Volrustomig Demonstrates Activity in Treatment-Naive Advanced ccRCC

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Volrustomig (MEDI5752) demonstrated efficacy when used as frontline treatment in patients with clear cell renal cell carcinoma (ccRCC) with a toxicity profile that is consistent with dual checkpoint inhibition, according to data from the RCC V750/V500 expansion cohorts of a phase 1 study (NCT03530397) during the 2023 ESMO Congress.¹

At a median follow-up of 22.7 months (range, 2.2-27.4), volrustomig given at 750 mg every 3 weeks resulted in an objective response rate (ORR) of 48.4% in response-evaluable patients in cohort V750 (n = 31); this included a complete response (CR) rate of 9.7%. The disease control rate (DCR) was 90.3%. Moreover, the median duration of response (DOR) was 17.0 months (95% CI, 9.8-not evaluable [NE]). The median progression-free survival (PFS) was 12.3 months (95% CI, 8.1-22.8), with a 12-month PFS rate was 51.7%.

At a median follow-up of 14.9 months (range, 1.6-21.7), volrustomig given at 500 mg every 3 weeks led to an ORR of 45.5%, with a CR rate of 6.1%, in response-evaluable patients in cohort V500 (n = 33). The DCR was 69.7% and the median DOR was 11.5 months (95% CI, 5.8-NE). The median PFS was 9.7 months (95% CI, 3.9-NE), with a 12-month PFS rate of 43.8%.

Volrustomig showed efficacy across the International mRCC Database Consortium (IMDC) risk groups. Within the V750 cohort, the ORRs with volrustomig in those with intermediate/poor (I/P; n = 23) or favorable (F; n = 8) risk were 56.5% and 25.0%, respectively. The median DOR in the I/P subset was 15.4 months (95% CI, 8.4-NE) and not reached (NR; 95% CI, NE-NE) in the F subset. Within the V500 cohort, volrustomig induced an ORR of 38.1% in those with I/P risk (n = 21) and 58.3% in those with F risk (n = 12). The median DOR was 8.4 months (95% CI, 2.9-NE) in the I/P subgroup and NR (95% CI, 2.8-NE) in the F subgroup.

“Volrustomig has the potential to improve outcomes in patients with advanced RCC,” Martin H. Voss, MD, clinical director of Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York, said in a presentation of the data.

The monovalent PD-1/CTLA-4 bispecific monoclonal antibody achieves full PD-1 blockade as well as preferential CTLA-4 inhibition on activated PD-1–positive T cells. When administered at doses of 500 mg or higher, the agent allows for CTLA-4 pharmacodynamic activity.

Prior data indicated that when volrustomig was given at 1500 mg every 3 weeks it had efficacy, with an ORR of 58%; however, dosing was limited by immune-related adverse effects (irAEs). Grade 3 or 4 liver toxicity was observed in approximately 25% of patients and more than 70% of patients discontinued treatment due to AEs.

The phase 1 study enrolled patients with ccRCC who were naive to immunotherapy and VEGF inhibition. Patients were randomly assigned 1:1 to the V750 cohort (n = 32) or the V500 cohort (n = 33). The trial’s primary objective was antitumor activity in the form of ORR by RECIST v1.1 criteria. Key secondary objectives included pharmacokinetics and immunogenicity.

The data cutoff date was August 25, 2023. In the V750 cohort, the median age was 59 years (range, 36-78). More than half of patients were male (68.8%), had an ECOG performance status of 0 (65.6%), and had a PD-L1 expression of less than 1% (65.6%). Moreover, 53.1% had prior nephrectomy. Regarding IMDC category, 25.0% had F risk and 71.9% had I/P risk. In the V500 cohort, the median age was 64 years (range, 47-86). Most patients were male (81.8%), had an ECOG performance status of 0 (63.6%), had prior nephrectomy (66.7%), and a PD-L1 expression of less than 1% (78.8%). Regarding IMDC category, 36.4% and 63.6% of patients had F and I/P risk, respectively.

Flow cytometry analysis indicated that volrustomig led to peripheral CD4 T-cell activation equivalent to tremelimumab (Imjudo) at 3 mg/kg to 10 mg/kg. Single cell multiomics and artificial intelligence analysis showed that volrustomig activated peripheral CD4 T-cell central memory that was consistent with anti–CTLA-4 effects and linked with clinical response.

Patients in the V750 cohort had a median exposure of 5.52 months (range, 0.7-23.4). Treatment-related AEs (TRAEs) were experienced by 96.9% of patients; these effects were grade 3 or 4 in 62.5% of patients. Moreover, 46.9% of patients experienced TRAEs that resulted in discontinuation of the agent. The most common TRAEs included pruritus (all, 50%; grade 3 or 4, 0%), hyperthyroidism (34.4%; 3.1%), hypothyroidism (28.1%; 0%), maculopapular rash (28.1%; 6.3%), diarrhea (25%; 3.1%), increased aspartate aminotransferase (AST; 25%; 6.3%), increased alanine aminotransferase (ALT; 18.8%; 9.4%), infusion-related reaction (15.6%; 0%), and pneumonitis (3.1%; 0%).

Those in the V500 cohort had a median exposure to volrustomig of 5.98 months (range, 0.7-20.0). All TRAEs occurred in 93.9% of patients and grade 3 or 4 TRAEs were reported in 42.4% of patients; TRAEs led to treatment discontinuation of 30.4% of patients. One treatment-related death occurred in the form of bronchopulmonary aspergillosis with immune neutropenia. Patients experienced pruritus (39.4%), hyperthyroidism (21.2%), hypothyroidism (18.2%), maculopapular rash (6.1%), diarrhea (21.2%), increased AST (12.1%), increased ALT (12.1%), infusion-related reaction (3%), pneumonitis (6.1%), and colitis (6.1%). Grade 3 or 4 TRAEs included diarrhea, increased AST, and increased ALT (6.1% each).

The safety and efficacy of volrustomig in combination with axitinib (Inlyta) is under exploration in patients with advanced RCC as part of an ongoing phase 1 trial (NCT04522323).²

Editor’s Note: Dr Voss disclosed serving as an invited speaker for IDEOlogy Health, WebMD, MedNet, Talem Health, OncLive, Axiom, and Clinical Care Options. He serves on advisory boards for Eisai, Exelixis, Merck, Calithera, Aveo, Genentech, Oncorena, Affimed, and MICU Rx. Sponsor or funding was received from Pfizer. With regard to non-financial interests, Dr Voss shared being a principal investigator for AstraZeneca, Pfizer, Merck, and Genentech; and an advisory role for Affimed, Aravive, onQuality, Immunitybio, AstraZeneca, Mertelsmann Foundation, Genentech, and Merck.

References

1. Voss MH, Garmezy B, Kim SH, et al. MEDI5752 (volrustomig), a novel PD-1/CTLA-4 bispecific antibody, in the first-line (1L) treatment of 65 patients (pts) with advanced clear cell renal cell carcinoma (aRCC). Ann Oncol. 2023;34(suppl 2):S1012. doi:10.1016/j.annonc.2023.09.1113
2. A study to evaluate MEDI5752 and axitinib in subjects with advanced renal cell carcinoma. ClinicalTrials.gov. Updated November 13, 2023. Accessed November 15, 2023. https://clinicaltrials.gov/study/NCT04522323