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EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

The HIF-2α inhibitor casdatifan elicited responses and provided disease control with acceptable tolerability in patients with metastatic clear cell renal cell carcinoma (ccRCC), according to findings from the phase 1/1b ARC-20 study (NCT05536141) presented at the 

2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

Data from the dose-escalation portion of the study in which patients received casdatifan at 20 mg once daily, 50 mg once daily, 50 mg twice daily, 150 mg once daily, and 200 mg once daily, did not reveal any dose-limiting toxicities (DLTs). The maximum tolerated dose had not been reached at daily doses up to 150 mg; the 200-mg portion of the study is ongoing. Investigators selected 50 mg twice daily for dose expansion.

At a median follow-up of 11 months (range, 3-15+), casdatifan elicited an objective response rate (ORR) of 31.3% (90% CI, 16.1%-50.0%).1 One patient achieved a response after data cutoff and nearly 1 year on treatment, which boosted the ORR to 34% (95% CI, 16%-50%).2 The median time to response was 2.8 months (range, 1.2-5.5). The disease control rate (DCR) was 81.3% (90% CI, 63.6%-92.8%). Moreover, the median progression-free survival (PFS) had not been reached; 18.8% of patients had progressive disease.

“Based on our experience in the ARC-20 study, we have seen casdatifan’s ability to quickly bring tumor growth under control and its high response and disease control rates,” Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, the Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, and lead investigator of ARC-20, stated in a news release.

 “Based on these data, casdatifan has the potential to be a future treatment option for kidney cancer. I am particularly interested in planned research into novel combinations for casdatifan in both first- and second-line ccRCC.”

It is known that HIF-2α plays a role in the development and progression of ccRCC, and casdatifan is an orally bioavailable small-molecule inhibitor of the target.1 The agent has been found to have high potency and an acceptable human pharmacodynamic (PD) and pharmacokinetic (PK) profile, which shows dose-proportional exposure increase with mean terminal half-life of approximately 18 to 24 hours. Findings from a healthy volunteer study revealed that administration of the agent at 50 mg twice daily leads to drug exposure that is comparable to 100-mg once daily dosing.

ARC-20 enrolled patients with ccRCC and other advanced solid tumors who had at least 1 measurable lesion by RECIST 1.1 criteria and acceptable organ and bone marrow function.1,3 The trial utilizes a 3+3 design with a 21-day DLT window.1 In the dose-escalation phase, single-agent casdatifan is under evaluation at doses ranging from 20 mg once daily to 200 mg once daily.

In the dose-expansion phase, patients with second-line or later ccRCC (n = ~30/cohort) are given the drug at 50 mg twice daily, 50 mg once daily, and 150 mg once daily; the cohort examining dosing of 100 mg once daily is enrolling. The agent given at 100 mg once daily is also being explored in combination with cabozantinib (Cabometyx) in this population; this cohort is also enrolling.

The primary outcomes of the study are to evaluate adverse effects (AEs) and DLTs, and secondary outcomes include ORR and PK/PD profile of the drug.

Patients included in the analysis who received casdatifan at 50 mg twice daily had metastatic ccRCC that had progressed on at least 2 prior lines of treatment, including both a PD-1 and TKI inhibitor (n = 33). The median patient age was 62 years (range, 41-79) and 76% were male. Fifty-two percent of patients had an ECOG performance status of 1 and the remainder had a status of 0. With regard to International Metastatic Renal Cell Carcinoma Database Consortium risk score, 27% were favorable risk, 61% were intermediate risk, and 6% were poor risk; this information was unknown for 6% of patients.

Patients were heavily pretreated with 6%, 42%, 24%, and 27% of patients having previously received 1, 2, 3, or 4 or more lines of therapy, respectively. Moreover, 39%, 36%, 9%, and 15% of patients had received 1, 2, 3, or 4 or more regimens with any VEGFR TKI, respectively. Fifteen percent had received prior mTOR treatment.

Additional data from the dose-expansion phase showed that treatment with casdatifan showed a trend of reduction in target lesion diameters.

When looking at efficacy in the group of patients who received the agent at 50 mg once daily (n = 28), at a median follow-up of 8 months (range, 4-10+), the ORR was 25.0% (90% CI, 10.7%-44.9%). The confirmed ORR was 21.4% (90% CI, 8.3%-41.0%). The time to response was 4 months (range, 1.3-4.1). The DCR was 85.7% (95% CI, 67.3%-96.0%). Lastly, the median PFS was not reached and 14.3% of patients had progressive disease.

In the dose-escalation phase, the median treatment duration in those who received the agent at 50 mg twice daily (n = 6) was 2 months (range, 1-13). All patients experienced any treatment-emergent AEs (TEAEs), 83% of which were related to casdatifan. No TEAEs led to discontinuation for this group. TEAEs of interest related to the drug included anemia (83%) and fatigue (50%). Half of patients experienced serious TEAEs none of which were grade 4 or higher.

