ASCO 2019: IMmotion151 Subgroup Analysis: Atezolizumab + Bevacizumab versus Sunitinib in Patients with Untreated Metastatic Renal Cell Carcinoma and Sarcomatoid Histology

Chicago, IL (UroToday.com) The landscape of systemic therapy for metastatic renal cell carcinoma (mRCC) is rapidly changing. Beyond the addition of immune checkpoint inhibitor combinations (nivo/ipi) and additional tyrosine kinase innhibitors (TKIs) (cabozantinib), there are now combination therapies that are demonstrating excellent responses rates in the first line. The recent data from KEYNOTE‑426 has led to approval of axinitib/pemrbolizumab in the first line for mRCC, and as can be expected from this combination, seems to have efficacy for good, intermediate and poor risk patients.

The Phase 3 IMmotion151 trial demonstrated that the combination of atezolizumab (atezo) and bevacizumab (bev) demonstrated an improved PFS compared to sunitinib (sun) alone in untreated mRCC pts, 362 (40%) of 915 patients had PD-L1 positive disease. In that study, they found that in the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis.

In this presentation at ASCO 2019, the authors report the results of a prespecified subgroup analysis in patients whose tumors have sarcomatoid histology, which is an independent predictor of poor survival. 10-20% of patients with advanced disease are thought to harbor sarcomatoid histology and have a limited response to targeted therapies. The IMmotion-151 study only included patients with clear cell histology and sarcomatoid histology.

The full study protocol is seen below:
ASCO2019_studyprotocol_4512.png
As a reminder, in the original study, patients were randomized to receive atezolizumab 1200 mg IV q3w and bevacizumab 15 mg/kg IV q3w or sunitinib 50 mg po qd for 4w on, 2w off. Coprimary endpoints were reported previously, as indicated above. Secondary endpoints included INV-PFS and OS in sarcomatoid histology patients and are shown here. Also shown today are INV-ORR, safety, PRO and biomarker data.

Of the 915 patients, 142 randomized pts (16%) from IMmotion151 had tumors with any component of sarcomatoid histology. Full demographics of the 142 patients and the entire cohort are seen below:
ASCO2019_fulldemographics_4512.png
They note that patients with sarcomatoid histology were more likely to have PD-L1+ disease and be intermediate/poor risk than patients in the ITT population.

In this group with sarcomatoid histology, median PFS was 8.3 vs 5.3 mo with atezo + bev vs sun and median OS was 21.7 vs 15.4 mo, respectively. The table below summarizes results in all sarcomatoid patients and in patients who were PD-L1+ as well.
ASCO2019_efficiancysummary_4512.png
ORR was 49% vs 14% and CR rate was 10% vs 3% in the atezo + bev vs sun arms.

Looking at the KM curves for PFS and OS (below), patients with sarcomatoid histology treated with atezo/bev had significantly longer PFS and OS. This was true regardless of PD-L1 status.
ASCO2019_figure_2_3_4512.png
As with the larger cohort, Grade 3-4 AEs occurred in 27 pts (40%) with atezo + bev and 34 (49%) with sun. Using the MDASI scale, sarc pts reported longer median time to deterioration (TTD) of symptom interference with daily activities with atezo + bev vs sun (11.3 vs 4.9 mo), which is seen below:
ASCO2019_figure4_4512.png
There is an early and consistent separation of the curves.

Looking at the genomic evaluation, prevalence of Angiogenesis-High gene expression (GE) signature subset was lower (34% vs 65%) and T-effector-High GE subset was higher (54% vs 40%) in sarc vs non-sarc tumors. PD-L1+ disease was more common in sarc vs non-sarc tumors (63% vs 39%). These are summarized below:
ASCO2019_figure_5_4512.png
Based on this subset analysis, the authors note that mRCC pts with sarcomatoid histology had longer OS and PFS and a higher ORR/CR rate when treated with atezo + bev than with suninib, regardless of PD-L1 status. Biomarker data supports a biological correlate for the increased responsiveness to atezo + bev in sarcomatoid patients.

Clinical Trial information: NCT02420821

Presented by: Brian I. Rini, Medical Oncologist, Cleveland Clinic, Cleveland, OH 

Co-authors: Robert J. Motzer, Thomas Powles, David F. McDermott, Bernard Escudier, Frede Donskov, Robert E. Hawkins, Sergio Bracarda, Jens Bedke, Ugo De Giorgi, Camillo Porta, Alain Ravaud, Francis Parnis, Enrique Grande, Wei Zhang, Mahrukh A. Huseni, Susheela Carroll, Roxana Ioana Sufan, Christina Schiff, Michael B. Atkins

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology, at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References:
  1. Rini et al. “Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.” Lancet. 2019 May 9. pii: S0140-6736(19)30723-8. doi: 10.1016/S0140-6736(19)30723-8. [Epub ahead of print]
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