Abstract PR008: MYTHIC: First-in-human (FIH) biomarker-driven phase I trial of PKMYT1 inhibitor lunresertib (lunre) alone and with ATR inhibitor camonsertib (cam) in solid tumors with <i>CCNE1</i> amplification or deleterious alterations in <i>FBXW7</i> or <i>PPP2R1A</i>
Notice bibliographique
Résumé
Abstract Background: Lunre (RP-6306), a first-in-class membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase (PKMYT1) inhibitor, disrupts G2/M checkpoint causing DNA damage in cells with synthetic lethal alterations. Lunre plus the ATR inhibitor cam (RP-3500) promotes premature mitosis via CHK1/Cdc25 regulation and tumor regression. The FIH phase 1 MYTHIC trial assessed lunre alone or in combo with cam (lunre + cam) (NCT04855656). Methods: Pts &gt;12yrs with advanced solid tumors and CCNE1 amplification, or deleterious FBXW7 or PPP2R1A mutations received oral lunre alone (QD or BID) or lunre (QD or BID) + cam (QD) continuously or intermittently using BOIN design. Endpoints: safety, tolerability, RP2D, preliminary efficacy (RECIST v1.1, GCIG CA-125), clinical benefit rate (CBR; RECIST/GCIG CA-125 or therapy duration ≥16w), ctDNA molecular response, PK and PD. Results: As of June 1, 2023, 108 pts were treated; n=66 lunre alone; n=42 lunre + cam. Tumors: uterine (31.5%), colorectal (20.4%), ovarian (16.7%), others (31.5%); median 3 prior therapies. 39.8% had CCNE1, 36.1% FBXW7, 19.4% PPP2R1A, and 4.6% had 2 or no alterations. Treatment-related AEs for lunre alone vs lunre + cam: nausea/vomiting (31.8% vs 64.3%; G3 1.5% vs 0%), anemia (21.2% vs 64.3%; G3 7.6% vs 38.1%), rash (34.8% vs 31%; G3 7.6% vs 2.4%), fatigue (22.7% vs 38.1%; G3 1.5% vs 0%). Lunre DLTs included G2/3 rash reversible with drug holds +/- supportive care. Preliminary RP2Ds: (1) lunre alone 100mg BID 5 days (d) on/2d off or 240mg QD continuous; (2) lunre 80mg BID + cam 80mg QD, both 3d on/4d off. Lunre exhibited linear PK up to daily doses ~240mg with ~9h half-life. No lunre + cam drug-drug interaction was observed. Target engagement (CDK1-Thr14 IHC) was confirmed in paired tumor biopsies treated with lunre alone (p=0.001; n=17) and with cam (p=0.039; n=11). DNA damage induction (gH2AX) was observed across both treatment groups (p=0.013; n=36). ctDNA molecular responses were achieved in 10/18 pts (55.6%) on lunre + cam. For lunre alone, 1 pt with uterine carcinosarcoma/PPP2R1A & FBXW7 had RECIST PR. For lunre + cam, among evaluable pts, 8 had either RECIST response (confirmed or unconfirmed; n=6: bile duct/CCNE1, breast/FBXW7, CRC/FBXW7, endometrial/FBXW7, PPP2R1A & CCNE1, or PPP2R1A & FBXW7) or CA-125 response (n=2: ovarian/CCNE1), including 5/15 pts (33.3%) with endometrial/ovarian cancers; CBR was 43.2% in all pts, and 66.7% in pts with endometrial/ovarian cancers. Conclusion: Lunre is safe and well-tolerated with robust PK/PD proof-of-mechanism. Antitumor responses or durable clinical benefit was observed in tumors with CCNE1, FBXW7, and PPP2R1A alterations at biologically active doses of lunre + cam, especially in gynecological cancers. These data provide the first clinical proof-of-concept for synthetic lethal targeting of PKMYT1 in cancer medicine. Dose optimization and efficacy expansions are ongoing. Trial registration number: NCT04855656 Citation Format: Timothy A Yap, Alison Schram, Elizabeth K Lee, Fiona Simpkins, Mia C Weiss, Patricia LoRusso, Martin Højgaard, Benedito A Carneiro, Ryan H Moy, Ignacio Garrido-Laguna, Maria Koehler, Thaddeus J Unger, Emeline Bacque, Elia Aguado-Fraile, Sunantha Sethuraman, Snehal Dhake, Yajun Liu, Adrian J Fretland, Xizi Sun, Yi Xu, Nathan Hawkey, Jen Truong, Stephanie Lheureux. MYTHIC: First-in-human (FIH) biomarker-driven phase I trial of PKMYT1 inhibitor lunresertib (lunre) alone and with ATR inhibitor camonsertib (cam) in solid tumors with CCNE1 amplification or deleterious alterations in FBXW7 or PPP2R1A [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR008.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 tête enseignante, 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 ».