AstraZeneca charts new course for Imfinzi in liver cancer, but FDA path remains uncertain

With the metastatic liver cancer field growing increasingly crowded for immunotherapies, AstraZeneca is trying to reach new ground with Imfinzi in locoregional disease. But a regulatory hurdle lies ahead before the company can blaze the trail.

Adding Imfinzi and bevacizumab (Avastin) to traditional transarterial chemoembolization (TACE) reduced the risk of disease progression or death by 23% in patients with liver cancer that’s eligible for TACE, the phase 3 EMERALD-1 trial has shown. Patients who got the Imfinzi-bevacizumab-TACE combo went a median 15 months without tumor progression, versus 8.2 months for those treated with TACE alone.

The results, which are being shared at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, “have the potential to establish a new standard of care for the treatment of unresectable hepatocellular carcinoma,” Cathy Eng, M.D., from the Vanderbilt University Medical Center and an ASCO expert in GI cancers, said in a statement.

But having the potential to advance patient care doesn’t quite mean the job is done. From a regulatory standpoint, AstraZeneca may need to clear a couple more hurdles in order to convince the FDA and formally introduce the regimen to doctors.

TACE has been the global standard of care for locoregional liver cancer for more than 20 years, ASCO noted in a release. Of the estimated 900,000 new liver cancer diagnoses each year worldwide, about 20% to 30% of patients are eligible for embolization, which is a relatively straightforward procedure that blocks the blood supply to the tumor and may involve the simultaneous administration of cancer-fighting drugs directly to the liver, according to AZ.

Patient survival data are crucial in this locoregional setting, AZ’s oncology R&D chief, Susan Galbraith, Ph.D., noted during the company’s third-quarter earnings call in November.

Investigators are still following EMERALD-1 for overall survival data, and Galbraith suggested on the call that AZ might be able to file for an FDA approval based on the progression-free survival data at first. Under that approach, AZ would plan to submit results from the overall survival analysis later on during the review period.

“We are discussing these positive EMERALD-1 data with global regulatory authorities while awaiting the final overall survival results from the trial,” Galbraith said in a statement Friday.

Further, it’s important for AZ to prove the contribution of each component in the triplet regimen, Galbraith has said. However, Imfinzi’s role here looks less than convincing.

In the study’s third arm, investigators looked at Imfinzi—without bevacizumab—on top of TACE. The Imfinzi-TACE pairing showed marginal benefits, demonstrating a mere 6% reduction in the risk of progression or death versus TACE. The median progression-free survival result was 10 months versus 8.2 months, respectively.

The lack of efficacy showing for the Imfinzi-TACE duo means that the EMERALD-1 trial has missed one of its secondary endpoints, with data on overall survival, another key secondary endpoint, remaining immature.

This isn’t the first time that the contribution of Imfinzi in a bevacizumab-containing regimen has been called into question. In a very similar situation in ovarian cancer, the DUO-O trial recently showed that adding Lynparza and Imfinzi to standard chemotherapy and Avastin significantly improved progression-free survival in certain newly diagnosed patients. At the same time, the addition of Imfinzi itself only lowered the risk of progression by 13%.

When the DUO-O data were shared at ASCO’s annual meeting last year, a trial investigator came right out and said Imfinzi’s role in that combo “requires further

Since then, AZ has indicated that it will wait for longer-term data before considering filing the DUO-O regimen with the FDA.

Back to the liver cancer results, the Imfinzi-bevacizumab-TACE regimen had its own drawbacks, as the addition of bevacizumab increased both efficacy and toxicity. The rate of grade 3 or 4 treatment-related adverse events was 32.5%, 15.1% and 13.5% for the triplet, the sans-bevacizumab doublet and TACE regimens, respectively.

Besides EMERALD-1, AZ is running the EMERALD-3 study to test Imfinzi in combination with AZ’s own CTLA-4 agent Imjudo, Eisai’s Lenvima and TACE in embolization-eligible liver cancer. Imfinzi and Imjudo are currently approved to treat unresectable liver cancer.

Meanwhile, the EMERALD-2 trial is evaluating Imfinzi and bevacizumab as a post-surgery adjuvant therapy in resectable liver cancer, with a data readout expected in the second half of 2024. Last year, Roche reported positive disease recurrence outcome for its Tecentriq-Avastin combo in the adjuvant liver cancer setting, but immature overall survival data prevented the Swiss pharma from filing with the FDA.