Targeted Therapies

The most common oncogenic event in ccRCC pathogenesis is the loss of chromosome 3p and subsequent VHL tumor suppressor gene alterations with either absence or malfunction of the VHL protein; hypoxia-inducible factors accumulate and prompt overexpression of growth factors, including VEGF and platelet-derived growth factor B, culminating in tumor cell growth, proliferation, and aberrant angiogenesis. Targeted therapies that block the VEGF pathway were the first breakthrough treatment of patients with mRCC.

In 2006, Motzer and colleagues reported the survival and response outcomes of first-line sunitinib versus IFN-α, with results favoring sunitinib in all major measures, including ORR, PFS, OS, and quality of life. Soon after, sunitinib was granted US Food and Drug Administration (FDA) approval, initiating a shift in the RCC treatment landscape from traditional immunotherapies (ie, high-dose interleukin and IFN-α) to the more tolerable and effective targeted therapies. Concurrently, temsirolimus, an mTOR inhibitor, showed improved PFS and OS compared with IFN-α and the combination of IFN-α and temsirolimus in patients with poor prognostic features. Single-agent temsirolimus was better tolerated and provided the greatest benefit. This study remains important by both demonstrating efficacy of temsirolimus in this vulnerable patient population and highlighting the value of offering a balance between efficacy and toxicity profiles during treatment planning. Pazopanib also has been utilized and evaluated widely, with initial studies among patient populations who were either treatment-naïve or pretreated with cytokine therapies. Studies suggested that there was significant PFS improvement compared with placebo, results that led to a clinical trial comparing pazopanib with sunitinib in the first-line setting. In this noninferiority trial, clinical outcomes were comparable between arms with PFS of 8.4 months (95% CI, 8.3–10.9) versus 9.5 months (95% CI, 8.3–11.1), respectively, and OS of 28.4 months (95% CI, 26.2–35.6) versus 29.3 months (95% CI, 25.3–32.5), respectively, for pazopanib and sunitinib. The toxicity profile of pazopanib was more favorable, particularly in terms of fatigue, hand-foot syndrome, and thrombocytopenia.

The more recent next-generation targeted therapies tested in the first-line setting include axitinib, which demonstrates highly selective activity on target VEGF receptors, and cabozantinib, which inhibits multiple tyrosine kinases. Axitinib, a selective inhibitor of VEGF receptors 1, 2, and 3, failed to show a PFS improvement over sorafenib in first-line treatment. ^, Despite that the higher ORR with axitinib than with sorafenib might suggest activity signals, the study did not meet its primary endpoint.

Evidence suggests that cabozantinib, a multikinase inhibitor of VEGF receptor, AXL, and MET, has MET and AXL receptor tyrosine kinases that are up-regulated by the accumulated hypoxia-inducible factors under pseudohypoxia conditions commonly present in RCC cells. ^, The combined inhibition of multikinases by cabozantinib was tested against sunitinib in the phase II CABOSUN study in first-line treatment of mRCC patients with IMDC intermediate-risk and poor-risk disease. ^, In a cohort of 157 mRCC patients, median PFS was 8.6 months with cabozantinib versus 5.3 months with sunitinib, per independent review committee assessment ( Table 1 ). The difference in PFS was statistically significant, with a hazard ratio (HR) of 0.48, with 20% of patients in the cabozantinib arm achieving objective responses compared with only 9% of patients with sunitinib. ^, Whereas one-fifth of patients achieved an objective response in the cabozantinib arm, only 9% achieved a similar response with sunitinib. Toxicity profiles of the 2 regimens were comparable. Updated OS data after a median follow-up of 34.5 months revealed a numerical difference between the cabozantinib and sunitinib arms; however, statistical significance was not achieved.

Perhaps more importantly, the results of the CABOSUN study in the patient population with bone metastases raised significant interest. Bone is the second most common metastatic site, with approximately one-third of patients developing bone metastases during the course of their mRCC progression. Several studies, including a meta-analysis, have shown that bone metastasis is a poor prognostic feature for patients treated with targeted therapies. The CABOSUN trial involved stratification and randomization based on the presence of bone metastasis, thus allowing in-depth analysis of outcomes in this vulnerable patient population. Subsequently, a significant PFS benefit was observed with cabozantinib over sunitinib in patients with bone metastasis. This elevated cabozantinib to the preferred first-line treatment option for IMDC intermediate-risk and poor-risk patients with bone involvement, per National Comprehensive Cancer Network (NCCN) guidelines.

