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Key Studies in Urothelial, Prostate, and Kidney Cancer: CCO Independent Conference Highlights of the 2021 Genitourinary Cancers Symposium

Robert Motzer, MD
Daniel P. Petrylak, MD
Released: March 26, 2021

Kidney Cancer

CLEAR: First-line Lenvatinib + Pembrolizumab or Everolimus vs Sunitinib in Advanced RCC

Robert J. Motzer, MD:
We will continue our discussion with an update on the phase III CLEAR trial.13 CLEAR is an ongoing, randomized, open-label trial comparing lenvatinib plus pembrolizumab or lenvatinib plus everolimus to sunitinib as first-line therapy in 1069 patients with previously untreated, advanced, clear-cell RCC. Patients are stratified by region (Western Europe and North America vs rest of the world) and by Memorial Sloan-Kettering Cancer Center (MSKCC) risk category of favorable vs intermediate vs poor. Patients received lenvatinib 20 mg/day PO plus pembrolizumab 200 mg IV every 3 weeks, or lenvatinib 18 mg/day PO plus everolimus 5 mg/day PO, or sunitinib 50 mg PO on the standard 4 weeks on, 2 weeks off schedule. Pembrolizumab can be given to a maximum of 35 doses. The primary endpoint is PFS (by independent review committee), and secondary endpoints include OS, ORR by independent review committee (per Response Evaluation Criteria in Solid Tumors v1.1), HRQoL, and safety.

The analysis my colleagues and I presented at ASCO GU 2021 was with a cutoff for PFS and OS of August 28, 2020, and had a median follow-up of 27 months. The analysis was performed based on approximately 338 PFS events, with assessment at 90% power and a 2-sided α of .045.


Robert J. Motzer, MD:
The trial met its primary endpoint: median PFS was improved vs sunitinib with both lenvatinib plus pembrolizumab vs sunitinib and lenvatinib plus everolimus vs sunitinib. The HR was 0.39 for lenvatinib plus pembrolizumab vs sunitinib, which was statistically significant (P <.001). The median PFS in this group is 23.9 months vs 9.2 months with sunitinib.

The median PFS was also significantly superior with lenalidomide plus everolimus vs sunitinib, with an HR for this comparison of 0.65 (P <.001). The median PFS for lenvatinib plus everolimus was 14.7 months, again compared with 9.2 months with sunitinib.

Subgroup analyses also showed a PFS benefit across all patient categories for both lenalidomide plus pembrolizumab and lenalidomide plus everolimus vs sunitinib.


Robert J. Motzer, MD:
OS was a key secondary endpoint, and in this analysis, it was statistically improved with lenvatinib plus pembrolizumab vs sunitinib (HR: 0.66; P = .005). By contrast, no survival benefit was seen for lenvatinib plus everolimus vs sunitinib (HR: 1.15). Median OS has not yet been reached in any of the 3 arms.

CLEAR: OS in Patient Subgroups

Robert J. Motzer, MD:
Looking at the subgroup analyses for OS, in all key subgroups the HR for OS favors lenvatinib plus pembrolizumab vs sunitinib. These included age, sex, PD-L1 expression level, and prior nephrectomy. The sole exception was patients with favorable risk (per IMDC), where the HR of 1.15 slightly favors sunitinib. However, it must be emphasized that there were only 29 OS events in favorable-risk patients and the confidence intervals are very wide. In fact, when we looked at favorable risk by MSKCC risk group, the HR still favored lenvatinib plus pembrolizumab vs sunitinib, again with very few OS events.


Robert J. Motzer, MD:
The ORR was a key secondary endpoint, and was substantially higher with both lenvatinib plus pembrolizumab (71.0%) and lenvatinib plus everolimus (53.5%) vs sunitinib (36.1%). Of note, 16.1% of patients achieved a CR with lenvatinib plus pembrolizumab, and very few patients (5.4%) had progressive disease as their best response. The relative risk vs sunitinib was 1.97 for lenvatinib plus pembrolizumab and 1.48 for lenvatinib plus everolimus (both P <.001).


Robert J. Motzer, MD:
The median DoR for lenvatinib plus pembrolizumab was 25.8 months (95% CI: 22.1-27.9) compared with 14.6 months (95% CI: 9.4-16.7) with sunitinib. Patients receiving lenvatinib plus everolimus had a median DoR of 16.6 months compared with 14.6 months with sunitinib. The DoR with lenvatinib plus pembrolizumab is impressive and aligns with the PFS, ORR, CR, and OS benefit previously seen with this combination compared to sunitinib.

