling will have occurred * Documented ALK-positive disease according to an FDA-approved and CE-marked test * Eligible to receive a platinum-based chemotherapy regimen according to the local labels or guidelines * Eastern Cooperative Oncology Group Performance Status of Grade 0 or 1 * Adequate hematologic and renal function * For women of childbearing potential: agreement to remain abstinent or use contraceptive methods with a failure rate of \< 1% per year during the treatment period and for at least 90 days after the last dose of alectinib or according to local labels or guidelines for chemotherapy * For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm for at least 90 days after the last dose of alectinib or according to local labels or guidelines for chemotherapy. Men must refrain from donating sperm during this same period * Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures Key
Exclusion criteria
* Pregnant or breastfeeding, or intending to become pregnant during the study or within 90 days after the last dose of alectinib or according to local labels or guidelines for chemotherapy * Prior adjuvant radiotherapy for NSCLC * Prior exposure to systemic anti-cancer therapy and ALK inhibitors * Stage IIIA N2 patients that, in the investigator's opinion, should receive post-operative radiotherapy treatment are excluded from the study * Known sensitivity to any component of study drug to which the patient may be randomized. This includes, but is not limited to, patients with galactose intolerance, a congenital lactase deficiency or glucose-galactose malabsorption. * Malignancies other than NSCLC within 5 years prior to enrollment, except for curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, ductal carcinoma in situ, papillary thyroid cancer, or any cured cancer that is considered to have no impact on disease free survival or overall survival for the current NSCLC * Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection * Liver disease characterized by aspartate transaminase and alanine transaminase \>= 3 × upper limit of normal or impaired excretory function or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, or bleeding from esophageal varices or active viral or active autoimmune, alcoholic, or other types of acute hepatitis * Japanese patients participating in the serial/intensive PK sample collection only: administration of strong/potent CYP450 3A inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment with alectinib up to Week 3 * Any
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival (DFS), as Assessed by the Investigator | Approximately 58 months | DFS, defined as the time from randomization to the first documented recurrence of disease or new primary NSCLC as determined by the investigator through use of an integrated assessment of radiographic data, biopsy sample results (if clinically feasible), and clinical status or death from any cause, whichever occurs first |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From the date of randomization until death due to any cause up to approximately 8 years | Primary OS analysis at approximately 5 years after FPI and final OS analysis at approximately 8 years after FPI. OS, defined as the time from randomization to death from any cause. |
| Percentage of Participants With Adverse Events (AEs) | Until 28 days after the last dose of alectinib (up to 2 years) or 28 days after end of last cycle of chemotherapy (up to 4 cycles) | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events. |
| AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Until 28 days after the last dose of alectinib (up to 2 years) or 28 days after end of last cycle of chemotherapy (up to 4 cycles) | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events. |
| Plasma Concentration of Alectinib | Predose (2 hours) Week 3 - Week 96 | — |
| Plasma Concentration of Alectinib Metabolite M4 | Predose (2 hours) Week 3 - Week 96 | — |
Countries
Australia, Austria, Belarus, Bosnia and Herzegovina, China, Denmark, Egypt, France, Germany, Greece, Hungary, Israel, Italy, Japan, Kazakhstan, North Macedonia, Poland, Romania, Russia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Alectinib Participants received 600 mg oral alectinib twice daily (BID) for 2 years | 130 |
| Platinum-Based Chemotherapy Participants received platinum-based chemotherapy for 4 cycles (cycle length = 21 days). | 127 |
| Total | 257 |
Baseline characteristics
| Characteristic | Platinum-Based Chemotherapy | Total | Alectinib |
|---|---|---|---|