Sunitinib has remained the standard-of-care targeted therapy and main comparator arm to clinical trials in first-line mRCC treatment for more than a decade. ^, Development of first-line combination therapies, however, discussed later, subordinated sunitinib. In addition, the observed PFS and ORR benefits with cabozantinib over sunitinib also have encouraged the utilization of cabozantinib in first-line treatment, as opposed to sunitinib. Currently, among the many available first-line targeted therapy agents, cabozantinib represents a suitable targeted therapy option, especially among immunotherapy-ineligible patients, such as those with active autoimmune disease or systemic steroid use ( Fig. 2 ).

Authors’ proposed management algorithm for patients with mRCC.

Immunotherapies

In addition to possessing angiogenic characteristics, RCC bears high immunogenicity. ^, Traditional immunotherapies, cytokines, had been the mainstay of mRCC treatment in the era prior to targeted therapies. By the early 2000s, identification of immune checkpoint molecules, such as CTLA-4 and PD-1 on the surface of T cells and PD-L1 on dendritic cells and tumor cells, restored scientific interest in immuno-oncology agents. In the realm of RCC therapeutics, the PD-1 inhibitor, nivolumab, was the first immunotherapy to establish activity, with better OS outcomes and tolerability over everolimus in patients who failed on treatment with a targeted therapy.

The immuno-oncology approach later was adopted in the first-line setting as part of a more aggressive strategy, including a combination nivolumab and ipilimumab in the phase III CheckMate 214 clinical trial. The results of this study brought essential insights on the efficacy of immunotherapeutics in mRCC. In total, 1096 treatment-naïve mRCC patients were enrolled and received either a combination of nivolumab and ipilimumab or single-agent sunitinib (see Table 1 ). Randomization was stratified based on IMDC risk categories (favorable risk vs intermediate–high risk) and geographic region. The treatment regimen in the combination arm employed administration of nivolumab, 3 mg/kg, and ipilimumab, 1 mg/kg, every 3 weeks for 4 courses, and then maintenance nivolumab, 3 mg/kg, every 2 weeks, whereas a traditional treatment schedule was used in the sunitinib arm, with 50 mg/d orally, with 4 weeks on 2 weeks off.

The initial results of 25 months follow-up revealed notable activity of the combination over sunitinib in a patient population with IMDC intermediate-risk or high-risk disease. OS was not reached in the combination arm versus 26 months in the sunitinib arm. Moreover, HR for death was 0.63, reflecting a 37% reduction of risk of death with the combination agent, and the 18-month OS rates were 75% and 60% in the combination arm and the sunitinib arm, respectively. PFS accordingly was longer in the combination arm, but the difference was not statistically significant (11.6 months vs 8.4 months; HR 0.82; 99.1% CI, 0.64–1.05). Response rates favored the combination treatment, with ORRs of 42% and 27%, respectively, with 9% of the patients experiencing a complete response in the immunotherapy arm versus 1% in the sunitinib arm. Direction of benefit, however, was the inverse in the favorable-risk patient population; the 18-month OS rate was 88% with combination therapy and 93% with sunitinib and demonstrated an HR of 1.45 (99.8% CI, 0.51–4.12). Median PFS was 15.3 months in the combination arm versus 25.1 months in the sunitinib arm (HR 2.18; 99.1% CI, 1.29–3.68), and ORR was 29% with the combination versus 52% with sunitinib. Importantly, the combination of nivolumab and ipilimumab provided a complete response in 11% of the patients in the favorable-risk population, whereas only 6% achieved a similar response with sunitinib.

