Commentary
Article
Author(s):
Casdatifan was well tolerated and had durable clinical activity in patients with metastatic clear cell renal cell carcinoma.
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.1,2
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.1
“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.2 “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.