JAVELIN Renal 101 clinical trial

Check Troponin in RCC Patients Before Checkpoint-VEGFR Inhibitor Combo

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In JAVELIN Renal 101, those with high levels had more heart events with avelumab-axitinib

A photo of a blue rubber gloved hand holding a test tube of blood labeled: Troponin T - Test

Advanced renal cell carcinoma (RCC) patients with high serum levels of troponin T had a greater risk of serious cardiac events when treated with an immune checkpoint inhibitor and VEGFR inhibitor combination, data from the phase III JAVELIN Renal 101 trial indicated.

For patients assigned to the avelumab (Bavencio) plus axitinib (Inlyta) arm, 17.1% of those with high troponin T values had a major cardiovascular adverse event (MACE) versus 5.2% of those with lower values (relative risk 3.31, 95% CI 1.19-9.22), reported Brian I. Rini, MD, of Vanderbilt University Medical Center in Nashville, and colleagues.

But this difference was not seen in the sunitinib (Sutent) arm, at 5.1% versus 5.7% for those with high and low troponin T levels, respectively (RR 0.89, 95% CI 0.20-3.98), according to findings appearing in the Journal of Clinical Oncology.

“We suggest that baseline assessment of troponin T levels may be considered when starting treatment with an ICI [immune checkpoint inhibitor] plus a VEGFR inhibitor, particularly in patients with cardiovascular risk factors,” Rini and his colleagues wrote. “Patients with high troponin T levels should be monitored closely for cardiac symptoms during treatment, potentially including ECG monitoring, and a cardiologist should be involved in patient management from the outset of treatment.”

However, the authors added, cardiac history “should not exclude patients from receiving ICI plus VEGFR combination therapy.”

Left ventricular ejection fraction (LVEF) decline in the trial was significantly more frequent in the combination arm (8.5% vs 1.6%), but most patients recovered and the decline was not associated with other significant cardiac events or symptoms, Rini’s group reported. Thus, “routine monitoring of LVEF in asymptomatic patients is not recommended.”

JAVELIN Renal 101 randomized 866 RCC patients with previously untreated advanced disease 1:1 to either the PD-L1 checkpoint inhibitor avelumab plus VEGFR inhibitor axitinib or to sunitinib, a multi-targeted receptor tyrosine kinase inhibitor. Results of the phase III study led to the FDA approval of avelumab-axitinib in this setting.

The rationale for the current study, the authors noted, is that checkpoint inhibitors and VEGFR inhibitors have been associated with cardiovascular adverse events, “creating a theoretical potential for an increased incidence of MACE with combination treatment.” This study, they said, is the first to prospectively assess LVEF decline and serum cardiac biomarkers in patients treated with a checkpoint inhibitor plus VEGFR inhibitor.

Approximately 60% of patients in each arm of the study had a history of hypertension. At data cutoff, median exposure to avelumab, axitinib, and sunitinib was 37.2, 39.2, and 31.7 weeks, respectively.

Overall, MACE (defined as grade ≥3 cardiovascular adverse events) occurred in 31 patients (7.1%) in the combination arm, and 17 patients (3.9%) in the sunitinib arm, a non-significant difference that was reduced in exposure-adjusted analyses, Rini and his colleagues observed.

Other cardiovascular baseline risk factors and serum cardiac biomarkers were not significantly predictive for MACE, the authors noted, although there was trend toward an association with dyslipidemia in the combination arm.

“Because of the small number of patients with MACE in our study, the predictive value of serum biomarkers other than troponin T cannot be ruled out,” wrote Rini and his colleagues. “Larger studies are needed to confirm the findings in this study.”

JAVELIN Renal 101 clinical trial

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There are truthfully many stories in renal cell carcinoma (RCC) that can be considered the story of the year. However, as a point of discussion, I have selected the JAVELIN Renal 101 clinical trial, which compares axitinib and avelumab versus sunitinib as first-line treatment in advanced RCC.1 The premise of combining VEGF inhibitors with immunotherapy stems from the possibility of having not just additive, but synergistic, effects with the combination. In particular, VEGF-directed agents are thought to have some immune-related properties: increasing immune cell tumor infiltration and decreasing immune suppressor cells. These effects have been observed in a varying fashion for each of the VEGF inhibitors but have been observed in the context of agents such as sunitinib and pazopanib, including in studies that we ourselves have done.

