Sunitinib is an oral TKI that acts on VEGF receptors. It was granted accelerated approval by the FDA in 2006, based on two single-arm trials in patients with mRCC. Sunitinib demonstrated partial responses (PR) in 25.5% and 36.5% of patients ^[1][2][25,26]. In 2007, a randomized, multicenter phase III trial demonstrated the superiority of sunitinib over interferon alfa ^[3][9]. The sunitinib group had a longer median PFS and higher RR than the interferon alfa group (11 months vs. 5 months), as well as better quality of life ^[3][9]. With these results, sunitinib replaced interferon alpha as the standard-of-care therapy in RCC.

In a later study, pooled data were used to identify which patients would benefit most from sunitinib. Predictors of long-term OS (≥30 months) included ethnic origin (50.2 vs. 38.4 months in white vs. nonwhite patients), bone metastases (42.7 vs. 54.5 months for patients with vs. without metastases), and corrected calcium (41.7 vs. 50.2 months for patients with >10 vs. ≤10 mg/dL calcium) ^[4][27]. More recently, sunitinib was approved as an adjuvant treatment for patients with locoregional, high-risk ccRCC after a nephrectomy and demonstrated a longer median duration of disease-free survival than the placebo (6.8 years vs. 5.6 years) ^[5][28]. Overall, sunitinib was the first agent in the new era of targeted therapies to improve survival for patients with mRCC compared to prior cytokine-based treatments. In August of 2021, pembrolizumab was granted priority review for the adjuvant treatment of patients with RCC at intermediate or high risk of recurrence following a nephrectomy.

Ipilimumab, a CTLA-4 inhibitor, and nivolumab, a PD-1 inhibitor, were the next therapies to be studied in mRCC, and the first and only dual ICI combination therapy to be approved for use in mRCC. The randomized, phase III CheckMate 214 trial assigned patients to receive either a combination of ipilimumab and nivolumab or sunitinib, and the primary outcome was 18-month OS in the patients with intermediate- or poor-risk groups by the International Metastatic RCC Database Consortium (IMDC) ^[6][24]. The 18-month OS rate was 75% with nivolumab and ipilimumab as compared to 60% with sunitinib, and the CR rate was 9% compared to 1%. This landmark trial established ipilimumab and nivolumab combination therapy as the first ICIs to demonstrate a durable response to therapy ^[6][24].

In 2020, the extended four-year follow-up data from the CheckMate 214 trial were published ^[7][29]. OS remained superior for the nivolumab and ipilimumab group compared to the sunitinib group, and the four-year PFS probability for the nivolumab and ipilimumab group was 31.0% compared to 17.3% in the sunitinib group ^[7][29]. Additionally, the probability of response for greater than four years was higher with nivolumab and ipilimumab than with sunitinib (59% vs. 30%), again suggesting the durability of response with combination ICI therapy. These data suggest that the combination therapy with nivolumab and ipilimumab offers a potentially long-lasting response for patients with mRCC, although more long-term data are needed to further quantify this.

Bevacizumab is an antibody that inhibits the VEGF receptor and was investigated in combination with atezolizumab, an anti-PD-L1 antibody, for patients with ccRCC or sarcomatoid histology RCC in the IMmotion151 phase III trial ^[8][13]. The trial enrolled 915 patients for a minimum of 12 months of follow-up. The median PFS for the patients receiving atezolizumab and bevacizumab (11.2 months) was significantly longer than for the patients receiving sunitinib (8.4 months) ^[8][13]. In the atezolizumab and bevacizumab group, 37% of patients achieved an objective response (OR), and 5% achieved a CR, whereas 33% of patients in the sunitinib group achieved an OR, and 2% achieved a CR, neither of which reached significance ^[8][13]. However, at a longer follow-up of 40 months, there was no survival benefit with atezolizumab and bevacizumab compared to sunitinib ^[9][30]. While this combination did not show a survival benefit or statistically significant CR rate, we are still treating three patients at our institution for over seven years now as part of this trial, which suggests again that this combination can produce durable responses in a subset of patients, even if it has not received FDA approval. Interestingly, a similar phase II trial is in progress for the treatment of naïve patients with mRCC looking at atezolizumab and bevacizumab in combination with a selective inhibitor of phosphoinositide-3-kinase (PI3K)–gamma (IPI-549) ^[10][31]. The study has completed accrual; however, no data are available at the time of this manuscript ^[10][31].

The next combination therapy investigated was axitinib, a highly selective VEGF receptor TKI, and avelumab, an anti-PD-L1 antibody. This combination was initially studied in a phase Ib trial that established its safety as combination therapy and suggested antitumor activity in patients with advanced ccRCC ^[11][32]. The phase III clinical trial, JAVELIN Renal 101, randomized 873 patients to receive either axitinib and avelumab or sunitinib ^[12][14]. The initial data were published in March 2019. Overall, the patients in the axitinib and avelumab group had significantly longer PFS (13.8 months) than those in the sunitinib group (8.4 months) ^[12][14]. The subgroup of patients with PD-L1-positive tumors also had significantly longer PFS after treatment with axitinib and avelumab (13.8 months) than the patients with PD-L1-positive tumors who received sunitinib (7.2 months) ^[12][14]. This subgroup also had significantly higher OR rates (55.2%), defined as a PR or CR than the patients who received sunitinib (25.5%) ^[12][14]. However, confirmed CR rates were only 4.4% in the axitinib and avelumab group compared to 2.1% in the sunitinib group ^[12][14].

