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The Evolving Role of Cytokine Therapy for Renal Cell Carcinoma: Past, Present, and Future

Brendan D. Curti, MD
Released: October 1, 2020

Moving Beyond Sunitinib

CARMENA: Phase III Study of Nephrectomy Followed by Sunitinib vs Sunitinib in Metastatic RCC

CARMENA was a randomized, noninferiority phase III study in patients with metastatic clear-cell RCC comparing nephrectomy followed 3-6 weeks later by sunitinib vs sunitinib monotherapy.[1] In both arms, sunitinib 50 mg/day was given for 4 weeks on and 2 weeks off. The 450 patients enrolled on this study had no previous systemic RCC treatment and were stratified by treatment center and Memorial Sloan Kettering Cancer Center risk group (intermediate vs high risk). The primary endpoint was OS, with secondary endpoints including PFS, objective response using Response Evaluation Criteria in Solid Tumors (RECIST), clinical benefit, and safety.

CARMENA: Overall Survival

In the intention-to-treat population, there was no statistically significant difference in OS between patients who received sunitinib monotherapy vs those who received nephrectomy followed by sunitinib. At a median follow-up of more than 50 months, median OS was 18.4 months with sunitinib alone vs 13.9 months if preceded by nephrectomy (HR: 0.89).

CARMENA: Main Findings and Conclusions

Of 450 patients enrolled, 226 were assigned to the nephrectomy group and 224 to sunitinib without nephrectomy. Approximately 115 patients in each group received subsequent lines of therapy at the time of progression, most commonly everolimus and axitinib. The median duration of sunitinib treatment after nephrectomy was 6.7 months compared with 8.5 months in the sunitinib‑only group.

There were no statistically significant differences in OS or PFS. Results from CARMENA clearly show that sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with intermediate-risk or high-risk metastatic RCC. Although patients in the nephrectomy arm did slightly worse than the sunitinib-alone arm, nephrectomy can be considered in selected patients with RCC receiving immunotherapy.

CheckMate 214: Nivolumab Plus Ipilimumab vs Sunitinib for Untreated Advanced RCC

For the patient case example, it is important to determine the optimal systemic therapy based on his specific patient and disease characteristics. In recent years, the options for first-line treatment of RCC have expanded to include ipilimumab plus nivolumab, pembrolizumab plus axitinib, cabozantinib or other TKI monotherapy or HD IL-2.

CheckMate 214 is an ongoing, randomized phase III trial comparing a combination of the ICIs nivolumab and ipilimumab vs sunitinib in patients with untreated advanced clear-cell RCC (N = 1096).[3] Major selection criteria included a Karnofsky performance status ≥, no brain metastases, and no autoimmune disease. Measurable disease per RECIST 1.1 criteria was required. Patients were stratified by IMDC risk group (0 vs 1/2 vs 3‑6) and geographic region (US vs Canada and Europe vs other global sites).

Patients in the combination ICI arm (n = 550) were treated with nivolumab 3 mg/kg IV plus ipilimumab 1 mg/kg IV every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 3 weeks. In the sunitinib arm (n = 546), patients received the standard dose of 50 mg orally daily for 4 weeks with cycles repeated every 6 weeks.

CheckMate 214: OS, PFS, and Response by Subgroup

In patients with intermediate-risk or poor-risk RCC, there was a strong OS advantage at 18 months to the ICI combination, with 75% vs 60% with sunitinib (HR: 0.66; P < .0001).[3]

The ORR also favored the ICI combination in this group, at 42% vs 27% for sunitinib with a highly significant P value of < .0001. There was also a significant PFS difference, with a median PFS of 26 months with dual checkpoint inhibitor therapy vs 8.4 months for sunitinib (HR: 0.76; P < .01).

However, if you look at the secondary endpoints of ORR, PFS, and OS in the intention-to-treat patient population (those with favorable-, intermediate-, or poor-risk disease), whereas the median OS was improved with nivolumab plus ipilimumab, there was no significant difference in median PFS or ORR. Furthermore, in an exploratory analysis of patients with favorable-risk disease, efficacy data favored treatment with sunitinib vs the ICI combination.