In the JAVELIN 101 clinical trial, patients with treatment-naïve advanced RCC with tumor tissue available for PD-L1 assessment were randomized to the combination of axitinib and avelumab or sunitinib at a dose of 50 mg, 4 weeks on, 2 weeks off. This study had two primary endpoints, including progression-free survival (PFS) by independent review committee in patients with PD-L1–positive disease and overall survival (OS) in the PD-L1–positive group. Key secondary endpoints included PFS in the overall population by independent review as well as OS. The study ultimately enrolled and randomized 886 patients. About 63% of patients were characterized as being PD-L1–positive, but it is important to bear in mind that this study used a threshold for PD-L1 positivity that differed, for instance, from that used in the trial of bevacizumab and pembrolizumab in combination. With this in mind, the PD-L1–positive group ultimately encompassed 560 patients. The median age and other characteristics were representative of a renal cell carcinoma population, with about 20% of patients considered favorable risk and the remainder considered to be intermediate or poor risk. This was similar in both the PD-L1–positive and overall patient populations. Roughly 80% to 90% of patients had undergone prior nephrectomy.

With respect to the primary endpoint of this study, PFS improvement with axitinib and avelumab was achieved, with a PFS of 13.8 months in the PD-L1–positive group versus just 7.2 months with sunitinib therapy. This reflects a hazard ratio of 0.61. In the overall population, a slightly smaller benefit was observed in PFS, with axitinib and avelumab achieving 13.8 months versus 8.4 months with sunitinib, reflecting a hazard ratio of 0.69. There was little discrepancy between this and investigator assessment of PFS. Response rates were higher with the combination of axitinib with avelumab, ranging between 50% and 55% depending PD-L1 status. This nearly doubled the PFS observed from sunitinib therapy.

One of the biggest questions that emerges is related to OS. At the time of this interim analysis, without sufficient events for final assessment, it did not appear that there was a significant difference in OS. The hazard ratio was 0.78 with a P-value of 0.0679. Toxicities were also a concern, with 51% of patients having grade 3/4 toxicities with the combination, although truthfully this was relatively similar to the rate of toxicities incurred with sunitinib therapy. Immune-related adverse effects were observed in a total of 38% of patients, with 9% of patients having grade 3/4 events. The most common events were hypothyroidism, liver function test abnormalities, and adrenal dysfunction. Also, 12% of patients developed infusion reactions.

In my clinical experience having participated in this study, the two major challenges are going to be the lack of OS gain observed thus far in this study as well as the challenges in administration. The available options for advanced RCC are multifold. Without an observation of improved OS, there may be some challenges in terms of implementation, particularly because this study now lives in the shadow of a phase III experience looking at axitinib with pembrolizumab versus sunitinib. Although we do not have those data in our hands yet, it appears that, based on the press release, there is improvement in PFS and OS. Furthermore, in terms of administration, the agent avelumab is given intravenously every 2 weeks and is associated with infusion reactions. This differs from other agents in the category, and, with few other things differentiating various PD-1 and PD-L1 inhibitors, the presence of something minor such as this may actually tilt the balance away from this agent and towards others that are easier to administer.

Nonetheless, the data are encouraging for emerging trials looking at combinations of VEGF-TKIs with immunotherapy. I am particularly excited about trials evaluating cabozantinib as the base of the combination. We recently reported at ESMO the combination of cabozantinib with atezolizumab achieving a 100% clinical benefit rate in a population of patients with treatment-naïve RCC. We observed one complete response as well as four partial responses in this limited cohort, reflecting an overall response rate of 50%.

Further data from this study and many others will be emerging, including data from a randomized phase III study comparing cabozantinib and nivolumab with sunitinib therapy. There are also combinations of lenvatinib with pembrolizumab being evaluated in a phase III context. As these studies emerge, we will look toward the subtle differences among these trials in picking the optimal agent for patients with metastatic RCC. At the end of the day, there should be a call for new agents. Many of the trials that are ongoing have been designed to evaluate agents with mechanistic similarities, but there is a great need to again revolutionize RCC therapy as we have done in years past.