lunresertib (RP-6306)

Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E-high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype.

"Foundation Medicine...announced that it has formed a collaboration with Repare Therapeutics, a leading clinical-stage precision oncology company, to provide prospective genomic profiling to patients in Repare’s ongoing Phase I/Ib MYTHIC study (NCT04855656) of lunresertib alone or in combinations in genomically-defined patient populations. The companies are also exploring opportunities to develop FoundationOne CDx, a tissue-based comprehensive genomic profiling test, as a companion diagnostic for the lunresertib program....Foundation Medicine is the global leader in companion diagnostic approvals with approximately 60% of all U.S. companion diagnostic approvals for next generation sequencing testing."

In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.

In a CCNE1-amplified triple-negative cell model (HCC1569), treatment with the PKMYT1 inhibitor RP-6306 significantly reduced tumor growth. CCNE1 amplification in BCs is associated with greater genomic instability and characterizes a group of metastatic BCs with poor response to standard of care therapies. Novel therapies targeting CCNE1-amplified tumors are under evaluation in preclinical and clinical studies.

P1, N=364, Recruiting, Repare Therapeutics | N=180 --> 364

P1, N=24, Active, not recruiting, University Health Network, Toronto | Not yet recruiting --> Active, not recruiting | Initiation date: Dec 2023 --> Mar 2024

P1, N=36, Active, not recruiting, Repare Therapeutics | Recruiting --> Active, not recruiting | N=104 --> 36

P1, N=180, Recruiting, Repare Therapeutics | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Oct 2023 --> Jun 2026

P1, N=104, Active, not recruiting, Repare Therapeutics | Recruiting --> Active, not recruiting | Trial primary completion date: Oct 2023 --> Dec 2024

P2, N=78, Recruiting, Canadian Cancer Trials Group

P1, N=24, Not yet recruiting, University Health Network, Toronto

No abstract available

No abstract available

No abstract available

P2, N=78, Recruiting, Canadian Cancer Trials Group | Not yet recruiting --> Recruiting | Initiation date: Jan 2023 --> Apr 2023

P1, N=180, Recruiting, Repare Therapeutics | N=120 --> 180 | Trial completion date: Apr 2024 --> Dec 2024

Substantial intratumoral spatial heterogeneity of CCNE1 copy number when measured by FISH was observed across ovarian and uterine tumors. The potential impact of CCNE1 amplification heterogeneity, cyclin E1 protein levels and CCNE1 amplification fragment size on response to RP-6306 in preclinical models are currently being investigated and will be reported.

P2, N=78, Not yet recruiting, Canadian Cancer Trials Group

RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.

P1, N=120, Recruiting, Repare Therapeutics | N=60 --> 120 | Trial completion date: Jun 2023 --> Apr 2024 | Trial primary completion date: Apr 2023 --> Oct 2023

To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumour regressions when combined with gemcitabine in models of CCNE1 amplification. CCNE1 overexpression disrupts CDK1 homeostasis at least in part through an early activation of the MMB-FOXM1 mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.

Our studies show that inhibition of PKMYT1 kinase activity impairs the growth of CCNE1 amplified cancer cell lines both in vitro and in vivo and stands to benefit cancer patients with CCNE1 amplification. A Phase I clinical trial (NCT04855656- Mythic Study) is currently underway to evaluate RP-6306 in patients with advanced solid tumors.

P1, N=60, Repare Therapeutics