Checkpoint Inhibitor/TKI Combos Increase Survival in Renal Cell Carcinoma


Recently approved combination therapies have contributed to significantly improved survival rates in renal cell carcinoma.

The evolution of checkpoint blockade and VEGF TKIs, as well as the regulatory approval of combination therapies involving these inhibitors, have led to a significant improvement in the 5-year survival rates of patients with renal cell carcinoma (RCC).1

“[We see that] there is a definitive role in having dual therapy,” said Laura S. Wood, RN, MSN, OCN, Renal Cancer Research Coordinator at Cleveland Clinic Taussig Cancer Center, in a presentation during the 5th Annual School of Nursing Oncology meeting. “We’re seeing a number of new combinations with PD-1/PD-L1 inhibitors plus 1 of our TKIs, so the story continues as far as the evolution of our therapies. And, this is what will account for improvements in response rate, progression-free survival, and overall survival.”

The shifted balance of treatment toward anticancer immunity with combination strategies involving PD-1/PD-L1 and VEGF inhibitors has been reported through several pivotal clinical trials that have led to improved outcomes in RCC: CheckMate-214 (NCT02231749), KEYNOTE-426 (NCT02853331), CheckMate-9ER (NCT03141177), and CLEAR (NCT02811861).

Such clinical findings led to the approvals of nivolumab (Opdivo) plus ipilimumab (Yervoy), pembrolizumab (Keytruda) plus axitinib (Inlyta), avelumab (Bavencio) plus axitinib, and cabozantinib (Cabometyx) plus nivolumab. While nivolumab/ipilimumab is approved in intermediate- and poor-risk patients only, the other dual strategies are approved for all-comers with RCC.

“It’s very difficult and challenging to do cross-trial comparisons,” said Wood. “It’s definitely not highly recommended, but it is what we use in clinical practice to help us in patients use shared decision-making to make treatment decisions.”

Pivotal Phase 3 Trials in RCC


The phase 3 CheckMate-214 trial was the basis for the April 2018 FDA approval of nivolumab/ipilimumab as first-line treatment for intermediate- and poor-risk patients with RCC.

In the trial, patients with metastatic clear cell RCC were randomized to receive 3 mg of nivolumab plus 1 mg of ipilimumab or sunitinib as first-line therapy. Four-year follow-up data showed that, at a median follow-up of 55 months, the combination led to a 31% reduction in the risk of death when compared with sunitinib (Sutent) in the intent-to-treat population.2 Specifically, the median overall survival (OS) was not reached with nivolumab/ipilimumab and 38.4 months with sunitinib (HR, 0.69; 95% CI, 0.59-0.81).

The median progression-free survival (PFS), however, was 12.2 months and 12.3 months, respectively; the ORR rates were 39% and 32%, respectively. The complete response (CR) rates were 11% vs 3%, respectively.

In intermediate- and poor-risk patients, nivolumab/ipilimumab was also favored over sunitinib for OS (HR, 0.65; 95% CI, 0.54-0.78).


Pembrolizumab and axitinib was tested up front in the phase 3, open-label KEYNOTE-426 trial, in which treatment-naïve patients with advanced clear cell RCC were randomized to receive the PD-1/VEGF TKI combination or sunitinib.

Extended follow-up results showed that the median OS was not reached compared with 35.7 months with sunitinib (HR, 0.68; 95% CI, 0.55-0.85; P = .0003) at a 30.6-month median follow-up.3 Additionally, the median PFS was 15.4 months and 11.1 months, respectively (HR, 0.71; 95% CI, 0.60-0.84; P <.0001). The combination elicited a 60% ORR while sunitinib’s ORR was 40% (P <.0001); the CR rates were 9% and 3%, respectively.

Based on earlier data from KEYNOTE-426, the FDA approved pembrolizumab and axitinib in the up-front setting for patients with RCC in April 2019.

Avelumab/axitinib is also available as a frontline combination regimen in patients with advanced RCC as of May 2019. The decision was based on the phase 3 JAVELIN Renal 101 trial, which showed that the combination led to a 31% reduction in the risk of disease progression or death vs sunitinib in the overall group of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.4


In the international, phase 3 CheckMate-9ER trial, investigators evaluated nivolumab plus cabozantinib compared with sunitinib in the frontline setting for patients with advanced clear cell RCC.

