Immunotherapy/TKI Combo Induces Favorable Findings in First-Line RCC

A combination of an immune checkpoint inhibitor and a VEGF inhibitor, avelumab and axitinib, induced 2-fold higher objective response rates compared with sunitinib in patients with treatment-naïve advanced renal cell carcinoma, regardless of their PD-L1 expression. Progression-free survival was also significantly improved over sunitinib, according to findings from the phase III JAVELIN Renal 101 trial presented at the 2018 ESMO Congress.

Robert J. Motzer, MD

A combination of an immune checkpoint inhibitor and a VEGF inhibitor, avelumab (Bavencio) and axitinib (Inlyta), induced 2-fold higher objective response rates (ORR) compared with sunitinib (Sutent) in patients with treatment-naïve advanced renal cell carcinoma (RCC), regardless of their PD-L1 expression. Progression-free survival (PFS) was also significantly improved over sunitinib, according to findings from the phase III JAVELIN Renal 101 trial presented at the 2018 ESMO Congress.

“This trial demonstrated longer progression-free survival and higher objective response rates for avelumab plus axitinib, a checkpoint inhibitor plus a VEGF inhibitor regimen, compared with sunitinib as first-line treatment for advanced RCC,” said lead study author Robert J. Motzer, a medical oncologist at Memorial Sloan Kettering Cancer Center. “The results support this being a new standard of care for first-line treatment of [patients with] advanced RCC.”

In this trial, 886 patients were enrolled with advanced or metastatic RCC and randomized 1:1 to receive 10 mg/kg of avelumab intravenously every 2 weeks plus 5 mg of oral axitinib twice daily in 6-week cycles or 50 mg of oral sunitinib once daily for a 4-weeks-on/2-weeks-off schedule. Patients with all MSKCC/Motzer Criteria with good- (21%), intermediate- (62%), and poor-risk disease (16%) were included.

The total population included 560 (63.2%) PD-L1—positive patients. In the PD-L1–positive group, 270 patients received the combination and 290 patients were treated with sunitinib. In the overall group, 442 patients were treated with the combination while 444 received sunitinib. PFS by blinded independent central review and overall survival (OS) in the PD-L1–positive group were the primary endpoints; secondary endpoints were PFS and OS in the overall population irrespective of PD-L1 status, ORR, and safety.

In the PD-L1—positive population, the median PFS was 13.8 months (95% CI, 11.1-NE) with avelumab/axitinib compared with 7.2 months (95% CI, 5.7-9.7) with sunitinib, leading to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95%, 0.475-0.790;P<.0001). The ORR with the combination was 55.2% (95% CI, 49.0-61.2), which included 4 complete responses (CRs) and 51 partial responses (PRs); the ORR with sunitinib was 25.5% (95% CI, 20.6- 30.9). Twenty-seven patients in the combination arm had stable disease (SD) and 11 had progressive disease (PD).

In the overall population, the median PFS with the combination of avelumab and axitinib versus sunitinib was 13.8 months (95% CI, 11.1-NE) and 8.4 months (95% CI, 6.9-11.1), respectively (HR, 0.69; 95% CI, 0.563-0.840;P= .0001). Moreover, the ORR with avelumab/axitinib was 51.4% (95% CI, 46.6-56.1) and 25.7% (95% CI, 21.7-30.0) with sunitinib. In the combination arm, the ORR included 3 CRs and 48 PRs; 30 patients had SD and 12 patients had PD.

In the PD-L1—positive and overall population arms, 73% and 70% of patients remained on avelumab/axitinib treatment, respectively, versus 65% and 71% of those on sunitinib. Median duration of response was not yet reached in either treatment arm in either population. OS data are not yet mature, said Motzer.

“The benefit was [observed] regardless of risk group and regardless of PD-L1 status,” Motzer explained. “I don’t believe you need to test [for PD-L1] to choose patients for this therapy. It may be that it helps you get a sense for the hazard ratio a little bit better in the PD-L1—positive group. But, I don’t think it’s required to use this medicine.”

The immunotherapy/tyrosine kinase inhibitor (TKI) regimen also elicited a favorable safety profile. Fifty-one (4%) patients on the combination arm and 48 (7%) patients on the sunitinib arm experienced grade 3/4 treatment-related adverse events (TRAEs), the most common being diarrhea (5% vs 3%). All-grade TRAEs were similar between arms. Four percent of TRAEs led to avelumab/axitinib discontinuation versus 8% with sunitinib; 1 patient on avelumab/axitinib died due to TRAEs.

Grade ≥3 TRAEs were reported in 71.2% of patients in the combination arm versus 71.5% of patients in the sunitinib arm, and led to treatment discontinuation in 22.8% versus 13.4%, respectively.

The rationale in combining these agents is that avelumab stimulates the immune system while axitinib inhibits tumor neoangiogenesis by preventing VEGF activity. Preclinical data have shown that combining this class of agents is effective, as their mechanisms of action complement each other, Motzer explained. Axitinib is currently FDA approved as a second-line therapy for patients with advanced RCC.

“We’re now, almost every year, receiving data from different combinations or single agents [in advanced kidney cancer], and it is very interesting that these data presented may increase the number of options for patients,” said Ignacio Durán, MD, PhD, of the Department of Medical Oncology at the Hospital University Virgen del Rocío and Instituto de Biomedicina de Sevilla, during a press briefing.

J.B.A.G. Haanen, MD, professor by special appointment, Department of Clinical Oncology of Leiden University Medical Center, also commented on the findings during the briefing.

“Kidney cancer was a very complicated disease to treat. The development of checkpoint molecules really let the idea in that perhaps kidney cancer could be sensitive to checkpoint inhibition,” said Haanen. “This is the first study of a TKI plus an anti—PD-L1 drug showing an improved PFS in this patient population. What we do not know is patients who fail this treatment—how do we treat them next? Those are the questions we need to answer. But for patients with this disease, this in itself is the real step forward.”

The release of these phase III data follows the release of topline findings from the phase III KEYNOTE-426 trial, highlighting that the combination of pembrolizumab (Keytruda) with axitinib significantly improved survival versus sunitinib as a first-line treatment for patients with advanced or metastatic RCC.

“From the information in the press release, it confirms the same approach—of a VEGF TKI plus an immunotherapy—showing benefit in kidney cancer patients,” said Motzer on the KEYNOTE-426 trial. “It also emphasizes the progress we’ve made in this disease in the last 20 years with these positive phase III trials showing benefit for our patients.”


Motzer RJ, Penkov K, Hannen 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). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA6_PR.