Updated data were published in August 2020, and again demonstrated significantly longer PFS in the axitinib and avelumab group than in the sunitinib group, as well as similar overall RR. However, CR rates in the combination group were only 3.8% compared to 2.0% in the sunitinib group ^[13][33]. Additional follow-up is still ongoing. The combination of axitinib and avelumab is a superior option to sunitinib for PFS but a durable CR has yet to be demonstrated. This study raises the question of whether the combination of targeted VEGF receptor inhibitor therapy and ICI have additive or synergistic effects.

A similar phase III trial comparing sunitinib to another VEGF receptor TKI and anti-PD-1 regimen was published at the same time as JAVELIN Renal 101. The KEYNOTE-426 trial randomly assigned 861 patients with advanced ccRCC to receive axitinib and pembrolizumab or sunitinib ^[14][34]. Initial follow-up data at 12.8 months demonstrated significantly longer PFS in the axitinib and pembrolizumab group (15.1 months) than in the sunitinib group (11.1 months) ^[14][34]. The OR rate was also significantly higher in the pembrolizumab and axitinib group (59.3%) than in the sunitinib group (35.7%), and these findings were noted across IMDC risk groups and PD-L1 expression groups ^[14][34]. In the axitinib and pembrolizumab group, 5.8% of patients achieved a CR, compared to 1.9% of patients in the sunitinib group ^[14][34].

The first interim analysis was published 15 months later, reporting a median follow-up time of 30.6 months ^[15][35]. PFS was significantly longer in the axitinib and pembrolizumab group (15.4 months) than in the sunitinib group (11.1 months) ^[15][35]. Additionally, the OR rate was higher in the axitinib and pembrolizumab group (60%) than in the sunitinib group (40%), and 9% of patients in the axitinib and pembrolizumab group achieved a CR compared to 3% in the sunitinib group ^[15][35]. The second interim analysis data were presented at the American Society of Clinical Oncology Annual Meeting in June 2021, with a 42.8-month median follow-up, the longest follow-up of any ICI and TKI combination therapy ^[16][36]. Again, patients who received pembrolizumab and axitinib had significantly longer PFS (15.7 months) and a significantly higher rate of PFS (25.1%) than those who received sunitinib (11 months, 10.6%) ^[16][36]. The OR rate was also higher for patients who received pembrolizumab and axitinib (60.4%) than for patients who received sunitinib (39.6%) ^[16][36]. The CR rate was higher in the pembrolizumab and axitinib group (10.0%) than in the sunitinib group (3.5%), but the trend did not achieve statistical significance ^[16][36]. This was the final analysis of the KEYNOTE-426 trial and demonstrates the improved PFS and OR rates with axitinib and pembrolizumab ^[16][36].

The CheckMate 9ER trial studied nivolumab, an anti-PD-1 antibody, and cabozantinib, a tyrosine kinase inhibitor that regulates tumor cell proliferation, neovascularization, and immune cell regulation through the inhibition of VEGF, cMET, and other receptor-based targets ^[17][16]. The phase III clinical trial enrolled 651 patients with previously untreated advanced ccRCC, defined as either unamenable to curative surgery or radiation or metastatic disease ^[17][16]. At a median follow-up of 18.1 months, the median PFS was significantly longer for the patients in the cabozantinib and nivolumab group (16.6 months) than for the patients in the sunitinib group (8.3 months) ^[17][16]. Significantly more patients had an OR with cabozantinib and nivolumab (55.7%) compared to with sunitinib (27.1%) ^[17][16]. In the cabozantinib and nivolumab group, 8.0% of patients achieved a CR, compared to 4.6% of patients in the sunitinib group ^[17][16]. These findings persisted across IMDC risk subgroups and tumor PD-L1 expression subgroups ^[17][16]. Updated analyses from extended follow-up have not yet been published. Based on these findings, the combination of nivolumab and cabozantinib is now one of the first-line combination ICI and targeted therapies recommended for treatment-naïve mRCC ^[18][37]. Although the available data suggest a trend towards a CR with combination therapy, statistical significance has not yet been established. However, there is hope that this trend may be established with an extended follow-up of the CheckMate 9ER trial, especially as more patients now have the option to be treated with this combination given its recent FDA approval ^[19][38].

The most recent phase III combination trial to be published was the three-armed CLEAR trial. This trial studied lenvatinib, an antiangiogenic agent, and pembrolizumab, an anti-PD-1 antibody, or lenvatinib and everolimus, an mTOR kinase inhibitor, versus sunitinib ^[20][39]. A total of 1069 patients were randomized for a median of 17 months of follow-up and found that PFS was significantly longer with lenvatinib and pembrolizumab (23.9 months) than with sunitinib (9.2 months) ^[20][39]. The proportion of patients with an OR was significantly higher in the lenvatinib and pembrolizumab group (71.0%) than in the sunitinib group (36.1%), and 16.1% of patients in the lenvatinib and pembrolizumab group achieved a CR compared to 4.2% of patients in the sunitinib group ^[20][39]. Longer-term follow-up data are being collected, and the study is set to end 31 July 2022 ^[21][40].