Prospective Cardiovascular Surveillance With ICI-Based Combination Treatment in Patients With Advanced RCC
TAKE-HOME MESSAGE
- This analysis of the JAVELIN Renal 101 trial compared the frequency of major adverse cardiovascular events (MACE) in patients with renal cell carcinoma (RCC) treated with an immune checkpoint inhibitor (avelumab) plus VEGFR inhibitor (axitinib) versus those treated with sunitinib. Of all patients receiving combination therapy, 7.1% had MACE. Patients in the combination arm with high baseline troponin T values were at higher risk of MACE than those with low values. Most patients with a decrease in left ventricular ejection fraction improved back to baseline.
- These findings suggest that, in patients with RCC, combination therapy with axitinib and avelumab increased rates of MACE compared with sunitinib and that patients with elevated troponin T level at baseline may benefit from careful monitoring of cardiac function.
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
Both immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for advanced renal cell carcinoma treatment and can cause cardiovascular events (CVs); thus, combination therapy could lead to major adverse CV events (MACE). Cardiac serum biomarker assessment and imaging, including left ventricular ejection fraction (LVEF) monitoring, can be used to evaluate MACE.
METHODS
To our knowledge, the JAVELIN Renal 101 trial, assessing avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma, is the first randomized study of ICI plus VEGFR inhibitor treatment to include prospective serial cardiac monitoring of LVEF and serum cardiac biomarkers.
RESULTS
MACE (defined as grade ≥ 3 CV AEs) occurred in 31 patients (7.1%) in the combination arm and 17 patients (3.9%) in the sunitinib arm. Patients in the combination arm who had high baseline troponin T values were at higher risk of MACE versus patients with low values (MACE in 6/35 v 7/135, respectively; relative risk, 3.31; 95% CI, 1.19 to 9.22). This association was not observed in patients treated with sunitinib. Other CV baseline risk factors and serum cardiac biomarkers were not significantly predictive for MACE, although a trend toward an association with dyslipidemia was seen in the combination arm. No clinical value of on-treatment routine monitoring of LVEF in relation to MACE was observed. Although LVEF decline was significantly more frequent in the combination arm, most patients recovered, and decline was not associated with other significant cardiac events or symptoms.
CONCLUSION
Patients with high baseline troponin T levels receiving ICI and VEGFR combinations may need to be monitored more closely for MACE. Routine monitoring of LVEF in asymptomatic patients is not recommended.
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Additional Info
Disclosure statements are available on the authors' profiles:
Prospective Cardiovascular Surveillance of Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Cancer: Data From the Phase III JAVELIN Renal 101 Trial
J. Clin. Oncol 2022 Mar 03;[EPub Ahead of Print], BI Rini, JJ Moslehi, M Bonaca, M Schmidinger, L Albiges, TK Choueiri, RJ Motzer, MB Atkins, J Haanen, M Mariani, J Wang, S Hariharan, J LarkinFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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In the JAVELIN Renal 101 phase III trial, avelumab plus axitinib significantly improved progression-free survival and the objective response rate versus sunitinib in previously untreated patients with advanced RCC (aRCC). In this post hoc analysis, the investigators analyzed the incidence of major adverse cardiovascular (CV) events (MACE) in patients with aRCC receiving avelumab plus axitinib versus sunitinib in this trial, including the association between MACE and changes in LVEF or baseline levels of serum cardiac biomarkers. From March 29, 2016, to December 19, 2017, 886 patients were assigned to the avelumab plus axitinib (n = 442) or sunitinib (n = 444) arms; 873 patients received study treatment (434 and 439, respectively) and were evaluated for safety outcomes. The median exposures to avelumab, axitinib, and sunitinib were 37.2 weeks (range, 2.0–110.0 weeks), 39.2 weeks (range, 0.1–108.3 weeks), and 31.7 weeks (range, 0.9–99.9 weeks), respectively. Approximately 60% of patients in each arm had a history of hypertension; however, other cardiac risk factors were not prevalent. MACE were reported in 31 patients (7.1%) in the avelumab plus axitinib arm and 17 patients (3.9%) in the sunitinib arm, while, after adjusting for exposure to study treatment, the difference between arms was smaller than in the comparison of non-adjusted data. The median time to first onset of MACE was 7.7 weeks (range, 0.1–73.3 weeks) in the combination arm and 17.6 weeks (range, 2.0–44.0 weeks) in the sunitinib arm. There were 6patients in the avelumab plus axitinib arm and 1 patient in the sunitinib arm who suffered cardiac death. Relatively more cardiac adverse events occurred with avelumab plus axitinib and more nonfatal CNS vascular events occurred with sunitinib.
The difference in MACE rates between the study arms could not be attributed to higher hypertension rates in the avelumab plus axitinib group (52.1%) compared with that in the sunitinib group (39.0%) because MACE rates were similar in patients with and without hypertension (7.5% vs. 6.8%, respectively). No significant correlation was observed between MACE and the baseline risk factors that were evaluated, except for a trend toward an association with dyslipidemia in the avelumab plus axitinib arm. In the avelumab plus axitinib and sunitinib arms, 37 patients (8.5%) and 7 patients (1.6%), respectively (P = .0001), experienced an LVEF decline. In the avelumab plus axitinib arm, a higher proportion of patients with high baseline troponin T level developed MACE versus patients without high baseline troponin T (6/35 [17.1%] vs. 7/135 [5.2%]; RR, 3.31; 95% CI, 1.19–9.22; P = .022). The occurrence of MACE did not correlate with baseline levels of other cardiac biomarkers in either arm.
The authors should be applauded for conducting the first randomized study of ICI plus VEGFR inhibitor treatment in JAVELIN Renal 101 to include prospective serial cardiac monitoring of LVEF and serum cardiac biomarkers. The take-away points are that combination therapy may increase the risk of MACE, but this is not dependent on baseline CV risk factors, and the overall risk of MACE remains low for both the combination therapy and sunitinib arms. Therefore, cardiac history should not exclude patients from receiving ICI plus VEGFR combination therapy. Notably, routine monitoring of baseline serum cardiac biomarkers in asymptomatic patients was not found to be useful for early identification of myocarditis in this study. This study shows a novel finding that high baseline troponin T levels were predictive of MACE with avelumab plus axitinib, suggesting that patients with high troponin T levels may require additional cardiac monitoring. These findings add important details to the literature as we understand more of the cardiotoxicities associated with VEGF-TKIs and ICIs.