Immunotherapy Regimens Reduce Toxicity in Advanced RCC Compared With Sunitinib


A pooled analysis of phase 3 clinical trials in advanced renal cell carcinoma showed that combination immunotherapy can reduce toxicity compared with sunitinib.

Regimens that feature an immune checkpoint inhibitor and VEGF inhibitor combinations to treat advanced renal cell carcinoma (RCC) have significant gastrointestinal (GI) and hepatic toxicities, emphasizing the need for close monitoring of patient symptoms and liver function. These were the conclusions of a meta-analysis presented during the 2020 ASCO Virtual Scientific Program.1

A team of authors from the Texas Technical University Health Sciences Center conducted this meta-analysis around phase III randomized controlled trials to determine the relative risk of gastrointestinal and hepatic toxicities associated with upfront use of immunotherapy-based regimens compared to sunitinib (Sutent) for advanced RCC.

The Texas Tech team found that the risk of any-grade and high-grade diarrhea, abdominal pain, and elevation of aspartate transaminase (AST) and alanine transaminase (ALT)was higher in combination arms compared to sunitinib arms. The risk of all-grade dyspepsia and nausea was lower in the combination arms. Additionally, “the risk of high-grade diarrhea, elevation of AST, and elevation of ALT was higher in combination arms compared to sunitinib [arms],” wrote the authors, led by Miguel Quirch, MD. “The careful monitoring of patient symptoms and liver function with the initiation of appropriate supportive care is critically important.”

After screening 3,111 citations, the authors eliminated all abstracts, review articles and letters to the editor. Only 4 studies met the eligibility criteria of reporting results for phase III randomized clinical trials that used an immunotherapy in the intervention arm for the first-line treatment of advanced RCC. Studies must also have reported and analyzed the number of GI and hepatic toxicities such as diarrhea, vomiting, and transaminitis for both intervention and control arms.

Quirch et al eliminated 2 studies that did not use the immunotherapy/sunitinib combined regimen. They conducted their review using the remaining 2 studies, JAVELIN Renal 101 (NCT02684006) and KEYNOTE-426 (NCT02853331),2,3

JAVELIN Renal 101 used avelumab (Bavencio) and axitinib (Inlyta) in its study arm, while KEYNOTE-426 used pembrolizumab (Keytruda) and axitinib. Sunitinib was used for both control arms. The two trials randomized 1727 patients on a 1:1 basis.

In the present study, Quirch et al calculated the pooled risk ratio of common any-grade GI and hepatic toxicities. These include diarrhea at 1.26 (95% Confidence Interval [CI], 1.15-1.38; P < 0.00001), dyspepsia at 0.40 (95% CI, 0.30-0.53, P < 0.00001), and nausea at 0.87 (95% CI, 0.76 –1.00, P = 0.05). Other any-grade GI toxicities include vomiting at 0.88 (95% CI, 0.72 –1.07, P = 0.20) and abdominal pain at 1.50 (95% CI, 1.13 –1.99, P = 0.005).

For hepatic toxicities, the pooled risk ratio included the elevation of AST at 1.43 (95% CI, 1.10 – 1.87, P = 0.007). The pooled risk ratio for elevation of ALT was 1.66 (95% CI, 1.34 – 2.05, P < 0.00001).

The pooled risk ratio of grade 3 and higher GI and hepatic toxicities included diarrhea at 2.12 (95% CI, 1.40 – 3.19, P = 0.0003) and nausea at 0.91 (95% CI, 0.39 – 2.14, P = 0.83,). The pooled risk ratio for vomiting was 0.47 (95% CI, 0.16 – 1.37, P = 0.17), while abdominal pain was 1.44 (95% CI, 0.19 – 10.64, P = 0.72)

For the risk ratio of hepatic toxicities, elevation of AST was 2.45 (95% CI, 1.45 – 4.15, P = 0.0009), while elevation of ALT was 3.32 (95% CI, 1.85 – 5.95, P < 0.0001).

In JAVELIN Renal 101, a total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Nearly two-thirds of patients (n = 560, 63.2%) had PD-L1–positive tumors. The median progression-free survival (PFS) among these patients was 13.8 months with the combined regimen, compared with 7.2 months with sunitinib (hazard ratio [HR] for disease progression or death, 0.61; 95% CI, 0.47 - 0.79; P < 0.001). In the overall trial population, the median PFS was 13.8 months, compared with 8.4 months (HR, 0.69; 95% CI, 0.56-0.84; P < 0.001). Among the patients with PD-L1–positive tumors, the objective response rate was 55.2% with avelumab in combination with axitinib and 25.5% with sunitinib.

Adverse events (AEs) during treatment in JAVELIN Renal 101occurred in 99.5% of patients in the avelumab plus axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.

In KEYNOTE-426, nearly 90% of patients (89.9%) in the pembrolizumab + axitinib group were still alive with a median follow-up of 12.8 months. This compares with a 12-month survival of 78.3% in the sunitinib group (HR for death, 0.53; 95% CI, 0.38-0.74; P < 0.0001). The median PFS was 15.1 months in the pembrolizumab plus axitinib group and 11.1 months in the sunitinib group (HR for disease progression or death, 0.69; 95% CI, 0.57-0.84; P < 0.001).

The objective response rate was 59.3% in the pembrolizumab plus axitinib group (95% CI, 54.5-63.9) and 35.7% in the sunitinib group (95% CI, 31.1-40.4, P < 0.001). The benefit of pembrolizumab /axitinib was seen regardless of PD-L1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab plus axitinib group and in 70.6% in the sunitinib group.

Quirch et al concluded that immunotherapy-based regimens have significantly reduced risk of both any-grade and high-grade hematological toxicities compared to sunitinib in patients with advanced RCC.


1. Jahan N, Ball S, Quirch M, et al. J Clin Oncol. 2020;38(suppl 6):675. doi: 10.1200/JCO.2020.38.6_suppl.675

2. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1103-1115. Published online March 21, 2019. doi: 10.1056/NEJMoa1816047

3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1116-1127. Published online March 21, 2019. doi: 10.1056/NEJMoa1816714

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