Immunotherapy Combinations Are King in Frontline RCC Treatment

Kristi Rosa
Published: Friday, Mar 13, 2020

Dr. Primo Lara
Primo N. Lara Jr, MD
In metastatic renal cell carcinoma (mRCC), the use of frontline combination immunotherapy regimens has led to significant survival benefits for patients, and efforts are now being focused on exploring novel options for those who become refractory to this approach, said Primo N. Lara Jr, MD, in a presentation during the New York GU 13th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.

Historically, monotherapies dominated the mRCC treatment landscape, according to Lara, with the FDA approvals of several angiogenesis inhibitors, such as sunitinib (Sutent), pazopanib (Votrient), cabozantinib (Cabometyx), axitinib (Inlyta), sorafenib (Nexavar), and bevacizumab (Avastin); mTOR inhibitors, such as everolimus (Afinitor) and temsirolimus (Torisel); and single-agent immunotherapies, such high-dose interleukin-2 (HD IL-2) and nivolumab (Opdivo). However, in recent years, a shift from the use of single agents to combination approaches has occurred.

In the phase III CheckMate-214 trial, the combination of nivolumab plus ipilimumab (Yervoy) was found to significantly improve survival and induce higher objective response rates (ORRs) compared with sunitinib among intermediate- and poor-risk patients with previously untreated advanced or metastatic RCC.

At a median follow-up of 25.2 months, the 18-month OS rate was 75% (95% CI, 70-78) with the combination versus 60% (95% CI, 55-65) with sunitinib in the intermediate- and poor-risk patients.1 The median OS was not reached with nivolumab/ipilimumab versus 26.0 months with sunitinib (HR, 0.63; P <.001). The median PFS with the combination was 11.6 months versus 8.4 months with sunitinib (HR, 0.82; 99.1% CI, 0.64-1.05; P =.0331).

Furthermore, the ORR with nivolumab/ipilimumab was 42% (95% CI, 37-47) versus 27% (95% CI, 22-31) with sunitinib (P <.001). The median duration of response (DOR) with the combination was not reached versus 18.2 months with sunitinib; 72% of patients on the combination arm had an ongoing response at the time the data were reported. The combination received regulatory approval in April 2018 for use in this patient population based on early data from this trial.

Updated data presented at the 2020 Genitourinary Cancers Symposium showed sustained OS benefit with the combination in the intermediate- and poor-risk patients (HR, 0.66; 95% CI, 0.55-0.90; P <.0001).2 Notably, however, in the favorable-risk patients, no OS benefit was observed with the combination (HR, 1.19; 95% CI, 0.77-1.85; P = .44). The intent-to-treat (ITT) analysis revealed an OS benefit that was observed across all risk groups (HR, 0.72; 95% CI, 0.61-0.86; P = .0002).

The FDA approved the combination of avelumab (Bavencio) and axitinib for the frontline treatment of patients with advanced RCC based on data from the pivotal phase III JAVELIN Renal 101 trial, which had demonstrated that the combination was associated with a 31% reduction in the risk of disease progression or death versus sunitinib in an ITT population of patients with treatment-naïve disease, regardless of PD-L1 expression.3

Specifically, results showed that in the PD-L1–positive population, the median PFS was 13.8 months (95% CI, 11.1–not evaluable) with the combination versus 7.2 months (95% CI, 5.7-9.7) with sunitinib; this translated to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95% CI, 0.475-0.790; P <.0001).

The OS data are still immature, with the median OS not reached in either arm (HR, 0.78; 95% CI, 0.554-1.084; P =.0679).

The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) was examined in patients with treatment-naïve advanced or metastatic RCC in the phase III IMmotion151 trial. In the PD-L1¬¬–positive population (n = 362), the median PFS with the combination was 11.2 months versus 7.7 months with sunitinib (HR, 0.74; 95% CI, 0.57-0.96). The results were comparable in the ITT population (n = 915), with a median PFS of 11.2 months versus 8.4 months with the combination versus sunitinib, respectively (HR, 0.83; 95% CI, 0.70-0.97).4

At a median follow-up of 15 months, the median OS was not reached in the PD-L1¬–positive population versus 23.3 months with sunitinib (HR, 0.68; 95% CI, 0.46-1.00). Median OS was not reached in either arm in the ITT population (HR, 0.81; 95% CI, 0.63-1.03).

Another key combination that has emerged in the RCC treatment paradigm is pembrolizumab (Keytruda) plus axitinib, which was evaluated in patients with newly diagnosed or recurrent stage IV clear-cell RCC in the phase III KEYNOTE-426 trial.

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