CLEAR: Treatment Exposure and Safety

Robert J. Motzer, MD:
In this analysis, the median duration of therapy for lenvatinib plus pembrolizumab was 17 months, which is considerably longer than with sunitinib (7.8 months). Most patients had at least 1 TRAE, with grade 3/4 AEs in more than 70% of patients receiving a lenvatinib regimen vs 59% with sunitinib.

Most patients treated with lenvatinib required a dose modification, which is common when used in combination regimens for RCC. In the lenvatinib plus pembrolizumab arm, 67.3% of patients required a dose reduction, although only 18.5% had to discontinue treatment due to TRAEs. Similar rates of dose-reductions and dose-discontinuations were seen with lenvatinib plus everolimus. This indicates that toxicity was adequately managed in most patients by dose modification as well as by supportive care measures. Of note, grade 5 TRAEs occurred in 1.1% of patients receiving lenvatinib plus pembrolizumab vs 0.8% with lenvatinib plus everolimus and 0.3% with sunitinib.

CLEAR: TRAEs in ≥20% of Patients (LEN + PEMBRO vs SUN)

Robert J. Motzer, MD:
The proportion of TRAEs was calculated for the lenvatinib arms vs sunitinib arm. For the most part, any-grade TRAEs in the lenvatinib plus pembrolizumab vs sunitinib were largely class effects of TKI, including diarrhea (54.5 vs 44.4%), hypertension (52.3% vs 39.1%), and stomatitis (32.1% vs 37.4%). In the lenvatinib plus pembrolizumab arm, hypothyroidism was seen quite frequently (42.6%; grade 3, 1.1%) and was the most common AE associated with pembrolizumab. Proteinuria—a known AE of lenvatinib—was seen in 27.6% of patients treated with pembrolizumab plus lenvatinib (7.4% grade ≥3). Physicians must monitor carefully for proteinuria in patients receiving lenvatinib.

However, there was a relative lack of hepatic toxicity with the lenvatinib plus pembrolizumab combination: alanine aminotransferase (ALT) elevation was observed in 9.7% of patients on lenvatinib plus pembrolizumab and was grade 3 or higher in only 3.1%. Similarly, aspartate aminotransferase (AST) elevation was seen in 9.4% with 2.6% at grade 3/4; these rates are lower than with other combinations of immunotherapy and TKIs. Likewise, myelosuppression was absent and high-grade hand–foot syndrome was seen in only approximately 4% of patients in the lenvatinib plus pembrolizumab arm. These are positive results that support the use of lenvatinib plus pembrolizumab in the treatment of advanced RCC.

CLEAR: TRAEs in ≥20% of Patients (LEN + EVE vs SUN)

Robert J. Motzer, MD:
Similarly, the AE profile for lenvatinib plus everolimus largely reflects that of TKI inhibition. Frequent AEs in the lenvatinib plus everolimus vs sunitinib included diarrhea (59.7% vs 44.4%), stomatitis (45.6% vs 37.4%), and hypertension (43.1% vs 39.1%). Toxicities attributable to everolimus included stomatitis, hypertriglyceridemia, and rash. As with lenvatinib plus pembrolizumab, the proportion of patients with high‑grade hepatic dysfunction was very low: 2.1% with grade ≥3 ALT elevation and 1.4% with elevated AST.

CLEAR: Conclusions

Robert J. Motzer, MD:
At ASCO GU 2021, the standout report was from the CLEAR trial, where the combination of pembrolizumab plus lenvatinib showed excellent efficacy vs sunitinib in terms of PFS, ORR, OS, and manageable toxicity.13 Based on these data, this regimen should become a preferred standard of care and first-line choice for this disease. Current standards of care for advanced RCC include nivolumab plus either ipilimumab or cabozantinib. Given the positive results from this study, physicians should plan to integrate lenvatinib plus pembrolizumab into their current practice. 

