Stereotactic ablative body radiotherapy in combination with pembrolizumab shows efficacy in first-line for oligometastatic clear cell renal cell carcinoma

Results of the phase I/II RAPPORT trial demonstrate the feasibility of stereotactic ablative body radiotherapy followed by pembrolizumab as a treatment modality for patients with oligometastatic clear cell renal cell carcinoma. The results obtained in this study compare favourably to the results obtained with pembrolizumab alone in this setting and justify further evaluation of this treatment modality in patients with ccRCC.

Introduction

Stereotactic ablative body radiotherapy (SABR) is a treatment option for patients with oligometastatic clear cell renal cell carcinoma (ccRCC), however, patients often experience distant progression. Although it is not the current standard of care (SoC), the PD-1 inhibitor pembrolizumab did demonstrate clinical activity in previously untreated advanced ccRCC patients with an overall response rate (ORR) of 34% and a median progression-free survival (PFS) of 7.1 months (KEYNOTE-427). In the phase I/II RAPPORT trial, the combination of SABR with pembrolizumab is being studied as a treatment modality for ccRCC patients with oligometastatic disease.

This single arm trial enrolled 30 oligometastatic ccRCC patients to receive SABR to all metastatic sites (20Gy single dose, or 30Gy across 10 fractions of conventional radiotherapy [CRT] if SABR was not feasible) followed by pembrolizumab (200 mg every 3 weeks) for 8 cycles. The primary endpoint of this study was safety, but the study also looked into f PFS, overall survival (OS), disease control rate (DCR) and ORR as secondary study objectives.

SABR and pembrolizumab induces an ORR of 63%

The median age of participants in this study was 62 years and 77% of them were being male. More than three quarters (77%) of patients did not receive prior therapy. 30% underwent a metastasectomy and 20 % received prior therapy with a tyrosine kinase inhibitor. A total of 83 oligometastatic sites were irradiated (median 3 per patient), of which 77% received SABR and 33% received CRT. This included 8 adrenal, 11 bone, 43 lung, 12 lymph node and 9 soft tissue metastases. All 8 cycles of pembrolizumab were completed by 80% of patients. Thirteen had to discontinue pembrolizumab due to pneumonitis and a further 7% discontinued due to disease progression. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 13% of patients, with the most common TRAEs being pneumonitis (N=2), dyspnoea (N=1) and elevated ALP/ALT (N=1). No grade 4/5 AEs were reported.

At a median follow-up of 2.3 years, an ORR of 63% was achieved with the therapeutic combination, including 40% complete responders (CR) and 23% of patients obtaining a partial response (PR). The DCR was reported at 83%. The median OS was not reached at time of this analysis, with 1- and 2-year OS estimates of 90% and 74%, respectively. The median PFS was 15.6 months, with 1- and 2-year estimated PFS rates of 60% and 45%, respectively. Median duration of response (DoR) was also not reached, with 6- and 12-month reported at 84% and 72%, respectively.

Conclusion

This single-arm, phase I/II study successfully demonstrated the safety and efficacy of SABR in combination with pembrolizumab in oligometastatic ccRCC patients. The results obtained from RAPPORT demonstrate excellent local control and durable responses, which warrant further investigation in this first-line metastatic setting.

Reference

Siva S et al., Stereotactic radiotherapy and pembrolizumab for oligometastatic renal tumours: The RAPPORT trial. Presented at ASCO GU 2021; Abstract 277.