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>
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".