KEYNOTE-426: Outcomes in Patients With RCC Completing 2 Years of Pembrolizumab + Axitinib

Robert J. Motzer, MD:
At ASCO GI 2021, Plimack and colleagues presented a follow-up analysis of the KEYNOTE-426 randomized phase III trial that compared pembrolizumab plus axitinib to sunitinib as first-line therapy for RCC.14,15 KEYNOTE-426 enrolled 861 patients with newly diagnosed stage IV or metastatic recurrent clear-cell RCC, without prior systemic therapy. Patients were stratified by IMDC risk group and global region, then randomized to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles plus axitinib 5 mg PO vs sunitinib 50 mg PO on the standard 4 weeks on, 2 weeks off schedule. The trial reached its coprimary endpoints, showing significant, dramatic benefits in both OS (HR: 0.68; P <.0003) and PFS (HR: 0.71; P <.0001).14

The current update was an exploratory analysis in 103 patients from KEYNOTE-426 who completed 2 years of pembrolizumab plus axitinib but did not discontinue because of progression of disease.15

KEYNOTE-426 Subgroup Analysis: Baseline Characteristics

Robert J. Motzer, MD:
In this analysis, baseline characteristics for the 103 patients who completed 2 years of treatment with pembrolizumab plus axitinib were compared to the 432 patients originally assigned to that arm and found to be fairly balanced. Among completers, 61.2% had IMDC intermediate risk, 35.0% had favorable risk, and only 3.9% had poor risk. Also, in this group, 64% had at least 2 sites of metastases and 16.5% had sarcomatoid features.

KEYNOTE-426 Subgroup Analysis: OS and PFS in Completers

Robert J. Motzer, MD:
Both OS and PFS were calculated based on a landmark analysis at Month 24, which is when pembrolizumab was discontinued. At the 36-month cutoff, 95% of patients were still alive and 75% were progression free following completion of pembrolizumab.

KEYNOTE-426 Subgroup Analysis: ORR and Safety in Completers

Robert J. Motzer, MD:
In the 103 patients who completed pembrolizumab treatment, the response rate was 88%, and it included 16 patients who achieved a CR. Including those with a PR or stable disease, 95% of patients had some measure of disease control.

However, all patients experienced at least 1 TRAE and 60% had a grade 3/4 TRAE. Among the pembrolizumab completers, 14.6% had discontinued axitinib due to a TRAE.

KEYNOTE-426 Subgroup Analysis: Univariate Analysis of Patients Most Likely to Complete 2 Years of Therapy

Robert J. Motzer, MD:
The investigators conducted a univariate analysis to determine what factors potentially contributed to patients completing 2 years of therapy. They identified these as high Karnofsky performance status (odds ratio [OR]: 2.44; P = .010), having just 1 organ site with metastases (OR: 1.74; P = .023), and a prior nephrectomy (OR: 2.02; P = .043) as some of the most important.

KEYNOTE-426 Subgroup Analysis: Multivariate Analysis of Patients Most Likely to Complete 2 Years of Therapy

Robert J. Motzer, MD:
On multivariate analysis, the factors that seemed to be important for completing 2 years of therapy included age younger than 65 years (OR: 1.76; P = .025), high Karnofsky performance status (OR: 2.10; P = .039), few poor-risk features (OR: 4.99; P = .014), and sarcomatoid features (OR: 2.19; P = .028).

KEYNOTE-426 Subgroup Analysis: Conclusions

Robert J. Motzer, MD:
Plimack and colleagues presented an important update of KEYNOTE-426 study with a subgroup analysis of patients who had completed 2 years of pembrolizumab treatment, which showed promising outcomes (3-year OS: 94.7%), and most had IMDC favorable-risk or intermediate/poor-risk disease.15

Immunotherapy + TKIs in RCC: How Should These Combinations be Integrated Into Clinical Practice?

Robert J. Motzer, MD:
Recently, several phase III studies have evaluated combinations that include immunotherapy in first-line treatment for advanced RCC. An important result was identification of a long-term survival benefit for ipilimumab plus nivolumab vs sunitinib in intermediate-risk and poor-risk patients (CheckMate 214).16

Axitinib plus avelumab was also compared to sunitinib as first-line therapy for advanced RCC in the phase III JAVELIN Renal 101 trial.17 Results showed a PFS benefit but no OS benefit, which appears to be a discriminating factor for that particular program and has removed that regimen from our first choices.

Axitinib plus pembrolizumab was compared to sunitinib as first-line therapy for advanced RCC in the phase III KEYNOTE-426 study.14 Results showed superior PFS and OS compared to sunitinib, and this regimen became the first of the immunotherapy plus TKI combinations to be approved in RCC. It is now an established standard of care.

