Sotorasib KRAS-Mutation, Evidenzprofil_CodeBreaK100

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A Phase 1/2, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Sotorasib (AMG 510) Monotherapy in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation and Sotorasib (AMG 510) Combination Therapy in Subjects With Advanced NSCLC With KRAS p.G12C Mutation (CodeBreaK 100) (NCT03600883)
Short Name Design Population Intervention Comparator Outcomes
CodeBreaK100
20170543		 Randomized, Sequential Assignment, Phase 1,Phase 2 Open Label study Pretreated with Stage 3-4 and ECOG 0-1 KRAS p.G12C Mutant Advanced Solid Tumors for 2nd Line, 3rd Line or >3rd Line treatment 1. Phase 1 Dose Exploration Part 1 monotherapy (N=0)1
2. Phase 1 Dose Expansion Part 2 monotherapy (N=0)2
3. Phase 2 monotherapy (N=0)3
4. Phase 1 combination arm with sotorasib and anti PD-1/L1 (N=0)4
5. Phase 1 monotherapy treatment naive advanced NSCLC (N=0)5
6. Phase 2 monotherapy dose comparison (N=0)6
7. Patients with previously treated KRAS p.G12C–mutated NSCLC (N=124)7
  1. Primary: Treatment-emergent adverse events
  2. Primary: Treatment-related adverse events
  3. Primary: Treatment-emergent adverse events Grade ≥3
  4. Primary: Serious adverse events
  5. Primary: Objective response rate
  6. Primary: Duration of response
  7. Primary: Disease control
  8. Primary: Time to response
  9. Secondary: Progression-free survival
  10. Secondary: Overall survival
  11. Secondary: Impact of treatment on HRQOL as assessed by EORTC QLQ-C30
  12. Secondary: Impact of treatment on HRQOL as assessed by EORTC QLQ-LC13
  13. Secondary: Impact of treatment on HRQOL as assessed by NSCLC SAQ
  14. Secondary: Impact of treatment on HRQOL as assessed by PGIS
  15. Secondary: Impact of treatment on HRQOL as assessed by PGIC (cough, dyspnea and chest pain for NSCLC)
  16. Secondary: Treatment-related symptoms and impact on the subject as assessed by selected questions from the PRO-CTCAE library
  17. Secondary: Treatment-related symptoms and impact on the subject as assessed by a single item about symptom bother, item GP5 of FACT-G
Levels of Evidence
GRADE ⊕⊖⊖⊖a,b,c We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
1: Cohorts with food effect and alternative dosing regimens Enrollment into the dose exploration cohorts may be from any eligible solid tumor type. Dose escalation will begin with 2-4 subjects treated at the lowest planned dose level of 180 mg. If no DLT is observed, dose escalation will continue to the next planned dose cohort; 2: Upon completing the dose exploration part of the study, dose expansion may proceed with 3 groups consisting of subjects with KRAS p.G12C mutant advanced solid tumors. Dose expansion in these 3 groups may be done concurrently; 3: Additional subjects will be enrolled in the dose expansion to confirm the recommended phase 2 dose. Enrollment into phase 2 will be opened after confirmation of the recommended phase 2 dose; 4: Additional subjects will be enrolled into the combination arm with sotorasib in combination with an anti (PD-1/L1); 5: Separate cohort of part 1 dose expansion subjects to evaluate the safety and clinical activity of sotorasib administered orally once daily in subjects with previously untreated advanced non-small cell lung cancer (NSCLC). Drug-drug interaction will be evaluated in 6 of the subjects enrolled in the treatment naive cohort by adding Midazolam alone on Day -1 and in combination with sotorasib on Day 15 of Cycle 1, where each cycle is 21 days.; 6: Subjects with NSCLC will be enrolled in a dose comparison study evaluating safety and efficacy; 7: Patients received at least one dose of sotorasib
a: Open Label Study;b: Non-randomized Study;c: Studydesign - Phase II

Outcome Patients with previously treated KRAS p.G12C–mutated NSCLC
N=124		 GRADE
Sotorasib for Lung Cancers with KRAS p.G12C Mutation.: Skoulidis, F 2021. Sotorasib for Lung Cancers with KRAS p.G12C Mutation.. ; 384 (25); 2371-2381*
Dichotomous Outcomes
OS - Time To Event N=126 12.5 [10; ] ⊕⊕⊕⊕
PFS - Time To Event N=124 6.8 [5.1; 8.2] ⊕⊖⊖⊖a
DCR - Time To Event N=124 100 (80.65%) ⊕⊖⊖⊖
DOR - Time To Event N=124 11.1 [6.9; ] ⊕⊖⊖⊖
ORR - TuDD N=124 46 (37.1%) ⊕⊖⊖⊖
TTR - TTE N=124 1.4 [1.2; 10.1] ⊕⊖⊖⊖
AE (Any) N=126 125 (99.21%) ⊕⊖⊖⊖
AE (CTCAE ≥3) N=126 77 (61.11%) ⊕⊖⊖⊖
TAE (Any) N=126 88 (69.84%) ⊕⊖⊖⊖
TAE (CTCAE ≥3) N=126 26 (20.63%) ⊕⊖⊖⊖
TAE-Disc (Any) N=126 9 (7.14%) ⊕⊖⊖⊖
TAE-Disc (CTCAE ≥3) N=126 5 (3.97%) ⊕⊖⊖⊖
*Database cutoff: 13.05.2021
a: Fehlende Einzelauswertung der Komponenten des zusammengesetzten Endpunktes (Progression)
AE: Adverse Events; Any: Any Grade; CTCAE ≥3: Common Terminology Criteria for Adverse Events, Grade ≥3; DCR: Disease Control Rate; DOR: Duration Of Response; ORR: Objective Response Rate; OS: Overall Survival; PFS: Progression-Free Survival; TAE: Treatment-related Adverse Events; TAE-Disc: Treatment-related Adverse Events Leading to Treatment Discontinuation; TTE: Time To Event ; TTR: Time To Response; TuDD: Time to Definitive Deterioration