New Drug Combo Potentially Practice Changing in Advanced HCC

SAN FRANCISCO — For patients with unresectable hepatocellular carcinoma (HCC), the combination of atezolizumab (Tecentriq, Genentech) plus bevacizumab (Avastin, Genentech) has already shown better efficacy than standard treatment with sorafenib (Nexavar, Bayer) in the IMbrave150 trial.

Now an analysis of quality-of-life data from that study shows that the combination significantly delayed deterioration, and the difference between the two treatment arms was "remarkable," said the lead author, Peter Galle, MD, PhD, director of the medical department at University Medical Center Mainz in Germany.

The median time to deterioration, which was assessed by two validated patient-reported quality-of-life tools, was 11.2 months for the combination treatment vs 3.6 months for sorafenib.

Deterioration of physical functioning was also delayed with the two-drug regimen as compared with sorafenib (by a median of 13.1 vs 4.9 months).

These results could potentially change clinical practice, suggested one expert.

"My thinking is that this is practice changing, and we will likely be considering this for frontline therapy," said A. Craig Lockhart, MD, of the University of Miami Sylvester Comprehensive Cancer Center, Florida.

Results of the study were presented here at the Gastrointestinal Cancers Symposium (GICS) 2020. Lockhart served as a discussant of the paper.

Improved Overall Survival

The aim of the new analysis was to show the patient perspective on overall clinical benefit, explained Galle, who is also president-elect of the German Association for the Study of the Liver for 2020.

"Quality of life matters — it matters to all of us and especially to cancer patients," Galle told the audience. "This is particularly true in the palliative setting, when the life span is limited and the quality of the remaining life span is of the utmost importance. And for that reason, the voice of the patient needs to be heard."

The efficacy data from the IMbrave150 trial were presented in November 2019 at the European Society for Medical Oncology (ESMO) Asia Congress, Galle noted, and he briefly summarized the main findings.

The trial included 501 patients with unresectable HCC who were randomly assigned in a 2:1 ratio to receive either atezolizumab 1200 mg IV and bevacizumab 15 mg/kg IV, both on day 1 of each 21-day cycle, or oral sorafenib 400 mg twice daily on each day of the 21-day cycle.

"The overall survival was significantly different between the two groups," he said. "There was a 42% reduced risk of death favoring the combination group."

Overall survival was 13.2 months for patients who received sorafenib; it was not reached for the combination arm (stratified hazard ratio [HR], 0.58; P = .0006). Likewise, progression-free survival was superior in the combination therapy arm: 6.8 months vs 4.3 months. The overall response rate was 27% with atezolizumab plus bevacizumab and 12% for sorafenib.

The rates of adverse events were similar but varied by treatment. Grade 3–4 events occurred in 57% of patients who received combination therapy and in 55% of those who received sorafenib. "Patients on sorafenib were more prone to diarrhea, decreased appetite, alopecia, and asthenia, whereas those on the combination protocol had higher rates of hypertension, hepatitis, proteinuria, and pyrexia," he said.

New Analysis of Quality-of-Life Data

To assess quality of life, time to deterioration (TTD) was used as a prespecified secondary endpoint of the study. It was defined as a decrease of 10 points from baseline in key patient-reported outcomes.

"A drop of 10 points or larger is considered in the literature to be clinically meaningful," said Galle.

Patients filled out two questionnaires at baseline, then every 3 weeks during therapy, and then every 3 months after treatment ended. One questionnaire was specific to HCC. Quality of life, physical functioning, and role functioning were assessed.

Completion rates for these questionnaires were high, noted Galle, at more than 92%, which means that most patients were included in the analysis.

As compared with sorafenib, combination therapy delayed TTD of patient-reported quality of life (median TTD, 11.2 vs 3.6 months; HR, 0.63; 95% confidence interval [CI], 0.46 – 0.85), physical functioning (median TTD, 13.1 vs 4.9 months; HR, 0.53; 95% CI, 0.39 – 0.73), and role functioning (median TTD, 9.1 vs 3.6 months; HR, 0.62; 95% CI, 0.46 – 0.84).

"There was a smaller proportion of patients deteriorating in the atezolizumab plus bevacizumab group, and if they deteriorated, it happened later," he emphasized.

In addition, fewer patients in the combination arm experienced clinically meaningful deterioration in specific symptoms, including appetite loss, fatigue, pain, and diarrhea. Time to deterioration was longer in comparison with sorafenib.

"IMbrave150 demonstrated statistically significant and clinically meaningful improvement at a level not seen before," Galle concluded. "Patient-reported outcomes demonstrated clinically meaningful benefit in clear aspects of the patient experience, and the patient voice continues to support the positive risk profile."

Worth the Money?

In his discussion of the paper, Lockhart noted that patient-reported outcomes, which the US Food and Drug Administration defines as outcomes derived directly from the patient, "add value because they provide a more comprehensive outcomes measure."

Patient-reported outcomes can also help with symptom management interventions and with assessments of economic value. "If they're really expensive, which is what we're talking about now ― really great patient- reported outcomes can add some economic impetus that may show that, despite the expense, it is having a positive impact on the patient's quality of life."

Lockhart pointed out that in this study, there appear to be clinically meaningful and statistically significant patient-reported outcomes, and these data also correspond with progression-free and overall survival data. "That is reassuring because not only are we seeing improvement in survival, but the patient-reported outcomes seem to concur."

Overall, the regimen showed efficacy, there were no new safety signals, and it was a high-quality study. "The expense will be something that we will have to consider, but we will weigh that in the context of the patient-reported data that we just saw," Lockhart said.

The study was funded by F. Hoffmann-La Roche, Ltd. Galle and the study's coauthors have disclosed a variety of relationships with industry, as noted in the abstract. Lockhart has disclosed no relevant financial relationships.

Gastrointestinal Cancers Symposium (GICS) 2019: Abstract 476. Presented January 24, 2020.

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