Evolving Role of TKI Monotherapy
in Front Line Metastatic Clear Cell RCC

Keywords: tyrosine kinase inhibitor, monotherapy, front-line, prognostic classification, IMDC model, sunitinib, cabozantinib. 

Corresponding Author: Bradley A. McGregor, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston MA, 02215 Email: Bradley_McGregor@DFCI.HARVARD.EDU


Tyrosine kinase inhibitors (TKI) directed against the Vascular Endothelial Growth Factor (VEGFR) were unquestionably the gold standard for front-line therapy in advanced renal cell carcinoma for years. Results from combination immunotherapy trials have challenged this approach. The field is in flux as we await data from several ongoing already accrued phase 3 trials comparing the combinations of immunotherapy and VEGF/VEGFR inhibitors with TKI monotherapy. Nevertheless, it is important to revisit guidelines on the use of front-line TKI monotherapy, not only to identify special considerations and recognize subsets of patients who could still benefit from them, but also to consider how other hypothesis-generating studies could further refine current strategies in the context of biomarkers development.   

As the biology of renal cell carcinoma (RCC) has unraveled, the molecular rationale for the use of targeted therapy has been clearly delineated in numerous reports. With the recognition that the majority of sporadic clear-cell RCC (ccRCC) tumors are characterized by VHL tumor suppressor gene inactivation leading to VEGF overexpression, small molecules with inhibitory effects against the VEGF receptor transformed the landscape and displaced cytokine therapies, established during the 1990s as the first-line standard of care. As such, tyrosine kinase inhibitors (TKIs), initially sunitinib and pazopanib and more recently, cabozantinib, profoundly affected the management of first line advanced RCC, ushering in new treatment algorithms.

With new combinations of immunotherapies with and without VEGF/VEGFR targeted agents showing promising results in the first-line setting, it is tempting to suggest that the era of TKI monotherapy is over (Figure). Already, the combination of nivolumab and ipilimumab has been approved by the FDA for the first line treatment of those with poor or intermediate risk RCC. As the time of writing of this article, two large phase 3 trials of atezolizumab or avelumab (both PD-L1 inhibitors) in combination with VEGF inhibitors met their primary end-point of superiority in term of progression-free survival (PFS) over single agent sunitinib.1,2  Yet, depending on prognostic factors and patient risk profiles, TKI mono-therapy may still play a role in the frontline setting. This report will review most recent trials evaluating frontline TKIs, offering perspectives on their sustained importance in the therapeutic sequence and essential considerations about patient selection. 

Figure. Ongoing trials in front line ccRCC.

Prognostic Considerations
The importance of TKI monotherapy for metastatic ccRCC should be put into perspective with the IMDC or MSKCC prognostic classifications,3 of which the IMDC was the first validated model to assess overall survival (OS) in the era of VEGFR-directed TKIs. Since then, numerous clinical trials of TKI monotherapy and immunotherapy stratified the study population according to these prognostic factors. 

In the IMDC model, 6 factors were independently associated with poor survival: hemoglobin less than the lower limit of normal, corrected calcium greater than the upper limit of normal, Karnofsky performance status less than 80%, time from diagnosis to treatment of less than 1 year, neutrophils greater than the ULN and platelets greater than the ULN. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7%. All these prognostic factors may reflect increased tumor burden, aggressive tumor biology, and/or paraneoplastic processes, which might account for their high discriminatory power.4–6 This classification is widely applicable, as it involved real-world patients from multiple sites, and was validated in additional cohorts and prospective clinical trials.7,8

Sunitinib vs Pazopanib vs Cabozantinib:
TKI Monotherapy Comparisons, Criteria for Selection
TKI monotherapy has been the mainstay of therapy for over 10 years. Evidence is still accumulating from prospective trials on the relative merits of these three TKIs, while emerging data highlight their distinct activity and safety profiles. Until 2017, sunitinib and pazopanib were the two approved agents used most often in the first-line setting. The COMPARZ phase 3 non-inferiority study showed that pazopanib was not inferior to sunitinib in term of PFS (primary endpoint) and OS (secondary endpoint).9 Objective responses were higher in the pazopanib group. Although the study found similar rates of dose reduction and drug discontinuation due to adverse events, differences were revealed in safety profiles:  patients assigned to pazopanib had less fatigue, gastrointestinal adverse events, hand-foot syndrome, mouth sores, but experienced higher rates of liver toxicity. Eleven out of 14 quality of life metrics favored pazopanib over sunitinib. Therefore, the safety profile would be key to determine therapeutic strategies in the setting of similar efficacy.10,11

Further evidence regarding the importance of patient-reported outcomes and how they can help treatment choices came from the phase II cross-over trial PISCES.12 This study raised the importance of patient evaluation to assess differences in tolerability that may not be accurately captured by the standard measures used for adverse event reporting. This could be especially true in the case of low-grade but chronic toxicities, that can still impact the quality of life of patients.13 Pazopanib was preferred to sunitinib in 70% of patients and 67% of physicians, given quality-of-life and fatigue concerns. 

