ASCO GU 2021: THE HIF-2 alpha inhibitor Belzutifan is visible in advanced renal transparent cell carcinoma

Belzutifan (MK-6482) is a small molecule HIF-2 alpha inhibitor that has been shown in preclinical studies to induce tumor subsidion in renal cell carcinoma models, and the first Phase I study of human solid tumors has been reported.
oral report of the 2021 ASCO GU Conference, a phase I./II. study of MK-6482 monodrative therapy and a phase II. study of MK-6482 combined with cabodinib were retested, and HIF-2 alpha inhibitors showed great potential in the treatment of advanced kidney cancer! Dr. Toni Choueiri presented the preliminary results of a phase 2 study that combined belzutifan (MK-6482) with the U.S. Federal Drug Administration (FDA) approved a variety of TKI, kabatinib.
As described in other presentations at this year's American Society of Clinical Oncology's Urogenespheric Tract Cancer Symposium (ASCO GU), more than 90 percent of patients with transparent cell nephroblastoma (ccRCC) have occasional genomic changes that lead to defective VHL proteins and false hypoxia.
the 30th point is the basic principle of targeting HIF2alpha with belzutifan.
, transparent cell carcinoma (ccRCC) accounts for about 70 percent of kidney cancer cases.
first-line treatments have been approved for ccRCC, but few patients can achieve complete remission, with most patients progressing within 5 to 11 months.
leading cancer-causing factor in RCC is transcription factor hypoxia-induced factor 2 alpha (HIF-2 alpha).
MK-6482 is a small molecule HIF-2 alpha inhibitor that blocks the heterogeneous copolymer of HIF-2 alpha and HIF-1 beta, inducing tumors to subside in mice transplanting renal cell carcinoma models.
the HIF-2 alpha inhibitor Belzutifan (MK-6482) has been shown to have good anti-tumor activity and safety in phase I. studies in patients with metastases ccRCC.
study (NCT03634540) further explores the efficacy of Belzutifan in combining cabotinib with patients with advanced cCRCC who were treated for the first time (queue 1) or who had previously received immunotherapy and TKIs (queue 2).
study consisted of two groups of patients with late-stage transparent cellSRCC.
patients were not treated in Queue 1, and in Queue 2, patients had previously received immunotherapy and/or TKI.
presentation focused on the preliminary results of Queue 2.
in Queue 2, all subjects had metastatic renal transparent cell carcinoma (ccRCC) and had received no more than 2 systematic treatments in the past.
At the beginning of the study, 6 patients in Queue 1 or Queue 2 were orally oral once a day with Belzutifan (120 mg) combined with cabotinib (60 mg) for 21 days, thus determining the recommended dose for Phase II (RPTD).
this preliminary analysis provided data from Queue 2 to assess the efficacy of patients who received ≥1 dose and followed ≥ for six months.
end point of the study was the observation mitigation rate (ORR) assessed by the researchers based on RECIST v1.1.
secondary endpoints include No Progress Lifetime (PFS), Total Lifetime (OS), and Mitigation Duration (DOR).
all queue participants are evaluated for security.
53 patients were included in the safety analysis population.
64 years old, 73.6% male and 54.7% ECOG status 1.
28 (52.8%) received first-line treatment and 24 (45.2%) received second-line treatment.
follow≥ 6 months of follow-up (n-41) had a medium follow-up time of 11.3 months from registration to data cut-off (range: 5.6-24.0).
ORR was 22.0% (9 cases reached PR) and 90.2% had tumor shrinking.
disease control rate (CR-PR-SD) was 92.7%.
DOR does not arrive (range: 3.7 plus to 14.8 plus months) (cutoff time is October 15, 2020).
PFS was 16.8 months (95% CI: 9.2 to NR) and the 6-month PFS was 78.3%.
95.0% for the first six months of the year.
safety, 52 out of 53 patients experienced treatment-related adverse events (TRAEs), but 92% of them were level 1 and level 2.
the most common TRAEs (≥30%) were anemia (75.5%), fatigue (67.9%), hand-foot syndrome (52.8%), diarrhea (45.3%), hypertension (43.4%), nausea (35.8%) and elevated ALT/AST (32-34%).
≥5 percent of the subjects experienced level 3 TRAE as hypertension (22.4 percent), anemia (11.3 percent), fatigue (11.3 percent) and elevated ALT (5.7 percent).
two subjects experienced level 3 hypoxia.
did not occur level 4 TRAP or die.
TRAEs resulted in the deactivity of berzutifan and eight subjects (15.1 per cent) of cabozantinib by six subjects (11.3 per cent).
this preliminary analysis, belzutifan and cabodinib showed good anti-tumor activity in the backline therapy of metastasis ccRCC patients.
security is as expected.
, Queue 2 is still being followed up and the data for Queue 1 (previously untreated cCRCC patients) is still pending.
But it is gratifying to note that the mechanism pathophysiology that targets false hypoxia at the level of transcription factors that control downstream signal conduction can also be targeted (e.g. VEGFRs with cabotinib).
the future must include an assessment of subjects who may be resistant to (or resistant to) these therapies and compare them in head-to-head studies.