: Could you first provide an overview on some of the latest updates in metastatic renal cell carcinoma (RCC) regarding VEGF tyrosine kinase inhibitors (TKIs)]?

: VEGF TKIs were initially developed between 15 and 20 years ago, and over the course of the following 10 years, there were a number that were studied and approved and made up the backbone of our treatment for metastatic RCC. They included sunitinib, pazopanib, axitinib, and sorafenib. For the most part, treatment for patients was based on initially starting with 1 TKI and then, if there was progression of disease, switching to another. Over of time, patients benefited from the use of multiple TKIs given in sequence. More recently, there have been a number of second- and third-generation TKIs, and 2 of them have been approved, cabozantinib and lenvatinib. Cabozantinib was compared with everolimus, primarily in second-line therapy, and lenvatinib was combined with everolimus and compared with everolimus in second-line therapy. Now these newer TKIs also seem to have a good activity and are commonly being used.

: Recently there have been updates in terms of VEGF TKIs in advanced RCC. One of the important updates is the preliminary press release on the 9ER trial [NCT03141177], which has a cabozantinib and nivolumab combination in the frontline setting. The actual results of the study have not yet been presented, and based on the extent of the benefit, we will have to consider this as a potential frontline regimen.

The other [results that were] recently published were from the TIVO-3 study, which compared tivozanib, a novel VEGFR TKI that inhibits VEGF 1, 2, and 3 receptors, and sorafenib, which is an established agent in advanced RCC [NCT02627963]. This was a randomized comparison, and for the first time, we have an experience that was published on post–VEGF TKIs and immunotherapy: What is the experience, and what kind of efficacy can we expect? Because a considerable number of the patients had prior immunotherapy as well as VEGF TKIs, the eligibility of the study included, only at a minimum, 1 prior VEGF TKI therapy, but because of current treatment patterns, a lot of them had both immunotherapy and VEGF TKI. In that study, the primary end point was progression-free survival [PFS], and tivozanib showed a statistically significant benefit compared with sorafenib, with the median PFS of 5.6 months compared with sorafenib at 3.9 months (

 = .016). There was a benefit seen for a pure VEGF TKI in the third-line setting for the most part in advanced RCC.

How is tivozanib currently being used in the RCC landscape, and what is its role in the later-line setting?

: Tivozanib is a highly potent selective VEGFR inhibitor that was initially brought into clinical trials [and] compared with sorafenib in the large phase 3 TIVO-1 trial [NCT01030783]. The TIVO-1 trial reached its primary end point by showing improvement in PFS, but there lacked an overall survival benefit. Because of the way the trial was planned, the survival favored sorafenib over tivozanib, mostly because many patients on the sorafenib arm received additional TKIs after progression and not in the tivozanib arm. In the United States, tivozanib has remained an investigational agent in the first-line setting but has been approved in Europe in select circumstances.

: At present, tivozanib is not FDA approved in the United States. It does have [European Commission] approval in Europe, and 1 of their treatment options is to use it as a single-agent VEGF TKI in advanced RCC. In the United States, in the third-line setting, given the results of the TIVO-3 study, this agent could be a reasonable option to consider for patients post both VEGF TKI and immuno-based therapies. [It is] also a treatment that seems to prolong PFS, is relatively well tolerated, and may give patients that additional efficacy benefit in the pretreated setting.

The 2020 [American Society of Clinical Oncology] meeting presented updated overall survival results on the phase 3 TIVO-3 trial, which compared tivozanib and sorafenib in metastatic RCC. Could you provide an overview of that trial as well as its presented findings?

: One of the burning questions we had following the TIVO-1 trial was around the survival benefit—the lack of survival benefit seen in the TIVO-1 trial—and that there was a trend toward a survival improvement with sorafenib. This was due to the subsequent therapy that was received in the sorafenib arm. TIVO-3 investigated tivozanib compared with sorafenib again only in a heavily pretreated population. In the trial design for TIVO-3, which is tivozanib versus sorafenib and has now become more commonly used in a later line of therapy, there wasn’t this crossover built into the trial. In that study, which is really the first phase 3 trial that I’m aware of that looked at RCC-specific agents in heavily pretreated patients, tivozanib had a longer PFS compared with sorafenib and a better safety profile, and the survival between the 2 arms was very similar.

: In terms of efficacy, tivozanib has shown superior efficacy in PFS. However, in the overall survival setting, there was not a statistically significant benefit that favored 1 agent over the other. The toxicity profiles of both agents and the mechanism of action have to be considered. Sorafenib has RAF kinase inhibitor activity as well as VEGF TKI activity, whereas tivozanib is a preferential VEGF TKI inhibitor with selective activity against VEGF TKI. The toxicity profile seems to reflect those with higher risk of hand-foot syndrome and skin rashes with sorafenib compared with tivozanib. The risk of hypertension and other toxicities that are VEGF related seems to be comparable between both agents.

In June 2020, the FDA accepted a new drug application for tivozanib for the treatment of patients with relapsed/refractory RCC. How do you believe that its approval will affect the treatment paradigm?

