Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with <i>KRAS</i> G12C-mutant advanced solid tumors.
Notice bibliographique
Résumé
3007 Background: Olomorasib is a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, which preclinically delivers >90% sustained target occupancy. Here, we report updated results from LOXO-RAS-20001, a phase 1/2 study of olomorasib in patients with KRAS G12C-mutant advanced solid tumors (NCT04956640). Methods: Patients (pts) with advanced solid tumors positive for KRAS G12C (tissue or plasma) were eligible. Dose escalation used a mTPI-2 method, followed by expansion cohorts in NSCLC (with/without prior G12Ci), CRC, and other solid tumors. Safety was evaluated across all pts dosed. Antitumor activity per RECIST v1.1 was studied in all pts who had ≥1 post-baseline response assessment (PBRA) or had discontinued before the first PBRA. Serial ctDNA analysis was performed using FoundationOne Liquid CDx. Results: As of 30 October 2023, 157 pts (58 NSCLC, 32 CRC, 24 PANC, 43 other solid tumors) received single agent olomorasib (50-200 mg BID PO); 29 pts with NSCLC had received a prior KRAS G12Ci. Median age was 65 yrs (range, 36-85), median number of prior systemic therapies was 3 (range, 0-11). Any grade TRAEs were 62%; TRAEs ≥10% were diarrhea (24%), fatigue (10%), and nausea (10%); grade ≥3 TRAEs were 5%. TRAEs led to dose hold in 10% of pts, dose reduction in 3%, and discontinuation in 2%. Among 10 pts treated after discontinuing prior G12Ci due to toxicity (5/10 due to LFT increase), 1 pt (10%) required olomorasib dose reduction and none discontinued due to toxicity. 68 pts are ongoing and 89 discontinued treatment. 146 pts were efficacy evaluable (120 G12Ci-naïve; 26 with prior G12Ci) with a median follow-up of 10 months (95% CI, 7-13). As anticipated, ORR was lower in 32 pts with CRC (9%, 3 PR; DCR 84%)1 and higher in 88 pts with non-CRC tumors (40%, 30 PR and 5 uPR pending/ongoing in 13 unique tumor types; DCR 90%). mPFS ranged across tumor types from 4 months (CRC, 95% CI, 3-7) to 9 months (NSCLC, 95% CI, 3-NE). In the 26 efficacy evaluable NSCLC pts with prior KRAS G12Ci treatment (16 discontinued due to PD, 9 due to AE), the ORR was 39% (9 PR, 1 uPR pending/ongoing; DCR 73%); mPFS was 6 months (95% CI, 3-NE). In 37 pts with ctDNA results at baseline and ongoing, ctDNA response (>50% KRAS G12C VAF reduction) was seen in pts with PR (11/11), SD (17/22), and PD (1/4). Conclusions: Olomorasib demonstrates efficacy across a range of KRAS G12C-mutant solid tumors with a favorable safety profile including in pts with prior G12Ci intolerance. Activity of the second-generation G12Ci olomorasib after prior exposure to G12Ci demonstrates the increased potency and target coverage these agents can deliver compared to first generation inhibitors. Phase 2 expansion is currently enrolling pts with PANC, and a global registrational study investigating olomorasib in combination with pembrolizumab in first-line NSCLC is ongoing (NCT06119581). 1. Hollebecque A. et al. ASCO-GI 2024. Clinical trial information: NCT04956640 .
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».