At a median follow-up of 23.5 months, the median OS with the combination was not reached vs 29.5 months with sunitinib (HR, 0.66; 95% CI, 0.50-0.87; P = .0034), and the median PFS was doubled at 17.0 months vs 8.3 months with sunitinib (HR, 0.52; 95% CI, 0.43-0.64; P <.0001).5 The ORRs were 55% and 27% with nivolumab/cabozantinib and sunitinib, respectively; the CR rates were 9% vs 4%, respectively.

The FDA approved nivolumab plus cabozantinib in this setting in January 2021, based on the earlier phase 3 CheckMate-9ER data. The recommended dose is 240 mg of nivolumab every 2 weeks via a 30-minute intravenous (IV) infusion, or at 480 mg every 4 weeks via 30-minute IV infusion, in combination with oral, once-daily cabozantinib at 40 mg once daily without food until either progressive disease or intolerable toxicity.


The efficacy behind the combination of lenvatinib (Lenvima) and pembrolizumab, also compared with sunitinib, in the frontline setting of RCC was recently presented at the 2021 Genitourinary Cancers Symposium.6,7 Additionally, investigators tested the efficacy and safety of lenvatinib plus everolimus (Afinitor) vs sunitinib in this setting as a separate cohort.

At a median follow-up of 27 months in the phase 3 CLEAR trial, pembrolizumab/lenvatinib had a 34% reduction in the risk of death when compared with sunitinib; the median OS was not reached in either arm at a median 27-month follow-up (HR, 0.66; 95% CI, 0.49-0.88; P = .005). The median PFS was 23.9 months and 9.2 months, respectively (HR, 0.39; 95% CI, 0.32-0.49; P <.001); the ORRs were 71% vs 36% and the CR rates were 16% vs 4%, respectively.

Regarding the arm of lenvatinib plus everolimus vs sunitinib, the data showed statistically significant improvements in PFS and ORR, but not in OS (HR, 1.15; 95% CI, 0.88-1.5; P = .3).

Based on the CLEAR findings, the FDA granted a priority review designation in May 2021 to a supplemental biologics license application to the combination of lenvatinib and pembrolizumab as a frontline treatment for patients with advanced RCC. The agency is expected to make a decision on the approval by August 25, 2021.

“What’s important to note is that even though [lenvatinib and pembrolizumab] has one of the shorter overall duration of evaluation for the date, [it has a] 71% overall response rate and 16% complete response rate in just 27 months of follow-up for patients on active treatment,” Wood explained. “So, we are continuing to see improvements in our combinations and improvements in outcomes for these regimens.”

Utilizing Guidelines, Prognostic Factors and More for the Best RCC Treatment

The regulatory decisions and encouraging clinical data have also made an impact on the National Comprehensive Cancer Network (NCCN) guidelines for frontline therapy in advanced kidney cancer, and combination therapies are now defined by favorable, intermediate-, and poor-risk status.

Preferred regimens (category 1) for favorable-risk patients include axitinib/pembrolizumab, nivolumab/cabozantinib, and lenvatinib/pembrolizumab; poor-/intermediate-risk patients are recommended to receive axitinib/pembrolizumab, nivolumab/cabozantinib, nivolumab/ipilimumab, lenvatinib/pembrolizumab (all category 1), or cabozantinib.

Preferred agents, listed as category 1 recommendations, for subsequent lines of treatment in clear cell RCC include cabozantinib, lenvatinib/everolimus (Afinitor), and nivolumab.

Updates to NCCN guidelines have also occurred in the advanced non–clear cell RCC setting, Wood noted; preferred regimens include cabozantinib, sunitinib, and a clinical trial.

Overall, evidence-based decision-making, International Metastatic RCC Database Consortium (IMDC) risk stratification, histology, biomarkers, and comorbidities are all factors to consider when choosing treatment for a patient with RCC, Wood emphasized.

Regarding biomarkers, she added that based on data with pembrolizumab/axitinib, avelumab/axitinib, and nivolumab/ipilimumab, PD-L1 expression does not predict benefit or response in RCC compared with other malignancies.

“Patients irrespective of biomarker status will benefit from these combination therapies, so we’re continuing to try to identify biomarkers which will contribute to the knowledge of treatment decision-making,” Wood said.