Critics of the study point out that sunitinib was given on a 4/2 schedule in both PISCES and COMPARZ, while alternative schedules have since been evaluated to improve toxicity. Nonetheless, a randomized phase 2 trial comparing continuous dosing of sunitinib 37.5 mg daily with conventional dosing showed a trend towards improved PFS with traditional schedule (9.9 vs 7.1 months, hazard ratio (HR) 0.77; 95% CI, 0.57 to 1.04; P = .090), with no difference in side effects profile, or patient-reported kidney cancer symptoms.14  However, a randomized phase 2 trial  comparing a 2/1 dosing schedule to traditional dosing showed improved failure free survival at 6 months (63 vs 44%) as well as less toxicities with alternative dosing.15 Another phase 2 study exploring the 2/1 dosing schedule did not meet the primary end point of decreased grade 3 toxicity though it was associated with a lack of grade 4 toxicity and a high response rate of 57%.  Given the desire to maximize dosing, it is appealing to start with the highest dose possible. The prospective phase IIB SURF trial [NCT02689167], accruing now, starts with traditional dosing; when toxicities arise, patients are randomized to sunitinib 37.5 mg on a 4/2 schedule vs sunitinib 50 mg on a 2/1 schedule.

Cabozantinib vs Sunitinib in the CABOSUN Trial
Cabozantinib is a VEGFR inhibitor that also targets multiple kinases, including MET and AXL receptors.  MET is a receptor to the hepatocyte growth factor (HGF), which activates pathways involved in survival, proliferation and invasion. MET can also regulate cortical bone osteogenesis,16 making it an interesting target in the context of bone metastases. AXL is binds to growth arrest specific 6 (GAS6), involved in growth, migration and differentiation in multiple cell types. Expression of MET and AXL have been associated with tumor progression and resistance to VEGF-pathway inhibition in preclinical models, and adverse outcomes in clinical studies. Initial approval for cabozantinib came from the VEGF-refractory setting with METEOR, a randomized phase 3 trial that compared the efficacy and safety of cabozantinib versus the mTOR inhi- bitor everolimus.17 Later on, the randomized ALLIANCE phase 2 trial CABOSUN evaluated cabozantinib against sunitinib in the first-line setting, and a recent update evaluated the primary endpoint of PFS by central review.18,19 Among 157 patients, cabozantinib significantly prolonged PFS compared with sunitinib in poor or intermediate risk patients, from 5.3 to 8.6 months. Toxicity rates were comparable between the two arms, with increased grade 3/4 fatigue and hematologic abnormalities with sunitinib, but increased liver function test abnormalities, anorexia and dysgeusia with cabozantinib.  With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6-not estimable) with cabozantinib and 21.2 months (95% CI 16.3-27.4) with sunitinib (HR 0.80 [95% CI 0.53-1.21]. Another element that might account for the improved PFS of cabozantinib over sunitinib is the low performance of the sunitinib arm, as prior studies rather demonstrated longer PFS with sunitinib in the first line setting. However, the population of CABOSUN had only patients harboring intermediate or poor risk disease, 30% having bone metastases and 13% with a performance status of 2.  Notwithstanding this selected population, the recent FDA approval of cabozantinib was granted to all patients presenting with untreated advanced RCC independently of risk classification.

The Importance of Patient Classification
The importance of patient stratification to determine the best therapeutic approach was highlighted by the CheckMate 214 trial of nivolumab and ipilimumab vs sunitinib.20 The coprimary endpoints were objective responses rate, PFS, and OS among IMDC intermediate- and poor-risk patients. At a median follow-up of 25.2 months, nivolumab plus ipilimumab had a significant OS benefit over sunitinib among intermediate- and poor-risk patients: median OS was not reached with nivolumab plus ipilimumab vs 26.0 months with sunitinib (HR  0.63, 99.8% CI = 0.44–0.89, P < .001). Based on these results, the FDA granted approval to nivolumab plus ipilimumab for the treatment of intermediate- and poor-risk treatment-naive patients with advanced renal cell carcinoma.

However, the CheckMate 214 trial also demonstrated that prognostic risk strata differentially impacted the outcomes in each study arm. In the favorable-risk cohort (35 % of all patients by MSKCC), the objective response rate was higher in sunitinib-trea-ted patients than in those receiving nivolumab plus ipilimumab—29% with nivolumab plus ipilimumab vs 52% with sunitinib (P < .001), although complete responses were higher with nivolumab and ipilimumab, observed in 11% vs 6% of patients respectively. Additionally, PFS favored sunitinib over nivolumab plus ipilimumab (25.1 months for sunitinib vs 15.2 months for nivolumab plus ipilimumab, P < .001). The near double improvement in PFS and ORR with sunitinib in the favorable risk patients is notable, though the marked improvement in CR with the combination arm can support this immunotherapy combination as an option for those with good risk disease despite its FDA label. The combination is not without its toxicities. While grade 3 and 4 toxicities were less frequent with nivolumab+ipilimumab (46 vs 63%), 60% of patients receiving the immunotherapy combination received corticosteroids in the course of their treatment; of those with immune related adverse events 35% required high dose (>40 mg per day of prednisone) 