: There have been a number of highly effective therapies that have come in and have led to a new paradigm in first- and second-line therapy for RCC. They include the use of PD-1 inhibitors, or IO [immuno-oncology] therapy, but there’s an unmet need to identify treatments for late-line therapy, where safety profile is very important because in patients who have had prior therapy, some of the toxicities are cumulative. Utilizing agents with minimal toxicity and late-line therapies is particularly important, and that’s where tivozanib fits into our paradigm well. Two roles for tivozanib would be in late-line therapy based on its excellent safety profile or to combine it with immunotherapies and look at earlier lines of therapy.

: I think the FDA approval of tivozanib will give physicians another option in the VEGF TKI setting to be used post an initial VEGF TKI therapy in advanced kidney cancer. The tolerability of the patients is going to be critical in that setting but especially with bulky disease and pretreated prior toxicities of prior treatments. Balancing the risk-benefit ratio in this patient population and factoring in the toxicity and how it would affect patients’ quality of life will be worthy of consideration as you weigh the treatment option with tivozanib, but it definitely expands the treatment options for the pretreated patients in advanced RCC.

Can you speak a little more about the utility of tivozanib when patients progress on immunotherapy?

: Tivozanib has been shown to prolong PFS compared with sorafenib in the TIVO-3 trial, and many of those patients had prior immunotherapy. There are very few data for drugs in RCC and patients who have progressed on prior IO therapy, and that’s another area where we’ve established evidence with tivozanib in that setting.

: Tivozanib has mainly been evaluated in the phase 3 or randomized setting only as a single agent. The combination therapy and results reported from combinations of tivozanib with nivolumab show some promising response rates. However, as of now, this cannot be considered as something…for clinical management outside a clinical trial.

What other emerging approaches are coming down the pipeline in this space that you’re excited about?

: There’s another new class of drugs: the HIF-PH [hypoxia-inducible factor prolyl hydroxylase] inhibitors, which also target the same axis as the TKIs around angiogenesis, but they attack it at a different place right at the HIF molecule. I’m particularly excited about these drugs in terms of novel drugs being studied in RCC and, hopefully, benefiting patients.

: There is a combination of lenvatinib and pembrolizumab in the frontline setting. That phase 3 trial comparing that combination to sunitinib has been completed, but the results are not yet reported. Besides that, novel TKIs that are in development are still at the early-stage, phase 1 type of levels, so not much preliminary efficacy is available on those agents.

Where do you believe future research efforts should focus?

: Most of our drugs for RCC are based on 3 different mechanisms of action: VEGF-targeted drugs, mTOR inhibitors, which are not commonly used these days, or immunotherapy. I think it’s very important to do studies of underlying biology to identify novel targets so that we can develop novel agents outside the mechanism of actions already utilized.

: I think future research efforts have to focus on the patients who are not responding to any of the existing therapies. There is at least a third of our patients who do not benefit or are very rapidly progressing on the existing 2 main mechanisms of action, both the VEGF TKIs and the immune checkpoint inhibition options. Further development of immunotherapy combinations is required, especially for the immune-refractory patient population, but that patient population has a huge unmet need as of now. We are not curing everybody and maybe making a long-term impact on about 10% to 20% of our patients with advanced kidney cancer.

Do you want to highlight anything else or provide a general take-home message from the RCC workshop?

: I think that tivozanib is a very well-tolerated TKI with a high level of activity. It initially was not approved in RCC, which was probably a result of trial design. I think that those developing tivozanib should be praised for their persistence—both the investigators and the sponsor—in moving this drug into additional clinical trials and, hopefully, receiving regulatory approval in the United States so that we can begin to provide it as an option for our patients.

: There are some novel cytokines and novel targets that are being studied in advanced kidney cancer. One example would be an agent called ALKS 4230, which I studied in a phase 1 trial with expansion cohorts [and] is a novel form of IL-2 with a much better tolerability profile that may show efficacy down the road as we explore more in the phase 2 setting in kidney cancer. The other agent to watch is CB-839, which is in combination with cabozantinib. The study is a randomized trial and completed, and [we are waiting to see from] the results whether that enhances our current VEGF TKI activity. NKTR-214 is another cytokine-based regimen that is also now in a randomized clinical trial. That is another one to watch in combination with nivolumab for efficacy considerations in the advanced setting.

There are novel targets that are being identified, for instance, the STING [stimulator of interferon genes] pathway, which is in very early-stage clinical trials now. Then further advanced is the HIF2 inhibitors, which are exceedingly interesting and are already in phase 3 trials that are ongoing in comparison with everolimus.

Articles

Robert J. Motzer, MD, and Ulka Nitin Vaishampayan, MD, MBBS, FAB, discuss some of the latest updates in metastatic renal cell carcinoma.

Expert Perspectives in the Evolving Treatment Landscape for Metastatic Renal Cell Carcinoma

Targeted therapy and immunotherapy have improved survival outcomes for patients with metastatic renal cell carcinoma (mRCC).

 Results from an international, multi-center study of 7498 patients from the International mRCC Database Consortium (IMDC), analyzing use of several targeted therapies and an immune checkpoint inhibitor (ICI) after first-line therapy, showed that 51.4% of patients received second-line therapy, 24.2% of patients received third-line therapy, and 7.9% of patients received fourth-line therapy.

 At the time the study was published (2018), the only approved ICI for treatment of mRCC was nivolumab.

