First-line treatment for renal cell carcinoma (RCC) is changing rapidly and it has been updated number of times during the last decade, from vascular endothelial growth factor (VEGF) inhibitors to immune checkpoint inhibitors (anti-PD-1).1 Lately, combined therapies with anti-PD-1 as first-line therapy has been taken for the front line.2 And the latest interest in this area is combined therapies with anti-PD-1 and VEGF inhibitors. In the Genitourinary Cancers Symposium (GuCS), held in San Francisco on 14-16th February 2019, findings of the phase 3 KEYNOTE-426 trial that compared the pembrolizumab (anti-PD-1) plus axitinib (VEGF inhibitor) vs. sunitinib (VEGF inhibitor) were presented and concurrently published at The New England Journal of Medicine.3,4
Anti-PD-1 therapy plus VEGF inhibition in RCC: What do we know so far?
The treatment of advanced renal-cell carcinoma (RCC) has been revolutionized twice in the past 12 years. At first, data showed that VEGF inhibition can induce tumor shrinkage and increase progression-free survival.5 Then, anti-PD-1 was proven to induce durable response and increase overall survival.6 Sunitinib, a tyrosine kinase inhibitor with potent VEGF inhibition, became the standard of care when a trial in 2007 showed its superiority over interferon alpha (IFN).5 In 2018, a combination of two immune check point inhibitors, nivolumab and ipilimumab, were shown to have better efficacy than sunitinib.7 This combination upon approval by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), is the new standard of care, exclusively in intermediate- and poor-risk patients.2
Updated guidelines in the management of advanced RCC: European Society for Medical Oncology (ESMO) clinical practice guidelines
The ESMO clinical practice guidelines for RCC has updated the recommendations on first-line therapy.2 The guidelines were implemented according to risk categorization using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score. In good-risk patients, VEGF-targeted agents remained the standard of care with sunitinib, pazopanib or bevacizumab combined with IFN.2 Tivozanib is another standard of care when available. In intermediate-risk patients, combination of nivolumab and ipilimumab is the new standard of care.2 If this combination is not available, VEGF-targeted agents were recommended among good-risk patients, with cabozantinib being another option in this patient population.2
Similarly, in poor-risk patients, combination of nivolumab and ipilimumab is the new standard of care.2 When considering targeted therapies, cabozantinib is an attractive option if available. Furthermore, among this group of patients, temsirolimus remains an option, as well as tyrosine kinase inhibitors (sunitinib or pazopanib).2 However, in some poor-risk patients with poorer prognosis, only palliative care should be recommended.2
Overall survival and progression-free survival upsurges with pembrolizumab plus axitinib versus sunitinib
In the recent GuCS held in San Francisco, results of the phase 3 KEYNOTE-426 trial were presented, and the findings were subsequently published at The New England Journal of Medicine.3,4 KEYNOTE-426 trial was an open-label, phase 3 trial, with randomly assigned 861 patients with advanced untreated RCC.4 They received pembrolizumab (200mg) intravenously once every 3 weeks plus axitinib (5mg) orally twice daily (432 patients) or sunitinib (50mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients).4 The primary end points were overall survival and progression-free survival in the intention-to-treat population.4 Objective response rate was the key secondary end point.4
The overall survival rates of the combination of pembrolizumab and axitinib for 12- and 18- months was 89.9% and 82.3% respectively, compared with the sunitinib group at 78.3% and 72.1%.4 It is further noted that the benefit of pembrolizumab-axitinib was observed across all subgroups tested, including in all IMDC risk groups and in patients who had tumors with PD-L1 expression as well as tumors without PD-L1 expression (Figure 1).4
In light of these findings, the principal investigator of the trial, Dr.Thomas Powles, MD, Barts Cancer Institute of London, United Kingdom, stated that, at 12.8 months median follow-up, patients randomized to the anti-PD-1 plus VEGF tyrosine kinase inhibitor combination had a 47% reduction in the risk of death compared to those treated with sunitinib alone, with the benefit seen regardless of PD-L1 status of risk group (HR=0.53; 95% CI: 0.38-0.74; p<0.001).8
Furthermore, the overall response rate of pembrolizumab-axitinib was significantly higher than sunitinib alone (59.3% vs. 35.7%, p<0.0001). Among the respondents, the dual therapy arm did not reach a median duration of treatment, while sunitinib reported 15.2 months.4 In view of the higher significance of the dual treatment of pembrolizumab-axitinib, Dr. Powles suggested, “pembrolizumab and axitinib should be a standard of care in this setting”.8