More recently, the phase III study CheckMate 9ER study of cabozantinib plus nivolumab showed improvements in PFS and OS vs sunitinib as first-line therapy for RCC,18 as has the current CLEAR study of lenvatinib plus pembrolizumab vs sunitinib.13

To date, we have 3 effective choices of first-line combination immunotherapy plus TKI regimens for RCC. That said, these combinations have not been compared to each other, which impedes cross-study comparisons. It will be important for community physicians to gain experience with these different regimens to reach their own decisions for patients, including feedback on toxicity. Although to date there is no clear winner, the PFS data from lenvatinib plus pembrolizumab, plus a response rate greater than 70% with 16% CRs, are very positive and compelling. In addition, prescribers’ expertise in treating patients with a given regimen will improve over time as they become more familiar with it.

One outstanding question is what to offer patients who have progressed on prior immune checkpoint inhibitor? At ASCO GU, Pal and colleagues reported data for the combination of lenvatinib at 2 starting doses, 18 mg vs 14 mg daily, plus everolimus in patients with relapsed RCC who had previous immune checkpoint inhibitor.19 In that study, lenvatinib at a starting dose of 18 mg compared with the 14-mg dose showed numerically improved outcomes, regardless of prior immune checkpoint inhibitor. In a related report by Bergerot and colleagues, evaluating HRQoL and patient-reported outcomes, lenvatinib at a starting dose of 18 mg was associated with better HRQoL due to less-severe disease-related symptoms than those receiving the 14-mg dose.20

Belzutifan in Advanced Clear-Cell RCC: Study Design

Robert J. Motzer, MD:
At ASCO GU 2021, Bauer and colleagues presented updated results from a dose-escalation/dose-expansion phase I/II study of the novel HIF-2α inhibitor belzutifan (MK-6482) in 55 patients with previously treated advanced clear-cell RCC and ≥1 previous therapy.21,22 In this study, patients received belzutifan 120 mg PO once daily until progression or unacceptable toxicity. The primary endpoint of this study was safety, and in an earlier report belzutifan at this dose was shown to be well tolerated with a favorable safety profile.22 Secondary endpoints include ORR, DoR, and PFS.

The current median follow-up for this analysis was 27.7 months, which was 11 months longer than the previous report. The data cutoff for this analysis was June 1, 2020. At the time of this update, 80% of patients had discontinued therapy, most commonly due to disease progression.

Belzutifan in Advanced RCC: Safety

Robert J. Motzer, MD:
Belzutifan was, overall, very well tolerated. Most patients developed a grade ≥3 AE (71%) and 22 (40%) developed a grade 3 TRAE. However, in most instances, this was manageable: only 5 patients had to discontinue treatment due to an AE, and only 2 patients discontinued due to TRAE of hypoxia. AEs leading to discontinuation included hypoxia, abdominal pain, cardiac arrest, decreased appetite, disease progression, and fatigue. 

Belzutifan in Advanced RCC: All-Cause AEs

Robert J. Motzer, MD:
The AE profile for belzutifan demonstrates prominent AEs of anemia as well as hypoxia. Of the 55 patients, 42 (76%) developed any-grade anemia and 15 (27%) had grade 3 anemia. Any-grade hypoxia was reported for 17 (31%) patients, and grade 3 or worse hypoxia was reported in 9 (16%) patients. Less-frequent AEs included mild peripheral edema (27%), some nausea (all grade, 36%), and, occasionally, dyspnea (all grade, 50%; grade 3, 5%). All-cause events of any grade reported in greater than 20% of patients included arthralgia (25%), headache (25%), blood creatinine increase (25%), diarrhea (22%), and hyperkalemia (22%). Grade 4 AEs were reported in 2 patients (2 events each) and included 2 events of sepsis and 1 event each of hypercalcemia and respiratory failure. There were 4 deaths reported in this study; none were deemed related to treatment.

Belzutifan in Advanced RCC: ORR (Clear-Cell RCC Cohort)

Robert J. Motzer, MD:
The ORR was 54% (all PRs) and the DCR was 80%, with a high proportion of patients (54%) achieving stable disease. Only 8 (15%) patients had progression as their best response to belzutifan. This is fairly remarkable in a group of patients with heavily pretreated disease. Though small numbers, response rates were somewhat higher in those with favorable vs intermediate/poor risk disease (per IMDC category).

Belzutifan in Advanced RCC: Best Tumor Change From Baseline per Investigator Assessment

Robert J. Motzer, MD:
Of the 55 patients who were treated, 35 had at least some reduction in their target lesion size, and very few had overt progression as their best response. 

Belzutifan in Advanced RCC: DoR

Robert J. Motzer, MD:
A swimmer plot from this study shows that of the 55 patients treated with belzutifan, 19 (35%) continued on treatment beyond 12 months; 10 of the 14 responders experienced a response for longer than 6 months. At the time of the analysis, 11 patients were still being treated beyond 25 months.