With the approval of immunotherapies, more patients may move on to later lines of therapy, and it is important to have drugs that are active in later line settings. This article will review the current treatment recommendations for mRCC, including results from some of the larger, recent clinical trials on which the recommendations were based, and will continue with a description of other recent and ongoing trials of possible future treatments for mRCC.

Tyrosine kinase inhibitors (TKIs) and anti-vascular endothelial growth factor (VEGF) antibodies are widely used in first- and second-line treatments for mRCC, appearing as recommended treatment in guidelines for the disease.

 Risk models may be used to evaluate treatment options.

An example treatment algorithm from the Society for Immunotherapy of Cancer is shown in (

 It is an immunotherapy treatment algorithm for advanced RCC based on treatments that were approved by the FDA at the time the recommendations were published (2019) and provides guidelines for diagnostic workups, patient selection, initial therapy, and therapy for patients who are refractory.

After first-line treatment, recommendations from the National Comprehensive Cancer Network organization for subsequent treatment of mRCC consist of fewer options for progressive disease (second-, third-, and fourth-line treatment). For patients with clear cell histology, there are 3 preferred regimens for subsequent therapy: cabozantinib or nivolumab, both of which have a category 1 recommendation (based on high-level evidence and uniform consensus within the members of the organization that the intervention is appropriate); or ipilimumab plus nivolumab, which has a category 2A recommendation (based on lower-level evidence but uniform consensus within the organization that the intervention is appropriate). Other regimens that are recommended, but not preferred, include category 1 VEGF receptor (VEGFR) axitinib or lenvatinib plus mTOR inhibitor (mTORI) everolimus, category 2A: axitinib plus pembrolizumab, everolimus, and pazopanib or sunitinib, and category 3 (based on any level evidence but with major disagreement within the organization that the intervention is appropriate) axitinib plus avelumab. Additionally, treatments that are useful in certain circumstances include VEGFR bevacizumab or sorafenib, high-dose interleukin-2 for selected patients, and temsirolimus (all category 2B, which is based on lower-level evidence but consensus within the organization that the intervention is appropriate).

Evidence for cabozantinib includes results of the phase 3 METEOR study, which evaluated the impact of cabozantinib versus everolimus on overall survival (OS) of patients with advanced RCC. In the study, 658 patients with previously treated advanced RCC were randomized to receive either cabozantinib 60 mg every day (n=330) or everolimus 10 mg every day (n=328). Median follow-up was 28 months (interquartile range: 25, 30). Results from the study showed that median time to objective response with cabozantinib was 1.91 months (range, 1.6-11.0), versus 2.14 months with everolimus (range, 1.9-9.2). A greater proportion of patients had early tumor shrinkage (eTS) of at least 30% with cabozantinib (19.7% of patients, n=65) versus everolimus (4.9%, n=16). Additionally, the rate of any eTS was higher in the cabozantinib arm (73.3%, n = 242) than in the everolimus arm (47.3%, n = 155), and the percentage of patients with no eTS was lower in the cabozantinib arm (23.3%, n=77) than in the everolimus arm (47.6%, n=156). For patients with at least 30% eTS, median OS was not reached (NR) (95% CI, 23.7-NR) for those receiving cabozantinib, versus 10.2 months (95% CI, 3.9-not evaluable [NE]) for those receiving everolimus (stratified HR, 0.45; 95% CI, 0.21-0.95; 

=.05). For patients with any eTS, median OS was 23.7 (95% CI, 21.7-27.7) for those receiving cabozantinib, versus 17.3 months (95% CI, 15.4-20.8) for those receiving everolimus (stratified HR, 0.62; 95% CI, 0.48-0.80; 

 = .05). For patients with no eTS, OS was similar between the 2 groups.

The phase 3 CheckMate 025 trial demonstrated superior OS with nivolumab for previously treated patients with advanced RCC compared with everolimus.

An updated final analysis with a minimum follow-up of 64 months was reported.5 In the study of 821 patients with previously treated predominantly clear cell advanced RCC, patients were randomized to receive nivolumab 3 mg/kg intravenously (IV) every 2 weeks (n = 410) versus everolimus 10 mg orally once daily (n = 411). The primary end point was OS, and secondary end points were objective response rate (ORR), progression-free survival (PFS), and safety. At more than 5 years of minimum follow-up, response rates and survival were superior with nivolumab compared with everolimus. Median OS was 25.8 months (95% CI, 22.2-29.8) for patients receiving nivolumab versus 19.7 months (95% CI, 17.6-22.1) for patients receiving everolimus (HR, 0.73; 95% CI, 0.62-0.85).

 Society for Immunotherapy of Cancer Recommendations

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OS at 60 months was 26% for the nivolumab group versus 18% for the everolimus group.

Median PFS per investigator was 4.2 months (95% CI, 3.7-5.4) in the nivolumab group versus 4.5 months (95% CI, 3.7-5.5) for the everolimus group (HR, 0.84; 95% CI, 0.72-0.99). PFS at 60 months was 5% of patients receiving nivolumab versus 1% of patients receiving everolimus. ORR per investigator was 23% (95% CI, 19-27) in the nivolumab group versus 4% (95% CI, 2-7) for the everolimus group (odds ratio, 6.86 [95% CI, 4.01-11.74]). Complete response was experienced by 4 patients (1%) in the nivolumab group versus 2 (0.5%) in the everolimus group. Median duration of response (DOR) was 18.2 months (95% CI, 12.9-25.8) for the nivolumab group versus 14.0 months (95% CI, 8.3-19.2) in the everolimus group.

