PD-1 Inhibition Reigns Supreme in Frontline Advanced RCC

The role of immunotherapy in metastatic renal cell carcinoma has grown tremendously with dual immune checkpoint inhibition and combinations of anti–PD-1/VEGF inhibitors.

Mario Sznol, MD

The role of immunotherapy in metastatic renal cell carcinoma (mRCC) has grown tremendously with dual immune checkpoint inhibition and combinations of anti—PD-1/VEGF inhibitors, explained Mario Sznol, MD, in a presentation during the 13th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.

These advances are owed in large part to the understanding of the PD-1/PD-L1 pathway, wherein T-cells, through PD-1/PD-L1 inhibition, retain their ability to activate the immune system.

“The hypothesis is if we block this pathway, either at PD-1 or PD-L1, we would see meaningful activity in those patients who already have antigen-specific T cells in the tumor microenvironment,” said Sznol, who is a professor of medicine and co-director of the Yale SPORE in Skin Cancer at Yale Cancer Center.

Such activity was shown in the initial data with nivolumab (Opdivo) monotherapy, in which patients who had been pretreated with high-dose interleukin-2 or VEGF TKI monotherapy experienced an objective response rate (ORR) of 29%.1

The PD-1 inhibitor was then tested in combination with ipilimumab (Yervoy) in the phase I CheckMate-016 trial to determine the activity of dual anti—PD-1 and anti–CTLA-4 blockade. The combination not only showed a high ORR of 40.4%, but also led to durable responses even once treatment had been discontinued.2

Although the combination had generated some concern for toxicity in melanoma, the inverse dosing schedule of 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab led to a significant reduction in the rate of grade 3/4 adverse events.

These data served as the basis for the phase III CheckMate-214 trial, in which previously untreated patients with advanced RCC were randomized to the combination followed by single-agent nivolumab or sunitinib (Sutent) monotherapy. Initial results showed that the combination led to a significant improvement in overall survival (OS) versus sunitinib in patients with intermediate- and poor-risk disease, leading to the April 2018 approval of the combination in this setting.3 The progression-free survival (PFS) also favored the combination in this group of patients, but it did not meet the prespecified criteria for significance.

At 42 months, the combination continued to showcase an OS advantage (HR, 0.66; 95% CI, 0.55-0.80; P <.0001) and displayed a more pronounced and lasting PFS benefit in 35% of intermediate- and poor-risk patients (HR, 0.76; 95% CI, 0.63-0.91; P <.01).4

“A subset of these patients are probably cured, which is why we tend to favor giving nivolumab and ipilimumab in the frontline setting,” said Sznol.

The combination failed to demonstrate an OS benefit in favorable-risk patients at any point during treatment. However, at 42 months, the PFS curves appear to overlap, suggesting that there may be a subgroup of favorable-risk patients who could derive long-term PFS, said Sznol.

Prior to the phase III KEYNOTE-426 trial, which evaluated the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) in the same setting, pembrolizumab was evaluated as monotherapy in the phase II KEYNOTE-427 trial. The data showed a comparable ORR and a favorable toxicity profile to that of nivolumab/ipilimumab in intermediate- and poor-risk patients, said Sznol.5 Moreover, the ORR was 24.8% in patients with non-clear cell histology, suggesting that anti—PD-1 inhibition could be an alternative frontline approach to everolimus (Afinitor) or VEGF inhibition.6

In the KEYNOTE-426 trial, investigators were able to demonstrate the synergistic effects of combining VEGF inhibition with PD-1 inhibition by way of improved OS (HR, 0.52), PFS (HR, 0.67), and ORR (55.8%), irrespective of risk status.7 In April 2019, the combination received regulatory approval for the frontline treatment of patients with advanced RCC. Notably, the 1-year OS rate was 87.3% with pembrolizumab/axitinib versus 71.3% with sunitinib monotherapy, which is not dissimilar to what was seen with nivolumab/ipilimumab, said Sznol.

Although the 1-year PFS rate of pembrolizumab/axitinib was superior to nivolumab/ipilimumab, Sznol warned that it may not translate to an OS advantage.

“We need further follow-up to determine whether pembrolizumab/axitinib or nivolumab/ipilimumab will produce a late tail on the PFS curve in favorable-risk patients,” said Sznol.

For patients who previously received ≥1 VEGF inhibitor up front, it is not unreasonable to consider nivolumab monotherapy at the time of progression, said Sznol. According to data from the phase III CheckMate-025 study, patients who received nivolumab in this setting experienced a median OS of 25.0 months versus 19.6 months with everolimus, translating to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.57-0.93; P = .002).8 Additionally, the 30-month OS favored the use of nivolumab in all patients, irrespective of whether patients had favorable-risk (HR, 0.80), intermediate-risk (HR, 0.81), or poor-risk disease (HR, 0.48).9

“We tend to dismiss the activity of immunotherapy in the favorable-risk subgroup, but I believe there is a subset of patients with favorable-risk disease who can develop durable responses with immunotherapy,” said Sznol.

Regarding biomarkers of response, data from the KEYNOTE-427 trial showed that patients with a PD-L1 combined positive score (CPS) ≥1 experienced a higher response rate with pembrolizumab versus those with PD-L1 CPS <1. However, Sznol stated that PD-L1 alone is not a sufficient biomarker of response to immunotherapy, citing the results of the CheckMate-214 and CheckMate-025 trials, which showed an OS advantage with nivolumab alone and in combination with ipilimumab in patients regardless of PD-L1 expression.

In conclusion, Sznol stated that he tends to favor the combination of nivolumab/ipilimumab as frontline therapy in the majority of patients with mRCC, irrespective of risk status, and turn to anti—PD-1/VEGF TKI inhibition at the time of progression in order to provide patients with the best chance of durable benefit.


  1. McDermott DF, Drake CG, Sznol M, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015;33(18):2013-2020. doi: 10.1200/JCO.2014.58.1041
  2. Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate-016 study. J Clin Oncol. 2017;35(34):3851-3858. doi: 10/1200/JCO.2016.72.1985
  3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126
  4. Tannir NM, McDermott DF, Escudier B, et al. Overall survival and independent review of response in CheckMate 214 with 42-month follow up: first-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2020;38(suppl 6; abstr 609). doi: 10.1200/JCO.2020.38.6_suppl.609
  5. McDermott DF, Lee JL, Szczylik C, Donskov F, et al. Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): results from cohort A of KEYNOTE-427. J Clin Oncol. 2018;36(suppl 15; abstr 4500). doi: 10.1200/JCO.2018.36.15_suppl.4500
  6. McDermott DF, Lee JL, Ziobro M, et al. First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): results from KEYNOTE-427 cohort B. J Clin Oncol. 2019;37(suppl 7; abstr 546). doi: 10.1200/JCO.2019.37.7_suppl.546
  7. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Eng J Med. 2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714
  8. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi: 10.1056/NEJMoa1510665
  9. Escudier B, Sharma P, McDermott D, et al. CheckMate-025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017;72(6):962-971. doi: 10.1016/j.euro.2017.02.010