Einleitung
In der Krebsbehandlung setzen Ärzte immer auf innovative Therapieansätze. Eine neue Studie gibt nun einen tiefen Einblick in die Kombination von Ifebemtinib und Garsorasib, zwei potenziell lebensrettenden Medikamente. Diese Kombination könnte den Standard der Behandlung erheblich verbessern.
Studienergebnisse & Methodik
Die Studie untersuchte die Kombination von Ifebemtinib, einem Focal Adhesion Kinase-Inhibitoren, und Garsorasib, einem KRAS-Inhibitoren. In der Phase 1b wurde die Sicherheit und Toleranz dieser Kombination in 15 Patienten getestet. Die Phase 2 umfasste eine Single-Arm-Studie mit 15 Patienten und eine zufallsgeteilte Studie mit 36 Patienten. Die Haupteffizienzmarke war der objektive antikeptive Effekt, bei dem die bestätigten objektiven Antworten in der Sicherheitsanalysegruppe und im zufallsgeteilten Studienbevölkerung (Intention-to-Treat-Population) geprüft wurden.
- Probandenzahl: 51 Patienten
- Vorgehen: 3+3-Design, Centralized Computer-Generated Block Randomisation, Maskierte Untersuchung
- Zeitraum: April 7, 2023 – Dezember 13, 2024
In der Single-Arm-Studie zeigte sich eine bestätigte objektive Antwortrate von 46,7%. In der zufallsgeteilten Studie war die bestätigte objektive Antwortrate mit der Kombination 38,9%, im Monotherapiearm 16,7%. Obwohl die Erhöhung der Antwortrate statistisch nicht signifikant war, bestätigt diese Studie die klinische Wirksamkeit der Kombination.
Kritische Einordnung
Die Studie ist ein beachtenswerter Schritt, um die Wirksamkeit dieser Kombination zu beweisen, und bietet wichtige Erkenntnisse für die Behandlung von Metastatisenkolorektalkrebs mit KRAS-Mutationen. Allerdings hat die zufallsgeteilte Studie keine statistisch signifikante Erhöhung der Antwortrate gezeigt, was die Interpretation der Ergebnisse verlangsamt.
Dielimitations der Studie sind die relativ geringe Probandenzahl und die Kürze der beobachteten Zeit. Zudem war die zufallsgeteilte Studie ungetrennt von der Single-Arm-Studie, was die Analyse erschwert.
Praxis-Fazit
- Ernährung: Keine spezifischen Ernährungsempfehlungen basierend auf dieser Studie.
- Bewegung: Fortgesetzte Bewegung ist wichtig, um die Immunabwehr zu stärken, ohne spezifische Aktivitäten zu empfehlen.
- Routinen: Patienten sollten regelmäßig bei ihrem Arzt über ihre Therapie und mögliche Nebenwirkungen berichten. Eine Kombinationstherapie sollte nur unter Anleitung eines Experten durchgeführt werden.
Original-Abstract (Englisch)
BACKGROUND: Ifebemtinib is a potent oral focal adhesion kinase inhibitor. Preclinical evidence supports combining ifebemtinib with the KRAS inhibitor garsorasib. This study aimed to evaluate this combination in KRAS-mutated solid tumours.
METHODS: This multicentre, phase 1b/2 study had a phase 1b component to establish the recommended phase 2 dose and a phase 2 multitumour expansion component. In phase 1b, the safety and tolerability of ifebemtinib combined with garsorasib was assessed using a 3 + 3 design in KRAS-mutated solid tumours. No dose-limiting toxic effects were observed, and the recommended phase 2 dose was established as ifebemtinib 100 mg orally once daily plus garsorasib 600 mg orally twice daily. Here, we report the results of the cohort of previously treated KRAS-mutated metastatic colorectal cancer from phase 2 expansion. Eligible patients (aged ≥18 years) who had histologically confirmed locally advanced or metastatic colorectal cancer harbouring the KRAS mutation, an Eastern Cooperative Oncology Group performance-status score of 0 or 1, and had disease progression after previous irinotecan-based or oxaliplatin-based combination therapy, were recruited from seven of nine participating tertiary hospitals in China. On the basis of the recommended phase 2 dose, phase 2 comprised a single-arm study to evaluate the safety and efficacy of ifebemtinib combined with garsorasib and an open-label, randomised study in which patients were randomly assigned (1:1) to receive ifebemtinib plus garsorasib or garsorasib alone, by use of centralised computer-generated block randomisation with no stratification. Investigators were masked to the block size. The primary efficacy endpoint of phase 2 was investigator-assessed objective response rate (Response Evaluation Criteria in Solid Tumours, version 1.1), assessed in the safety analysis set in the single-arm study and in all randomly assigned patients (intention-to-treat population) in the randomised study. At least six objective responses (safety analysis set) were required in the single-arm study to proceed to the randomised study. This study is registered with ClinicalTrials.gov, NCT06166836 and NCT05379946, and is active but not recruiting.
FINDINGS: Between April 7, 2023 and Dec 13, 2024, 51 patients were enrolled in phase 2 (15 in the single-arm study and 36 in the randomised study). In the single-arm study, the median age was 53 years (IQR 39 to 63), nine (60%) patients were female, six (40%) were male, and all were Asian. In the randomised study, the median age was 51 years (IQR 42 to 59) in the combination group and 63 years (IQR 54 to 66) in the monotherapy group, 24 (67%) were female, 12 (33%) were male, and all patients were Asian. In the single-arm part, the confirmed objective response rate was 46·7% (95% CI 21·3 to 73·4). Seven patients had partial responses, triggering progression to the randomised study. In the randomised study, the confirmed objective response rate was 38·9% (95% CI 17·3 to 64·3) with the combination therapy versus 16·7% (95% CI 3·6 to 41·4) with garsorasib alone (between-group difference 22·2%, 95% CI -7·7 to 49·1; one-sided p=0·068). In the single-arm study, grade 3 treatment-related adverse events occurred in four (27%) of 15 patients, and in the randomised study, grade 3 treatment-related adverse events occurred in six (33%) of 18 patients in the combination group and five (28%) of 18 in the garsorasib group. Grade 3 treatment-related adverse events occurring in at least two patients were diarrhoea (six [18%]), proteinuria (two [6%]), and intestinal obstruction (two [6%]) in patients treated with combination therapy (combined), and increased alanine aminotransferase and γ-glutamyltransferase (two [11%] each) in patients treated with garsorasib alone. Serious adverse events occurred in ten (30%) patients in the combination group and in four (22%) patients in the monotherapy group. One patient in the garsorasib monotherapy group died due to the underlying malignancy within 30 days after completing study treatment, which was reported as a serious adverse event. The death was assessed by the investigators as not related to garsorasib. No grade 4 treatment-related adverse events or treatment-related deaths were reported across all cohorts.
INTERPRETATION: The combination of ifebemtinib and garsorasib showed promising anticancer activity and manageable safety profile in previously treated patients with KRAS-mutated metastatic colorectal cancer. Although the improvement in response rate did not reach statistical significance in the randomised study, these findings support further evaluation of ifebemtinib plus garsorasib in this population.
FUNDING: InxMed, InventisBio, National Natural Science Foundation of China, the Jian Bing Ling Yan + X Research and Development Program of Zhejiang Province, and the Zhejiang Province Medical and Health Science and Technology Plan Project.