 Ongoing responses were observed in 28% of patients (26 of 94) receiving nivolumab versus 18% of patients (3 of 17) receiving everolimus.

Treatment Outcomes Among Patients Treated With VEGFR TKIs and Those Treated With mTORIs After IO Treatment

Research has also been conducted on other targeted and immuno-oncology (IO) therapies, including sequencing for second-line VEGF therapies after first-line ICIs. A retrospective, longitudinal cohort study of VEGF therapy after treatment with an ICI was undertaken using data from 8 international cancer centers. The study evaluated adult patients with mRCC who received IO therapy in any line (including second, third, fourth, or higher) and then initiated targeted therapy after discontinuing IO therapy (TABLE).

 Interventions were VEGFR TKIs (which include axitinib, bevacizumab, cabozantinib, pazopanib, sorafenib, and sunitinib) or mTORIs (which include everolimus and temsirolimus). Outcome measures were time to treatment discontinuation (TTD), OS, and ORR. The study included 314 patients; 276 received VEGFR TKIs and 38 received mTORIs. Median TTD among patients treated with VEGFR TKIs or mTORIs after IO treatment was 6.1 months (95% CI, 5.4-7.8) for all lines of VEGFR TKIs and 2.8 months (95% CI, 2.0-3.4) for all mTORI lines. OS 1-year probability was 65% (95% CI, 58-72) for all lines in patients treated with VEGFR TKIs and 47% (95% CI, 30-63) in all lines for those receiving mTORIs. The ORR was 29.8% (n = 57) for all lines of those treated with VEGFR TKIs and 3.6% (n = 1) in all lines for those treated with mTORIs.

Second-line VEGF therapy after first-line ICI treatment was also studied in a medical record review that analyzed patients with mRCC treated with nivolumab plus ipilimumab who received a subsequent VEGFR TKI (n = 33) as part of the CheckMate 214 study (NCT02231749). Outcome measures were PFS, OS, and toxicities. PFS from second- line therapy was significantly longer when the duration of nivolumab plus ipilimumab was at least 6 months (PFS of 8 months for responders of at least 6 months versus 5 months for responders of less than 6 months (

 = .03). OS for the study population was 54% after 12 months and 37% after 24 months. Grade 3 and 4 adverse events (AEs) were experienced by 14 patients (42.4%).

Future Trends and Opportunities: Additional Potential Treatments Ahead 

Additional treatments for mRCC are continuing to be 

studied, as described in the following section. The evolving treatment landscape includes treatments such as further VEGFR TKI therapy, combination therapy such as lenvatinib plus pembrolizumab, hypoxia-inducible factor (HIF) inhibitor, and a multikinase inhibitor with an ICI.

Tivozanib is a novel VEGFR TKI that is already approved by the European Medicines Agency for first-line treatment of adults with RCC. With a half-life of 4 to 5 days, tivozanib is designed to optimize the VEGFR blockade while minimizing off-target effects. The phase 3 TIVO-1 trial (NCT01030783) evaluated tivozanib versus sorafenib for first-line treatment of mRCC. Results showed that PFS was 11.9 months for patients receiving tivozanib versus 9.1 months for patients who received sorafenib (HR, 0.797; 95% CI, 0.639-0.993; 

 = .04). OS favored sorafenib, in which just 13% of patients (34 of 260) who received tivozanib were given subsequent targeted therapy, compared with 63% of patients (162 of 257) who received sorafenib. Additionally, tivozanib showed activity among patients who received the treatment after sorafenib (median PFS of 11.0 months [95% CI, (7.3–12.7)] and OS of 21.6 months [95% CI, (17.0–27.6)] from the start of treatment).

In this pivotal phase 3 trial evaluating tivozanib in heavily pretreated patients, TIVO-3 compared the efficacy and safety of tivozanib versus sorafenib in patients with advanced RCC that have progressed after multiple systemic therapies.8 Key eligibility criteria were that patients had been diagnosed with advanced clear cell RCC; had failed 2 or 3 prior regimens, including at least 1 VEGFR TKI (1 of which was not tivozanib or sorafenib); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior regimens could have been a VEGFR TKI and ICI, 2 VEGFR TKIs, or a VEGFR TKI and 1 other therapy. Patients were also stratified by the IMDC risk categories of favorable, immediate, and poor. Patients were randomized to tivozanib 1.5 mg orally once daily (21 days on, 7 days off per cycle) (n = 175) or sorafenib 400 mg orally twice daily (continuously in a 28-day cycle) (n = 175) until treatment progression or unacceptable toxicity. The primary end point was PFS, and secondary end points were OS, ORR, DOR, and safety.

