Christina Schiff

Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumabu2009+u2009bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69–1.45) and 1.19 (95% CI, 0.82–1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38–1.08) and 1.03 (95% CI, 0.63–1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.An exploratory randomized controlled clinical trial of renal cell carcinoma identifies molecular patterns distinguishing responders to immune checkpoint blockade alone or combined with angiogenesis inhibitor versus angiogenesis inhibitor alone.

Abstract CT081: Molecular correlates of differential response to Atezolizumab +/- Bevacizumab vs Sunitnib in a Phase II study in untreated metastatic renal cell carcinoma (RCC) patients

Background: The addition of bevacizumab (bev) to atezolizumab (atezo) has demonstrated enhanced anti-tumor immune responses in pts with solid tumors (Wallin 2016). In IMmotion150 (NCT01984242), a phase II trial that compared atezo+/-bev vs sunitinib (sun) in untreated mRCC, encouraging antitumor activity of atezo+bev vs sun was observed in PD-L1 expressing tumors. We performed integrated tumor genomic analyses to correlate molecular signatures with clinical outcomes. Methods: PD-L1 status on tumor infiltrating immune cells (IC) was assessed with the SP142 IHC assay (IC0, IC1, IC2/3) (n=297). Exploratory analyses included mutation evaluation by WES (n=170) and gene expression analysis by RNA-Seq (n=263). Established gene signatures at median (high) expression levels representing T effector and IFNγ response (Teff) and angiogenesis (Ang) were evaluated in relation to PFS (RECIST v1.1 by independent review). Results: PFS was longer in PD-L1 IC2/3 and in PD-L1 IC1/2/3 in atezo+bev pts vs sun pts and in PD-L1 IC2/3 in atezo pts vs sun pts. High Teff signature expression was associated with PD-L1 IHC and longer PFS in atezo+bev pts vs sun pts. High Ang expression was associated with improved clinical activity in the sun arm; but not the atezo+bev arm. Atezo+bev had improved PFS vs sun in the Ang low subset. Additional data exploring association of high prevalence mutations with clinical outcome will be presented. Conclusions: These data indicate that the addition of bev to atezo may improve clinical benefit in patients with pre-existing anti-tumor immunity (as determined by high Teff score or PD-L1 IHC) compared to sun. Molecular profiles identified in these analyses suggest that prediction of differential outcomes to VEGF TKI and immunotherapy may be possible in front line mRCC. These results will be further explored in the ongoing phase III study IMmotion151 (NCT02420821). Citation Format: David McDermott, Mahrukh Huseni, Brian Rini, Robert Motzer, Michael Atkins, Berard Escudier, Dorothee Nickles, Zach Boyd, Shruthi Sampath, Jennifer Doss, Ning Leng, Christina Schiff, Daniel S. Chen, Gregg Fine, Thomas Powles, Priti S. Hegde. Molecular correlates of differential response to Atezolizumab +/- Bevacizumab vs Sunitnib in a Phase II study in untreated metastatic renal cell carcinoma (RCC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT081. doi:10.1158/1538-7445.AM2017-CT081

Publisher Correction: Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma

In the version of this article originally published, there was an error in Fig. 2n. The top line of the HR comparison chart originally was Atezo + bev vs sun. It should have been Atezo + bev vs atezo. The error has been corrected in the HTML and PDF versions of this article.

Abstract CT031: A phase Ib trial to study the safety and tolerability of atezolizumab with radium-223 dichloride in patients with metastatic castrate-resistant prostate cancer (mCRPC)

Background: In patients (pts) with mCRPC, bone metastases (mets) occur up to 80% of the time and are a significant cause of morbidity and mortality. Radium-223 dichloride (Ra-223) is a targeted α-emitter and extends overall survival (OS) in mCRPC pts with symptomatic bone mets. While several therapies, including Ra-223, have recently been approved for mCRPC, pts ultimately develop resistance and progressive disease. Therefore, there is a high unmet need for new treatments for mCRPC pts. Atezolizumab (atezo) is a humanized mAb that targets PD-L1 and blocks its interaction with its receptors, PD-1 and B7.1, which is expected to enhance T-cell responses and improve anti-tumor activity. A pre-clinical study found that tumor and dendritic cells have higher PD-L1 expression after ionizing radiation (IR) exposure and that combining anti-PD-L1 therapy with IR enhanced the inhibition of tumor growth. Radiotherapy leads to immune modulation and may help prime an immune response by releasing tumor-associated antigens that may target tumors distant from the local radiation field (i.e., abscopal effect). These data support the hypothesis that atezo + Ra-223 may be an effective therapy for CRPC pts with bone and soft tissue mets. Methods: A phase Ib clinical trial (NCT02814669) is being conducted to assess the safety and tolerability of atezo + Ra-223 in pts with mCRPC after progression on an androgen pathway inhibitor and to identify a recommended treatment schedule. Pts will have mCRPC with at least 2 bone mets and either measurable visceral (non-liver) mets or lymphadenopathy. Eligibility criteria include ECOG PS 0-1, progression on an androgen pathway inhibitor, and soft tissue disease amenable for serial biopsy. Exclusion criteria include small cell or neuroendocrine prostate cancer, autoimmune disease, eligible for and willing to receive treatment with taxanes, and prior treatment with Ra-223. Pts will receive atezo (840 mg q2w) and Ra-223 (55 kBq/kg q4w). The study includes a cohort phase, to evaluate a concurrent dosing regimen, and if safe and tolerable, a randomization phase to compare concurrent and staggered dosing. Regimens that are safe and tolerable may undergo expanded enrollment. A recommended schedule will be based on incidence of dose-limiting toxicities during first cycle of combination treatment. A preliminary assessment of efficacy will include ORR per RECIST v1.1, DOR, rPFS, OS, and PSA response rate. Approximately 45 pts will initially be enrolled in the United States. Citation Format: Lawrence Fong, Michael Morris, Andrew Armstrong, Daniel Petrylak, Ulka Vaishampayan, Ajjai Alva, Jean Hoffman-Censits, Indrani Sarkar, Susheela Carroll, Christina Schiff, Oliver Sartor. A phase Ib trial to study the safety and tolerability of atezolizumab with radium-223 dichloride in patients with metastatic castrate-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT031. doi:10.1158/1538-7445.AM2017-CT031