The purpose of this trial was to evaluate the safety and efficacy of capmatinib in combination with spartalizumab in adult participants with epidermal growth factor receptor (EGFR) wild type (for exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK) rearrangement negative in locally advanced (stage IIIB, not eligible for definitive chemo-radiation) or metastatic (stage IV) Non-small cell lung cancer (NSCLC) after failure of platinum doublet and checkpoint inhibitor treatment.
This was a two-part prospectively designed, multicenter, open-label, randomized phase II study. Part 1: Run-in. Prior to the randomized part of the study, a run-in to assess the safety and tolerability as well as preliminary efficacy of the capmatinib and spartalizumab combination was conducted. Participants were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days. A review was planned to take place after all participants had at least 24 weeks of follow-up. The decision to expand the study to the randomized part was to be based on the safety, tolerability, and preliminary efficacy of the capmatinib and spartalizumab combination. Part 2: Randomized. Subjects were planned to be randomized to one of the following arms in a 2:1 ratio: 1) combination of capmatinib 400 mg BID and spartalizumab 400 mg i.v. once every 28 days; 2) docetaxel 75 mg/m2 i.v. following local guidelines as per standard of care and product labels. Based on the results obtained in the run-in part of the study, the randomized part was not opened. For the run-in part of the study, the treatment period began on Cycle 1 Day 1 and continued in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of informed consent, pregnancy, lost to follow-up, or death irrespective of start of new anti-neoplastic therapy. After treatment discontinuation, all subjects were followed for safety evaluations during the safety follow-up period, and the subject's status was collected every 8 weeks as part of the survival follow-up
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
Capmatinib 400 mg (tablets) orally taken twice daily
Spartalizumab 400 mg via intravenous infusion once every 28 days
Docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days
Highlands Oncology Group
Fayetteville, Arkansas, United States
Novartis Investigative Site
Leuven, Belgium
Novartis Investigative Site
Grenoble, France
Novartis Investigative Site
Lille Cédex, France
Run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs)
A DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
Time frame: From the day of the first dose of study medication up to 56 days
Run-in Part: Percentage of Participants With Adverse Events (AEs)
Percentage of participants with AEs, including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0: Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: Death
Time frame: From the day of the first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib (whichever is later) up to maximum duration of approximately 1.7 years
Run-in Part: Percentage of Participants With at Least One Dose Reduction.
Percentage of participants with at least one dose reduction. Dose reductions were only allowed for capmatinib
Time frame: From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks
Run-in Part: Percentage of Participants With at Least One Dose Interruption
Percentage of participants with at least one dose interruption. Dose interruptions were allowed for capmatinib and spartalizumab.
Time frame: From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks
Run-in Part: Relative Dose Intensity Received by Participants
The relative dose intensity of capmatinib and spartalizumab is computed as the ratio of dose intensity and planned dose intensity, multiplied by 100.
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NONE
Enrollment
18
Novartis Investigative Site
Cologne, Germany
Novartis Investigative Site
Tel Aviv, Israel
Novartis Investigative Site
Barcelona, Catalonia, Spain
Novartis Investigative Site
Madrid, Spain
Time frame: From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks
Randomized Part: Overall Survival (OS)
OS is defined as the time from date of start of treatment to date of death due to any cause. If a participant was not known to have died, survival was censored at the date of last known date patient alive. Results are not available because randomized part never started.
Time frame: From start of treatment to death due to any cause, assessed until the end of the study (up to a planned duration of 18 months)
Objective Response Rate (ORR) Based on RECIST 1.1 and as Per Investigator Assessment
ORR is defined as the percentage of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. ORR results for randomized part are not available because randomized part never started.
Time frame: From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)
Disease Control Rate (DCR) Based on RECIST 1.1 and as Per Investigator Assessment
DCR is defined as the percentage of subjects with best overall response of CR or PR or stable disease based on RECIST 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. DCR results for randomized part are not available because randomized part never started.
Time frame: From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)
Progression Free Survival (PFS)
PFS is defined as the time from the date of start of treatment to the date of the first documented radiological progression or death due to any cause. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. Progression is defined using RECIST 1.1 and as per investigator assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS results for randomized part are not available because randomized part never started.
Time frame: From start of treatment until the first documented radiological progression or death, whichever comes first, assessed up to 68 weeks (run-in part)
Time to Response (TTR) Based on RECIST 1.1 and as Per Investigator Assessment
TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed. TTR was evaluated according to RECIST 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. For run-in part, TTR results are not available because there were no participants achieving response (CR or PR) For randomized part , TTR results are not available because randomized part never started.
Time frame: From start of treatment to the first documented response of either complete response or partial response, assessed up to 68 weeks (run-in part)
Duration of Response (DOR) Based on RECIST 1.1 and as Per Investigator Assessment
DOR is the time between the date of first documented response(CR or PR) and the date of first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator assessment. If progression or death has not occurred, the subject is censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm. Results are not available because there were no participants achieving response in the run-in part and randomized part never started
Time frame: From first documented response (CR or PR) to first documented progression or death, whichever came first, assessed up to 68 weeks (run-in part)
AUClast of Capmatinib
AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
AUCtau of Capmatinib
AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
Maximum Plasma Concentration (Cmax) of Capmatinib
The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
Time to Reach Maximum (Tmax) Plasma Concentration of Capmatinib
Tmax is the time to reach maximum (peak) plasma concentration of capmatinib after single dose administration (time). Tmax was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
AUClast of Spartlizumab
AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.
Time frame: CCycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days
AUCtau of Spartlizumab
AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days
Maximum Plasma Concentration (Cmax) of Spartlizumab
The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days
Time to Reach Maximum (Tmax) Plasma Concentration of Spartlizumab
Tmax is the time to reach maximum (peak) plasma concentration of spartlizumab after single dose administration (time). Tmax was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days
Spartalizumab Antidrug Antibodies (ADA) Prevalence at Baseline
ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline
Time frame: Cycle 1 Day 1 at predose. Each Cycle is 28 days
Spartalizumab ADA Incidence On-treatment
ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
Time frame: Predose at Cycle (C)1 Day (D)1, C2D1, C3D1, C4D1, C6D1, C8D1, C10D1, C12D1, thereafter every 6 cycles until discontinuation, and end of treatment (EOT), 30-day and 150-day after EOT