RP-3500 Shows Promising Safety, Clinical Activity in Solid Tumors With Synthetic Lethal Genomic Alterations

Timothy A. Yap, PhD

The ATR inhibitor RP-3500 demonstrated a manageable safety profile and promising early antitumor efficacy in patients whose tumors harbor select genomic alterations when administered at doses of 100 mg or more, according to results from the phase 1/2 TRESR trial (NCT04497116).¹

Results from the study, which were presented during the 2021 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, showed that meaningful clinical benefit was observed in 49% of 69 patients, with 12 patients experiencing objective tumor responses. Of the 12 responses, 8 were RECIST v1.1 confirmed/unconfirmed partial responses (PRs), 2 were Prostate Cancer Clinical Trials Working Group 3 (PCWG3) prostate-specific antigen (PSA) responses, and 2 were Gynecological Cancer Intergroup (GCIG) cancer antigen 125 responses.

Additionally, 14 patients had ongoing stable disease, per RECIST criteria, for approximately 16 weeks, and 8 patients experienced early significant decreases in tumor markers with less than 30% tumor shrinkage.

“Not only did RP-3500 demonstrate a favorable and differentiated safety profile, but our initial data also showed promising and distinct early efficacy,” principle investigator Timothy A. Yap, PhD, associate professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, stated in a press release.² “Although this phase 1 study has only had approximately 9 months of dosing at efficacious doses of 100 mg or more of RP-3500, we are encouraged by what we have observed so far in this hard-to-treat advanced cancer patient population.”

ATR inhibition is synthetically lethal and genomic alterations affect DNA damage response (DDR). Moreover, ATR is a key mediator of cellular DDR and is activated in response to DNA replication stress. RP-3500 is a potent and highly selective ATR inhibitor, with low nanomolar potency in biochemical and cell-based assays; a more than 2,000-fold selectivity over ATM, DNA-PK and PI3Ka; and demonstrated single-agent activity in tumor models of varying histologies and DDR defects.

A genome-wide CRISPR-based screening platform has identified the following synthetic lethal genomic alterations that predict for sensitivity: ATM, ATRIP, BRCA1/2, CHEK2, CDK12, CHTF8, FZR1, MRE11, NBN, PALB2, RAD17, RAD50, RAD51B/C/D, REV3L, RNASEH2A/B, SETD2.

In the TRESR study, investigators sought to examine the agent in patients with advanced solid tumors. To be eligible for enrollment, patients needed to be 18 years of age or older and have solid tumors that were resistant, refractory, and/or intolerant to standard therapy. Additionally, patients had to have tumors with centrally reviewed deleterious STEP2 alterations, an ECOG performance status of 0 or 1, hemoglobin levels of 9.5 g/dL or more, platelets of 140 K/uL or more, and an absolute neutrophil count of 1.7 K/uL or more.

In total, 101 patients were enrolled at a data cutoff of August 15, 2021. The primary end points of the study were safety and tolerability, as well as identifying the recommended phase 2 dose (RP2D) of the agent. Other end points of interest included pharmacokinetics, pharmacodynamics in paired tumor biopsies, preliminary antitumor activity, and kinetics of circulating tumor DNA (ctDNA).

Among the 101 patients enrolled, the median age was 63 years (range, 33-77), 42 were male, and 49 were female. Forty-eight patients had an ECOG performance status of 0, and 53 had a performance status of 1. Additionally, 51 patients had received 1 to 3 prior therapies, and 45 had received 4 or more. Moreover, 62 patients had received prior platinum-based chemotherapy, 28 had received prior treatment with a PARP inhibitor, and 20 had previously received a PD-1/PD-L1 inhibitor.

Nineteen patients enrolled on the trial had ovarian cancer, 18 had prostate cancer, 13 had breast cancer, 8 had pancreatic cancer, 8 had sarcoma, and 35 had another form of cancer (including colorectal cancer, bile duct cancer, gastrointestinal cancer, endometrial cancer, lung cancer, melanoma, mesothelioma, etc.).