The IMmotion 151 phase 3 that evaluates the anti-PD-L1 atezolizumab plus bevacizumab sunitinib highlights the importance of VEGF/ VEGFR-targeted therapies in favorable risk patients.1 In this study, atezolizumab plus bevacizumab provided a PFS improvement in PD-L1 positive advanced RCC compared to sunitinib (HR 0.74, P = 0.02), which was the primary endpoint of the study. The benefit of bevacizumab plus atezolizumab in IMmotion 151 was found to be consistent regardless of the risk groups. Taken together, the recent results of CheckMate 214 and IMmotion 151 suggest that anti-angiogenic therapies can still have a place in the frontline setting. 

The Role of PD-L1 Staining
PD-L1 staining by immunohistochemistry (IHC) to guide therapy in RCC remains controversial. In the second line setting, PD-L1 expression was shown to be associated with a poor prognosis independent of the treatment (nivolumab or everolimus).21 In the CheckMate 214 trial, analysis of outcomes by PD-L1 expression status demonstrated again that PD-L1 expression was prognostic though the degree of benefit from the combination of nivolumab plus ipilimumab was noticeably different based on PD-L1 status. Using the Dako PD-L1 IHC 28-8 pharmDx test with a cutoff of 1% on tumor cells, PFS was markedly improved in PD-L1 positive patients treated with nivolumab plus ipilimumab compared to sunitinib, from 5.9 months to 22.8 months. No benefit was reported with the combination in the PD-L1 negative group (<1%), with respective PFS of 10.4 vs 11 months.  However, OS benefit was maintained independently of PD-L1 status, though again the degree of benefit was more pronounced in the PD-L1 positive patients. 

In the IMmotion 151 phase III study of atezolizumab and bevacizumab compared with sunitinib, treatment with atezolizumab and bevacizumab resulted in improved investigator-assessed PFS in PD-L1–positive patients, achieving the study’s primary endpoint (11.2 vs 7.7 months, HR 0.74, 95% CI: 0.57-0.96, P = 0.02)1   PDL-1 positivity was defined as ≥ 1% in the tumor infiltrating cells using expression by immunohistochemistry with the SP142 assay. Taken in aggregate, these studies indicate that the chance for improved efficacy may be higher in PDL-1 positive tumors in the frontline setting, at least with combination of nivolumab/ipilimumab and atezolizumab/bevacizumab, though responses are seen in PDL-1 negative tumors. Ongoing trials exploring different immune checkpoint and VEGFR inhibitors may also stratify patients using different PD-L1 tests and cutoffs for positivity. Thus, the role of PD-L1 as a predictive and prognostic biomarker may continue to evolve. As such, refined predictive biomarkers to select patients for VEGF-targeted therapy alone, checkpoint blockade, or combination therapy are warranted to inform treatment decision making.   

Perspectives From Genomic Profiling
Genomic profiling continue to evolve in RCC; there are several biomarker driven trials currently open in non-clear cell RCC. SAVOIR explores the role of a pure MET inhibitor savolitinib vs sunitinib in those with MET-driven papillary RCC (NCT 03091192), while PAPMET is comparing PFS in patients with metastatic papillary renal cell carcinoma treated with sunitinib vs several MET (+/-VEGF) Kinase inhibitors (NCT 02761057).  However, currently the role of universal tumor profiling in advanced ccRCC is unclear.  In clinical practice it is most commonly used in later lines to try and find potentially targetable mutations.  Several reports mention that tumors harboring mutations in the TOR/Akt/PI3K pathway may increase responses to mTOR inhibitors.22,23 One report in advanced ccRCC showed that patients with PBRM1 mutations may respond better to immune checkpoint blockers.24 

Gene expression signatures, while not readily available in clinical practice to date, may also help improve therapeutic strategies. The IMmotion 150 phase 2 trial included three cohorts: sunitinib, atezolizumab, atezolizumab plus bevacizumab.25 Correlative analyses for biomarkers revealed that patients with a high angiogenic genes expression had better outcomes with sunitinib compared to the other 2 arms. Validation of genomic profiling to assess the optimal therapeutic sequence might come from prospective trials, such as the phase 2 BIONIKK trial, which will randomize patients to dedicated treatment arms according to their molecular profile (NCT02960906).

Novel treatment strategies involving the use of immunotherapeutic and targeted agents have ushered in a new era and challenged TKI monotherapy in the frontline setting, with combination therapies that will likely become the standard of care for most patients. However, TKI monotherapy may represent a preferred option in subtypes of patients in this setting. At this point, patient comorbidities, IMDC risk classification are critical to guide treatment strategies. Future clinical trials should help refine these classifications and help physicians achieve a more personalized approach for treatment strategies.

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