Updated outcomes of the CheckMate 214 trial, after a minimum follow-up of 42 months, have confirmed the sustained OS and ORR benefits associated with this combination therapy in intermediate-risk and poor-risk populations. In addition, over this extended follow-up period, the difference in PFS between the combination arm and the sunitinib arm increased and reached statistical significance (12.0 months vs 8.3 months, respectively; HR 0.76 [0.63–0.91]). In the overall population, the 42-month OS rate was 56% in the combination arm versus 47% with sunitinib, recording a P value of 0.0002. Similar to the results of the initial analyses, a median OS was not reached and the difference between arms was not significant in the favorable-risk patient group. The combination of nivolumab and ipilimumab demonstrated higher complete response rates over sunitinib in the overall cohort, intermediate–poor-risk disease cohort, and favorable-risk cohort, with rates of 11% versus 2%, respectively; 10% versus 1%, respectively; and 13% versus 6%, respectively. Notably, 86% of complete responses were ongoing at the time of data cutoff, and 28 of the 59 complete responders did not require a subsequent treatment after discontinuation of nivolumab and ipilimumab after a median duration of 34.6 months.

Concerning safety outcomes, both all-grade and grade 3–4 adverse events were seen more frequently in the sunitinib arm. Despite this, treatment discontinuation due to adverse events was more common with immunotherapy (22%) than sunitinib (12%), patient-reported outcomes reported by Cella and colleagues suggested better tolerability of the immunotherapy combination over sunitinib.

The substantial survival benefit and the longevity of the responses observed with nivolumab and ipilimumab combination led to approval of the combination agents for metastatic ccRCC patients with IMDC intermediate-risk and poor-risk patients. The NCCN and Society for Immunotherapy of Cancer (SITC) guidelines now recommend nivolumab and ipilimumab combination as preferred treatment in metastatic ccRCC patients with IMDC intermediate-risk or poor-risk disease. ^,

Importantly, the contrasting benefit patterns in different IMDC risk classes with 2 mechanistically distinct approaches brought about a new perspective to the field. IMDC risk classification originally was developed as a prognostic tool among a large cohort of mRCC patients receiving targeted therapy. Benefit from immunotherapy in this patient population, which was previously identified as bearing poor prognosis, extended this domain of investigation to identifying molecular correlates of response to immunotherapies. The CheckMate 214 study included exploratory analyses of clinical outcomes based on PD-L1 expression; however, among the intermediate-risk and high-risk cohorts, OS benefit with the immunotherapy combination over sunitinib was independent of PD-L1 expression levels. When a positive PD-L1 expression level was defined by greater than or equal to 1%, ORR favored immunotherapy in both PD-L1–positive and PD-L1–negative patients. Therefore, the predictive capability of PD-L1 expression was considered inconclusive and possibly not clinically significant with the nivolumab and ipilimumab combination.

Pembrolizumab also was studied in the first-line treatment of mRCC in the phase II Keynote-427 study. An analysis of the 107 enrolled patients demonstrated efficacy with ORR of 33.6% and the treatment had favorably safety. Single-agent pembrolizumab has not been investigated further, however, given the profound efficacy of combination therapy involving pembrolizumab in first-line treatment of mRCC, data that are discussed later. Single-agent immunotherapy currently is not considered appropriate first-line therapy.

Instead, combination nivolumab and ipilimumab is a standard-of-care option for immunotherapy-eligible patients with IMDC intermediate-risk and poor-risk disease (see Fig. 2 ).

Combination Therapies

Following the success of targeted therapies and immunotherapies in mRCC treatment, further efforts were directed to evaluating combination therapies that could inhibit angiogenesis and foster immune surveillance simultaneously. ^, Investigators sought to attain immediate decreases in tumor burden with PFS benefit, combined with durable responses and OS benefit, with a favorable toxicity profile. In addition, basic science research showed that targeted therapies bear immunomodulatory effects within the tumor microenvironment by prompting regulatory T cells, myeloid-derived suppressor cells, and cytokines to suppress ongoing immune escape. Thus, a combination of the two active compounds could possess a potential synergistic activity beyond their additive effects.