In the expansion phase, 97% of patients in the 50-mg twice daily group (n = 33) experienced any TEAEs, 94% of which were related to the study drug. Any grade 3 TEAEs were reported in 45% of patients and 42% of them were related to casdatifan. Serious TEAEs occurred in 12% of patients, 3% of which were related to study treatment. All-grade anemia occurred in 85% of patients, with 36% of patients experiencing grade 3 anemia. This toxicity led to interruptions or reductions for 33% and 6% of patients, respectively. All-grade hypoxia occurred in 15% of patients and 9% of patients experienced grade 3 events. Hypoxia led to dose interruptions or reductions for 12% and 3% of patients, respectively.

“These data demonstrate the therapeutic potential of casdatifan as a potential best-in-class HIF-2α inhibitor and support further development of casdatifan in ccRCC,” the study authors concluded.

Choueiri TK, Garmezy B, Park SH, et al. Casdatifan in patients with previously treated clear cell renal cell carcinoma and other solid tumors: preliminary results from ARC-20, a phase 1, open-label, dose-escalation and expansion study. Presented at: 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 23-25, 2024; Barcelona, Spain.

First clinical data for Arcus Biosciences’ HIF-2α inhibitor, casdatifan, showed promising clinical activity and tumor shrinkage in patients with metastatic kidney cancer. News release. Arcus Biosciences, Inc. October 24, 2024. Accessed November 1, 2024. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/First-Clinical-Data-for-Arcus-Biosciences-HIF-2a-Inhibitor-Casdatifan-Showed-Promising-Clinical-Activity-and-Tumor-Shrinkage-in-Patients-with-Metastatic-Kidney-Cancer/default.aspx

A phase 1 study of AB521 monotherapy and combination therapies in renal cell carcinoma and other solid tumors (ARC-20). ClinicalTrials.gov. Updated October 28, 2024. Accessed November 1, 2024. https://clinicaltrials.gov/study/NCT05536141

Casdatifan was well tolerated and had durable clinical activity in patients with metastatic clear cell renal cell carcinoma.

Casdatifan Demonstrates Durable Activity in Metastatic Clear Cell Renal Cell Carcinoma

The MAT2A inhibitor IDE397 showed antitumor activity, generated responses, and had a manageable safety profile among patients with MTAP-deletion urothelial cancer or non–small cell lung cancer (NSCLC), according to interim results from the expansion cohort of a phase 1 trial (NCT04794699) presented at the 

36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

In the monotherapy cohort, 33% of evaluable patients (n = 27) achieved a confirmed overall response with the daily 30 mg recommended phase 2 dose (RP2D) of IDE397, including 1 complete response and 8 partial responses (PRs). Further assessment of responses by tumor type showed confirmed overall response rates (ORRs) of 38% in patients with squamous NSCLC (n = 8), 22% in those with non–small cell adenocarcinoma (n = 9), and 40% in patients with urothelial carcinoma (n = 10). The disease control rate (DCR) was 93%.

Fifteen patients are continuing treatment as of the data cutoff date of August 22, 2024, including 7 responders. The median duration of treatment has not been reached but is greater than 6.2 months. The median time to response is approximately 2.7 months. Duration of response (DOR) and progression-free survival (PFS) data are immature.

Among patients who received IDE397, circulating tumor DNA (ctDNA) reduction was observed in those with evaluable samples (n = 21). The ctDNA molecular response rate (MMR) was 81%. Furthermore, 17 patients experienced a 50% or greater ctDNA reduction and 33% achieved a 90% or greater ctDNA reduction. All molecular responses were reported at the first ctDNA evaluation.

“We are excited by the clinical efficacy and safety profile observed with the potential first-in-class MAT2A inhibitor IDE397 at the 30-mg once-a-day RP2D, including multiple confirmed responses observed as a monotherapy agent in NSCLC and [patients with] urothelial cancer with MTAP-deletion,” Benjamin Herzberg, MD, presenting author and assistant professor of medicine at Columbia University in New York, New York, stated in a news release.

 “In addition, at the 30-mg once-a-day expansion dose, we observed a manageable safety profile with no drug-related serious adverse effects [AEs] or discontinuations. These data support potential combination development.”

IDE397 is a potent and selective allosteric MAT2A inhibitor that exploits the synthetic lethal relationship between MTAP and MAT2A for potential therapeutic benefit. The loss of MTAP typically confers dependence on MAT2A, thereby resulting in both accumulation of the metabolite MTA, which inhibits the methyltransferase PRMT5, and a reduction of SAM through MAT2A inhibition. This leads to pre-mRNA splicing defects, as well as the prevention of effective DNA replication and DNA damage repair modulation.

To assess the therapeutic potential of IDE397, several early-phase studies were conducted. In the current open-label, multicenter, multiple dose, phase 1 dose-escalation study, the agent is being evaluated in patients with NSCLC or urothelial cancer harboring a MTAP homozygous deletion by next-generation sequencing (NGS) or MTAP loss by immunohistochemistry (IHC).

 Patients are also required to have measurable disease by RECIST 1.1 criteria, an ECOG performance status (PS) of 0 or 1; and adequate organ function. Those with NSCLC must have received at least 1 prior line of therapy in the metastatic setting and progressed on a prior anti–PD‐(L)1 and/or targeted therapy.For those with urothelial cancer, previous exposure to more than 1 prior line of therapy and progression on prior cytotoxic and anti–PD‐(L)1 therapy is required.

