Laurence Albigès, MD, PhD, is a medical oncologist and head of the Department of Oncology at Institut Gustave Roussy in Paris, France.

Dr Albiges on Survival Outcomes With Cabozantinib Plus Nivolumab and Ipilimumab in RCC

“With more follow-up, we see a sustained benefit in PFS favoring the triplet. …Unfortunately, there was no differences in terms of OS between the two treatment arms.”

Laurence Albigès, MD, PhD, medical oncologist, head, Department of Oncology, Institut Gustave Roussy, Paris, discusses final overall survival (OS) data and exploratory analyses from the phase 3 COSMIC-313 trial (NCT03937219) evaluating the triplet combination of cabozantinib (Cabomety) plus nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC).

At 45 months of follow-up, the final analysis of COSMIC-313 was presented during the 

, and demonstrated a sustained progression-free survival (PFS) benefit with cabozantinib plus nivolumab and ipilimumab vs nivolumab and ipilimumab alone, Albiges reports. PFS increased from 11.2 months (95% CI, 9.3-14.0) with nivolumab plus ipilimumab plus placebo to 16.6 months (95% CI, 14.0-22.6) with the triplet, with the benefit primarily observed in patients with International Metastatic RCC Database Consortium intermediate-risk disease (n = 75), she states.

Despite the improvement in PFS, overall survival (OS) outcomes did not differ significantly between the triplet and doublet arms in this final analysis, Albiges notes. The safety profile remained consistent with prior reports, reinforcing the challenges of administering a triplet regimen in a blinded trial setting, Albiges adds.

This final analysis also included the first biomarker analysis from the trial, which utilized RNA sequencing (RNA-seq) data to explore molecular correlates of response, Albiges continues. Two approaches were used: molecular clustering and a deconvolution model to assess immune cell populations. The molecular clustering analysis, based on the framework established in the IMmotion program, identified seven molecular clusters; however, these were not specifically associated with the benefit of the triplet regimen, she notes.

In the deconvolution model, the relative abundance of immune cell populations was estimated. Notably, a population of M2-like macrophages was identified as a biomarker associated with worse prognosis in patients receiving the doublet, Albiges details. The addition of cabozantinib in the triplet regimen appeared to mitigate this poor prognosis, suggesting that patients with high M2-like macrophage expression may derive greater benefit from the inclusion of a TKI into treatment, she says. This finding is hypothesis-generating and requires further prospective validation, Albiges concludes.

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Laurence Albigès, MD, PhD discusses final OS data and biomarker analyses with cabozantinib plus nivolumab and ipilimumab in intermediate- or poor-risk RCC.

Dr Albigès on Survival Outcomes With Cabozantinib Plus Nivolumab and Ipilimumab in RCC

Laurence Albigès, MD, PhD, discusses the potential predictive and prognostic value of circulating KIM-1 in patients with renal cell carcinoma.  

Laurence Albigès, MD, PhD, medical oncologist, head, Department of Oncology, Institut Gustave Roussy, Paris, discusses the potential predictive and prognostic value of circulating kidney injury molecule-1 (KIM-1) in patients with renal cell carcinoma (RCC), as well as ongoing efforts to validate this biomarker.

In the phase 3 IMmotion010 trial (NCT03024996), patients with RCC at a high risk of disease recurrence following resection were treated with adjuvant atezolizumab (Tecentriq). Following the readout of topline findings from the trial, which demonstrated that atezolizumab did not extend disease-free survival (DFS) vs placebo, 

a biomarker analysis of circulating KIM-1

 levels in this clinical trial population was conducted.

Results from the analysis were presented at the 

, and confirmed that KIM-1 has prognostic value, as patients with high baseline KIM-1 levels in IMmotion010 had a significantly higher risk of recurrence and a poorer prognosis, Albigès explains. Secondly, patients with high KIM-1 levels receiving atezolizumab experienced prolonged DFS compared with those given placebo, indicating that KIM-1 has predictive value for treatment outcomes with immune checkpoint inhibitors, she states. Thirdly, an increase in KIM-1 levels during treatment was associated with worse DFS, indicating its use as a monitoring tool in this setting, Albigès adds.

The analysis shows that circulating KIM-1 may be a noninvasive marker of MRD and disease recurrence and could be used as a monitoring tool in the adjuvant setting, Albigès outlines. KIM-1 has previously been explored as a diagnostic tool, but it is now being evaluated as a prognostic or predictive tool in the adjuvant setting, Albigès says. Recent analyses of KIM-1 levels from the phase 3 CheckMate 914 trial (NCT03138512) similarly highlighted the predictive utility and validity of this circulating biomarker, she states. This study evaluated adjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) vs placebo, or adjuvant nivolumab monotherapy vs placebo in patients with localized RCC at a high risk of disease recurrence post-nephrectomy, Albigès details.

Prospective validation of this biomarker is needed, and further datasets will be required to confirm these findings, Albigès concludes.

Laurence Albigès, MD, PhD, discusses the potential predictive and prognostic value of circulating KIM-1 in patients with renal cell carcinoma.