| Age, Continuous | 56.6 years STANDARD_DEVIATION 11.3 | 54.9 years STANDARD_DEVIATION 12 | 53.4 years STANDARD_DEVIATION 12.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 122 Participants | 249 Participants | 127 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 71 Participants | 143 Participants | 72 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) White | 52 Participants | 107 Participants | 55 Participants |
| Sex: Female, Male Female | 59 Participants | 134 Participants | 75 Participants |
| Sex: Female, Male Male | 68 Participants | 123 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 130 | 5 / 127 |
| other Total, other adverse events | 124 / 128 | 110 / 120 |
| serious Total, serious adverse events | 17 / 128 | 10 / 120 |
Outcome results
Primary
Disease-free Survival (DFS), as Assessed by the Investigator
DFS, defined as the time from randomization to the first documented recurrence of disease or new primary NSCLC as determined by the investigator through use of an integrated assessment of radiographic data, biopsy sample results (if clinically feasible), and clinical status or death from any cause, whichever occurs first
Time frame: Approximately 58 months
Population: The ITT population consisted of all randomized participants, whether or not the participant received the assigned treatment.~The Stage II-IIIa population consisted of all participants in the ITT population with Stage II-IIIa NSCLC.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alectinib | Disease-free Survival (DFS), as Assessed by the Investigator | Stage II-IIIA population | NA months |
| Alectinib | Disease-free Survival (DFS), as Assessed by the Investigator | ITT population | NA months |
| Platinum-Based Chemotherapy | Disease-free Survival (DFS), as Assessed by the Investigator | ITT population | 41.3 months |
| Platinum-Based Chemotherapy | Disease-free Survival (DFS), as Assessed by the Investigator | Stage II-IIIA population | 44.4 months |
p-value: 0.000195% CI: [0.13, 0.45]Log Rank
p-value: 0.000195% CI: [0.13, 0.43]Log Rank
Secondary
AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events.
Time frame: Until 28 days after the last dose of alectinib (up to 2 years) or 28 days after end of last cycle of chemotherapy (up to 4 cycles)
Population: The safety-evaluable population consisted of all participants who received at least one dose of study treatment, with participants assigned to treatment groups according to the treatment received. All participants who received any dose of alectinib are included in the alectinib treatment arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alectinib | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | White blood cell count decreased | 0 Percentage of participants |
| Alectinib | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Appendicitis | 3.1 Percentage of participants |
| Alectinib | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Blood creatinine phosphokinase increased | 6.3 Percentage of participants |
| Alectinib | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Neutropenia | 0 Percentage of participants |
| Alectinib | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Nausea | 0 Percentage of participants |
| Alectinib | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Asthenia | 0 Percentage of participants |
| Alectinib | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Neutrophil count decreased | 0 Percentage of participants |
| Platinum-Based Chemotherapy | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Asthenia | 2.5 Percentage of participants |
| Platinum-Based Chemotherapy | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Neutrophil count decreased | 10.0 Percentage of participants |
| Platinum-Based Chemotherapy | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Blood creatinine phosphokinase increased | 0.8 Percentage of participants |
| Platinum-Based Chemotherapy | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | White blood cell count decreased | 3.3 Percentage of participants |
| Platinum-Based Chemotherapy | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Nausea | 4.2 Percentage of participants |
| Platinum-Based Chemotherapy | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Appendicitis | 0 Percentage of participants |
| Platinum-Based Chemotherapy | AEs Grade 3-5 With a Difference in Incidence Rate of at Least 2% Between Treatment Arms | Neutropenia | 8.3 Percentage of participants |
Secondary
Overall Survival (OS)
Primary OS analysis at approximately 5 years after FPI and final OS analysis at approximately 8 years after FPI. OS, defined as the time from randomization to death from any cause.
Time frame: From the date of randomization until death due to any cause up to approximately 8 years
Secondary
Percentage of Participants With Adverse Events (AEs)
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events.
