Immunotherapy and Tyrosine Kinase Inhibitor Combination in Advanced Renal Cell Carcinoma

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In the JAVELIN Renal 101 phase III study, the combination of the immune checkpoint inhibitor avelumab (Bavencio), a programmed death ligand-1 (PD-L1) blocking antibody, plus the tyrosine kinase inhibitor axitinib (Inlyta) significantly improved progression-free survival in previously untreated patients with advanced renal cell carcinoma, according to the results presented at the European Society for Medical Oncology (ESMO) 2018 Congress.1 The benefit of the combination over sunitinib (Sutent), the standard of care since 2005, was observed in patients regardless of programmed cell death ligand 1 (PD-L1) expression.

The median progression-free survival was 13.8 months in the combination therapy arm vs 7.2 months in the sunitinib arm, a significant improvement favoring the combination (P < .0001) in patients with PD-L1–positive tumors. The median progression-free survival was improved by the combination in the entire study population irrespective of PD-L1 expression status: 13.8 vs 8.4 months, respectively (P = .0001). The confirmed objective response rate was 55.2 % and 25.5%, respectively, representing a doubling in response rates with the novel combination.

The findings support the potential of avelumab plus axitinib as a new standard of care for patients with advanced renal cell carcinoma.
— Robert Motzer, MD

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“JAVELIN Renal 101 is the first positive phase III study combining an immune checkpoint blocker with a tyrosine kinase inhibitor compared to a tyrosine kinase inhibitor alone in the first-line treatment of advanced renal cell carcinoma,” commented lead author Robert Motzer, MD, of the Memorial Sloan Kettering Cancer Center, New York.

“This interim analysis showed a profound effect with the combination. The findings support the potential of avelumab plus axitinib as a new standard of care for patients with advanced renal cell carcinoma. The combination benefit was shown in all subgroups of patients by independent review as well as by investigators, including all risk groups and PD-L1 expression status,” he continued.

Dr. Motzer said that PD-L1 testing is not necessary to select candidates for the combination therapy and that all comers should be considered for first-line treatment. He said that although renal cell carcinoma is one of the most immune-sensitive cancers, the search for biomarkers to identify patients who will benefit has been frustrating.

To put these results in context, nivolumab (Opdivo)/ipilimumab (Yervoy) is another immunotherapy combination strategy currently recommended for intermediate/poor-risk metastatic renal cell carcinoma, based on the results of CheckMate-214 reported recently.2

Rationale for Combination Therapy

New therapies are needed for advanced renal cell carcinoma, despite treatment advances over the past decade. Less than 10% of these patients survive 5 years postdiagnosis.

Sunitinib is considered the standard of care for front-line treatment of advanced renal cell carcinoma. Axitinib, a next-generation tyrosine kinase inhibitor approved for second-line treatment of renal cell carcinoma, has been associated with much less toxicity than sunitinib and thus may be considered a better partner for combination therapy, Dr. Motzer said.

“Tyrosine kinase inhibitors, and checkpoint blockers like avelumab, both have potential immune-modulating functions. When combined, they may provide clinical benefit in patients with advanced renal cell carcinoma that exceeds the effects of the respective drugs alone, without compromising toxicity,” Dr. Motzer explained. Preclinical evidence suggested synergy for these drugs, with complementary activity in renal cell carcinoma cell lines.

Study Description

The global, randomized, phase III JAVELIN Renal 101 trial included 886 patients with advanced renal cell carcinoma with a clear cell component not amenable to surgical care. All prognostic risk groups—good, intermediate, and favorable according to Memorial Sloan Kettering Cancer Center (MSK) criteria—were enrolled. Patients were randomly assigned to treatment with avelumab at 10 mg/kg intravenously every 2 weeks in combination with axitinib at 5 mg orally twice weekly (6-week cycle, n = 442). The comparator group of 444 patients received sunitinib at 50 mg orally once daily for 4 weeks on and 2 weeks off (1 cycle).

PD-L1 status was defined as at least 1% staining of immune cells. Sixty-three percent of participants (n = 560) had PD-L1–positive disease.