As of the data cutoff date, 27 patients were enrolled onto the study at the RP2D. The median age was 67 years (range, 50-78), the majority of patients were male (70%), and 41% of patients had an ECOG PS of 1. MTAP loss was detected by NGS in 48% of patients and IHC in 52% of patients. The median number of prior lines of therapy was 2 to 3 (range, 1-7), with most patients receiving 1 to 2 lines (67%). Prior chemotherapy and checkpoint inhibition was reported in 96% and 74% of patients, respectively.

The study’s primary end points are dose-limiting toxicities with IDE397 and identification of the maximum tolerated dose and/or RP2D of the agent. Secondary end points include pharmacokinetics, pharmacodynamics, and initial antitumor activity.

No treatment-related discontinuations or serious AEs were observed with IDE397 in the safety population (n = 28), and long-term tolerability was reported among several patients treated with at least 6 cycles of the agent. Any-grade treatment-related AEs (TRAEs) were observed in 54% of patients, 18% of which were grade 3 or higher. Any-grade treatment-emergent AEs (TEAEs) were reported in 82% of patients, 39% of which were grade 3 or higher.

Common any-grade TEAEs and TRAEs included fatigue (TEAE, 32%; TRAE, 11%), peripheral neuropathy (29%; 25%), decreased appetite (25%; 11%), constipation (21%; 4%), blood creatinine increase (18%; 11%), nausea (18%; 11%), and asthenia (18%; 7%).

Further Investigations of IDE397 as Monotherapy and in Combination

Results from the first preliminary clinical case study of IDE397 and sacituzumab govitecan-hziy (Trodelvy) in MTAP-deletion urothelial cancer were also reported in the current analysis. One patient with both a MTAP-deletion and a

fusion achieved a PR by RECIST 1.1 criteria at 12 weeks and is continuing on treatment. Moreover, 2 patients with MTAP-deletion urothelial cancer reported a greater than 95% reduction in ctDNA at their first molecular response evaluation, suggesting rapid responses with the combination. 

Based on these data, investigators plan to initiate a phase 1 combination expansion cohort evaluating IDE397 plus sacituzumab govitecan in MTAP-deletion urothelial carcinoma in addition to their ongoing phase 1/2 combination study (NCT05975073) assessing AMG 193 plus IDE397 in MTAP-deletion solid tumors.

The monotherapy expansion cohort study of IDE397 will continue at the RP2D in both NSCLC and urothelial carcinoma. Data revealing the agent’s mechanism of action and differentiated toxicity profile from this cohort provide a clear rationale for further combination testing

with PRMT5 and topoisomerase payload–containing antibody-drug conjugates in MTAP‐deletion solid tumors.

“IDE397 is rapidly advancing as a monotherapy agent in MTAP-deletion urothelial cancer and NSCLC. Next, we are well positioned to advance our broad and potential first-in-class IDE397 rational combination strategy, including the targeted expansion in the fourth quarter with sacituzumab govitecan in urothelial cancer, the ongoing combination with AMG 193 with targeted expansion in NSCLC, combinations with IDEAYA’s internal MTAP-deletion pipeline that includes a targeted development candidate by year-end, among others,” Yujiro S. Hata, president and chief executive officer of IDEAYA Biosciences, concluded in the news release.

 Dr Herzberg reports employment at Columbia University;

Involvement in corporate sponsored research with AstraZeneca (Institutional), Repare Therapeutics (Institutional), IDEAYA Biosciences (Institutional), Amgen (Institutional), Revolution Medicines (Institutional), Astellas (Institutional), Monte Rosa Therapeutics (Institutional), Prelude Therapeutics (Institutional), Nested Therapeutics (Institutional), Stand up to Cancer (Personal), NIH/NCI ECIA 3P30CA013696‐49S2 (Personal), NIH/NCI Cancer Moonshot Biobank supplementary funding (Personal); serving as a consultant for Amgen, Astellas, AstraZeneca, Eli Lilly, Guidepoint Advisors; and receiving honoraria from Boxer Capital, OncLive/MJH Life Sciences, IDEOlogy Health, and Eisai.

Herzberg B, Johnson M, Kim CG, et al. Phase 1 expansion results of IDE397, a first-in-class, oral, MAT2A inhibitor in MTAP deleted non-small cell lung cancer and urothelial cancer. Presented at: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 23-25, 2024; Barcelona, Spain. Abstract LBA501.

IDEAYA announces positive interim phase 1 expansion data of IDE397 in MTAP-deletion urothelial and lung cancer as late-breaker oral presentation at EORTC-NCI-AACR 2024. News release. IDEAYA. October 25, 2024. Accessed October 29, 2024. https://www.prnewswire.com/news-releases/ideaya-announces-positive-interim-phase-1-expansion-data-of-ide397-in-mtap-deletion-urothelial-and-lung-cancer-as-late-breaker-oral-presentation-at-eortc-nci-aacr-2024-302286733.html

Study of IDE397 in participants with solid tumors harboring MTAP deletion. ClinicalTrials.gov. Updated June 27, 2024. Accessed October 29, 2024. https://clinicaltrials.gov/study/NCT04794699?tab=history&a=1

IDE397, a MAT2A inhibitor, demonstrated promising antitumor activity and a manageable safety profile in patients with MTAP-deletion urothelial cancer and NSCLC. In a phase 1 trial, 33% of patients achieved a confirmed overall response, with a disease control rate of 93%. The study reported significant ctDNA reductions, indicating molecular responses. IDE397 showed no serious adverse effects, supporting its potential for combination therapies. Ongoing studies aim to explore IDE397's efficacy in combination with other agents, such as sacituzumab govitecan, in MTAP-deletion cancers.

