Frontline Immunotherapy-Based Regimens Shift Survival Outcomes for Patients With Metastatic RCC

Moshe C. Ornstein, MD, MA

Great progress has been made using immunotherapy in the frontline setting for the treatment of patients with metastatic renal cell carcinoma (RCC), including in 2021; however, most patients still die of the disease and more options and new targets are needed, according to a presentation by Moshe C. Ornstein, MD, MA, during the 2021 International Kidney Cancer Symposium.¹

In 1998, the median overall survival (OS) with interferon α-2a was 13 months, 12 months with interleukin-2, and 17 months with a combination of the agents.2 Since then, numerous combination trials have also yielded significant improvements in survival in the first-line setting (TABLE). For instance, in 2018, the median OS with immunotherapy agents nivolumab (Opdivo) plus ipilimumab (Yervoy) was 55.7 months compared with 38.4 months with sunitinib (Sutent; HR, 0.72; 95% CI, 0.62-0.85; P < .0001).^3,4

CheckMate 214 (NCT02231749), which evaluated nivolumab and ipilimumab vs sunitinib found both the combination and sunitinib monotherapy had a median progression-free survival (PFS) of 12.3 months (HR, 0.86; 95% CI, 0.73-1.01). The landmark 12-month OS rate was 83% with the combination vs 78% with the monotherapy. At 24 months, the landmark OS rate was 71% and 61%, respectively. The overall response rate (ORR) was 39% in the combination arm vs 32% in the monotherapy arm, with a complete response (CR) rate of 12% and 3% respectively.⁴

The KEYNOTE-426 trial (NCT02853331) found that the combination of pembrolizumab (Keytruda) and axitinib (Inlyta), a tyrosine kinase inhibitor (TKI), had an OS of 45.7 months compared with 40.1 months with sunitinib monotherapy (HR, 0.73; 95% CI, 0.60- 0.88; P < .001). The land-mark OS rate at 12 months was 90% with the combination and 79% with the monotherapy. At 24 months, the landmark OS rate was 74% and 66%, respectively. With the combination, the median PFS was 15.7 months compared with 11.1 months with the monotherapy (HR, 0.68; 95% CI, 0.58-0.80; P < .0001). The ORR was 60.4% with the combination and 39.6% with sunitinib monotherapy, and the CR rate was 10% and 4%, respectively.^5,6

The CheckMate 9ER study (NCT03141177) looked at PD-1 inhibitor nivolumab plus cabozantinib (Cabometyx), a TKI, vs sunitinib. The median OS was not reached with the combination vs 29.5 months with the monotherapy (HR, 0.66; 95% CI, 0.50-0.87; P = .0034). The 12-month OS rate was 86% for the combination and 76% for the monotherapy with the 24-month OS rate being 72% and 60%, respectively. The median PFS was 17.0 months with the combination vs 8.3 months with sunitinib alone (HR, 0.52; 95% CI, 0.43-0.64; P < .0001). The ORR was 55% with the combination and 27% with the monotherapy, with a CR rate of 9% and 4%, respectively.7 The FDA approved the combination regimen as first-line treatment of patients with advanced RCC in January 2021.⁸

The CLEAR trial (NCT02811861) evaluated the efficacy of pembrolizumab and the multitargeted TKI lenvatinib (Lenvima) vs pembrolizumab plus everolimus (Afinitor) vs sunitinib monotherapy. Although the median OS was not reached with either pembrolizumab/lenvatinib or sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = .005), the 12-month OS rate for the lenvatinib combination was 90% vs an estimated rate of 79% for monotherapy, and the 24-month OS rate was 79% and 70%, respectively. The median PFS was 23.9 months with the combination and 9.2 months with the monotherapy (HR, 0.39; 95% CI, 0.32-0.49; P < .001). The ORR was 71% in the combination arm and 36% with the monotherapy, with a CR rate of 16% and 4%, respectively.9 The FDA approved the combination of pembrolizumab and lenvatinib for the first-line treatment of adult patients with advanced RCC in August 2021.¹⁰

“Although immunotherapy is great now, there is still a way to go,” said Ornstein, a genitourinary medical oncologist at the Cleveland Clinic Taussig Cancer Center. According to Ornstein, even with the higher and durable response rates seen with these frontline immunotherapy regimens, most patients still progress and die of metastatic RCC.

There are treatment options that have yet to be explored, according to Ornstein. These include using the metabolic pathway to improve immunotherapy response rates and cellular therapy. Additionally, the inhibition of anti-inflammatory cytokines is an option to help improve outcomes in the metastatic RCC population. “Understanding the local environment, the peripheral environment, in a static environment is how we develop the next wave of immunotherapy agents,” said Ornstein.

_REFERENCES

_{1. Ornstein M. Novel immunotherapy targets. Presented at: 2021 International Kidney Cancer Symposium; November 4-5, 2021; Austin, TX.}

_{2. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleu-kin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d’Immunothérapie. N Engl J Med. 1998;338(18):1272-1278. doi:10.1056/NEJM199804303381805}

_{3. Powles T, Albiges L, Bex A, et al; ESMO Guidelines Committee. Renal cell carcinoma treatment recommendations. ESMO. September 28, 2021. Accessed November 5, 2021. https://bit.ly/3woKId8}

_{4. Motzer RJ, Tannir NN, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126}

_{5. Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714}

_{6. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500}

_{7. 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}

_{8. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed November 22, 2021. https://bit.ly/3FZiid2}

_{9. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716}

_{10. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed November 22, 2021. https://bit.ly/3FZdy7q}