  • Superior progression-free survival and response rates were achieved with the combination of the PD-L1 inhibitor avelumab and the next-generation tyrosine kinase inhibitor axitinib vs sunitinib, a current standard of care for the first-line treatment of advanced renal cell carcinoma.
  • Outcomes were improved in all comers, regardless of PD-L1 expression status and risk group.
  • Avelumab/axitinib is a potential new first-line treatment of advanced renal cell carcinoma and may find a niche in the treatment of favorable-risk patients.
  • Other immunotherapy combinations also have shown favorable outcomes in this setting.

Primary outcomes were progression-free survival and overall survival in PD-L1–positive patients. The median progression-free survival in PD-L1–positive patients (n = 560) by independent review was 13.8 months with avelumab plus axitinib vs 7.2 months with sunitinib, representing a 39% improvement favoring the combination (P < .0001).

In the overall study population (n = 886), the intent-to-treat analysis also showed a significant benefit in progression-free survival with the combination therapy: median of 13.8 months vs 8.4 months, respectively (P = .0001). Confirmed objective response rates were almost double with the combination therapy: 55% vs 26% for sunitinib in PD-L1–positive patients, and 51% vs 26%, respectively, in the overall study population.

Safety Profile

Treatment-emergent adverse events of grade 3 and higher were experienced by 50% of patients in both arms. Adverse events leading to discontinuation of therapy were reported in 4% of the combination arm and 8% of the sunitinib arm.

“About 50% of patients on each arm over the course of the treatment had moderately severe or severe toxicity. Side effects were similar, but sunitinib had more high-grade toxicities,” Dr. Motzer said. “There were no new safety signals.”

“We expect the progression-free survival and complete response rates will increase [on the combination arm] with longer follow-up. Seventy-three percent of patients in response are still on study,” he noted. Survival data are immature and will be presented in the future.

Additional Commentary

ESMO expert John Haanen, MD, of the Netherlands Cancer Institute, Amsterdam, The Netherlands, commented on this study. “Renal cell carcinoma is highly vascularized. Patients benefit enormously from tyrosine kinase inhibitors, but these drugs are not curative. This cancer is sensitive to immunotherapy with checkpoint inhibition, as has been shown in several trials. Based on preclinical data, it makes sense to combine an angiogenesis inhibitor and checkpoint inhibitor,” Dr. Haanen said.

We think this combination represents a real paradigm shift. Using the best treatment option in the beginning hopefully will translate to improved survival.
— John Haanen, MD

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“We think this combination represents a real paradigm shift. We don’t yet know how to treat patients who fail [to respond to] these treatments. But for our patients, this is a real step forward. Using the best treatment option in the beginning hopefully will translate to improved survival. We need to get the survival data from this and other trials,” Dr. Haanen stated.

KEYNOTE-426 Trial

In addition to the JAVELIN Renal 101 results released at the European Society for Medical Oncology (ESMO) 2018 Congress, the first interim analysis of the phase III KEYNOTE-426 trial (announced 2 days earlier) showed improved overall and progression-free survival using the anti–programmed cell death protein 1 (PD-1) antibody pembrolizumab (Keytruda)/-axitinib vs sunitinib as first-line therapy for advanced renal cell carcinoma.


For more on the use of immunotherapy for renal and bladder cancers from the ESMO 2018 Congress, see an interview with Cora N. Sternberg, MD, on The ASCO Post Newsreels at

Commenting on the KEYNOTE-426 trial, Dr. Motzer said, “This confirms the value of the same approach using this combination in renal cell carcinoma and emphasizes the progress we have made in the past 20 years.” 

DISCLOSURE: JAVELIN Renal 101 was sponsored by Pfizer and is part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany. Dr. Motzer is a consultant/advisor with Pfizer, Novartis, Eisai, Exelixis, Merck, and Genentech/Roche; has received institutional research funding from Novartis, Genentech/Roche, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, and Merck; and has received travel expenses from Bristol-Myers Squibb. Dr. Haanen is a consultant/advisor with MSD Oncology, Pfizer, Bristol-Myers Squibb, Novartis, Neon Therapeutics, Roche/Genentech, Gadeta BV, Immunocore, and Seattle Genetics and has received institutional research funding from GlaxoSmithKline, MSD, Neon Therapeutics, and Bristol-Myers Squibb.


1. 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. ESMO 2018 Congress. Abstract LBA6_PR. Presented October 21, 2018.

2. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277-1290, 2018.

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