Dr Albigès on the Predictive and Prognostic Utility of KIM-1 in High-Risk RCC

Laurence Albigès, MD, PhD discusses a biomarker analysis which evaluated the presence of circulating KIM-1 in patients with renal cell carcinoma.

Laurence Albigès, MD, PhD, medical oncologist, head, the Department of Oncology, Institut Gustave Roussy, Paris, discusses a biomarker analysis which evaluated the presence of circulating kidney injury molecule-1 (KIM-1) in patients with renal cell carcinoma (RCC) who were enrolled on the phase 3 IMmotion010 trial (NCT03024996).

IMmotion010 is a multicenter, randomized, placebo-controlled, double-blind study which enrolled patients with RCC at a high risk of developing metastasis following nephrectomy; these patients were treated with adjuvant atezolizumab (Tecentriq). 

Investigators launched this biomarker analysis

 of the clinical trial to evaluate circulating KIM-1 in this patient population and findings were shared at the 

The biomarker analysis revealed that high baseline levels of KIM-1 correlated with worse disease-free survival (DFS). Moreover, atezolizumab improved DFS in patients with high baseline KIM-1.

This potential biomarker is of interest because it is stable and can be measured in both serum and plasma, making it a strong candidate for a blood biomarker, Albigès begins. This led investigators to an analysis, which involved using high-sensitivity assays on sequential blood samples collected in IMmotion010, she explains. These samples were taken at baseline, cycle 4 day 1, and either at the time of disease recurrence or at treatment discontinuation if there was no recurrence, Albigès reports.

She goes on to stay that several key points were established at study lauch. Firstly, investigators confirmed the prognostic value of KIM-1, as patients with high KIM-1 levels in IMmotion010 had a significantly higher risk of recurrence, marking it as a circulating biomarker, she elucidates. Secondly, KIM-1 also appears to have predictive value; patients receiving atezolizumab had better disease-free survival (DFS) compared with those on placebo, indicating its potential predictive utility, Albigès states. Thirdly, an increase in KIM-1 levels during treatment was associated with worse DFS, suggesting it could be used as a monitoring tool in this setting, Albigès emphasizes.

Lastly, at the time of recurrence, more sensitive assays confirmed that patients who experienced disease recurrence had a two-fold increase in KIM-1 levels, while those who did not relapse did not show high levels of KIM-1, Albigès concludes.

Dr Albigès on a Biomarker Analysis of KIM-1 in RCC

Laurence Albigès, MD, PhD, medical oncologist, head, Genitourinary Unit, Department of MedicalOncology, Gustave Roussy Institute, France, discusses on the safety and efficacy of cabozantinib (Cabometyx) in patients with unresectable, locally advanced or metastatic renal cell carcinoma (RCC) with a clear cell component.

The phase 2 multicenter, open-label CaboPoint trial (NCT03945773) evaluated the activity and safety of cabozantinib in patients with unresectable, locally advanced or metastatic clear cell RCC whose disease progressed following treatment with first-line immune checkpoint inhibitor–based therapies. Cohort A consisted of patients who experienced failure on an immune checkpoint inhibitor doublet of nivolumab (Opdivo) plus ipilimumab (Yervoy), and cohort B included patients who had progressed on a VEGF TKI plus immune checkpoint inhibitor combination.

Cabozantinib elicited an overall response rate (ORR) of 29.5% (95% CI, 20.3%-40.2%) across both cohorts, including an ORR of 31.7% (20.3%-45.0%) in cohort A (n = 60) and an ORR of 25.0% (95% CI, 10.7%-44.9%) in cohort B (n = 28). In cohort A, among patients evaluable for best overall response (n = 57), the partial response (PR) rate was 33.3% in cohort A. In cohort B (n = 25), the PR rate was 24.0%, and 1 patient (4.0%) had a complete response. The vast majority of those patients had intermediate-risk disease per International mRCC Database Consortium (IMDC), Albigès says. Notably, among 10 patients who were IMDC intermediate risk at the start of second-line therapy with cabozantinib following nivolumab plus ipilimumab, the ORR was 40%, Albigès notes.

The safety profile within the study was consistent with previous reports, Albigès continues. Based on previous safety data observed in CaboPoint, no new safety signals were reported, and cabozantinib is a potent VGF-TKI that investigators have learned to manage, Albigès notes. In this study, patients were treated at the full dose of 60 mg per day, but in case of toxicity, investigators could reduce the dosing, Albigès concludes.

Laurence Albigès, MD, PhD, discusses on the safety and efficacy of cabozantinib in patients with unresectable, locally advanced or metastatic renal cell carcinoma with a clear cell component.

Laurence Albigès, MD, PhD

Articles

Dr Albigès on Survival Outcomes With Cabozantinib Plus Nivolumab and Ipilimumab in RCC

Dr Albigès on the Predictive and Prognostic Utility of KIM-1 in High-Risk RCC

Dr Albigès on a Biomarker Analysis of KIM-1 in RCC

Dr Albigès on the Efficacy of Cabozantinib in Pretreated RCC