Time frame: Until 28 days after the last dose of alectinib (up to 2 years) or 28 days after end of last cycle of chemotherapy (up to 4 cycles)
Population: The safety-evaluable population consisted of all participants who received at least one dose of study treatment, with participants assigned to treatment groups according to the treatment received. All participants who received any dose of alectinib are included in the alectinib treatment arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alectinib | Percentage of Participants With Adverse Events (AEs) | At least one AE | 98.4 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | AE with fatal outcome | 0 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | Grade 3-5 AE | 29.7 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | Serious AE (SAE) | 13.3 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | SAE leading to treatment withdrawal | 0.8 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | SAE leading to dose modification/interruption | 5.5 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | Related SAE | 1.6 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | AE leading to treatment withdrawal | 5.5 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | AE leading to dose modification/interruption | 43.0 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | Related AE | 93.8 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | Related AE leading to treatment withdrawal | 5.5 Percentage of participants |
| Alectinib | Percentage of Participants With Adverse Events (AEs) | Related AE leading to dose mod./interruption | 38.3 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | Related AE leading to treatment withdrawal | 11.7 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | At least one AE | 93.3 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | Related SAE | 6.7 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | AE with fatal outcome | 0 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | Related AE | 89.2 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | Grade 3-5 AE | 30.8 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | AE leading to treatment withdrawal | 12.5 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | Serious AE (SAE) | 8.3 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | Related AE leading to dose mod./interruption | 21.7 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | SAE leading to treatment withdrawal | 3.3 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | AE leading to dose modification/interruption | 22.5 Percentage of participants |
| Platinum-Based Chemotherapy | Percentage of Participants With Adverse Events (AEs) | SAE leading to dose modification/interruption | 3.3 Percentage of participants |
Secondary
Plasma Concentration of Alectinib
Time frame: Predose (2 hours) Week 3 - Week 96
Population: The PK-evaluable population consisted of all participants who received at least one dose of alectinib and who had at least one post-baseline PK sample available. This population did not include participants from the platinum-based chemotherapy arm, who did not receive alectinib.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Plasma Concentration of Alectinib | Week 3 | 382 ng/mL | Geometric Coefficient of Variation 276.2 |
| Alectinib | Plasma Concentration of Alectinib | Week 6 | 611 ng/mL | Geometric Coefficient of Variation 70.6 |
| Alectinib | Plasma Concentration of Alectinib | Week 9 | 593 ng/mL | Geometric Coefficient of Variation 91.4 |
| Alectinib | Plasma Concentration of Alectinib | Week 12 | 581 ng/mL | Geometric Coefficient of Variation 94.9 |
| Alectinib | Plasma Concentration of Alectinib | Week 24 | 619 ng/mL | Geometric Coefficient of Variation 93.2 |
| Alectinib | Plasma Concentration of Alectinib | Week 36 | 639 ng/mL | Geometric Coefficient of Variation 54.1 |
| Alectinib | Plasma Concentration of Alectinib | Week 48 | 551 ng/mL | Geometric Coefficient of Variation 90.1 |
| Alectinib | Plasma Concentration of Alectinib | Week 60 | 588 ng/mL | Geometric Coefficient of Variation 58.9 |
| Alectinib | Plasma Concentration of Alectinib | Week 72 | 527 ng/mL | Geometric Coefficient of Variation 96.5 |
| Alectinib | Plasma Concentration of Alectinib | Week 84 | 515 ng/mL | Geometric Coefficient of Variation 91.1 |
| Alectinib | Plasma Concentration of Alectinib | Week 96 | 478 ng/mL | Geometric Coefficient of Variation 106.4 |
Secondary
Plasma Concentration of Alectinib Metabolite M4
Time frame: Predose (2 hours) Week 3 - Week 96
Population: The PK-evaluable population consisted of all participants who received at least one dose of alectinib and who had at least one post-baseline PK sample available. This population did not include participants from the platinum-based chemotherapy arm, who did not receive alectinib.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 84 | 198 ng/mL | Geometric Coefficient of Variation 65.4 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 3 | 178 ng/mL | Geometric Coefficient of Variation 111.7 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 6 | 214 ng/mL | Geometric Coefficient of Variation 86.3 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 9 | 213 ng/mL | Geometric Coefficient of Variation 78.9 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 12 | 205 ng/mL | Geometric Coefficient of Variation 94.7 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 24 | 237 ng/mL | Geometric Coefficient of Variation 73.2 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 36 | 238 ng/mL | Geometric Coefficient of Variation 50.7 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 48 | 209 ng/mL | Geometric Coefficient of Variation 51.7 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 60 | 217 ng/mL | Geometric Coefficient of Variation 49.7 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 72 | 213 ng/mL | Geometric Coefficient of Variation 62.6 |
| Alectinib | Plasma Concentration of Alectinib Metabolite M4 | Week 96 | 191 ng/mL | Geometric Coefficient of Variation 76.8 |