The randomized phase III IMmotion151 trial was the first to report outcomes of the combination approach in first-line treatment of mRCC patients with clear cell or sarcomatoid histology (see Table 1 ). The study enrolled 915 patients randomized to sunitinib or a combination of bevacizumab and atezolizumab. Stratification factors included PD-L1 expression (<1% vs ≥1%) on tumor-infiltrating lymphocytes, presence of liver metastasis, and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic group. Median PFS in the PD-L1–positive population and in the intention-to-treat population both favored the bevacizumab/atezolizumab combination over sunitinib (11.2 months vs 7.7 months, respectively, HR 0.74; and 11.2 months vs 8.4 months, respectively, HR 0.83). OS was comparable, however, across both arms in both PD-L1–positive and the intention-to-treat analyses. In this study, important results emerged among those with sarcomatoid histology ; 61% of patients with sarcomatoid histology were PD-L1–positive and there was substantial improvement observed in ORR and PFS when those patients were treated with bevacizumab/atezolizumab. In the PD-L1–positive sarcomatoid RCC patients, PFS results favored bevacizumab/atezolizumab, with an HR of 0.46. More importantly, the superior efficacy of bevacizumab/atezolizumab in terms of ORR and PFS was independent from PD-L1 status among sarcomatoid RCC patients. Despite that, the IMmotion151 trial met its first coprimary endpoint, the PFS benefit in a PD-L1–positive patient population, the second co-primary endpoint of OS benefit in the overall population was not met, and thus the combination has not received regulatory approval.

Two other breakthrough studies in the realm of mRCC treatment were reported in 2019; the KEYNOTE-426 and JAVELIN Renal 101 trials (see Table 1 ). KEYNOTE-426 compared the combination of pembrolizumab and axitinib with sunitinib, whereas JAVELIN Renal 101 compared the combination of avelumab and axitinib with sunitinib. ^, Both combinations obtained immediate FDA approval within months. In the KEYNOTE-426 study, pembrolizumab and axitinib met primary endpoints of OS and PFS along with the key secondary endpoint of ORR. At the 12-month cutoff of OS analysis, 89.9% versus 78.3% of the patients were alive in the combination and sunitinib arms, respectively. The statistical difference favored pembrolizumab/axitinib with an HR of 0.53. Median PFS was 15.1 months in the pembrolizumab/axitinib arm versus 11.1 months in the sunitinib arm. In the combination arm, 59.3% of the patients achieved an objective response, with 5.8% having complete response; in contrast, ORR was 35.7% and only 1.9% of the patients achieved complete response in the sunitinib arm. The randomization of the study was stratified based on IMDC risk status of patients, and the results showed that OS and PFS benefits with the combination were independent of IMDC risk status or PD-L1 expression status.

In the JAVELIN Renal 101 study, the combination of avelumab and axitinib demonstrated improved PFS over sunitinib in both the PD-L1 positive (≥1% on immune cells) and overall population (13.8 months vs 7.2 months, respectively [HR 0.61; 95% CI, 0.47–0.79], and 13.8 months vs 8.4 months, respectively [HR 0.69; 95% CI, 0.56–0.84]. In the overall population, ORR was 51.4% with the combination treatment versus 25.7% with sunitinib, with complete response rates of 3.4% and 1.8%, respectively. At the time of the first publication, OS data of the study were not mature and only a small number of patients were deceased in each group.

When evaluating the results of the 2 FDA-approved combination therapies involving a targeted therapy and immunotherapy, toxicity profile becomes an important area of consideration. The proportions of the patients who developed any grade adverse event appeared comparable in KEYNOTE-426 and JAVELIN Renal 101, 98.4% and 95.4%, respectively, with 10.7% and 7.6%, respectively, of patients requiring discontinuation of the combination due to side effects. ^, Rates of fatigue, hypertension, and rash were similar in both combination therapies. The combination of pembrolizumab/axitinib was associated with a higher rate of hypothyroidism (35.4% vs 24.9%) and gastrointestinal toxicities, such as diarrhea (62.2% vs 54.3%) and nausea (34.1% vs 27.7%) compared with avelumab/axitinib. Overall, the toxicity profiles of the pembrolizumab/axitinib and avelumab/axitinib were similar.

Whereas both combinations obtained almost immediate FDA approval, most current guidelines of NCCN and SITC both recommend pembrolizumab/axitinib as the preferred immunotherapy-targeted therapy combination in the first-line setting, regardless of IMDC risk category, due primarily to the lack of OS data in the JAVELIN 101 clinical trial. ^, The authors’ preferences are in line with these guideline recommendations (see Fig. 2 ).