IDE397 is the first MAT2A inhibitor to show clinical activity and safety in patients with MTAP-deletion urothelial cancer and non–small cell lung cancer. 
		 	 	 		


IDE397 Shows Early Antitumor Activity, Safety in MTAP-Deletion Urothelial Cancer and NSCLC 

Solid Tumors | Image Credit: © tonstock 

Treatment with the first-in-class CDK8/19 inhibitor RVU120 showcased early signs of clinical activity and a favorable toxicity profile in patients with relapsed/refractory metastatic or advanced solid tumors, according to data from part 2 of the phase 1/2 RVU120-SOL-021 (AMNYS-51) trial (NCT05052255) presented at the 

36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

In part 2, patients received RVU120 at doses of 100 mg (n = 6) or 150 mg (n = 5) once daily; of the 11 total patients, 9 were determined to be evaluable for food-effect and 7 were evaluable for dose-limiting toxicities (DLTs). The most visible benefit was observed in patients with adenoid cystic carcinomas enrolled in parts 1 and 2 (n = 8). Five of these patients achieved a longer duration of treatment on RVU120 vs their most recent prior line of therapy. Additionally, a reduction of more than 10% of target lesion size was observed in 3 patients.

Among these patients, one with parotid adenoid cystic carcinoma (patient 4801-059) achieved an 11% reduction in target lesion size and remains on treatment for over 8 months. Another patient with nasopharyngeal adenoid cystic carcinoma (patient 3403-023) experienced a 20% reduction and discontinued treatment after more than 12 months. The last patient who had adenoid cystic carcinoma of the tongue (patient 3403-047) had a 14% reduction in lesion size and discontinued treatment after more than 5 months.

“RVU120 demonstrates a favorable safety profile in a heavily pretreated, unselected all-comer population of patients with solid tumors,” the lead study author Magdalena Błaszkowska, PhD, noted during a presentation of the data. “No [DLTs] or other safety signals were observed confirming CDK8/19 inhibition as a viable approach for cancer therapies.” For part 2, gastrointestinal-related events such as nausea and vomiting were the most common treatment-emergent adverse effects (AEs). These events were predominantly low-grade and manageable with supportive care.

Diving Into the Study Design and Patient Characteristics

The open-label, multicenter, multinational, single-group assignment, dose-escalation AMNYS-51 trial utilized a 3+3 design and enrolled patients with histologically confirmed and/or documented advanced or metastatic solid tumors who have exhausted all standard therapeutic options and or progressed on at least 1 prior systemic therapy and were not eligible to receive further available treatment.

 Patients needed to be at least 18 years of age, have measurable or evaluable disease by RECIST 1.1 criteria, an ECOG performance status ranging from 0 to 2, and an estimated life expectancy of at least 12 weeks.

The study was comprised of 2 parts. The first phase enrolled patients with relapsed/refractory solid tumor patients who have exhausted available standard of care.

 The primary objective was to examine the safety and tolerability of RVU120 monotherapy; secondary objectives included evaluating preliminary antitumor response and the agent’s pharmacokinetic (PK) profile.

Part 2 of the trial further evaluated the safety and tolerability of RVU120. The drug was administered at a starting dose of 100 mg daily, with dose escalation up to 150 mg in a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or withdrawal from the study. Safety assessments were based on the incidence of serious AEs and DLTs.

Investigators also explored the pharmacokinetics of RVU120, specifically assessing the impact of food intake on drug absorption. Patients were evaluated under both fed and fasted conditions. Fed status was defined by consuming at least 50% of a standard high-calorie meal, whereas fasted status was defined as no food intake for at least 10 hours before and 4 hours after dosing.

Pharmacodynamic activity was assessed by monitoring changes in STAT5 phosphorylation levels using flow cytometry. This was measured through ex-vivo plasma inhibitory assays, where cancer cells were exposed to patient plasma samples at baseline and on day 13 of cycle 1, once steady-state levels of RVU120 were achieved.

At the data cutoff date of September 16, 2024, 11 patients had been treated with RVU120 in part 2 of the trial. Of the 11 patients, 4 had adenoid cystic carcinoma, 2 had pancreatic adenocarcinoma, 2 had hormone receptor–positive/HER2-negative breast cancer, 1 had non–small cell lung cancer adenocarcinoma, 1 had melanoma, and 1 had colon cancer. The median patient age was 58 years, and the median number of previous lines of therapy was 5, indicative of a heavily pretreated population.