The most commonly occurring genotypes observed in patients were ATM (n = 37), BRCA1 (n = 31), BCRA2 (n = 13), CDK12 (n = 7), and other STEP2 genotypes (n = 23; including CHEK2, NBN, PALB2, RAD51C/B, RNASEH2, SETD2, FZR1).

RP-3500 was evaluated at multiple doses and schedules as part of an adaptive BOIN design; sufficient cohort sizes were used to ensure a robust maximum tolerated dose (MTD)/RP2D decision. Once and twice daily doses were evaluated. Dose-limiting toxicities (DLTs) included anemia and thrombocytopenia. The MTD/RP2D was established to be a daily dose of 160 mg to be given on a 3-days-on, 4-days-off schedule.

In terms of safety, all-grade treatment-emergent adverse effects (TEAEs) occurred in 76.3% of the 76 patients who received the MTD/RP2D. Of those TEAEs, 25.0% were grade 3 in severity, and 1.3% were grade 4. Notably, 52.2% of patients experienced any-grade anemia, and 14.5% experienced grade 3 anemia. Other common TEAEs reported in this group included fatigue (25.0%), decreased appetite (22.5%), and nausea (21.1%).

Additionally, dose interruptions, reductions, and transfusions were noted to be infrequent on this dosing schedule, and no discontinuations related to the study drug were reported.

Regarding the pharmacokinetic profile of RP-3500, the agent was found to achieve its efficacy targets when given at doses of 100 mg or higher. Moreover, the half-life of the agent was approximately 6 hours and the linear Cmax and area under the curve was found to be consistent across all doses examined. The daily regimen was selected for the RP2D over the twice daily regimen based on minimal differences observed in target coverage. Moreover, the drug was found to be safe to administer with or without food.

Regarding the pharmacodynamics of the agent, RP-3500 demonstrated robust pathway modulation in paired tumor biopsies, with consistent and statistically significant on-treatment increases in DNA damage-induced γH2AX and p-KAP1 across tumor genotypes.

Early analysis of treatment duration showed that 54% of patients were receiving ongoing therapy with the RP-3500 (n = 54/101), and that clinical activity was demonstrated across multiple tumor types and STEP2 alterations, including castration-resistant prostate cancer (ATM and CDK12), ovarian cancer (BRCA1 and RAD51C), estrogen receptor–positive breast cancer (BRCA1), head and neck squamous cell carcinomas (BRCA1), and melanoma (BRCA2).

Deep molecular responses in ctDNA were also observed in 37 patients with tumors that harbored STEP2 genomic alterations. The best mean variant allele frequency (mVAF) was calculated as the percent decrease from baseline in patients with 1 or more on-treatment ctDNA samples, and early and significant decreases in mVAFR in were observed in tumors with multiple genotypes.

Moreover, a preliminary analysis of the data suggests that ctDNA response may predict clinical benefit with the agent, as patients with clinical PRs showed early and frequently significant reductions in mVAFR in ctDNA with RP-3500. Further analyses will be performed to correlate ctDNA responses with clinical efficacy and duration of response to evaluate the ability of ctDNA to predict clinical benefit with the agent.

“Our promising early clinical data of this potent and highly selective ATR inhibitor offer a clear direction for further development of RP-3500,” Yap added. “We will continue to assess RP-3500 in patients with defined molecular alterations and also in novel rational combinations.”

References

1. Yap T, Lee E, Spigel D, et al. First-in-human biomarker-driven Phase I TRESR trial of ATR inhibitor RP-3500 in patients with advanced solid tumors harboring synthetic lethal genomic alterations. Presented at: 2021 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 7-10, 2021; virtual.
2. ATR inhibitor RP-3500 demonstrates safety and early clinical benefit. News release. The University of Texas MD Anderson Cancer Center. October 08, 2021. Accessed October 14, 2021. https://bit.ly/3mNALS0