In the TIVO-3 trial, a significant reduction in the risk of progressive disease was observed for tivozanib versus sorafenib in the intention-to-treat (ITT) population (HR 0.73, 95% CI 0.56–0.94; P = .016) and in 1 of the study subgroups, patients previously treated with an ICI and VEGFR TKI (HR 0.55, 95% CI 0.32–0.94; P = .028). FIGURE 2 shows estimated PFS in both study populations.8 Median PFS in the ITT population (n = 350) was 5.6 months for patients receiving tivozanib (95% CI, 5.29-7.33) versus 3.9 months for those receiving sorafenib (95% CI, 3.71-5.55) (HR, 0.73; 95% CI, 0.56-0.94; P = .016). For patients who received a prior ICI plus a VEGFR TKI (n = 91), median PFS was 7.3 months (95% CI, 4.8-11.1) in the tivozanib group versus 5.1 months (95% CI, 3.2-7.4) in the sorafenib group (HR, 0.55; 95% CI, 0.32-0.94). For patients who received 2 prior VEGFR TKIs (n = 159), median PFS for patients receiving tivozanib was 5.5 months (95% CI, 3.6-7.4) versus 3.7 months (95% CI, 3.6-3.9) for patients receiving sorafenib (HR, 0.58; 95% CI, 0.4-0.8).

In the IMDC favorable risk group, median PFS for patients receiving tivozanib was 11.1 months (95% CI, 7.4-14.6) versus 6.0 months (95% CI, 3.7-7.5) for sorafenib (HR, 0.46; 95% CI, 7.4-14.6). In the IMDC intermediate risk group, median PFS for patients receiving tivozanib was 5.6 months (95% CI, 4.8-7.4) versus 5.5 months (95% CI, 3.7-6.8) for sorafenib (HR, 0.69; 95% CI, 4.8-7.4). In the IMDC poor risk group, median PFS for patients receiving tivozanib was 2.1 months (95% CI, 1.8-3.5) versus 3.7 months (95% CI, 2.0-3.7) for sorafenib (HR, 1.15; 95% CI, 1.8-3.5).

For the secondary end point in the TIVO-3 trial, OS between tivozanib and sorafenib groups were similar.

Median OS in the ITT population was 16.4 months (95% CI, 13.4-22.2) for patients receiving tivozanib versus 19.7 months (95% CI, 15.0-24.2) for patients receiving sorafenib (HR, 0.99; 95% CI, 0.76-1.29; log-rank 

 = .95). However, significantly more patients achieved a response with tivozanib than with sorafenib.

ORR (secondary end point) was 18% (n = 31) for the tivozanib group (95% CI, 12-24) versus 8% (n = 14) for the sorafenib group (95% CI, 4-13).8 Median duration of response (secondary end point) was NR in the tivozanib group (95% CI, 12.9-NR) and 5.7 in the sorafenib group (95% CI, 5.6-NR).

Tivozanib appeared to be well tolerated with AEs consistent with what has been previously reported.

Serious treatment-related AEs (TRAEs) occurred in 19 (11%) of patients receiving tivozanib and 17 (10%) of patients receiving sorafenib. Fewer dose interruptions (83 [48%] vs 107 [63%]) and dose reductions (41 [24%] vs 65 [38%]) due to AEs occurred for patients receiving tivozanib than for those receiving sorafenib, respectively.

 The most frequent AEs leading to treatment discontinuation were the following: malignant neoplasm progression, which affected 3% (n = 5) of patients receiving tivozanib and 1% (n = 2) of patients receiving sorafenib; and fatigue, which occurred for 1% (n = 1) of patients receiving tivozanib and 4% (n = 6) of patients receiving sorafenib. No TRAEs resulted in death in either treatment group.

Additionally, real-word results have been reported for tivozanib. Tivozanib was approved in Europe in August 2017.

 The University of Munich reported the results of a retrospective analysis of a prospective database, including data from 23 patients undergoing tivozanib treatment between November 2017 and November 2018. Median PFS was 14.9 months (95% CI, 5.1-24.8). Regarding tumor response, 9 patients (39.1%) had a partial response, 12 (52.2%) maintained stable disease, and 2 (8.7%) experienced progressive disease. Median duration of therapy was 12.5 months (range, 2.3-30.6). No new safety signals were detected.

ORR at week 12 (n=91) was 51% (95% CI, 39.9-61.2). Disease control rate (complete response + partial response + stable disease; n = 91) was 91% (95% CI, 83.4-96.1).

 Median DOR (n = 91) was 9.9 months (95% CI, 6.9-NE). Median time to response (TTR; n = 91) was 1.6 months (range, 1.2-7.6 months). Median PFS (n = 103) was 11.7 months (95% CI, 9.5-NE). The most common TRAEs were fatigue (49% of patients), diarrhea (44%), and proteinuria (37%). There was one grade 5 TRAE (upper gastrointestinal hemorrhage), and 43% of patients required dose reduction. TRAEs were responsible for discontinuation by 12% of patients.

 Kaplan-Meier Estimated Progression-Free Survival in (A) the Intention-to- Treat Population and (B) a Subgroup of Patients Who Had Been Previously Treated With a Checkpoint Inhibitor and a Tyrosine Kinase Inhibitor

In another effort to investigate possible treatments for mRCC, a phase 2 study of lenvatinib plus pembrolizumab after ICI therapy was initiated.

The trial was a multicenter, open-label study of patients with clear cell mRCC who experienced progressive disease during or after ICI therapy. Patients were treated with lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg IV every 3 weeks. The primary end point was ORR. In the study population, 58% of patients had at least 2 prior anticancer regimens, and 91 of 104 patients were evaluable for response at week 12. At data cutoff (January 12, 2020), 69% of patients (n = 71) were still on the study treatment.