“Continuous [daily] dosing of RVU120 at doses of 100 mg and 150 mg is considered safe and may improve tolerability of RVU120 compared [with] 250 mg every other day,” the study authors wrote. AEs reported with RVU120 included nausea (55%), increased aspartate aminotransferase levels (45%), increased alanine aminotransferase levels (45%), vomiting (36%), dyspepsia (36%), increased N-terminal pro-B-type natriuretic peptide (27%), increased blood alkaline phosphatase level (27%), thrombocytopenia (27%), anemia (27%), pyrexia (18%), increased Troponin T 18%), dizziness (18%), increased lipase (18%), reduced appetite (18%), QT prolongation (18%), asthenia (18%), fatigue (18%), increased amylase (18%), and headache (18%).

PK data for RVU120 was characterized across the dosing interval on cycle 1, day 1, and after multiple doses on cycle 1, day 13. Plasma exposure of RVU120 increased with dose across the range investigated for evaluable patients. The median time to maximum concentration for RVU120 was observed approximately 6 hours after the agent was dosed, with a half-life of about 40 hours. Daily dosing at 100 mg and 150 mg resulted in similar plasma exposure to the equivalent every-other-day dose when measured after repeated dosing at cycle 1, day 13.

“Pharmacodynamic analyses support PK findings as 100 mg and 150 mg QD dosing led to the expected target engagement levels in relation to the equivalent RVU120 QOD dose at [cycle 1 day 13],” the study authors wrote.

A total of 4 ongoing phase 2 trials are further evaluating RVU120 as a monotherapy and in combinations for patients with hematological malignancies such as acute myeloid leukemia, high-risk myelodysplastic syndrome (MDS), low-risk MDS, and myelofibrosis.

Błaszkowska M, Jędrzejewski Ł, Dziadziuszko R, et al. Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor, in patients with relapsed/refractory metastatic or advanced solid tumors (AMNYS-51). Presented at: 2024 ENA Symposium; October 23-October 25, 2024; Barcelona, Spain.

Ryvu Therapeutics presents clinical and preclinical data on RVU120, RVU305, and novel synthetic lethality programs at the 2024 EORTC-NCI-AACR Symposium. News release. Ryvu Therapeutics. October 23, 2024. Accessed October 28, 2024. https://ryvu.com/2024/10/23/ryvu-therapeutics-presents-clinical-and-preclinical-data-on-rvu120-rvu305-and-novel-synthetic-lethality-programs-at-the-2024-eortc-nci-aacr-symposium/

RVU120 (SEL120) in patients with relapse/refractory metastatic or advanced solid tumors. ClinicalTrials.gov. Updated October 28, 2024. Accessed October 28, 2024. https://clinicaltrials.gov/study/NCT05052255

RVU120, a CDK8/19 inhibitor, demonstrated early clinical activity and a favorable safety profile in patients with relapsed/refractory metastatic or advanced solid tumors. In the phase 1/2 trial, patients received RVU120 at doses of 100 mg or 150 mg daily, showing promising results, particularly in adenoid cystic carcinoma cases. The study highlighted manageable gastrointestinal-related adverse effects and no dose-limiting toxicities. Pharmacokinetic analysis revealed consistent plasma exposure with daily dosing. Ongoing phase 2 trials are exploring RVU120 in hematological malignancies, including acute myeloid leukemia and myelodysplastic syndromes.

The first-in-class CDK8/19 inhibitor RVU120 demonstrated early signs of clinical activity in patients with relapsed/refractory metastatic or advanced solid tumors.

RVU120 Shows Early Promise in R/R Metastatic or Advanced Solid Tumors

 G12D–mutant pancreatic ductal adenocarcinoma

RMC-9805 was proven safe and active in patients with previously treated, 

 G12D–mutant pancreatic ductal adenocarcinoma (PDAC), according to preliminary data from the phase 1/1b RMC-9805-001 trial (NCT06040541) that were presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

At the data cutoff date of September 2, 2024, the objective response rate was 30% (n = 12) and the disease control rate was 80% (n = 32) among patients with PDAC who received 1200 mg once daily (n = 20) or twice daily (n = 20).

“We are pleased to report the first clinical data for RMC-9805, our novel, oral RAS(ON) G12D-selective covalent inhibitor, which demonstrate encouraging initial safety, tolerability and antitumor activity evidenced by tumor regressions,” Mark A. Goldsmith, MD, PhD, chief executive officer and chairman of Revolution Medicines, said in a news release.1 “While preliminary, these data bolster our belief that RMC-9805 has the potential to play a role in an emerging treatment paradigm for patients living with pancreatic cancer, both as monotherapy and in combinations. With [this] presentation, RMC-9805 becomes the third tri-complex compound from the Revolution Medicines pipeline to demonstrate clinical proof-of-concept, and it reaffirms our commitment to bringing novel RAS(ON) inhibitors to patients with RAS-addicted cancers.”

The RMC-9805-001 phase 1/1b study is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-9805 in patients with advanced solid tumors harboring a 

 G12D mutation. The study is comprised of a monotherapy and combination arm, in which RMC-9805 will be evaluated in combination with RMC-6236.

To be eligible for enrollment in the phase 1 study patients needed to have a pathologically documented, locally advanced or metastatic solid tumor with a 

 G12D mutation, received prior standard therapy, and had an ECOG performance status of 0 or 1, adequate organ function, and no active brain metastases. Patients who had previously received an investigational KRAS G12D inhibitor, pan- or multi-RAS inhibitor, or had prior exposure to any direct RAS-targeted therapy were excluded from enrollment.