Given the fact that CheckMate 214 trial shifted the upfront RCC management to ipilimumab plus nivolumab, Dr. Robert Dreicer, MD, University of Virginia, American Society of Clinical Oncology (ASCO)-designated expert, United States, the briefing moderator of the event, anticipated that the current results from KEYNOTE-426 would alter the management of RCC.8
“This is practice changing” commented Dr. Dreicer, indicating that these results might be the most significant in the meeting.8 He further added “assuming this passes regulatory muster, which I think most of us anticipate, you are going to have a therapy that could theoretically be utilized across the clear cell kidney cancer spectrum for untreated patients with metastatic disease”.8
The median progression-free survival, the last time patient was known to be free from disease progression, was also improved with the combined therapy, which is 15.1 months vs. 11.1 months with sunitinib (HR=0.69; 95% CI: 0.506-0.840; p<0.001, Figure 2).4
In view of the progression-free survival data, Dr. Dreicer added “it’s certainly going to represent a standard of care”, signifying that the pembrolizumab-axitinib combination would not necessarily be the standard of care.8 Further to Dr. Dreicer’s comment, Dr. Powles added “there is nothing from these data to suggest that the sunitinib arm underperformed in this trial”, highlighting that 11.1 months of progression-free survival by sunitinib is already quite long for a control arm with this agent.8
Moreover, Dr. Powles also noted that there were no significant differences between the two arms in terms of patients who went on to second-line therapy with checkpoint inhibitors following disease progression.8
Exclusive of KEYNOTE-426 trial, axitinib has been proven effective with various combinations.9 For example, in the data presented at the ESMO 2018 congress, another combination of axitinib with avelumab, an anti-PD-L1 agent, showed significant benefit over sunitinib (progression-free survival 13.8 months vs. 8.4 months), similarly irrespective of tumor PD-L1 expression status (HR=0.69; 95% CI: 0.506-0.840; p=0.001).9
Similar safety profiles with sunitinib as control
Adverse events of any cause occurred in 98.4% of 429 patients in the pembrolizumab-axitinib group and in 99.5% of 425 patients in the sunitinib group.4 Diarrhea and hypertension were the most common adverse events of any cause and related to treatment in both groups.4
When considering severe (grade 3) or higher events, 75.8% of patients in the pembrolizumab-axitinib group and 70.6% of patients in the sunitinib group had at least one event during the full course of treatment.4 In the combined therapy group, adverse events of any cause led to the discontinuation of both drugs in 10.9% of patients, whereas in the sunitinib group, the discontinuation was in 13.9% of patients.4 The medium time for discontinuation of pembrolizumab-axitinib due to adverse events of any cause was 105.5 days.4 Treatment-related deaths occurred in 0.9% of the pembrolizumab-axitinib group and 1.6% of the sunitinib group.4
The state-of-the-art KEYNOTE-426 trial showed that among patients with previously untreated advanced RCC, pembrolizumab plus axitinib combined therapy resulted significantly longer overall survival, progression-free survival and objective response rate compared to sunitinib alone. Thus the KEYNOTE-426 trial results placed itself as the most significant in the meeting and the clinicians attended the meeting highly anticipated a novel paradigm shift in the current practice of RCC management.
1. Escudier B. Combination Therapy as First-Line Treatment in Metastatic Renal-Cell Carcinoma. N Engl J Med. 2019 Feb 16. doi: 10.1056/NEJMe1900887. [Epub ahead of print]
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 Feb 21. pii: mdz056. doi: 10.1093/annonc/mdz056. [Epub ahead of print]
3. Powles T, Plimack ER, V S, Gafanov RA, et al. Abstract.Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. 2019 Genitourinary Cancers Symposium; February 19 2019; San Francisco, California.
4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 February 16. doi: 10.1056/NEJMoa1816714. [Epub ahead of print]
5. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115-24.
6. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-13.
7. Powles T. Re: Nivolumab plus Ipilimumab Versus Sunitinib in Advanced Renal-cell Carcinoma. Eur Urol. 2018;74(5):679-80.
8. First-Line Combo ‘Practice Changing’ in Advanced Kidney Cancer, MEDPAGE TODAY. (Accessed March 4 2019, at https://www.medpagetoday.com/meetingcoverage/mgucs/77958).
9. Motzer R. Abstract. A randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC), ESMO 2018 Congress. October 21 2018; Munich, Germany.