Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma.
Atezolizumab (anti-programmed death-ligand 1 (PD-L1)) and bevacizumab (anti-vascular endothelial growth factor (VEGF)) combination therapy has become the new standard of care in patients with unresectable hepatocellular carcinoma. However, potential predictive biomarkers and mechanisms of response and resistance remain less well understood. We report integrated molecular analyses of tumor samples from 358 patients with hepatocellular carcinoma (HCC) enrolled in the GO30140 phase 1b or IMbrave150 phase 3 trial and treated with atezolizumab combined with bevacizumab, atezolizumab alone or sorafenib (multikinase inhibitor). Pre-existing immunity (high expression of CD274, T-effector signature and intratumoral CD8 T cell density) was associated with better clinical outcomes with the combination. Reduced clinical benefit was associated with high regulatory T cell (Treg) to effector T cell (Teff) ratio and expression of oncofetal genes (GPC3, AFP). Improved outcomes from the combination versus atezolizumab alone were associated with high expression of VEGF Receptor 2 (KDR), Tregs and myeloid inflammation signatures. These findings were further validated by analyses of paired pre- and post-treatment biopsies, in situ analyses and in vivo mouse models. Our study identified key molecular correlates of the combination therapy and highlighted that anti-VEGF might synergize with anti-PD-L1 by targeting angiogenesis, Treg proliferation and myeloid cell inflammation.
Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial.
Galle Peter R,Finn Richard S,Qin Shukui,Ikeda Masafumi,Zhu Andrew X,Kim Tae-You,Kudo Masatoshi,Breder Valeriy,Merle Philippe,Kaseb Ahmed,Li Daneng,Mulla Sohail,Verret Wendy,Xu Derek-Zhen,Hernandez Sairy,Ding Beiying,Liu Juan,Huang Chen,Lim Ho Yeong,Cheng Ann-Lii,Ducreux Michel
The Lancet. Oncology
BACKGROUND:Understanding patients' experience of cancer treatment is important. We aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival benefits with this combination therapy. METHODS:We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment allocation. Previously reported coprimary endpoints were overall survival and independently assessed progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PRO-evaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379. FINDINGS:Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2-10·8). EORTC QLQ-C30 completion rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88-100% in the atezolizumab plus bevacizumab group and 80-100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88-100%) and 21 of 24 cycles in the sorafenib group (range 89-100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite loss [hazard ratio (HR) 0·57, 95% CI 0·40-0·81], diarrhoea [0·23, 0·16-0·34], fatigue [0·61, 0·46-0·81], pain [0·46, 0·34-0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for analysis (fatigue [0·60, 0·45-0·80] and pain [0·65, 0·46-0·92], but not jaundice [0·76, 0·55-1·07]). At day 1 of treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: -3·29 (SD 17·56) versus -5·83 (20·63) for quality of life, -4·02 (19·42) versus -9·76 (21·33) for role functioning, and -3·77 (12·82) versus -7·60 (15·54) for physical functioning. INTERPRETATION:Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib, strengthening the combination therapy's positive benefit-risk profile versus that of sorafenib in patients with unresectable hepatocellular carcinoma. FUNDING:F Hoffmann-La Roche and Genentech.
Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial.
BACKGROUND:The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. OBJECTIVE:To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS:IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. INTERVENTION:Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. RESULTS AND LIMITATIONS:Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19-37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6-13.7) mo. The median event follow-up duration was 19.4 (12.9-21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. CONCLUSIONS:The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. PATIENT SUMMARY:Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.