One hypothesis for the observed benefit for patients with intermediate-risk or poor‑risk disease is the possibility that they have a higher tumor mutational burden, which can promote a more robust underlying immune response unlocked by the checkpoint immunotherapy.

CheckMate 214: Main Conclusions

Overall, CheckMate 214 demonstrated that nivolumab plus ipilimumab was superior to sunitinib in the first-line treatment of patients with intermediate-risk or poor-risk advanced clear-cell RCC.[3] Of note, the incidence of grade 3/4 adverse events was lower with the ICI group than with sunitinib. Based on these data, the combination of nivolumab plus ipilimumab was granted FDA approval for intermediate-risk or poor-risk patients with previously untreated advanced RCC.  

KEYNOTE-426: Pembrolizumab Plus Axitinib in Treatment-Naive Advanced RCC

KEYNOTE‑426 is an ongoing, randomized phase III trial comparing the combination of pembrolizumab and axitinib vs sunitinib in patients with previously untreated advanced RCC (N = 862).[4] Similar to CheckMate-214, patients had to have a Karnofsky performance status ≥ 70 and ≥ 1 measurable lesion. Patients with brain metastases, autoimmune disease, or poorly controlled hypertension were excluded. Patients were stratified by IMDC risk group (favorable vs intermediate or poor) and geographic region (US vs Canada and Europe vs other global sites).

Patients in the ICI/TKI combination arm were treated with pembrolizumab at a fixed dose of 200 mg given IV every 3 weeks plus axitinib at a starting dose of 5 mg orally twice daily. The axitinib could be escalated up to 10 mg/day in patients who were tolerating it without dose‑limiting toxicity. The sunitinib regimen used the standard dose of 50 mg/day orally for 4 weeks on and 2 weeks off with cycles repeated every 6 weeks. The primary endpoints in this study included PFS, OS, ORR, duration of response, and safety.

KEYNOTE-426: Pembrolizumab Plus Axitinib in Treatment-Naive Advanced RCC

As shown in these survival curves, the use of the combination of pembrolizumab plus axitinib significantly improved both OS and PFS vs sunitinib in the intention-to-treat population.[4] Median OS was not reached in the combination arm vs 35.7 months with sunitinib (HR: 0.68; P < .001). Median PFS was 15.4 months with pembrolizumab plus axitinib vs 11.1 months with sunitinib (HR: 0.71; P < .0001).

At 12 months, 90% of patients were alive in the combination arm vs 78% of patients in the sunitinib arm. At 18 months, those numbers were 82% and 72% respectively.

KEYNOTE-426: Response

Results from KEYNOTE-426 showed a significant enhancement of response in the pembrolizumab plus axitinib group: 59.3% responded (5.8% CRs) vs 35.7% with sunitinib (1.9% CRs).[4] The proportion of PRs was also significantly higher with pembrolizumab plus axitinib, at 53.5% vs 33.9%, respectively. The median duration of response was also significantly different, as it was not reached in the ICI/TKI group vs 15.2 months in the sunitinib group.

KEYNOTE-426: OS, PFS, and ORR by Subgroup Group

In an updated analysis, with a minimum follow-up of 23 months, efficacy was significantly improved with pembrolizumab plus axitinib in intermediate-risk and poor‑risk patients.[4] Median OS was not reached vs 28.9 months with sunitinib (HR: 0.63) and median PFS was 12.7 months vs 8.3 months, respectively (HR: 0.69). ORRs were similar to the overall population at 55.8% (8% CRs) and 35.2% (2% CRs) for the combination and sunitinib arms, respectively.

In the favorable‑risk group, again, the results favored pembrolizumab plus axitinib. OS was not significantly different and the curves overlapped (24-month OS: 85% vs 88%; HR: 1.06). However, median PFS was notably longer with the combination, at 20.8 months vs 18.0 months for sunitinib (HR: 0.76), and the ORR was 69.6% with pembrolizumab plus axitinib vs 50.4% with sunitinib.