Median DOR (n = 91) was 9.9 months (95% CI, 6.9-NE). Median time to response (TTR; n = 91) was 1.6 months (range, 1.2-7.6 months). Median PFS (n = 103) was 11.7 months (95% CI, 9.5-NE). The most common TRAEs were fatigue (49% of patients), diarrhea (44%), and proteinuria (37%). There was one grade 5 TRAE (upper gastrointestinal hemorrhage), and 43% of patients required dose reduction. TRAEs were responsible for discontinuation by 12% of patients.

Hypoxia is a key characteristic of solid tumors. Tumor adaptation to hypoxia is associated with an aggressive phenotype and poor prognosis. Adaptation to hypoxia is mediated by HIFs. HIFs regulate the expression of target genes that promote angiogenesis, glycolysis, metastasis, increased tumor growth, and resistance to treatments. The HIF-2α transcription factor is a key oncogenic driver in clear cell RCC. HIF-2α is present in highly vascularized organs and hypoxic tissues, such as kidney epithelial cells. Between 50% and 80% of patients with clear cell RCC have an inactivated von Hippel-Lindau (VHL) gene, the gene that normally mediates expression of HIF-2α.

HIF-2α pathways allow clear cell RCC to proliferate in a variety of ways. HIF-2α pathways include VEGF-α, which drives angiogenesis, along with GAS6/AXL, CXCR4/SDF1, and MET, which encourage metastasis. HIF-2α pathways also include TGF-α/EGFR signaling, c-Myc, cyclin D1, SLC7A5, and mTORC1, which facilitate the clear cell RCC cell cycle and proliferation. Other HIF-2α pathways include glucose transporter-1, through the pentose phosphate pathway, and antioxidant enzymes, which provide resistance against oxidative stress. HIF-2α pathways also include the mitochondria biogenesis factors carnitine palmitoyltransferase 1A and perilipin 2, which lead to reduced mitochondrial content, lipid accumulation, and resistance against endoplasmic reticulum stress.

MK-6482 is a first-in-class small molecule inhibitor of HIF-2α that blocks heterodimerization of HIF-2α with HIF-1β. In a phase 1/2 study of MK-6482 in patients with previously treated advanced RCC (n = 55), patients received MK-6482 120 mg once daily. The primary end point was safety, and key secondary end points were ORR, DOR, and PFS. The most common grade 3 AEs were anemia (26%) and hypoxia (15%). There were no grade 4 or 5 drug-related AEs. As of May 15, 2019, 30 patients (55%) discontinued due to progressive disease, and 2 (4%) discontinued due to AEs. ORR was 24%, median DOR was NR, and median PFS was 11.0 months.

Additionally, an open-label, phase 2 study was conducted of MK-6482 for treatment of VHL-associated clear cell RCC in adults with pathogenic germline VHL variation and no prior systemic anticancer therapy (n = 61). The treatment regimen consisted of MK-6482 120 mg orally once daily. The primary end point was ORR, and key secondary end points were DOR, TTR, PFS, safety, and tolerability. ORR was 27.9% (95% CI, 17.1-40.8). DOR was NR (range, 2.1-9.0 months). TTR was 5.5 months (range, 2.7-14.0). Median PFS was NR; the 12-month PFS rate was 98.3%.

The most common grade 3 AEs were fatigue (4.9%) and anemia (3.3%).

Inhibition of receptor tyrosine kinases (RTKs) has direct biological activity against advanced clear cell RCC. The process enhances immunotherapy by reducing immunosuppressive regulatory T cells, myeloid-derived suppressor cells, and type 2 tumor-associated macrophages. The RTK inhibitor sitravatinib is a multikinase inhibitor that targets TAM receptors (Tyro3, Axl, MerkTK), split family receptors (VEGFR2 and c-KIT), and c-Met. Results have been reported from a phase 1/2 trial of sitravatinib with nivolumab in patients with advanced clear cell RCC that progressed after up to 2 prior VEGF-targeted therapies. Tumors included mRCC with a clear cell component and progressive disease after VEGF treatment. Four sitravatinib dose levels were included in the trial: 60, 80, 120, and 150 mg per day. Results demonstrated median PFS of 10.5 months (95% CI, 7.6-13.5). The most common TRAEs included fatigue, diarrhea, palmar-plantar erythrodysesthesia, hypertension, and elevated lipase. One grade 5 TRAE was reported, myasthenia gravis, which was related to nivolumab.

The evolution of targeted therapy and immunotherapy has the potential to improve the treatment of mRCC. Targeted therapy and immunotherapy have improved survival outcomes for patients with mRCC. Clinical trials are ongoing to assess the safety and effectiveness of therapies that may further improve the current standard of care. Tivozanib has demonstrated favorable outcomes in phase 3 trials and may prove to be an important therapy for 

patients who are relapsed or refractory to multiple lines of therapy. Additional agents and combinations in clinical trials in which additional data are forthcoming also have the potential to affect the treatment landscape further.

Stukalin I, Wells JC, Fraccon A, et al. Fourth-line therapy in metastatic renal cell carcinoma (mRCC): results from the International mRCC Database Consortium (IMDC). Kidney Cancer. 2018;2:31-36. doi:10.3233/KCA-170020

Rini BI, Battle D, Figlin RA, et al. The Society for Immunotherapy of Cancer consen- sus statement on immunotherapy for the treatment of advanced renal cell carcino- ma (RCC). 