Within the dose-escalation phase, patients received RMC-9805 orally, once daily at 150 mg, 300 mg, 600 mg, 900 mg, or 1200 mg; or twice daily at 300 mg, 450 mg, or 600 mg in 21-day cycles.

 As of the data cutoff date, 179 patients had received escalating doses of RMC-9805 in the monotherapy cohort.

Key end points were safety and tolerability, pharmacokinetic (PK) activity, and antitumor activity.

All treated patients had received a median of 2 prior lines of therapy (range, 0-9).

PK data indicated that a candidate recommended phase 2 dose should be 1200 mg once daily.

Regarding safety, no grade 4 or 5 treatment-related adverse effects (TRAEs) or serious AEs have been reported at the 1200 mg daily dose (n = 99). TRAEs included nausea (grade 1, 23%; grade 2, 4%), diarrhea (grade 1, 16%; grade 2, 4%), vomiting (grade 1, 13%; grade 2, 2%), rash (grade 1, 10%), alanine aminotransferase elevation (grade 1, 5%; grade 3, 1%), and aspartate aminotransferase elevation (grade 1, 3%; grade 2, 1%). TRAEs led to dose reduction in 4 patients, all owing to grade 1 events, and no treatment-related discontinuation occurred.

No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached.

“Pancreatic cancer is the most RAS-addicted of all major cancers and the G12D variant is the most common 

 mutation in pancreatic cancer. No approved targeted therapies are available for these patients, making this an area of significant unmet need,” David Hong, MD, of The University of Texas MD Anderson Cancer Center in Houston, stated in a news release.

 “This is a challenging disease, but we observed a promising level of antitumor activity at generally tolerable doses in this phase 1 study.”

 G12D–mutant PDAC and other solid tumors is ongoing.

Revolution Medicines presents initial data from RMC-9805 monotherapy study in patients with advanced pancreatic ductal adenocarcinoma. News release. Revolution Medicines, Inc. October 25, 2024. Accessed October 28, 2024. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-initial-data-rmc-9805-monotherapy

Pancreatic cancer update. Revolution Medicines. 2024. Accessed October 28, 2024. https://ir.revmed.com/static-files/87b6dcb4-94c9-4e79-9d8c-d21f2bb7aaaf

Study of RMC-9805 in participants with KRAS G12D-mutant solid tumors. ClinicalTrials.gov. Updated July 25, 2024. https://clinicaltrials.gov/study/NCT06040541

Preliminary data from the phase 1/1b RMC-9805-001 trial indicate that RMC-9805 is safe and active in patients with KRAS G12D–mutant pancreatic ductal adenocarcinoma (PDAC). The trial reported a 30% objective response rate and an 80% disease control rate. The study, which includes monotherapy and combination arms, aims to evaluate RMC-9805 in advanced solid tumors with KRAS G12D mutations. No grade 4 or 5 treatment-related adverse effects were observed, and dose optimization is ongoing to address the unmet need in pancreatic cancer treatment.

RMC-9805 was proven safe and active in patients with previously treated, KRAS G12D–mutant pancreatic ductal adenocarcinoma.

RMC-9805 Triggers Tumor Regressions in KRAS G12D–Mutant Pancreatic Cancer

Treatment with the orally bioavailable, small molecule inhibitor APR-1051 appears safe and well tolerated in patients with advanced solid tumors and select cancer-associated gene alterations, according to preliminary data from the first-in-human phase 1 ACESOT-1051 study (NCT06260514) presented at the 

Investigators shared data on 3 patients enrolled onto the study, stating that as of October 7, 2024, 1 patient who was treated with 30 mg of the agent had been on treatment for 6 days; 1 patient treated with 20 mg of the agent remained on treatment for 36 days; and 1 patient treated with 10 mg of the agent was treated for 50 days. The first patient is continuing treatment, the second patient withdrew consent, and the third patient had progressive disease.

“Preliminary results indicate APR-1051 is safe and well tolerated with no hematologic toxicity and 1 possible treatment-related grade 1 AE at the dose levels assessed,” study authors wrote in a poster presentation of the data.

In several cancer models, APR-1051 has previously demonstrated in vivo anti-proliferative activity, positioning it as a potential therapeutic anticancer agent with high potency and selectivity with favorable drug exposure and tumor concentration. This is due to the agent’s low off-target inhibition of 

, which differentiates it from other WEE1 inhibitors and may confer an improved toxicity profile compared with other inhibitors in this class. These findings led investigators to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations.

Eligible patients for ACESOT-1051 include those who are 18 years of age or older with an ECOG performance status of 0 or 1 (or a Karnofsky performance sale of at least 70); a diagnosis of an advanced or metastatic solid tumor that is locally advanced and not amenable to curative therapy or a diagnosis of stage IV disease with specific gene alterations; measurable disease per RECIST 1.1 criteria; no grade 2 or higher adverse effects (AEs) from prior treatment, and adequate bone marrow and organ function. Patients with uterine serous carcinoma are permitted to enroll regardless of biomarker status.

Exclusion criteria for the study include prior systemic anticancer therapy within 3 weeks or at least 5 half-lives prior to the first day of APR-1051 treatment; treatment with an investigational agent within 30 days or 5 half-lives before the first day of APR-1051 treatment; prior WEE1 inhibitor therapy; or concomitant treatment with other anticancer therapy.