KEYNOTE-426: Conclusions

Overall, results from KEYNOTE-426 showed that the use of pembrolizumab plus axitinib significantly extended both OS and PFS and produced a significantly higher ORR compared with sunitinib alone in patients with previously untreated advanced RCC. Benefit was observed across all IMDC risk categories, and the incidence of grade 3/4 adverse events was quite comparable between arms (67% with pembrolizumab plus axitinib vs 62% with sunitinib).

Based on these data, the FDA approved the use of pembrolizumab plus axitinib as first-line therapy for patients with advanced RCC regardless of risk.

Randomized Phase II CABOSUN Trial: First-line Cabozantinib vs Sunitinib in Metastatic RCC

Yet, another practice‑changing study is the phase II CABOSUN trial, a randomized comparison of cabozantinib vs sunitinib as first-line treatment in patients with metastatic clear‑cell RCC.[5] This study enrolled 157 patients with IMDC intermediate-risk or poor-risk RCC and an Eastern Cooperative Oncology Group performance status of 0-2. This study allowed patients with treated brain metastases as long as they were stable or improved for at least 3 months after treatment of brain metastases. Patients with autoimmune disease or poorly controlled hypertension were excluded.

Patients were stratified by IMDC classification (intermediate vs poor) and the presence or absence of bone metastases. They were randomized 1:1 to cabozantinib 60 mg orally once daily vs sunitinib at the standard dose of 50 mg/day for 4 weeks with cycles repeated every 6 weeks. The primary endpoints were PFS, OS, ORR, and safety.

Results showed an ORR of 33% and a median PFS of 8.2 months with cabozantinib treatment vs a 12% ORR and a median PFS of 5.6 months with sunitinib. The median OS was 30.3 months with cabozantinib vs 21.8 months with sunitinib, an approximately 9-month difference. Of note, similar numbers of patients in each arm had grade 3/4 adverse events (~ 67%), dose modifications due to adverse events, and discontinuation due to those adverse events.

CABOSUN: OS and PFS

In CABOSUN, patients who received cabozantinib had superior median PFS (primary endpoint) vs those who received sunitinib, showing a reduction in the risk of disease progression or death by 34% (HR: 0.66; 95%, CI: 0.46-0.95; P = .012). Of interest, the PFS curves show separation both early and late in the study.

There was no statistically significant difference in OS at this early time point, but the preliminary data showed a 20% decrease in the rate of death with cabozantinib (HR: 0.80; 95% CI: 0.5-1.26). The study was not designed to test for differences in OS, but longer-term follow-up may provide additional insights with more mature results.

CABOSUN: Conclusions

Overall, results from CABOSUN showed superior PFS and ORR compared to sunitinib for the first-line treatment of patients with intermediate-risk or poor-risk metastatic RCC. Based on these data, the FDA expanded the approval of cabozantinib to include treatment as first-line therapy for patients with advanced RCC.

Furthermore, recent data presented at ESMO 2020 from the phase III CheckMate 9ER study demonstrated superior efficacy (ORR, PFS, and OS) with nivolumab plus cabozantinib vs sunitinib as first-line therapy,[6]  which may also serve to change practice standards in the near future.

Summary of Current Approvals for Advanced RCC

It is evident that patients now have a variety of treatment options for advanced RCC in addition to the historical standard of care with TKIs sunitinib or pazopanib.

For patients with favorable-risk disease, current preferred first-line treatment options are pembrolizumab plus axitinib or standard TKI monotherapy. For patients with intermediate-risk or poor-risk disease, current preferred first-line treatment options are nivolumab plus ipilimumab, pembrolizumab plus axitinib, or cabozantinib. In addition to these treatment options, many guidelines continue to recommend HD IL-2 therapy in certain circumstances, which we will talk about next.

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