Dealing with fast therapeutic metamorphosis 

James Fleck & Laura Albaneze: Anticancerweb 29(03), 2019

Renal cell carcinoma is a poorly symptomatic tumor. One-third of patients are diagnosed as advanced disease, making them unsuitable for curative resection. Half of these patients already have metastases. Previous therapeutic interventions in metastatic renal cell carcinoma (mCRC) revealed low response to radiotherapy and/or cytotoxic chemotherapy. In parallel, mRCC has been described as an immunogenic tumor. US Surveillance, Epidemiology, and End Results (SEER), updated in 2017, showed a mRCC 5-year survival of only 12%. At the turn of the century, studies on adoptive cellular immunotherapy, including the use of interleukin-2 and interferon-alpha have produced long-lasting mRCC complete responses, which could hopefully improve survival. However, meta-analysis of studies with longer follow-up revealed inconclusive results.

More recently, two new approaches have dominated the therapeutic scenario for mRCC: Inhibition of the signal transduction pathway associated to vascular endothelial growth factor (VEGF) and inhibition of immunological checkpoints. There were two important historical landmarks. The first, led by Motzer of Sloan Kettering Cancer Center, NY showing that patients treated with sunitinib had a higher rate of objective response and progression-free survival when compared to patients treated with interferon-alpha. Despite the outcomes being based on surrogates, in 2007 the FDA approved sunitinib as the standard in first-line treatment of mRCC. Other studies with sunitinib have shown an additional effect on non-clear cellular histology and the opportunity for intermittent use. In 2015, there was a new escalation in immunotherapy. Nivolumab revealed to be superior to everolimus in second-line treatment of mRCC. In 2018, double-blockade in immunological checkpoints (anti-PD1 and anti-CTLA-4) respectively with nivolumab+ ipilimumab proves to be more effective than sunitinib, becoming the new standard in first-line treatment of mRCC. In 2019, exploratory studies shown potential benefit associating a more potent, second-generation VEGF-inhibitor (axitinib) with immunological checkpoints inhibitors (anti-PD1) in first-line treatment of mRCC. Axitinib was moved into mRCC first-line therapy since it was shown to be superior to sorafenib. However, both in second-line and in first-line treatment, the advantage of axitinib over sorafenib was based on surrogates. In addition, axitinib was shown to be more toxic. Despite these limitations, the drug was incorporated into the test arm in the two most recent trials that evaluated its association with immunotherapy (anti-PD1 blockade). In the KEYNOTE-426, the test arm was composed of axitinib+ pembrolizumab, while in the study again led by Motzer of Sloan Kettering Cancer Center, NY the test arm was composed by the association axitinib+ avelumab. In both trials the control arm consisted of sunitinib. In both trials the majority of patients were PD-L1 positive (above 60%). In both trials, patients with intermediate or poor IMDC prognostic risk prevailed (68.8% in KEYNOTE-426 and about 80% in the Motzer study). Both studies were consistent in demonstrating a significant increase in progression-free survival favoring combined treatment arm. In KEYNOTE-426, there was a 47% reduction in the risk of death favorable to the test arm (HR = 0.53) with a median survival not yet reached in any of the arms of the study.

The 21^st century has witnessed a rapid metamorphosis in the treatment of mRCC. Its immunogenic character has been responsible for clinical trials testing adoptive immunotherapy and more recently blockade of immunological checkpoints. In parallel, the inhibition in VEGF-signal transduction pathway is also building the most recent therapeutic scenario. Considering the paucity mRCC systemic treatment options at the turn of the century, the emergence of two promising research lines generated enthusiasm but also ambivalence. The most recent studies attempt to combine the two strategies, but with some methodological limitations in the evaluation of the potential synergy. Additionally, speed in knowledge acquisition makes it difficult to identify which is the standard treatment. Since publications have being accelerated at the expense of interim analyzes and widespread use of surrogates, at the time of results' disclosure the control arm of studies is no longer the standard. Keeping historical control arm also led to an inequality between arms in the two most recent studies, since axitinib appears in the test arm while sunitinib appears in the control arm. The eligibility profile itself is heterogeneous, as it includes an expressive percentage of patients with favorable IMDC-prognostic risk, varying in the two studies from 21.4 to 31.2%. Considering that the purpose of the interventions in mCRC is a lift in overall survival plateau, studies are still immature and the butterfly flight might continue to be of short-lived.

References:

Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma, N Engl J Med356:115-24, 2007

Motzer RJ, Penkov K, Haanen J, et al: Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma, N Engl J MedDOI: 10.1056/NEJMoa1816047, 2019

Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma, N Engl J MedDOI: 10.1056/NEJMoa1816714, 2019

Bernard Escudier: Combination Therapy as First-Line Treatment in Metastatic Renal-Cell Carcinoma, N Engl J MedDOI: 10.1056/NEJMe1900887 Editorial, 2019