. 2019;7(1):354. doi:10.1186/s40425-019-0813-8

NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2021. Accessed October 1, 2020. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf 

4. Duran I, Maroto P, Suárez C, et al. Analysis of overall survival (OS) based on earlytumor shrinkage in the phase III METEOR study of cabozantinib (cabo) versus everolimus (eve) in advanced renal cell carcinoma (RCC) [ASCO abstract 550]. 

. 37(suppl 7):550. doi:10.1200/JCO.2019.37.7_suppl.550

Motzer RJ, Tykodi SS, Escudier B, et al. Final analysis of the CheckMate 025 trial comparing nivolumab (NIVO) versus everolimus (EVE) with >5 years of follow-up in patients with advanced renal cell carcinoma (aRCC) [ASCO abstract 617]. 

. 2020;38(suppl 6):617. doi:10.1200/JCO.2020.38.6_suppl.617

Graham J, Shah AY, Wells JC, et al. Outcomes of patients with metastatic renal cell carcinoma treated with targeted therapy after immuno-oncology checkpoint inhibitors. 

. 2019;S2588-S9311(19)30160-9. doi:10.1016/j.euo.2019.11.001

Auvray M, Auclin E, Barthelemy P, et al. Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma. 

. 2019 Feb;108:33-40. doi:10.1016/j.ejca.2018.11.031. Erratum in: 

Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. 

. 2020;21(1):95-104. doi:10.1016/ S1470-2045(19)30735-1

Staehler M, Spek AK, Rodler S, et al. Real-world results from one year of therapy with tivozanib. 

Lee CH, Shah AY, Hsieh JJ, et al. Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC) [ASCO abstract 5008]. 

. 2020;38(suppl 15):5008. doi:10.1200/JCO.2020.38.15_suppl.5008

Cuvillier O. The therapeutic potential of HIF-2 antagonism in renal cell carcinoma. 

. 2017;6(1):131-133. doi:10.21037/tau.2017.01.12

Meléndez-Rodríguez F, Roche O, Sanchez-Prieto R, Aragones J. Hypoxia-inducible factor 2-dependent pathways driving von Hippel–Lindau-deficient renal cancer. 

Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC) [ASCO abstract 611]. 

. 2020;38(suppl 6):611. doi:10.1200/JCO.2020.38.6_suppl.611

Jonasch E, Donskov F, Iliopoulos O. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma [ASCO abstract 5003]. 

. 2020;38(suppl 15):5003. doi:10.1200/JCO.2020.38.15_suppl.5003

Msaouel P, Thall PF, Yuan Y, et al. A phase I/II trial of sitravatinib (sitra) combined with nivolumab (nivo) in patients (pts) with advanced clear cell renal cell cancer (aCCRCC) that progressed on prior VEGF-targeted therapy [ASCO abstract 612]. 

Targeted therapy and immunotherapy have improved survival outcomes for patients with metastatic renal cell carcinoma.

Updates in Relapsed/Refractory Metastatic Renal Cell Carcinoma

Sumanta K. Pal, MD, an associate clinical professor, Department of Medical Oncology and Therapeutics Research; co-director, Kidney Cancer Program; and a medical oncologist with City of Hope, discusses the rationale behind the phase 3 TIVO-3 trial with tivozanib (Fotivda) in advanced renal cell carcinoma (RCC).

Tivozanib has a long history in kidney cancer, says Pal. Initially, the drug was looked at in the frontline setting and showed substantial activity based on data from the phase 3 TIVO-1 study. Unfortunately, because of the crossover design and other elements of design in the study, a survival benefit was not established in the frontline trial, adds Pal.

As such, it was mandated that further exploration with tivozanib occur, which led to the genesis of the TIVO-3 study. This trial compared tivozanib with sorafenib (Nexavar) in the third- and fourth-line setting in patients with RCC, concludes Pal.

Videos

Sumanta K. Pal, MD, discusses the rationale behind the phase 3 TIVO-3 trial with tivozanib in advanced renal cell carcinoma.

Dr. Pal on the Rationale for the TIVO-3 Trial With Tivozanib in Advanced RCC

Robert J. Motzer, MD, Kidney Cancer section head, genitourinary oncology service and Jack and Dorothy Byrne chair in Clinical Oncology with Memorial Sloan Kettering Cancer Center, discusses the phase 3 TIVO-1 trial comparing tivozanib (Fotivda) with sorafenib (Nexavar) in patients with advanced renal cell carcinoma.

Tivozanib is a highly selective and potent VEGF inhibitor. The agent was evaluated in the large TIVO-1 trial, where it was compared with sorafenib, says Motzer. The TIVO-1 trial reached its primary end point by showing improvement in progression-free survival with tivozanib, although an overall survival benefit was not observed. Additionally, because of the design of the trial, the survival favored sorafenib over tivozanib, explains Motzer.

Tivozanib has remained an investigational agent 

 The agent has been approved for use in Europe in select circumstances, concludes Motzer.

Robert J. Motzer, MD, discusses the phase 3 TIVO-1 trial comparing tivozanib with sorafenib in patients with advanced renal cell carcinoma.

