New Data Change Management of Frontline Metastatic Renal Cell Carcinoma

Pedro Barata, MD, MSc

Genitourinary Medical Oncologist

Assistant Professor of Medicine

Tulane University School of Medicine

New Orleans, Louisiana

Metastatic renal cell carcinoma (mRCC) has a heterogenous presentation that ranges from indolent growth to highly symptomatic disease.¹ Published models from the International Metastatic RCC Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center in New York, New York, include risk factors (anemia, neutrophilia, thrombocytosis, elevated serum calcium concentration, performance status, and time to initiation of systemic treatment) that categorize patients into favorable-, intermediate-, and poor-risk groups and offer prognostic information to the treating physician. Recently, new data were presented for patients in different risk categories that significantly changed the surgical and medical management of patients with newly diagnosed mRCC.

Table. Ongoing Phase III Trials for Metastatic, Clear-Cell Renal Cell Carcinoma

Cytoreductive nephrectomy (CN) has been a frequent approach since the so-called old immunotherapy era, when a prospective, randomized trial showed that CN followed by an interferon demonstrated a survival benefit compared with interferon treatment alone.² Later, results from retrospective studies investigating CN with targeted therapies suggested a similar advantage, leading to widespread application of this approach in mRCC. Up-front CN was recently challenged when the results from the prospective French study CARMENA, comparing CN followed by sunitinib (Sutent) versus sunitinib alone, were published in June 2018.¹ With a median follow-up of more than 4 years, the median overall survival (OS) was 18.4 months in the sunitinib arm compared with 13.9 months in the CN plus sunitinib arm, which met the study’s primary endpoint that sunitinib was noninferior to CN plus sunitinib (HR, 0.89; 95% CI, 0.71-1.10).³ Although these findings have underscored the importance of careful selection of patients undergoing CN, patients with favorable or intermediate risk and low volume of extrarenal disease are likely to benefit from up-front CN. Before 2018, vascular endothelial growth factor—targeted therapy was used for most patients with treatment-naïve mRCC.⁴ CheckMate 025 was the first phase III study to support the use of an immune checkpoint inhibitor, nivolumab (Opdivo), an anti—PD-1 antibody, in patients with refractory mRCC. After the approval of nivolumab in 2015, this same therapy was combined with an anti–CTLA-4 antibody, ipilimumab (Yervoy), in the phase III CheckMate 214 trial, which included overall response rate (ORR), progression-free survival (PFS), and OS as coprimary endpoints in patients with IMDC intermediate- and poor-risk mRCC.

After a median follow-up of 25 months, the ORR was 42% versus 27% (P <.001) and the complete response (CR) rate was 9% versus 1% for the ipilimumab plus nivolumab and sunitinib groups, respectively. The median OS was not reached for ipilimumab plus nivolumab (28.2 months-not estimable [NE]) and 26.0 months (22.1 months-NE) with sunitinib (HR, 0.63, 99.8% CI, 0.44-0.89; P <.001). Although this combination met the primary endpoint in patients with intermediate- and poor-risk mRCC, the benefit in favorable-risk mRCC was less clear, with lower response rates compared with sunitinib (39% vs 50%).

Significant adverse events (AEs) were observed in 63% and 46% of patients in the ipilimumab-plus-nivolumab and sunitinib groups, respectively. Treatment-related AEs leading to discontinuation occurred in 22% and 12%, respectively. Sixty percent of patients with immune-related AEs (irAEs) required systemic corticosteroids and 35% required high-dose glucocorticoids (≥40-mg prednisone or equivalent/day).

Subsequently, 3 phase III trials combining immune checkpoint inhibitors with anti-angiogenic therapy were presented. IMmotion 151 tested the combination of atezolizumab (Tecentriq), a PD-L1 inhibitor, with bevacizumab (Avastin) versus sunitinib in patients with untreated mRCC.⁵ The primary endpoints were PFS in PD-L1—positive disease and OS. This study met the primary endpoint of PFS in PD-L1–positive mRCC, with a difference of approximately 3.5 months favoring patients who received atezolizumab plus bevacizumab (HR, 0.74, 95% CI, 0.57- 0.96; P = .02). The OS was immature at time of analysis.

More recently, 2 other combinations were tested against sunitinib alone, including axitinib (Inlyta) with pembrolizumab (Keytruda), a PD-1 inhibitor, in KEYNOTE-426 and avelumab (Bavencio), a PD-L1 inhibitor, with axitinib in JAVELIN Renal 101.^6,7 In the phase III JAVELIN Renal 101 trial, patients with any-risk mRCC were allocated to axitinib plus avelumab or sunitinib. The median PFS among patients with PD-L1—positive disease was 13.8 months in the axitinib-plus-avelumab group versus 7.2 months in the sunitinib group (HR, 0.61, 95% CI, 0.47-0.79; P <.001), which met one of the coprimary endpoints of the study. At time of presentation, objective responses were observed in 51% of patients with intermediate- risk disease, with CRs observed in 3% of the overall population; OS data were still immature.

The phase III KEYNOTE-426 trial investigated pembrolizumab plus axitinib versus sunitinib in patients with previously untreated mRCC, with PFS and OS in the intent-to-treat population as coprimary endpoints.⁶ With a median follow-up of 12.8 months, both median PFS and OS were superior in the pembrolizumab-with-axitinib arm (HR for PFS, 0.69; 95% CI, 0.57-0.84; P <.001; HR for OS, 0.53; 95% CI, 0.38-0.74; P <.0001). In addition, the ORR was 59.3% in the pembrolizumab/axitinib group, including a CR rate of 5.8%.

Both combinations (axitinib/avelumab and axitinib/ pembrolizumab) had manageable AEs, although they accounted for 71.2% and 75.8% of significant AEs in JAVELIN 101 and KEYNOTE-426, respectively. The combination regimens were discontinued in 7.6% and 10.7% of patients in the respective studies.^6,7

Although all of these studies met their primary endpoints and are approved by the FDA for first-line mRCC, they have different safety and efficacy profiles. With longer follow-up, more information on durability of responses and mature OS will become available. Additionally, results from other phase III trials investigating other regimens with an immune checkpoint inhibitor as backbone treatment are expected (Table).

Notwithstanding the superiority of combinatorial regimens over sunitinib for first-line mRCC, antiangiogenic therapy will continue to be used in the frontline, including in patients with favorable-risk mRCC where efficacy is best. In other cases, clinical factors such as poor performance status and active immune disease will contraindicate the use of a combination regimen. Additionally, selected patients with favorable-risk mRCC may safely undergo active monitoring.⁸

In summary, the integration of data from multiple positive phase III trials in clinical practice remains to be defined, and the selection of the regimen of choice will depend on a number of factors, such as mature OS data, response rates, safety profiles, and dosing schedules. Additionally, a better understanding of the molecular characteristics of the tumors and biomarker research may optimize patient selection for all of these options and improve patient outcomes.

References

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2. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655-1659.
3. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi: 10.1056/NEJMoa1803675.
4. Motzer RJ, Tannir NM, 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, Powles T, Atkins MB, et al; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393(10189):2404-2415. doi: 10.1016/S0140-6736(19)30723-8.
6. 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.
7. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115. doi: 10.1056/NEJMoa1816047.
8. Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet. 2016;17(9):1317-1324. doi: 10.1016/S1470-2045(16)30196-6.