There have been two trials of VEGF and mTOR targeted therapy and both demonstrated minimal activity.
- ESPN (Tannir et al. EU 2016) – randomized sunitinib vs. everolimus. Median PFS 5.7 months vs. 4.1 months, respectively.
- ASPEN (Armstrong et al. Lancet Oncology 2016) – randomized sunitinib vs. everolimus. Median PFS 8.1 months vs. 5. months, respectively.
A currently ongoing trial (SWOG 1500 PAPMET trial led by Dr. Pal) randomizes patients with histologically confirmed metastatic papillary RCC to sunitinib, cabozantinib, crizotinib, or savolitinib. The primary endpoint is PFS, but secondary endpoints include OS, response rates, and adverse event profiles. Their accrual goal is 152 patients across 65 centers – currently, they are accruing 3.6 patients/month!
- As of 5/2020, looking at PFS, cabozantinib is the only agent with demonstrable improvement over sunitinib. ORR with cabozantinib (23%) significantly higher than sunitinib (4%)
He then touched upon the study by Choueri et al. (JAMA Oncology 2020) that initially evaluated savolitinib, a highly selective MET-tyrosine kinase inhibitor, against sunitinib. While there was no median PFS survival benefit, there was a higher ORR (27% vs 7%). He noted that prior studies suggested there may be a specific benefit in MET-driven papillary RCC.
Next, he looked at the rationale for immunotherapy in nccRCC. He notes that the nccRCC histologic subtypes had low expression of PD-L1 in the tumors (only 5% chromophobe, 20% collecting duct, 10% papillary, 30% translocation tumors had >5% expression) but have modest expression in the TIMC (tumor-infiltrating mononuclear cells).
He summarized select data for IO trials for papillary RCC:
- Keynote-427 (B) (McDermott et al. JCO 2021) – 118 papillary RCC patients, Pembrolizumab – 28% ORR, 6% CR
- HCRN GU16-260 (B) (Atkins et al. JITC 2023) – 19 papillary RCC patients, Nivolumab – 5.3% ORR, 5.3% CR.
- CheckMate920 (Tykodi et al. JITC 2021) – 18 papillary RCC, nivo/ipi combination – 27.*% ORR, 5.5% CR
In contrast, he then discussed IO based combinations:
- Cabozantinib/Atezolizumab – RR in papillary RCC patients was 47%
- Cabozantinib/Nivolumab – RR in papillary RCC patients was 47%
- Bevacizumab/Atezolizumab – RR in papillary RCC patients was 25%
- Lentantinib/Pembrolzimab – RR in papillary RCC patients was 53%
Naturally, there remains ongoing work in this space. He highlighted two ongoing trials:
- PAXIPEM (NCT05096390) – evaluating axitinib vs. axitinib/pembrolizumab
- SAMETA (NCT05043090) – evaluating Savolitinib/Durvalumab vs. Sunitinib monotherapy vs. Durvalumab Monotherapy in MET-Driven metastatic papillary RCC
- This is based on strong Phase II data to suggest benefit in the MET-driven tumors
The following are his take-home points:
- Non clear-cell RCC is a mixed bag of histologies, biologies, and responses to therapy
- VEGF and mTOR targeted therapy have minimal (but not 0!) activity as monotherapy
- Cabozantinib significantly improved PFS relative to sunitinib
- SWOG 2200 will evaluate cabozantinib/atezolizumab in advanced pRCC
- MET may be an important component of nccRCC biology and MET inhibitors have activity – but there are more ongoing studies
- IO has some activity as monotherapy, as do IO/TKI combinations
- There is NO real standard of care for nccRCC and better biological understanding, better targets, better drugs are needed!
Presented by: Brian Rini, MD, FASCO, Professor of Medicine, Vanderbilt University Medical Center, Nashville, TN
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis @tchandra_uromd @UCDavisUrology on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023