Handling histological liver tissue sample
Handling histological liver tissue sample

Patient-reported outcomes or PRPs from the phase-III IMbrave 150 study funded by Roche, demonstrated that health related Quality of Life (hrQoL) is maintained longer with a newer drug combination compared with standard of care for the treatment of patients with a specific type of colorectal cancer and unresectable hepatocellular carcinoma.

The results were be presented at the 2020 Gastrointestinal Cancers Symposium, taking place January 23-25, 2020 in San Francisco, California.

Atezolizumab and Bevacizumab
The combination of atezolizumab (Tecentriq®; Genentech/Roche), a programmed cell death ligand 1 (PD-L1) inhibitor, and bevacizumab (Avastin®; Genentech/Roche), a vascular endothelial growth factor (VEGF) inhibitor, delayed declines in hrQoL in a study comparing the two-drug treatment with the standard of care, sorafenib (Nexavar®; Bayer) for patients with unresectable hepatocellular carcinoma (HCC),  the sixth most common cancer and third leading cause of cancer-related death in the world. [1][2]

Important
“Because it reflects both the effects of disease and the side effects of treatment, sustained or improved quality of life is particularly important for patients,” explained lead author Peter R. Galle, MD, PhD, of the University Medical Center in Mainz, Germany.

“Patients with liver cancer are typically more fragile and frail than others. Toxicity of the treatments can be much more serious for these patients, and their quality of life can decline quite quickly,” Galle added.

The results come from the phase-III IMbrave 150 trial (NCT03434379), which compared atezolizumab plus bevacizumab with sorafenib alone as a first-line treatment for patients with HCC who had not received prior systemic therapy. The primary endpoint of overall survival was presented at the European Society for Medical Oncology (ESMO) Asia Congress in November 2019. [3]

The IMbrave150 study enrolled patients who had not received prior systemic therapy for HCC. Following 2:1 randomisation, 336 patients were treated with atezoliumab at 1200 mg i.v. plus bevicizumab at 15 mg/kg i.v. every 3 weeks and 165 patients received sorafenib at 400 mg twice daily. Both treatments were administered until unacceptable toxicity or loss of clinical benefit per investigator. The patients’ baseline demographics were well balanced between treatment arms.

At that time, median overall survival had not yet been reached for atezolizumab plus bevacizumab compared with overall survival of 13.2 months (95% confidence interval [CI], 10.4, NE) for patients receiving sorafenib alone. The overall response rate was 27% with atezolizumab plus bevacizumab and 12% for sorafenib (hazard ratio [HR] 0.58; 95% CI, 0.42-0.79;p = 0.0006).

Median Progression Free Survival with the combination was 6.8 months (95% CI, 5.7-8.3) versus 4.5 (95% CI, 4.0-5.6) with sorafenib (HR 0.59 (95% CI, 0.47-0.76; p < 0.0001).

The primary analysis of data from the phase III IMbrave150 trial, presented by professor Ann Lii-Cheng, MD, Ph.D, Director of the National Taiwan University Cancer Center and National Taiwan University Hospital in Taipei, Taiwan at the ESMO Asia Congress, confirmed that the combination of atezolizumab plus bevacizumab demonstrated statistically significant and clinically meaningful improvement in both overall survival (OS) and progression-free survival (PFS) in patients with unresectable HCC who did not receive prior systemic therapy. The safety of the combination was consistent with the known safety profile of each agent, and no new safety signals were identified.

Doubling response
The study results presented demonstrated Overall Response Rate (ORR) with the respective treatments of 27% versus 12% (p < 0.0001) per Independent Review Facility (IRF) RECIST v1.1. According to IRF HCC mRECIST criteria, the response was nearly 3-fold higher with atezolizumab plus bevacizumab compared to sorafenib; the ORR was 33% versus 13% (p < 0.0001), respectively.

According to the investigators, the results were generally consistent across the clinical subgroups evaluated. They also reported that atezolizumab in combination with bevacizumab delayed deterioration of hrQoL compared to sorafenib.

The median duration of treatment was 7.4 months with the combination and 2.8 months for sorafenib.

With a combined treatment of atezolizumab plus bevacizumab, 57% of patients reported Grade 3-4 adverse events (AEs) while 55% of patients receiving sorafenib reported similar Grade 3-4 AE. The frequency of Grade 5 AEs was also similar at 5% and 6%, respectively.

Based on findings from the phase III IMbrave150 trial Lii-Cheng and colleagues concluded that combined atezolizumab plus bevacizumab has the potential to be a practice changing treatment in the first-line setting for patients with unresectable HCC.

Patient Reported Outcomes
At the Gastrointestinal Cancers Symposium, researchers presented patient-reported outcomes results from the study. Time to deterioration, assessed by two validated patient-reported quality of life tools, was a prespecified secondary endpoint of the study. Time to deterioration was defined as a decrease of 10 points from baseline in key patient-reported outcomes. At baseline, every three weeks during therapy, and every three months after discontinuation of therapy, patients completed two questionnaires (one specific to HCC) to assess quality of life, physical functioning, and role functioning. Questionnaire completion rates were about 92%.

Time to deterioration was a median of 11.2 months for the combination treatment compared with 3.6 months for sorafenib. Declines in physical functioning were also delayed with the combination treatment, with a median delay of 13.1 months with atezolizumab and bevacizumab compared with 4.9 months for sorafenib.

Why important
Commenting on the results of the study, Richard L. Schilsky, MD, FACP, FSCT, FASCO, ASCO Chief Medical Officer and Executive Vice President of ASCO and former the Chief of Hematology/Oncology in the Department of Medicine and Deputy Director of the University of Chicago Comprehensive Cancer Center, Chicago, Illenois, noted “Patient-reported outcomes, or PROs, are now recognized as important endpoints of cancer clinical trials that provide important insights regarding the impact of treatment on patients’ (health related) Quality of Life.”

“PROs inform us about the tolerability of new therapies, which is just as important as efficacy in gauging their utility and acceptance by patients. There is also evidence that suggests that PROs can have prognostic value for cancer patients. As we get better at including quality of life measures in clinical trials, we will continue to see the importance of patient reports grow,” Schilsky concluded.

Clinical trials
A Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma [IMbrave150] – NCT03434379

Reference
[1] Galle PR. Patient-reported outcomes (PROs) from the Phase III IMbrave150 trial ofatezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-linetreatment (tx) for patients (pts) with unresectable hepatocellular carci-noma (HCC).First Author: , University Medical Center Mainz,Mainz, Germany 476 Oral Abstract Session, Gastrointestinal Cancers Symposium, January 2020 [Proceedings]
[2] Murata S, Mine T, Sugihara F, et al. Interventional treatment for unresectable hepatocellular carcinoma. World J Gastroenterol. 2014;20(37):13453–13465. doi:10.3748/wjg.v20.i37.13453
[2] LBA3 – Cheng A-L, Qin S, Ikeda M, et al. IMbrave150: Efficacy and Safety Results From a Ph 3 Study Evaluating Atezolizumab (atezo) + Bevacizumab (bev) vs Sorafenib (Sor) as First Treatment (tx) for Patients (pts) With Unresectable Hepatocellular Carcinoma (HCC).