Immuno-oncology + tyrosine kinase inhibitors: their role in intermediate- and poor-risk mRCC

Prof. Axel Merseburger reviewed the recent evidence testing immuno-oncology (IO) in combination with tyrosine kinase inhibitors (TKIs) in metastatic renal cell carcinoma (mRCC).

Prof. Axel Merseburger (University Medical Center Schleswig-Holstein, Lübeck, Germany) reviewed the recent evidence testing immuno-oncology (IO) in combination with tyrosine kinase inhibitors (TKIs) in metastatic renal cell carcinoma (mRCC)1.

Treatment of intermediate- and poor-risk mRCC has seen a rapid change in the treatment landscape in the last years, requiring multiple updates from the EAU RCC Guideline panel. Last year, the first-line recommended treatment for intermediate- and poor-risk patients was IO + IO: ipilimumab plus nivolumab. In addition, historic first-line monotherapy with TKIs cabozantinib, sunitinib, or pazopanib can be used, albeit with somewhat less strong data.

Based on recently published trials reviewed by Prof. Merseburger, the current recommendations for intermediate- or poor-risk patients has been extended to include IO + TKI: pembrolizumab with axitinib, or avelumab plus axitinib [2]. One of the reasons axitinib is an attractive TKI for combination therapies is because of its rapid pharmacological turnover, making dose adjustments due to side effects easy to adjust, or to distinguish a given symptom as either being an IO or TKI effect, the former being potentially more serious3.

The pivotal CheckMate-214 study showed that  IO nivolumab + IO ipilimumab improved objective response rate (ORR) and overall survival (OS), but only for patients with intermediate- or poor-risk mRCC patients4. Approval was therefore granted for only these risk groups (based on the Heng criteria5); it is not approved for favorable-risk patients.

The phase-3 JAVELIN Renal 101 study (n=886), however, investigated IO avelumab (10 mg/kg) intravenous every 2 weeks plus TKI axitinib (5 mg) oral twice daily (n=442) versus sunitinib (50 mg) once daily for 4 weeks (6-week cycle) (n=444). The primary and key secondary endpoints were progression-free survival (PFS) determined by an independent review committee (IRC) and OS in patients with prespecified subgroup analysis for tumors positive for PD-L1 expression. The median PFS was 13.8 versus 7.2 months (HR 0.61; 95% CI 0.475-0.790) in favor of the avelumab plus axitinib arm6. OS data at the time of reporting was immature but was suggestive of benefiting patients receiving avelumab plus axitinib (HR 0.78; 95% CI 0.554-1.084). In a recent update7, avelumab plus axitinib continued to show a PFS benefit (HR 0.69; 95% CI 0.574-0.825), but OS data remained immature (HR 0.80, 95% CI 0.616-1.027).

KEYNOTE-426 randomized mRCC patients to either first-line IO agent pembrolizumab (200 mg intravenous Q3W for up to 35 doses) plus TKI axitinib (5 mg twice daily; n=432) or to TKI sunitinib (50 mg once daily on a 4-week on/2-week off schedule; n=429)8. The data was significantly in favour of pembrolizumab plus axitinib for OS (HR 0.53; 95% CI 0.38-0.74; P<0.0001), PFS (HR 0.69; 95% CI 0.57-0.84; P=0.0001), and ORR (59.3% vs 35.7%; P<0.0001). An updated analysis presented at ASCO 2020 maintained the PFS (HR 0.71; 95% CI 0.60-0.84) and OS benefits (HR 0.68; 95% CI 0.55-0.85). Stratifying patients by risk categories underscored that those with intermediate- or poor-risk disease benefitted the most in key outcomes: PFS (HR 0.69; 95% CI 0.56-0.84), OS (HR 0.63; 95% CI 0.50-0.81), and ORR (55.8% vs 35.2%)9.

Prof. Merseburger spelled out the pros versus cons of IO + TKI approaches in mRCC. Certainly, among the pros are the OS advantage, improved PFS, the higher objective response rate, and fewer immune-related adverse events, as compared with IO + IO approaches. Conversely, it remains unclear if and when one can stop therapy; the data have shorter follow-up times than IO + IO, and the reality is that indirect comparison of quality of life data would probably favor IO + IO. In addition, Prof. Merseburger pointed out, beyond the reduction in PFS for IO + IO, that there is substantially less experience managing potentially severe immune-related safety events that can occur in IO +IO.

Key messages from Prof. Merseburger concerning IO + TKI combination therapy for first-line mRCC were that (i) PD-1 immune-checkpoint inhibition is the backbone of first-line therapy; (ii) pembrolizumab or avelumab plus axitinib is approved for all risk groups; (iii) nivolumab plus ipilimumab is only approved for intermediate- and poor-risk groups; and (iv) the major differences between IO + IO versus IO + TKI include maturity of data, efficacy endpoints, the side effect profile, quality of life, and possible differences regarding histology.

In conclusion, given the biology known about mRCC, TKIs are an effective approach to managing a disease with very well-known safety profiles and pharmacodynamics. Recent trials combining TKIs with IO agents are providing promising data, with durable and even complete responses.

References:
1. Merseburger A. Immunotherapy Combinations for Intermediate-Poor Risk mRCC: IO + TKI. EAU20 Virtual Congress, 17-26 July 2020, Thematic session Immunotherapy.
2. Albiges L, et al. Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibition is the New Backbone in First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma. Eur Urol 2019 Aug;76(2):151-156.
3. Grünwald V, et al. Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events [published online ahead of print, 2020 June 26]. Br J Cancer. 2020.
4. Motzer RJ, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378(14):1277-1290.
5. https://ikcc.org/wp-content/uploads/2018/08/IKCC_IMDC-Criteria_English.pdf 
6. Motzer RJ, et al. Avelumab plus axitinib versus sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1103-1115.
7. Choueiri TK, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol 2020 Apr 25;S0923-7534.
8. Rini BI, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1116-1127.
9. Plimack ER. ASCO Virtual Meeting, 29-31 May 2020, Abstract.

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