Dr. Motzer on the TIVO-1 Trial With Tivozanib in Advanced RCC

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the safety profiles of tivozanib (Fotivda) versus sorafenib (Nexavar) in advanced renal cell carcinoma.

In terms of efficacy, tivozanib has shown to be superior in progression-free survival compared with sorafenib, says Vaishampayan. However, a statistically significant benefit in overall survival had not been observed with tivozanib over sorafenib. 

When choosing between the agents, the toxicity profiles of both agents have to be considered, as well as their mechanisms of action. Sorafenib has a RAF kinase inhibitor activity, as well as VEGF TKI activity, whereas tivozanib is a preferential VEGF TKI inhibitor only with selective activity against VEGF.

The toxicity profile of sorafenib seems to reflect a higher risk of hand-foot syndrome and skin rashes as compared with tivozanib. The risk of hypertension and other toxicities that are VEGF-related appear to be comparable between the agents, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the safety of tivozanib versus sorafenib in advanced renal cell carcinoma.

Dr. Vaishampayan on the Safety of Tivozanib Versus Sorafenib in RCC

Sumanta K. Pal, MD, an associate clinical professor, Department of Medical Oncology and Therapeutics Research; co-director, Kidney Cancer Program; and a medical oncologist, City of Hope, discusses the benefit of tivozanib (Fotivda) in later-line setting treatment settings for patients with refractory renal cell carcinoma (RCC).

In the phase 3 TIVO-3 trial, tivozanib was compared with sorafenib (Nexavar) in patients with metastatic RCC. In the third- and fourth-line setting, tivozanib showed a significant benefit in progression-free survival over sorafenib, says Pal. Additionally, a more protracted benefit was associated with the experimental agent, adds Pal.

The Kaplan-Meier curves from the TIVO-3 trial, which were published in 

 show a tail on the curve, particularly in patients who received checkpoint inhibitors prior to entry on the trial. For those patients, there is a potential to consider tivozanib as a treatment for refractory disease, concludes Pal.

Sumanta K. Pal, MD, discusses the benefit of tivozanib in later-line setting treatment settings for patients with refractory renal cell carcinoma.
 

Dr. Pal on the Benefit of Tivozanib in Later-Line Settings for Refractory RCC

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the potential of tivozanib (Fotivda) in advanced renal cell carcinoma (RCC).

At present, tivozanib is not approved for use in the United States for patients with advanced RCC, although it has been approved in Europe; it is used as a single-agent VEGF TKI in this patient population, says Vaishampayan. In the United States, given the results of the phase 3 TIVO-3 trial, tivozanib could be a reasonable third-line option to consider for patients who have already received both VEGF TKI and immune-based regimens, adds Vaishampayan.

Tivozanib appears to prolong progressing-free survival, is relatively well-tolerated, and may provide patients with an additional efficacy benefit in the pretreated setting, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the potential of tivozanib in advanced renal cell carcinoma.

Dr. Vaishampayan on the Potential of Tivozanib in Advanced RCC

Robert J. Motzer, MD, medical oncologist, Kidney Cancer Section head, and Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, discusses the results of the phase 3 TIVO-3 trial with tivozanib (Fotivda) versus sorafenib (Nexavar) in patients with advanced renal cell carcinoma (RCC).

One of the pressing questions following the phase 3 TIVO-1 trial had to do with the survival benefit observed with tivozanib versus sorafenib, says Motzer. These questions mainly stemmed from the lack of survival benefit seen in the TIVO-1 trial, as well as the trend toward survival improvement with sorafenib, which was due, in part, to the subsequent therapy used in the sorafenib cohort, explains Motzer.

In the TIVO-3 trial, investigators compared with use of tivozanib with sorafenib, only in a heavily pretreated patient population, says Motzer. Unlike the TIVO-1 trial, no crossover was built into the TIVO-3 trial; it was 1 of the first phase 3 trials to examine this RCC-specific agent in heavily pretreated patients. 

Results showed that tivozanib resulted in a longer PFS compared with sorafenib, at 5.6 months versus 3.9 months, respectively. The agent was also found to have a better safety profile. However, the survival between the 2 arms were very similar, concludes Motzer.

Robert J. Motzer, MD, discusses the results of the phase 3 TIVO-3 trial with tivozanib versus sorafenib in patients with advanced renal cell carcinoma.

Dr. Motzer on the TIVO-3 Trial Examining Tivozanib in Advanced RCC

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the benefit of axitinib (Inlyta) and pembrolizumab (Keytruda) in advanced renal cell carcinoma (RCC).

Updated results from the phase 3 KEYNOTE-426 trial showed that at 24 months of follow-up, patients who were given axitinib/pembrolizumab still experienced an improvement in survival, says Vaishampayan. The 2-year overall survival rate for patients who received sunitinib (Sutent) was 66% versus 74% of those who received the combination. The difference in benefit continues to be statistically significant, and as such, the immunotherapy-based regimen is still considered as the frontline therapy of choice for patients with RCC. adds Vaishampayan.

However, when looking at the International Metastatic RCC Database risk criteria, the favorable-risk subgroup did not show a benefit with axitinib/pembrolizumab; both arms experienced relatively similar outcomes. In the intermediate- and poor-risk subgroup, the difference remained and favored the axitinib/pembrolizumab regimen, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the benefit of axitinib and pembrolizumab in advanced renal cell carcinoma.

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