Cabozantinib improves mRCC outcomes regardless of PD-L1 status

Cabozantinib (Cabometyx) demonstrated consistent improvement in progression-free survival (PFS) and overall survival (OS) over everolimus (Afinitor) and sunitinib (Sutent), irrespective of PD-L1 status, across two randomized controlled clinical trials in patients with metastatic clear cell renal cell carcinoma (mRCC).

In addition, using the patient populations from the METEOR and CABOSUN clinical trials, PD-L1 expression in tumor cells was found to be associated with shorter PFS and OS in both trials, reported Toni K. Choueiri, MD, at the 2018 European Society of Medical Oncology annual congress in Munich.

“These data support use of cabozantinib in a PD-L1 unselected population and, possibly, in combination with checkpoint blockers irrespective of PD-L1 status,” concluded Dr. Choueiri, director of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, in his poster presentation.

The CheckMate 214 study had previously demonstrated that PD-L1 expression in tumor cells correlated with improved outcomes with assignment to nivolumab (Opdivo) and ipilimumab (Yervoy) compared with sunitinib in patients with previously untreated advanced renal cell carcinoma.

In a trial of patients with metastatic renal cell carcinoma who were treated with sunitinib or pazopanib (Votrient), however, high expression of PD-L1 in tumor cells correlated with shorter survival.

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Dr. Choueiri and colleagues explored whether PD-L1 expression could serve as a prognostic and/or predictive biomarker for cabozantinib efficacy, using formalin-fixed paraffin-embedded baseline tumor tissue obtained from 110 patients from CABOSUN and 306 patients from METEOR. They assessed PD-L1 expression in both tumor cells and immune cells by performing immunohistochemical (IHC) double-staining for PD-L1 and CD45/CD163, two immune cell markers. Novel digital image analysis algorithms were used to allow scoring of PD-L1.

Twenty-nine percent of METEOR and 23% of CABOSUN tissue samples contained PD-L1-positive tumor cells.

In the comparison between cabozantinib and everolimus (Afinitor) in METEOR, the median PFS per Independent Review Committee (IRC) was 8.5 versus 5.6 months (p=.027) in favor of cabozantinib, and the median OS was 21.3 versus 15.1 months (p=.003). In patients with tumor cell PD-L1 expression <1%, median PFS was 8.5 months with cabozantinib versus 4.1 months with everolimus (HR: 0.46; 95% CI: 0.32-0.66). In patients with PD-L1 expression ≥1%, median PFS was 5.6 versus 3.7 months in the cabozantinib and everolimus arms, respectively (HR: 0.66; 95% CI: 0.40-1.11).

In CABOSUN, the median PFS per IRC was 8.3 months in the cabozantinib arm versus 5.5 months in the sunitinib arm (p=.059); and median OS was 28.1 versus 20.8 months, respectively (p=.05). Median PFS with cabozantinib versus sunitinib in patients with PD-L1 expression <1% was 11.0 versus 5.0 months (HR: 0.47; 95% CI: 0.26-0.86). Median PFS in patients with PD-L1 expression ≥1% was 8.4 months in the cabozantinib arm versus 3.1 months in the sunitinib arm (HR: 0.46; 95% CI: 0.18-1.21).

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The PFS advantage with cabozantinib in both trials was consistent according to PD-L1 expression and across PD-L1 measures, including immune cell PD-L1, combined PD-L1 score, and using different PD-L1 cut-offs.

By univariate analysis, patients with PD-L1 levels <1% on tumor cells had superior PFS and OS compared with patients with PD-L1-positive tumor cells in both trials, independent of therapy. The association between PD-L1 expression on tumor cells and OS was statistically significant in the multivariate analysis when combining the two trials.

“In the univariate analysis, PD-L1 expression was associated with shorter PFS and OS in both the METEOR and CABOSUN trials,” said invited discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron, Barcelona, Spain. “In the multivariate analysis, adjusting by IMDC prognosis, treatment, and bone metastases, PD-L1 was associated with poorer OS but not with PFS.”

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Dual-IHC staining is a robust and efficient manner to characterize PD-L1 status on tumor cells and immune cells, she added.

She noted that in all cases, cabozantinib was associated with improved OS and PFS compared to everolimus and sunitinib irrespective of PD-L1 expression.

Exelixis provided funding for the study. Dr. Choueiri’s institution receives research funding from Pfizer, Novartis, Roche, Exelixis, BMS, Merck, Tracon, and AstraZeneca. For a full list of disclosures, see bit.ly/cabozantinibdisclosures.