Belzutifan in Advanced RCC: PFS

Robert J. Motzer, MD:
Median PFS was 14.5 months, and not reached in the 13 patients with IMDC favorable risk. For those with IMDC intermediate or poor risk, the median PFS was 11 months.

Belzutifan (MK-6482) + Cabozantinib in Advanced Clear-Cell RCC

Robert J. Motzer, MD:
Following these promising results with belzutifan as monotherapy, Choueiri and colleagues presented results from a phase II trial of belzutifan plus cabozantinib in 102 patients with advanced or metastatic clear-cell RCC and no more than 2 prior regimens for advanced disease.23 This was a multicenter, open-label trial in 2 groups of patients: cohort 1 comprised 50 patients who were previously untreated; and cohort 2 comprised 52 patients who had received previous anti–PD-(L)1 inhibitor therapy. All patients received belzutifan 120 mg/day plus cabozantinib 60 mg/day. The primary endpoint was ORR, with secondary endpoints including PFS, time to response, DoR, OS, and safety.

The analysis presented at ASCO GU 2021 focused on data from cohort 2 in patients with previous anti–PD-(L)1 inhibitor therapy.

Belzutifan + Cabo in Advanced RCC: ORR

Robert J. Motzer, MD:
In total, 41 patients were evaluable for responses, which were seen in 9 patients (22%). Including PRs and stable disease, 90% of patients achieved some measure of disease control. That said, this was a relatively early look at the efficacy data in this small trial.

Belzutifan + Cabozantinib in Advanced RCC: Best Tumor Change From Baseline

Robert J. Motzer, MD:
In total, 36 patients had a decrease in their target lesion size, and only 1 patient developed overt progression.

Belzutifan + Cabozantinib in Advanced RCC: TTR and DoR

Robert J. Motzer, MD:
The median time to response was 1.9 months (range: 1.5-9.2). A swimmer plot showed that the median DoR had not been reached and that many of the confirmed responses were ongoing at the time of the data cutoff.

Belzutifan + Cabozantinib in Advanced RCC: PFS and OS

Robert J. Motzer, MD:
The median PFS with the combination of belzutifan plus cabozantinib was 16.8 months. At 6 and 12 months, PFS rates were 78% and 65%, respectively. The OS rate at 6 and 12 months was 95% and 81%, respectively. As previously mentioned, this was a very early look at this combination in this trial and many of the patients were censored. Certainly, longer follow-up is needed with more patients treated to better assess the efficacy of this combination regimen.

Belzutifan + Cabozantinib in Advanced RCC: Safety

Robert J. Motzer, MD:
Nearly all patients treated with belzutifan plus cabozantinib developed a TRAE. In most patients, this was attributed to both drugs. Grade 3 TRAEs were seen in 31 patients (60%); in most instances, it was attributed to cabozantinib (54%). However, there were a fair number of patients who had high-grade TRAEs attributed to belzutifan (33%).

Belzutifan dose reductions were required in 10 (19%) patients, and cabozantinib was dose reduced in 25 (48%) patients. AEs associated with belzutifan dose reductions included fatigue, alanine aminotransferase increase, decreased appetite, anemia, diarrhea, headache, hypoxia, and oral pain. AEs leading to discontinuation in the cabozantinib included fatigue, hand-foot syndrome, ALT increase, decreased appetite, nausea, platelets decreased, and stomatitis. Discontinuation due to a treatment-emergent AE (TEAE) occurred in 8 patients receiving the combination; a total of 6 patients discontinued belzutifan and 8 discontinued cabozantinib due to a TEAE. One death occurred on study, but it was not deemed related to treatment.

Belzutifan + Cabozantinib in Advanced RCC: TRAEs

Robert J. Motzer, MD:
For the most part, the TRAEs reported in this study reflect the safety profile of both drugs, most commonly anemia (77%; grade 3, 12%), which can occur with either agent, but is one of the hallmark toxicities of belzutifan. Fatigue (67%) and hand–foot syndrome (54%) were quite common as well. Fatigue was considered to be related to both drugs, whereas for hand–foot syndrome, diarrhea, hypertension, and other toxicities, cabozantinib was the likely contributing factor. In general, there was a relatively low proportion of grade 3 AEs other than hypertension, which was seen in 23% of patients. Overall, this particular combination was relatively well tolerated with 92% of the AEs being grade 1/2 with no grade 4/5 TRAEs.

