Under normal oxygen conditions, HIF-α molecules are subjected to a regulatory process leading to rapid von Hippel–Lindau (VHL) protein-mediated ubiquitination and proteasomal degradation. In contrast, when hypoxia is encountered (intra-tumoral hypoxia), or when genetic mutations that disrupt the function of VHL protein occur, instead of a degradation, the complete opposite occurs, with the activation of this pathway. Increased HIF-α activity leads to the upregulation of genes that are involved in many aspects of cancer progression, including metabolic adaptation, apoptosis resistance and especially angiogenesis. The somatic mutation of the VHL gene is the most frequent genetic alternation observed in RCC. Inappropriate accumulation of HIF-α via the stimulation of angiogenic gene induction results in the formation of intense vascular networks of the tumors. Vascular endothelial growth factor (VEGF) is one of the most potent pro-angiogenic factors, whose expression is transactivated by HIF-α. Elevated VEGF levels have therefore been reported in RCC.
Molecular-targeted therapies directed at (VEGF) and another important factor, the mammalian target of rapamycin (mTOR), are important signaling pathways shown to be involved in the pathogenesis of RCC, resulting in targeted therapies being involved specifically against these factors. TKI is one of those developed targeted therapies.
When TKI were used in the neoadjuvant setting, tumor shrinkage was shown in 10-20% of cases1, but no benefit in overall survival was seen. Therefore, neoadjuvant TKI is currently not recommended as standard of care in RCC. When assessing the role of TKI in the adjuvant setting, through phase 3 clinical trials of VEGF inhibitors in the adjuvant treatment of RCC, the results were disparate, with the ASSURE trial2 demonstrating no difference, and the S-TRAC trial3 showing a protective effect. The adverse effects with grade 3 or more caused by TKI in the adjuvant setting are reported at approximately 57-70% of patients. Currently, adjuvant TKI is not a standard of care for RCC in Europe.
Dr. Gizzi moved on to discuss the role of cytoreductive nephrectomy in the TKI era. The recently published CARMENA trial, was a prospective, multi-center, open-label, randomized phase 3 non-inferiority trial randomizing metastatic clear cell RCC patients with good performance status to either cytoreductive nephrectomy, followed by sunitinib, or to sunitinib alone. The primary endpoint was overall survival (Figure 1). 4
Figure 1 – CARMENA trial design:
In summary, this trial showed no difference in overall survival between the two arms. However, the majority of the patients in this trial were intermediate and poor risk patients. The favorable risk patients were not well represented in this trial, and so it is not clear if the conclusion of this trial applies to these patients.
Next, the setting of metastatic RCC was discussed. The COMPARZ trial demonstrated that Pazopanib is not inferior to sunitinib in first-line metastatic clear cell RCC patients.5 However, patients prefer Pazopanib due to the better adverse effect profile, compared to sunitinib.
Finally, the CABOSUN trial was discussed.6 This was a randomized phase 2 trial that recruited locally advanced or metastatic clear cell RCC patients with ECOG 0-2, and no prior systemic therapies, with an International Metastatic Renal Cell Carcinoma Database (IMDC) intermediate or poor prognosis risk group. The patients were randomized (1:1) to either sunitinib or Cabozantinib (another TKI), with the primary endpoint being progression-free survival. A total of 157 patients were recruited. Cabozantinib treatment significantly increased the median progression-free survival (8.2 v 5.6 months) and was associated with a 34% reduction in the rate of progression or death. The objective response rate was 46% for cabozantinib vs. 18% for sunitinib. The safety profile was quite similar in the two drugs. Cabozantinib had increased liver function test abnormalities, anorexia, and dysgeusia, while it had decreased hematologic abnormalities and fatigue, compared to sunitinib.
Dr. Gizzi summarized the presentation thus far, stating that these data demonstrate that there is still a need for TKI in first-line treatment in the era of immune checkpoint inhibitors, as some patients cannot receive immunotherapy. Moreover, TKI has a role, specifically in favorable risk patients. This was shown in the checkmate 214 trial, comparing sunitinib to nivolumab and ipilimumab. In this trial, the complete response rate was 9% for the Nivolumab arm, compared to 1% in the sunitinib arm. When looking at the progression-free survival and overall survival in the IMDC intermediate/poor risk patients, the nivolumab patients fared better with a hazard ratio of 0.82 (0.64-1.05), p=0.0331, and a hazards ratio of 0.63 (0.44-0.89), p<0.001, respectively. In contrast, in the favorable IMDC risk group, the sunitinib patients fared better with a hazard ratio of 2.18 (1.29-3.68), p<0.0001).7
The next logical step is the combination of TKI and immune checkpoint inhibitors. In the motion 151 phase 3 trial, sunitinib was compared to mepolizumab and bevacizumab. The combination treatment was shown to be better than sunitinib in PFS, objective response rate, and OS.8 A subgroup of clear cell RCC patients in this trial was shown to be particularly sensitive to TKI. There are currently several closed and ongoing trials combining both immunotherapy and TKI. These include multiple combinations, with results still pending.
Patients with non-clear cell papillary RCC have not been abandoned. There is an ongoing phase 3 trial called SAVOIR assessing patients with papillary type 1 RCC with the unresectable or locally advanced or metastatic disease, with no prior sunitinib or MET inhibitor therapy. These patients are randomized to either Savolitinib or sunitinib, with the primary endpoint being progression-free survival.
In conclusion, there is currently no place for TKI in localized RCC. In contrast, TKI is still used in all lines of metastatic clear cell RCC, either as monotherapy or in combination. A subgroup of clear cell RCC is particularly sensitive to VEGF-TKIs. TKI is the only approved therapy in patients that are not candidates for immunotherapy. The future is promising, showing the results of the trials with the combination therapy of TKI and immunotherapy in clear cell RCC patients. Lastly, TKI is the only approved treatment in non-clear-cell RCC.
Presented by: Marco Gizzi, Department of Oncology, Grand Hospital Charleroi, GHdC, Charleroi, Belgium
1. Abel et al. Eur Urol 2011
2. Haas N et al. Lancet 2016
3. Ravaud A et al. NEJM 2016
4. Mejean et al. NEJM 2018
5. Motzer et al. NEJM 2013
6. Choueri T et al. Eur J Cancer 2018
7. Escudier et al. ESMO 2017
8. Motzer et al. ASCO GU 2018
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23, 2018, Munich Germany