Stereotactic Radiotherapy and Short-course Pembrolizumab for Oligometastatic Renal Cell Carcinoma—The RAPPORT Trial - Beyond the Abstract

Surgery and stereotactic ablative body radiotherapy (SABR) are commonly utilised in the setting of oligometastatic renal cell carcinoma (RCC) with the potential for durable remission in select patients. A majority will, however, progress at other sites and ultimately require systemic therapy. Single-agent immune checkpoint inhibitor (ICI) therapy had shown promising activity in the second line (Checkmate 025)1 and treatment naïve setting (Keynote-427)2 and pre-clinical studies pointed to potential synergism with SABR.3 In this context, the single-arm RAPPORT clinical trial was designed to test the safety and efficacy of total metastatic ablation with SABR, followed by an abridged 6-month course of pembrolizumab in patients with oligometastatic (1- 5 lesions) clear cell RCC.4,5


Between 2016 and 2019, 30 participants with 83 metastases (median 3 per patient) were enrolled. Approximately half the cohort was IMDC favourable-risk with a median time from primary RCC diagnosis to metastases of 11 months (IQR 0-26), 30% had prior metastasis directed therapy and 20% had progressed after prior tyrosine kinase inhibitor (TKI) therapy. A single 20 Gy fraction of SABR was delivered to a minimum of one lesion but all lesions were feasible. A reduced dose of 30Gy in 10 fractions was used for 19 lesions in higher-risk locations, for example, hilar lymph nodes. Pembrolizumab 200 mg was delivered 3-weekly for a total of eight cycles, commencing 5 days (±3 days) from the last dose of SABR.

Grade 3 adverse events were reported in 4 (13%) patients including pneumonitis (n=2), dyspnoea (n=1), and transaminitis (n=1), all resolving with cessation of therapy and corticosteroids. Grade 1-2 adverse events were reported in 10 (63%) of patients. There were no grade 4 or 5 events. The objective response rate (ORR) was 63%, complete response (CR) 40%, and 2-year progression-free survival (PFS) was 45%. This compares favourably with Keynote-427 which used 2 years of pembrolizumab as monotherapy and reported 30% grade 3 to 5 adverse events, an ORR of 36%, CR in 3.6%, and 2 year PFS of 22%. The burden of disease in our study was likely lower than in Keynote-427 but higher than in series of metastasectomy alone reporting median PFS of 20-24 months.6 A recent prospective study of SABR alone for lower burden oligometastatic RCC (67% single site, 27% 2 sites) also reported a median PFS of 22.7 months with 10% grade 3 adverse events.7

The treatment paradigm in the first-line setting, however, has rapidly evolved with newer combination regimens. CheckMate-214 demonstrated improved survival for nivolumab and ipilimumab compared to sunitinib in intermediate and poor-risk disease and a number of ICI/VEGF combinations have now demonstrated improved survival across the IDMC risk groups.8-10 Keynote-564, which included a small cohort with resected synchronous oligometastases with no evidence of disease (M1 NED), recently reported improved PFS with 12 months adjuvant pembrolizumab.11

Whilst likely to be more convenient and less financially toxic from a patient perspective, future studies are required to help clarify whether total metastatic ablation with SABR (and/or surgery) combined with abridged ICI therapy offers a better therapeutic ratio than combination systemic therapies in higher risk oligometastatic cohorts. In low burden favorable oligometastatic cohorts, short course pembrolizumab may be an attractive addition to local therapy. A translational substudy of the RAPPORT trial is in process which may shed further light on the biological interaction of SABR and pembrolizumab in oligometastatic disease. However, two recent negative clinical trials which utilised SABR to only 1 or 2 sites in the context of higher disease burden suggests that the systemic immune priming effect of SABR may not be clinically significant unless a larger proportion of the tumor sites are irradiated.12-13

In summary, the combination of an abridged 6-month course of pembrolizumab and total metastatic ablation with SABR was feasible, associated with a promising PFS, and could be considered a reasonable experimental arm to take forward in future randomised studies.

Written by:

  • A. Prof David Pryor, Princess Alexandra Hospital, Brisbane, Australia.
  • A. Prof Shankar Siva, Peter MacCallum Cancer Center, Melbourne, Australia.

References:

  1. Motzer RJ, Escudier B, McDermott DF et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015; 373 (19): 1803-1813.
  2. D.F. McDermott, J.L. Lee, G.A. Bjarnason, et al. Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced clear cell renal cell carcinoma J Clin Oncol, 39 (2021), pp. 1020-1028
  3. Park, S. S., Dong, H., Liu, X, et. al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer immunology research, 3(6), 610-619; 2015.
  4. D. Pryor, M. Bressel, N. Lawrentschuk, et al. A phase I/II study of stereotactic radiotherapy and pembrolizumab for oligometastatic renal tumours (RAPPORT): clinical trial protocol. Contemp Clin Trials Commun, 21 (2021), p. 100703
  5. Siva S, Bressel M, Wood ST, et al. Stereotactic Radiotherapy and Short-course Pembrolizumab for Oligometastatic Renal Cell Carcinoma-The RAPPORT Trial. Eur Urol. 2021 Dec 23:S0302-2838(21)02214-4.
  6. M.F. Meagher, R. Autorino, M. Kriegmair, et al. Impact of metastasectomy on progression free and overall survival in metastatic renal cell carcinoma: analysis of the REMARCC registry J Clin Oncol, 38 (2020), p. 753.
  7. Tang C, Msaouel P, Hara K, et. al. Definitive radiotherapy in lieu of systemic therapy for oligometastatic renal cell carcinoma: a single-arm, single-centre, feasibility, phase 2 trial. Lancet Oncol. 2021 Dec;22(12):1732-1739. 
  8. R.J. Motzer, B.I. Rini, D.F. McDermott, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial Lancet Oncol, 20 (2019), pp. 1370-1385
  9. Choueiri TK, Powles T, Burotto M et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021; 384 (9): 829-841.
  10. Powles T, Plimack ER, Soulières D et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020; 21 (12): 1563-1573.
  11. Choueiri TK, Tomczak P, Park SH, et. al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694.
  12. Masini C, Iotti C, De Giorgi U, et al. Nivolumab in combination with stereotactic body radiotherapy in pretreated patients with metastatic renal cell carcinoma. Results of the phase II NIVES study. Eur Urol. Eur Urol. 2021 Sep 30:S0302-2838(21)02040-6. 
  13. H.J. Hammers, D. Vonmerveldt, C. Ahn, et al. Combination of dual immune checkpoint inhibition (ICI) with stereotactic radiation (SBRT) in metastatic renal cell carcinoma (mRCC) (RADVAX RCC) J Clin Oncol, 38 (6 Suppl) (2020), p. 614

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