Belzutifan Studies in Advanced RCC: Summary

Robert J. Motzer, MD:
The 2 belzutifan studies were important in part because of the need to identify drugs with novel mechanisms of action to further advance RCC treatment.22,23 In my opinion, belzutifan is the most promising of the novel agents currently in development for advanced RCC. The study showing efficacy as monotherapy is very important in establishing efficacy on principle, but also the combination with cabozantinib was very promising in previously treated patients with advanced clear-cell RCC. Importantly, single-agent belzutifan was well tolerated with the main grade 3 TRAEs to watch for are anemia (27%) and hypoxia (16%).

I think the next step will be combining this drug with additional agents; for example, a large phase III trial (estimated N = 708) recently launched that will compare belzutifan plus lenvatinib to cabozantinib monotherapy in patients with advanced RCC who have progressed on immune checkpoint inhibitors (NCT04586231). 

SWOG 1500: Cabozantinib, Crizotinib or Savolitinib vs Sunitinib in Metastatic Papillary RCC

Robert J. Motzer, MD:
SWOG 1500 was a randomized, open-label phase II trial that compared monotherapy with cabozantinib, crizotinib, or savolitinib vs sunitinib in 147 patients with metastatic papillary RCC and who had received 0-1 previous therapies.24 Patients received either cabozantinib 60 mg/day PO, crizotinib 250 mg PO twice daily, savolitinib 600 mg/day PO, or sunitinib 50 mg PO on the standard 4 weeks on, 2 weeks off schedule. Dose reductions were allowed for all 4 drugs as needed.

The primary endpoint was PFS, with secondary endpoints including OS, ORR, safety, and MET mutation status. Of note, the crizotinib and savolitinib arms were closed early for futility (compared with sunitinib) as of December 2018.

SWOG 1500: PFS and OS

Robert J. Motzer, MD:
In the crizotinib and savolitinib arms, median PFS was short at 2.8 months and 3.0 months, respectively, when compared with a median PFS of 5.6 months for sunitinib. By contrast, cabozantinib had a median PFS of 9.0 months. Interpreting these results should be done with caution, as the 95% confidence intervals do overlap and the number of patients in both of these arms was relatively small (cabozantinib, n = 44; sunitinib, n = 46). Taking this into account, the HR for PFS with cabozantinib vs sunitinib was 0.60 (95% CI: 0.37-0.97; P = .019).

SWOG 1500: ORR

Robert J. Motzer, MD:
ORR with cabozantinib was 23% vs 4% with sunitinib (P = .010), which is quite remarkable in this group of patients with metastatic papillary RCC. By contrast, both crizotinib and savolitinib showed no or negligible responses (0% and 3%). Symptomatic deterioration was seen in 2% of patients in both the cabozantinib and sunitinib arms.

SWOG 1500: Safety (Clinical Toxicity)

Robert J. Motzer, MD:
The clinical safety profiles of all agents evaluated were as expected. The safety profile for cabozantinib and the safety profile for sunitinib were very similar to what has previously been reported in other studies,25,26 and the safety profiles were similar between the 2 arms in this study. Grade 3/4 AEs were seen in 74% of patients on cabozantinib vs 68% with sunitinib.

SWOG 1500: Safety (Laboratory Abnormalities)

Robert J. Motzer, MD:
Laboratory abnormalities associated with cabozantinib and sunitinib were as expected, including myelosuppression (thrombocytopenia, anemia, and leukopenia, and neutropenia) in approximately 20% of patients. Of note, any-grade liver function test abnormalities and proteinuria were reported.

Overall, based on these data from SWOG 1500, it is my opinion that cabozantinib is the new standard of care for patients with metastatic, papillary RCC.

SWOG 1500: Conclusions and Takeaways

Robert J. Motzer, MD:
Overall, based on these data from SWOG 1500, it is my opinion that cabozantinib is a good option for patients with metastatic, papillary RCC. There’s clearly an unmet need to identify effective treatments for the non–clear-cell RCCs, of which papillary RCC is the predominant type. For many years, the standard of care has been sunitinib, but it has become clear, based on single-arm studies, that cabozantinib is preferable. Cabozantinib has a better targeting profile, including against MET and AXL. In SWOG 1500, the response rate and the PFS with cabozantinib were fairly moderate, which highlights the need to build on cabozantinib in an attempt to better the outcomes. One avenue is to combine it with immunotherapy. Our center is participating in a phase II clinical trial of cabozantinib plus the PD-1 inhibitor nivolumab (NCT03635892) that we expect to present at the ASCO 2021 annual meeting.

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