Part 1 of the 2-part study is designed to investigate dose escalation in up to 39 patients. Part 2 will investigate dose selection in up to 40 patients. In the dose-escalation portion of the investigation, the doses begin at 10 mg at dose level 1 and continue through 150 mg at dose level 8. In part 2, patients will be randomly assigned 1:1 to receive APR-1051 at 1 of 2 selected dose levels and continue treatment until a recommended phase 2 dose (RP2D) is determined.

The primary objectives of the study include the characterization of safety, dose-limiting toxicity (DLT), the maximum tolerated dose (MTD) or maximum administered dose, and the RP2D. The primary end points consist of AEs; DLTs; and changes in physical examinations, performance status, and clinical laboratory values from baseline.

Secondary objectives include the characterization of pharmacokinetics and evaluation of the preliminary efficacy of the treatment. Secondary end points include the measurement of AUC

, and the use of RECIST 1.1 and Prostate Cancer Clinical Trials Working Group 3 guidelines to assess metastatic castration-resistant prostate cancer.

Exploratory objectives and end points include pharmacodynamic effects, as well as 

Regarding the patient characteristics of the 3 enrolled patients in the preliminary analysis, 2 were male, 1 was female, and the median age was 70 years (range, 53-80). One patient was American Indian or Native Alaskan, 1 patient was White, and 1 patient did not report their race. All 3 patients had an ECOG performance status of 1. Additionally, the median number of prior lines of systemic chemotherapies was 3 (range, 3-5); 2 patients had received 3 to 4 prior lines, and 1 patient received more than 4 prior lines.

All 3 patients had previously received taxane-based treatment, and 2 had received platinum-containing chemotherapy; 1 patient each was previously treated with an EGFR inhibitor, a VEGF inhibitor, a topoisomerase inhibitor, and an investigational agent, respectively. All 3 patients presented with 

 mutations. Two patients had pancreatic cancer, and 1 patient had gastric cancer.

Regarding all-cause AEs, patients experienced grade 1 and 2 constipation, grade 1 and 2 vomiting, grade 3 gastric obstruction, grade 1 hypoalbuminemia, grade 1 hypocalcemia, grade 1 hyperkalemia, grade 2 decreased appetite, grade 2 fatigue, grade 1 general edema, and grade 2 hiccups. Notably, 1 instance of grade 1 abdominal distension was reported to be possibly related to APR-1051.

“The study is currently enrolling into cohort 3 of the accelerated titration dose-escalation [portion],” study authors concluded in the poster. “Active enrollment is ongoing at 3 sites in the United States with additional sites planned.”

Yap TA, Sommerhalder D, Cheedella NKS, et al. Preliminary results of APR-1051, a WEE1 inhibitor, in a phase 1 study of patients with cancer-associated gene alterations (ACESOT-1051). Presented at: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 23-25, 2024; Barcelona, Spain. Poster PB065.

APR-1051, an orally bioavailable WEE1 inhibitor, shows promise in treating advanced solid tumors with specific gene alterations, as evidenced by preliminary data from the ACESOT-1051 phase 1 study. The study's initial findings indicate that APR-1051 is safe and well tolerated, with minimal adverse effects. The study aims to determine the maximum tolerated dose and recommended phase 2 dose through dose escalation and selection. Secondary objectives include evaluating pharmacokinetics and preliminary efficacy. The study is actively enrolling patients across multiple sites in the United States.

Treatment with APR-1051 appears safe and well tolerated in patients with advanced solid tumors and select cancer-associated gene alterations.

The WEE1 Inhibitor APR-1051 Shows Early Safety and Tolerability in Advanced, Mutated Solid Tumors 

Treatment with the potential first-in-class, investigational, oral, selective FGFR3 inhibitor TYRA-300 was safe and produced preliminary antitumor activity in patients with metastatic urothelial cancer harboring 

 alterations, according to data from the phase 1/2 SURF301 trial (NCT05544552).

-altered metastatic urothelial cancer treated with TYRA-300 at a dose of at least 90 mg per day (n = 11) achieved a partial response (PR) rate of 54.5%, and 3 of the 6 responses were ongoing at data cutoff. The disease control rate was 100%.

Ten of these patients received the agent at 90 mg per day, and the PR rate in this group was 50%. The lone evaluable patient treated at 120 mg per day also experienced a PR

The agent was well tolerated, and toxicities associated with FGFR1 and FGFR2 were uncommon. Ten percent of patients treated at doses of TYRA-300 ranging from 10 mg per day to 120 mg per day experienced serious treatment-related adverse effects (TRAEs). One dose-limiting toxicity of grade 3 diarrhea was reported at the 90-mg dose level. One patient treated at 90 mg per day experienced a grade 3 TRAE of increased alanine aminotransferase levels, which led to treatment discontinuation.

 alterations are known to drive tumor biology in a subset of urothelial cancer.While pan-FGFR inhibitors have demonstrated benefit and are approved for use in 

