TIDE-A: Avelumab Plus Intermittent Axitinib in Previously Untreated mRCC

A recent phase 2 study provided proof of concept for the safety of tyrosine kinase inhibitor (TKI) discontinuation for select patients with metastatic renal cell carcinoma (mRCC) who show response to TKI-plus-immunotherapy combinations in the first-line setting.

Results of the study were presented at the European Society for Medical Oncology Congress 2023.

Combinations of VEGFR-TKI and anti-PD1/L1 immunotherapy are considered standard of care for first-line therapy of mRCC due to increased response rate, prolonged progression-free survival (PFS), and overall survival benefit. However, many treatment-related adverse events (AEs) from these combinations are due to the TKIs.

Roberto Iacovelli, MD, PhD, of Gemelli University Hospital, and colleagues designed the phase 2 TIDE-A study to determine if TKI discontinuation is feasible in this setting. A total of 79 patients with mRCC and no prior nephrectomy and no symptomatic or bulky disease nor liver metastasis were enrolled. Patients were treated with avelumab (800 mg flat dose Q2W) plus axitinib (5 mg PO BID for 36 weeks).

At 36 weeks, those who received partial response according to the Response Evaluation Criteria in Solid Tumors discontinued axitinib and continued avelumab until disease progression or unacceptable toxicity. In the event of disease progression, they restarted axitinib for 24 weeks and discontinued it again if a new partial response occurred. Patients with stable disease at 36 weeks continued the combination until disease progression or unacceptable toxicity.

The primary end point was rate of patients free of progression (FoP) after 8 weeks from axitinib discontinuation (≥48%). Secondary end points included median PFS, objective response rate (ORR), and safety.

Of the total patient population, 75 were evaluated for efficacy. Twenty-nine patients (38.2%) discontinued axitinib at 36 weeks. The rate of patients FoP after 8 weeks was 72.4%.

After a median follow-up of 19.3 months, the median PFS was 23.8 months (95% CI, not reached to not reached), with 70% of patients FoP at 18 months. The ORR was 76% (12% complete response, 64% partial response); 18.7% had stable disease and 4.0% had disease progression.

The median duration of first axitinib discontinuation was 16.0 weeks (95% CI, 10.9-21.1). Among the 29 patients who discontinued axitinib, 9 were still ongoing, 20 had disease progression, and 19 restarted axitinib (9 ongoing, 6 had further disease progression, and 4 discontinued axitinib again).

Dr. Iacovelli and colleagues further reported that 96.2% of patients had at least 1 AE and 40.5% had grade 3/4 AEs with no treatment-related deaths. All-grade and grade 3/4 axitinib-related AEs were noted in 34.2% and 11.4% of patients, respectively, and in 10.3% and 0% of those who discontinued axitinib, respectively.

“The TIDE-A study shows that TKI discontinuation is safe for selected mRCC patients with evidence of response to TKI-plus-immunotherapy combinations in the first-line setting,” they concluded. “Axitinib discontinuation allows for decreasing of toxicity while maintaining the possibility of axitinib benefit in the case of reintroduction.”