The standard of care for locoregional clear-cell renal cell carcinoma (RCC) is partial or radical nephrectomy, despite nearly half of patients eventually experiencing recurrence and distant metastasis after surgery. Additionally, no adjuvant therapy has been globally accepted and guidelines only recommend active surveillance or entry into a clinical trial. [1,2]
Angiogenesis has a known role in RCC, therefore vascular endothelial growth factor (VEGF) inhibitors, sorafenib and sunitinib, were evaluated against each other and a placebo control in the phase III ASSURE trial for patients who had kidney cancer that has been removed by surgery, but they failed to substantially improve disease-free survival. [3] Contradictorily, sunitinib, a VEGF inhibitor, was found to provide significant improvement in disease-free survival versus placebo in the S-TRAC trial for patients at high risk of recurrence of RCC, subsequently leading to approval for use in the US. [4] Despite the positive results in S-TRAC, the conflicting conclusions of the two trials and the toxicity profile of the treatment have kept sunitinib from being approved in the European Union, and have not solved the need for better therapy options in RCC. It is hypothesized that the differences, in part, could be due patient selection because the staging viewpoint inclusion criteria was different between the two trials. [5]
Immunotherapy a cancer treatment that harnesses the immune system fight cancer, with the most popular being immune checkpoint inhibitors (ICIs). In particular, the ICIs targeting anti-programmed death (PD-1) antibodies, such as pembrolizumab, have demonstrated activity as both monotherapy and combination therapy for renal cell carcinoma. [6-11] Therefore, the KEYNOTE-564 trial evaluated whether pembrolizumab after nephrectomy improved clinical outcomes in patients with intermediate to high-risk of recurrence, with the first interim analysis recently published in The New England Journal of Medicine. [12] Patients enrolled in the trial had histologically confirmed locoregional RCC with a clear-cell component and met protocol-defined criteria for high-risk recurrence. They could not have received previous systemic therapy for RCC and had to have undergone surgery with negative surgical margins within 12 weeks before randomization. A total of 994 patients were randomized 1:1 to receive pembrolizumab or placebo after nephrectomy, with or without metastasectomy.
109 events of disease recurrence or death occurred in the pembrolizumab group compared to 151 in the placebo group. There was a 32% lower risk of disease recurrence or death in the pembrolizumab group than with placebo (hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P=0.002 [two-sided]). At 24 months the estimated percentage of patients who were alive was 77.3% (95% CI, 72.8 to 81.1) in the pembrolizumab group and 68.1% (95% CI, 63.5 to 72.2) in the placebo group. The median disease-free survival was not reached in either group at the data cut-off date.
96.3% of the patients who received pembrolizumab had at least one adverse event of any grade or cause compared to 91.1% of those who received the placebo. In terms of severe events, 32.4% of patients treated with pembrolizumab and 17.7% of patients given the placebo had a grade 3 to 5 adverse event. The most common adverse event in both groups was fatigue followed by diarrhea, pruritus, and arthralgia. For patient reported outcomes, change from baseline to week 52 in the FKSI-DRS score was −1.12 (95% CI, −1.53 to −0.71) in the pembrolizumab group and −0.45 (95% CI, −0.84 to −0.05) in the placebo group. For the EORTC QLQ-C30 physical functioning score, the change from baseline was −1.81 (95% CI, −3.19 to −0.43) in the pembrolizumab group and −0.90 (95% CI, −2.23 to 0.44) in the placebo group. The scores were stable over time and not significantly different between groups.
The authors suggest that the preliminary results of the study indicate that the use of pembrolizumab as adjuvant immunotherapy might become a new standard of care in patients with RCC that is intermediate to high-risk of recurrence. The results from the longer follow-up at the next prespecified analysis timepoint should help further determine the effect of overall survival.
The success of immunotherapy has led to the use of checkpoint inhibitors in multiple tumor types. At MEDSIR we are also evaluating checkpoint inhibitors in our PECATI trial for thymic cancer and our ATRACTIB trial for breast cancer. For more information about our immunotherapy trials or if you want to be connected with our network of investigators, contact us!
References
1. NCCN clinical practice guidelines in oncology: kidney cancer, version 3.2021. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2021.
2. Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019;30: 706-20
3. Haas NB, Manola J, Dutcher JP, et al. Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high- risk subset of the ASSURE randomized trial. JAMA Oncol 2017;3:1249-4. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 2016;375:2246-54.
5. Porta C, Cheillino S. ASSURE vs. S-TRAC: conflicting results of adjuvant treatments for kidney cancer in the era of targeted agents and genomics. Ann Transl Med. 2016 Oct; 4(Suppl 1): S14.
6. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116-27.
7. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treat- ment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 2020;21:1563-73.
8. MotzerRJ, TannirNM,McDermott DF, et al. Nivolumab plus ipilimumab ver- sus sunitinib in advanced renal-cell carci- noma. N Engl J Med 2018;378:1277-90. 19. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for ad- vanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 2019;20:1370-85.
9. Motzer RJ, Escudier B, George S, et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: up- dated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer 2020;126: 4156-67.
10. Lee CH, Shah AY, Rasco D, et al. Len- vatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol 2021;22:946-58.
11. McDermott DF, Lee J-L, Bjarnason GA, 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 On- col 2021;39:1020-8.
12. Choueiri T. et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med 2021; 385:683-694 DOI: 10.1056/NEJMoa2106391
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