-altered urothelial cancer, they are associated with multiple intolerable on-target toxicities that limit their clinical utility. There remains an unmet need to deliver improved precision medicine for urothelial cancer patients, that allow patients to not only live longer, but live better,” Ben Tran, MD, an associate professor at Peter McCallum Cancer Centre in Melbourne, Australia, stated in a news release. “The initial results from TYRA-300 are very encouraging.I believe TYRA-300 has the potential to be a next-generation targeted therapy with high selectivity for FGFR3. These early data provide support that TYRA-300 can deliver improved antitumor activity and tolerability for our [patients with] 

-altered urothelial cancer. TYRA-300 has real potential to improve outcomes, and I look forward to its continued development in all 

SURF301 is a single-arm, multi-part, ongoing trial evaluating TYRA-300 in patients with 

 The phase 1 portion includes patients at least 18 years of age with histologically confirmed advanced solid tumors who have exhausted standard-of-care treatment options. Patients are required to have an ECOG performance status of 0 or 1. In part A of phase 1, patients must have evaluable disease per RECIST 1.1 criteria; measurable disease per RECIST 1.1 criteria is required for part B. Notably, histologically confirmed advanced solid tumors harboring eligible 

 mutations or fusions are only necessary for inclusion in part B.

Phase 2 comprises patients at least 18 years of age with 

-altered urothelial carcinoma who progressed on a prior FGFR inhibitor and harbor a resistance mutation or other kinase domain mutation; patients with 

-altered urothelial carcinoma who have not received a prior FGFR inhibitor; and patients with any solid tumor harboring an eligible 

Key exclusion criteria consist of any ocular condition likely to increase the risk of eye toxicity, a history of or current uncontrolled cardiovascular disease, and active, symptomatic, or untreated brain metastases.

Part A of phase 1 was the dose-escalation portion of the study, in which TYRA-300 was evaluated at doses ranging from 10 mg to 120 mg once per day. This portion of the study has concluded.

 Part B of phase 1 serves as the dose expansion portion of the study, and phase 2 will further evaluate TYRA-300 at doses determined in phase 1.

The study’s primary end points are determination of the maximum tolerated dose in phase 1, part A; determination of the recommended phase 2 dose in phase 1, part B; and overall response rate in phase 2.

Forty-one patients have been enrolled onto the phase 1 portion as of the data cutoff date of August 15, 2024. Among these patients, 44% received at least 3 prior lines of therapy. Seventy-six percent of patients with 

-altered metastatic urothelial cancer received at least 3 prior lines of therapy.

Pharmacokinetic and pharmacodynamic data from 41 evaluable patients showed that the plasma concentrations of TYRA-300 indicated adequate target coverage at doses of at least 90 mg per day.

"The preliminary data are what we were expecting to see with TYRA-300, being generally well-tolerated with fewer toxicities, and anti-tumor activity in [patients with] 

-altered metastatic urothelial cancer," said Doug Warner, MD, chief medical officer of TYRA Biosciences, stated in a news release. “The emerging profile of TYRA-300 supports further development in metastatic urothelial cancer, where an attractive opportunity exists for a more tolerable option in the second line.”

Tyra Biosciences reports interim clinical proof-of-concept data for TYRA-300, an investigational oral FGFR3-selective inhibitor, in phase 1/2 SURF301 study in patients with metastatic urothelial cancer (mUC). News release. Tyra Biosciences. October 24, 2024. Accessed October 25, 2024. https://www.prnewswire.com/news-releases/tyra-biosciences-reports-interim-clinical-proof-of-concept-data-for-tyra-300-an-investigational-oral-fgfr3-selective-inhibitor-in-phase-12-surf301-study-in-patients-with-metastatic-urothelial-cancer-muc-302286685.html 

Safety and preliminary anti-tumor activity of TYRA-300 in advanced urothelial carcinoma and other solid tumors with FGFR3 gene alterations (SURF301). ClinicalTrials.gov. Updated October 3, 2024. Accessed October 25, 2024. https://clinicaltrials.gov/study/NCT05544552

TYRA-300, an investigational oral FGFR3 inhibitor, demonstrated safety and preliminary antitumor activity in patients with FGFR3-altered metastatic urothelial cancer in the phase 1/2 SURF301 trial. A partial response rate of 54.5% was observed at doses of at least 90 mg per day, with a 100% disease control rate. The agent was well tolerated, with uncommon FGFR1 and FGFR2 toxicities. The trial aims to address the unmet need for more tolerable FGFR3-targeted therapies, with ongoing development in FGFR3-altered cancers.

TYRA-300 was safe and produced antitumor activity in metastatic urothelial cancer harboring FGFR3 alterations.

EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics | Conference

Casdatifan Demonstrates Durable Activity in Metastatic Clear Cell Renal Cell Carcinoma

IDE397 Shows Early Antitumor Activity, Safety in MTAP-Deletion Urothelial Cancer and NSCLC

RVU120 Shows Early Promise in R/R Metastatic or Advanced Solid Tumors

RMC-9805 Triggers Tumor Regressions in KRAS G12D–Mutant Pancreatic Cancer

The WEE1 Inhibitor APR-1051 Shows Early Safety and Tolerability in Advanced, Mutated Solid Tumors

TYRA-300 Is Safe, Generates Preliminary Antitumor Activity in FGFR3+ Metastatic Urothelial Cancer