Study Shows Feasibility of IO Maintenance After IO/VEGF TKI Response in Previously Untreated Metastatic ccRCC

Interrupting combination treatment with axitinib (Inlyta) and avelumab (Bavencio) and switching to avelumab maintenance after a response at 36 weeks led to a decrease in treatment-related toxicities and delayed tumor progression in previously untreated patients with metastatic clear cell renal cell carcinoma (ccRCC), according to data from the phase 2 TIDE-A trial (NCT04698213).

Findings presented at the 2023 ESMO Congress showed that in patients who discontinued axitinib, 72.4% (n = 21/29) remained free from progressive disease (PD) at week 8, meeting the primary end point of the study.

“TIDE-A is the first study showing the feasibility of VEGF TKI interruption with immunotherapy maintenance in patients with metastatic RCC achieving tumor response during combination therapy,” lead study author Roberto Iacovelli, MD, PhD, said in a presentation of the data. Iacovelli is a medical oncologist at the Fondazione Policlinico Gemelli IRCCS in Rome, Italy.

Although combination therapy with an immune-oncology (IO) agent and a VEGF TKI is a standard of care in the first-line setting for patients with metastatic RCC, adverse effects (AEs) have been associated with high rates of dose reductions of the VEGF TKI and treatment discontinuations. As such, the TIDE-A trial sought to evaluate IO maintenance in patients who achieved a response following 36 weeks of combination therapy.

The study enrolled patients with metastatic ccRCC who had measurable disease, no primary tumor, no bulky or symptomatic disease, no liver metastases, and an ECOG performance status of 0 or 1.

All patients received 800 mg of avelumab once every 2 weeks and 5 mg of axitinib twice per day for 36 weeks. Following tumor evaluation at week 36, patients who experienced a complete response (CR) or partial response (PR) received single-agent avelumab at 800 mg once every 2 weeks as maintenance therapy until PD. After PD, these patients then received 24 additional weeks of axitinib plus avelumab, at which point they either switched back to avelumab maintenance or continued with the combination, based on response or stable disease (SD) status.

“In cases of PD [during avelumab maintenance], patients restarted axitinib [plus avelumab] for 24 weeks, and we again interrupted axitinib in case of a new tumor response,” Iacovelli said.

Patients who had SD after 36 weeks of treatment with the combination continued receiving both agents until they experienced PD. Any patients who had PD during treatment with both agents stopped therapy.

Key secondary end points included progression-free survival (PFS), overall survival (OS), overall response rate, and safety.

As of the April 14, 2023, data cutoff, 89 patients were screened, and 79 who started treatment were included in the safety analysis. The efficacy analysis included 75 patients; 76% of these patients (n = 57) had a response, including 12% (n = 9) with a CR and 64% (n = 48) with a PR. In total, 29 patients stopped axitinib at week 36 (±2 weeks). Among the efficacy population, 40 patients remained on treatment at data cutoff. Twenty-two patients who stopped axitinib at week 36 remained on treatment.

In the efficacy population, the median age was 64 years (range, 42-84), and 65.3% were male. All patients underwent nephrectomy. Sites of metastases included lung (57.3%), lymph nodes (41.3%), pancreas (21.3%), bone (14.7%), kidney bed (14.7%), and soft tissue (14.7%). International Metastatic RCC Database Consortium prognostic class included favorable (40.0%), intermediate (57.3%), and poor (2.7%). Eighty percent of patients had an ECOG performance status of 0.

The median follow-up was 19.3 months for PFS and 18.9 months for OS. Patients evaluated for efficacy experienced a median PFS of 23.8 months (95% CI, not reached [NR]–NR). Median OS was NR. The 18-month PFS and OS rates were 70% and 94%, respectively.

“The selection of patients may have impacted the survival [data] reported in this analysis,” Iacovelli noted, pointing to the low proportion of patients with a poor prognosis and the lack of patients with liver metastases included in the study.

Among the 29 patients who received avelumab maintenance, the median duration of first maintenance was 16.0 weeks (95% CI, 10.9-21.1).

Regarding safety, the rates of any-grade and grade 3 or higher axitinib-related AEs were 34.2% and 11.4%, respectively, in the overall safety population. However, following the interruption of axitinib, 3.4% of patients experienced any-grade axitinib-related AEs; no grade 3 or higher toxicities were reported. The one patient who had an axitinib-related AE after interruption experienced grade 1 hand-foot syndrome and subsequently recovered.

In all patients, any-grade avelumab-related AEs were reported in 31.6% of patients, including 11.4% who had grade 3 or higher toxicities. Following the interruption of axitinib, 27.6% of patients had any-grade avelumab-related AEs, which were all grade 1 or 2. No treatment-related deaths were reported.

“These results warrant further investigation in a randomized trial,” Iacovelli concluded.

Disclosures: Dr Iacovelli reported being on the advisory board for Astellas, BMS, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, Bayer, and Eisai; being a consultant for Astellas, Ipsen, Merck, MSD, Pfizer, and Eisai; research support (inst) from BMS, MSD, and Pfizer; and being principal investigator on clinical trials for BMS, Exelixis, Ipsen, Lilly, MSD, and Seagen.

Reference

Iacovelli R, Ciccarese C, Bersanelli M, et al. Phase II study of avelumab (Ave) plus intermittent axitinib (Axi) in previously untreated patients (pts) with metastatic renal cell carcinoma (mRCC): the TIDE-A study. Ann Oncol. 2023;34(suppl 2):S1013. doi:10.1016/j.annonc.2023.09.1114