Other disease characteristics are being identified as poor prognostic features, including sarcomatoid histology. However, in the KEYNOTE-426 study, patients with advanced RCC who had sarcomatoid features had an improved response to pembrolizumab/axitinib (58.8%) vs sunitinib (31.5%), providing clinicians with an option to recommend to their patients with this poor prognostic indicator, Wood added.

Role of Cytoreductive Nephrectomy in RCC

Cytoreductive nephrectomy has been evaluated as an immediate or deferred approach in patients with metastatic RCC. However, Wood explained that it’s been demonstrated that deferred surgery may have improved outcomes compared with immediate cytoreductive nephrectomy.

“A delayed cytoreductive nephrectomy allows for the identification of patients with aggressive or inherently resistant disease to our VEGF-targeted therapies, and those are individuals who may not benefit from a nephrectomy up front” she said, adding that initial systemic therapy is preferred in those with Memorial Sloan Kettering Cancer Center/IMDC poor-risk disease, poor [Karnofsky performance score] and/or large-volume metastatic burden.

However, select patients are likely to benefit from an up-front surgery, including those with single-site metastatic disease and those with good performance status, Wood mentioned.

What About Adjuvant Treatment in RCC?

Sixty-five percent of patients with RCC present with localized disease, suggesting a need for adjuvant treatment in this malignancy. At the 2021 ASCO Annual Meeting, data from the phase 3 KEYNOTE-564 trial (NCT03142334) were presented and demonstrated the benefit of adjuvant pembrolizumab vs placebo in the post-nephrectomy setting for patients with RCC.7

In the double-blind, multicenter study, investigators explored pembrolizumab vs placebo following nephrectomy in patients with clear cell RCC. Eligibility criteria included categorizing patients as high risk for recurrence, which included: pT2, grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0; pT4, any grade, N0, M0; any pT, any grade, N-positive, M0; or M1 with no evidence of disease after surgery.

Patients had to have undergone nephrectomy within 12 weeks prior to randomization, could not have previously received systemic treatment, had to have an ECOG performance status of 0 or 1, and obtainable tissue sample for PD-L1 assessment.

All patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks or placebo every 3 weeks, both for approximately 1 year.

Data showed that, at a median follow-up of approximately 2 years, the median investigator-assessed disease-free survival (DFS) was not reached with either pembrolizumab or placebo (HR, 0.68, 95% CI, 0.53-0.87; P = .0010).8 The estimated 1-year DFS rates were 85.7% and 76.2% with pembrolizumab and placebo, respectively. The 2-year rates were 77.3% and 68.1%, respectively.

The Emphasis on Multidisciplinary Care in RCC

In conclusion, the spectrum of GU malignancies embodies the multidisciplinary care approach, with Wood expressing the importance of urologic surgeons, medical oncologists, radiation oncologists, and palliative care in a patient’s course of treatment.

“Palliative care is huge for us. At least for renal cell carcinoma, there are many patients who see palliative care for assistance with symptom management before we even get started on systemic therapy,” she concluded. “If we don’t get palliative care’s input to help us manage the underlying disease and the symptoms associated with it, patients are never going to tolerate an aggressive regimen, which is necessary to control the disease and improve their overall survival.”


  1. Wood LS. Renal cell carcinoma and supportive care in GU cancers. Presented at: 5th Annual School of Nursing Oncology; August 6-7, 2021; virtual.
  2. Albiges L, Tanniir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079
  3. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8
  4. FDA approves Bavencio (avelumab) plus Inlyta (axitinib) combination for patients with advanced renal cell carcinoma. Pfizer Oncology. May 14, 2019. Accessed August 9, 2021.
  5. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. J Clin Oncol. 2021;39(suppl 6):308. doi:10.1200/JCO.2021.39.6_suppl.308
  6. Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). J Clin Oncol. 2021; 39(suppl_6):269. doi:10.1200/JCO.2021.39.6_suppl.269
  7. Motzer RJ, Alekseev B, Rha S.-Y., et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
  8. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab vs placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase 3 KEYNOTE-564 study. J Clin Oncol. 2021;39(suppl 15):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5

This article was originally published on OncLive as “Checkpoint Inhibitor/TKI Combos Jump RCC Treatment to Next Level”

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