JAVELIN Renal 101 Does Not Provide Guidance for Patient Selection

ESMO expert commentator, John Haaner, MD, of the division of molecular oncology and immunology of the Netherlands Cancer Institute, Amsterdam, Netherlands, provided comments on the study.

He noted that metastatic RCC was difficult to treat and until 2005, interferon or high-dose interleukin-2 were the only available options. These options were toxic and had no impact on OS, he pointed out.

In 2006, the approval of sunitinib , the VEGFR TKI, changed the treatment for patients. Because RCC is a highly vascular disease, patients benefited with this treatment; however, the treatment is not curative, Dr Haaner pointed out.

Several options are now available for patients with advanced RCC, including the checkpoint inhibitor, nivolumab, and the combination of nivolumab and ipilimumab. Inhibitors of the mammalian target of rapamycin (mTOR), everolimus and temsirolimus, are also available to patients.5

However, for patients with advanced RCC, JAVELIN Renal 101 raises several questions, Dr Haaner said. “Is this the best step forward for all patients? We need to use the best drug(s) for the best patient.”

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Viktor Grünwald, MD, of the West German Cancer Center, University Hospital Essen, Germany, addressed some of these questions in his discussion following Dr Motzer’s presentation. He indicated that currently, guidelines suggest sequential treatment with a single agent as the standard of care in advanced RCC.5,6

For patients with good- and intermediate-risk advanced RCC, treatment with sunitinib, pazopanib, or the combination of bevacizumab and interferon is the standard. For patients with poor-risk advanced RCC, the standard option is temsirolimus. Other options include high-dose interleukin-2 or sorafenib.

“For more than 1 decade we’ve done that and what we have learnt is that quality of response matters and a fraction of patients have an excellent response to a TKI treatment, and depth of remission matters in terms of prognosis in these patients,” he noted.

He pondered whether the main goal of therapy was to chase complete response or stick to sequential therapies that provide tumor control. But in JAVELIN Renal 101, ORR responses were impressive: “For the first time we have 60% ORR,” he noted. “However, since ORR in patients with PD-L1 tumors are similar to those in the overall population, PD-L1 positivity as a strategy is not appropriate for the combination approach of VEFGR and immune inhibition.”

Although CR seen in this trial is higher than previously anticipated from historic controls, the follow-up is too short to make a proper judgment, he said.

“PD-L1 positivity as a selective strategy for the TKI-immune combination may not work in this setting,” Dr Grünwald said.

He proceeded to examine the data using the only marker oncologists have in RCC — risk classification (favorable, intermediate, or poor). He noted that clinical practice reflects disease biology. “Patients with favorable risk have an upregulation of the angiogenic profile and are more susceptible to TKI inhibition,” Dr Grünwald said.

However, in JAVELIN Renal 101, similar clinical outcomes are seen across all risk groups. “Therefore, the approach of looking at risk prognosis to identify who may benefit from the combination does not apply to the combination of TKI/immune inhibition,” he suggested.

Avelumab and Axitinib Combination Compared With Other Options

Although JAVELIN Renal 101 delivers on the efficacy, durability, and safety of the avelumab and axitinib combination, the lack of OS and quality of life data from this analysis does not definitely indicate that this combination is better than the sequential approach used in the setting of advanced RCC, Dr Grünwald noted.

In the real-life setting, the immunotherapy combination of nivolumab and ipilimumab is a real contender and is already approved and recommended for patients with intermediate/poor-risk advanced RCC based on CheckMate 214. In that study, median OS had not reached for treatment-naive patients with IMDC intermediate/poor-risk advanced RCC and was 25.9 months with sunitinib alone (P < .0001). ORR was 41.6% for the combination and 26.5% for sunitinib alone (P < .0001).7

 Dr Grünwald highlighted other first-line options that have also been reported. In IMmotion 151, a Phase 3 study, the combination of atezolizumab and bevacizumab (178 individuals) was compared with sunitinib (184 individuals) in treatment-naive patients with PD-L1+, advanced RCC. Median PFS was 11.2 months for the combination of atezolizumab and bevacizumab, and 7.7 months for sunitinib (HR, 0.74; P = .02). Although OS was not mature, HR for OS was 0.68 (95% confidence interval [CI], 0.46–1.00).9

In another study, cabozantinib (79 individuals), a VEGFR, MET, and AXL inhibitor, was compared with sunitinib (78 individuals) as first-line option in patients with poor- or intermediate-risk advanced RCC. With a HR of 0.66, cabozantinib was associated with a 34% reduction in the risk for progression or death (P = .012).9

Dr Grünwald called attention to an alert that Keynote 426 was positive for the combination of pembrolizumab and axitinib. Merck, the makers of the program death 1 (PD 1) inhibitor, pembrolizumab, sent out a press release the day prior to the JAVELIN Renal 101 presentation that suggested the combination of its checkpoint inhibitor, pembrolizumab, with axitinib significantly improved both PFS and overall survival (OS).10 However, no data from this study were released, and data for Keynote 426 will be presented at an upcoming medical meeting. 

Given these emerging data, how can the combination of avelumab and axitinib be integrated in a treatment algorithm for advanced RCC? The combination of nivolumab and ipilimumab delivers clinically relevant OS benefit; therefore, this combination should remain the standard of care for intermediate- or poor-risk advanced RCC, Dr Grünwald concluded. Given that the combination of avelumab and axitinib outperforms sunitinib, there is a niche for this combination in favorable-risk advanced RCC, where single-agent TKIs are currently used, Dr Grünwald concluded.   

Disclosure: The authors listed various pharmaceutical companies as supporters. For a full list of disclosures, please review the presentation materials.

References

  1. Motzer RJ, Penkov K, Haanen J, 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). Presented at: ESMO 2018 Congress; Munich, Germany: October 19-22, 2018. LBA-06.
  2. Roland CL, Lynn KD, Toombs JE, et al. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLoS One. 2009;4(11):e7669.
  3. Yasuda S, Sho M, Yamato I, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. 2013;172(3):500-506.
  4. Choueiri TK, Larkin J, Oya M, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19(4):451-460.
  5. The National Comprehensive Cancer Network. Kidney Cancer. Available at www.nccn.org. Accessed November 11, 2018.
  6. Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow up. Ann Oncol. 2016;27(suppl5):v58-v68.
  7. US Food and Drug Administration. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm604685.htm. Published April 16, 2018. Accessed November 11, 2018.
  8. Robert JM, 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(6):578.
  9. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591-597.
  10. Merck. Merck’s Keytruda® (pembrolizumab) in combination with Pfizer’s Inlyta® (axitinib) significantly improved overall survival (OS) and progression-free survival (PFS) as first-line therapy for advanced or metastatic renal cell carcinoma [press release]. https://www.mrknewsroom.com/news-release/oncology-newsroom/mercks-keytruda-pembrolizumab-combination-pfizers-inlyta-axitinib-sig. Published October 18, 2018. Accessed November 11, 2018.