Frontline Immunotherapy Approvals Raise Treatment Selection Challenge in RCC

Robert J. Motzer, MD

Within approximately 1 year, 3 combination regimens featuring immunotherapy agents were approved by the FDA for the frontline treatment of patients with metastatic renal cell carcinoma (RCC), said Robert J. Motzer, MD.

"We have made tremendous progress in the treatment of this disease through these large phase III trials, as well as through the development of TKIs and immunotherapy," said Motzer.

The first approval was granted in April 2018 to nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the treatment of intermediate- and poor-risk patients with advanced RCC after the regimen demonstrated a clinically significant overall survival (OS) improvement compared with sunitinib (Sutent) in the phase III CheckMate-214 trial.¹

In April 2019, the doublet of axitinib (Inlyta) and pembrolizumab (Keytruda) was approved for the treatment of patients with advanced RCC, based on the OS and progression-free survival (PFS) improvement reported from the KEYNOTE-426 trial. After 12 months, OS rates were 89.9% with the immunotherapy combination compared with 78.3% with sunitinib. The median PFS was 15.1 months versus 11.1 months, respectively (HR, 0.69; 95% CI, 0.57-0.84; P = .0001).²

Finally, the 31% reduction in the risk of disease progression or death observed with avelumab (Bavencio) and axitinib compared with sunitinib, regardless of PD-L1 expression, seen in the phase III JAVELIN Renal 101 trial led to the combination's approval in May 2019, also for patients with advanced RCC. The median PFS was 13.8 months with axitinib plus avelumab compared to 8.4 months with sunitinib (HR, 0.69; 95% CI, 0.56-0.84; 2-sided P = .0002) in the overall population.³

Given the multiple of new options, choosing the optimal frontline treatment for individual patients is a challenge, said Motzer.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Motzer, medical oncologist, Kidney Cancer Section Head, and Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center (MSK), discussed the current treatment landscape of mRCC amongst this influx of approvals.

OncLive^®: What does the current treatment paradigm look like in metastatic RCC?

Motzer: Historically, first-line treatment of this population was single-agent TKIs with sunitinib or pazopanib (Votrient).

More recently, immunotherapy with checkpoint inhibitors compared with sunitinib was studied in 3 large phase III trials. All the trials had positive results, resulting in regulatory approval for 3 new regimens: axitinib/pembrolizumab, axitinib/avelumab, and ipilimumab/nivolumab.

With these new combinations approved, what factors determine which regimen to give an individual patient in the first-line setting?

In clinical practice, pembrolizumab/axitinib and nivolumab/ipilimumab are the leading contenders for first-line therapy based on the highest level of evidence with improved OS with each of those doublets compared with sunitinib. Choosing the best option for each patient is still a challenge.

Are there any strategies trying to address that challenge?

In the past, choices have been based mostly on clinical features or risk groups. MSK developed the [MSKCC/Motzer Score for mRCC] that groups patients as favorable-, intermediate-, and poor-risk based on clinical characteristics.

Within these trials, extensive samples have been acquired for patients treated with these immunotherapy combinations. These samples are being studied to see if we can better predict who is going to do well with 1 treatment versus another based on underlying tumor biology.

Are there any ongoing clinical trials that appear promising in this space?

One trial I see as important moving forward is the COSMIC-313 trial, which is looking at nivolumab/ipilimumab plus cabozantinib (Cabometyx) versus nivolumab/ipilimumab plus placebo in first-line treatment for patients with intermediate- or poor-risk clear cell RCC.

Two adjuvant trials may also be promising. One is comparing single-agent pembrolizumab with placebo in patients with stage III RCC, and the other is an ongoing trial looking at nivolumab plus ipilimumab versus placebo in high-risk patients following complete resection by nephrectomy.

References

1. Motzer RJ, Tannir NM, McDermott DF, Frontera OA, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Eng J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.
2. Powles T, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Eng J Med. 2019;380:1116-1127. doi: 10.1056/NEJMoa1816714.
3. Motzer RJ, Konstantin P, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal cell carcinoma. N Eng J Med. 2019;380:1103-1115. doi: 10.1056/NEJMoa1816047.