Immunotherapy Combinations Are King in Frontline RCC Treatment

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.

Results from the trial showed that treatment with pembrolizumab/axitinib resulted in a 47% reduction in the risk of death versus sunitinib (HR, 0.53; 95% CI, 0.38-0.74; P <.001). The ORR with the combination was 59.3% (95% CI, 54.5-63.9) versus 35.7% (95% CI, 31.1-40.4) with sunitinib (P <.0001). The median DOR with the combination was not reached versus 15.2 months with sunitinib.⁵ Data from this trial led to the FDA’s decision to approve the combination in April 2019 for use in patients with advanced RCC.

With all of these promising combinations, the question now becomes, “Who deserves HD IL-2?” said Lara. Although HD IL-2 is still listed as a monotherapy option in some guidelines, it is typically reserved for robust patients with excellent performance scores and normal end-organ function.

“The subset of patients who benefit from checkpoint inhibitors likely overlaps with those who benefit from HD IL-2,” said Lara. “HD IL-2 has a rapidly diminishing and limited role.”

Another question that is raised by all of these advances made with combination regimens, is whether a role still exists for VEGFR TKI monotherapy. For those who are ineligible for, intolerant of, or who refuse immunotherapy, these agents could serve as an effective treatment option.

With regard to mTOR inhibitor monotherapies in the frontline treatment of patients with mRCC, Lara said that although temsirolimus monotherapy is FDA approved for use in this patient population, there is little justification for its routine use in the current era of more active, life-prolonging treatment options.

Although the field has largely shifted to combination use, single-agent sunitinib continues to be “king” in the treatment of patients with non-clear cell RCC, according to Lara, “at least for now.” The agent has been shown in several studies, such as ESPN, ASPEN, and RECORD-3, to result in improved ORR and PFS compared with everolimus in this patient population.

Although monotherapy does not have as much of a role in the frontline treatment of patients with RCC as it used to, nearly all patients are candidates for monotherapy in the second-line setting and beyond. For example, nivolumab is being used in patients who were VEGFR-pretreated and VEGFR targeted therapies are being used in patients who received prior treatment with immunotherapy. However, mTOR inhibitors still have a limited role in these later-line settings and there is no justification for the use of interferon in the modern era, concluded Lara.

References

1. 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/NEJMoa1712116
2. 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
3. Motzer RJ, Penkov K, Haanen JBAG, et al. JAVELIN renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). Ann Oncol. 2018;29(suppl 8):viii724. doi: 10.1093/annonc/mdy424.036
4. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2018;36(suppl 6; abstr 578). doi: 10.1200/JCO.2018.36.6_suppl.578
5. Powles T, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. J Clin Oncol. 2019;37(suppl 7; abstr 543). doi: 10.1200/JCO.2019.37.7_suppl.543

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