A combination therapy of the PD-L1 inhibitor atezolizumab (Tecentriq®; Genentech/Roche) and the VEGF inhibitor bevacizumab (Avastin®; Genentech/Roche) significantly improves overall survival (OS) and progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (HCC) compared to standard of care.
This is the conclusion based on results from a phase III study presented at the fifth European Society for Medical Oncology (ESMO) Asia 2019 Congress being held November 22 – 24, 2019 Suntec Singapore Convention & Exhibition Centre in Singapore. 
“This is the first study in [over a decade] to show an improvement in survival with a new fist-line treatment option compared to sorafenib (Nexavar®; Bayer), which has been the standard of care throughout this time,” said study first author Ann-Lii Cheng, MD, Ph.D, Director of the National Taiwan University Cancer Center, Taipei, Taiwan.
“Atezolizumab plus bevacizumab has the potential to be a practice-changing treatment option in hepatocellular carcinoma,” Cheng added.
Unresectable hepatocellular carcinoma or HCC is currently a major challenge in countries with a high prevalence of this cancer. And despite considerable knowledge about the scope and nature of the malignancy, the general prognosis is poor with overall survival rates of 3%–5%. The disease also remains incurable. 
Worldwide, HCC is the sixth most common cancer and the third leading cause of death. More than a half million patients are diagnosed annually, tripling the incidence of HCC over the past three decades. Most patients succumb to their primary hepatic malignancies within a year of diagnosis. If left untreated, survival is only 5 months. The poor outcome is associated with the absence of early observable symptoms and the common presentation of advanced disease at initial diagnosis. 
Most patients in countries without screening programs present with unresectable or advanced HCC because of the late appearance of symptoms, resulting in a very high mortality rate of nearly 80%.
“Despite many studies over the past 11 years, we have been unable to find any better treatment option. This has been very frustrating because sorafenib has a response rate of around 10% and is associated with severe side-effects,” he explained.
The phase III IMbrave150 study randomized patients with unresectable HCC to a combination of atezolizumab plus bevacizumab or sorafenib. Atezolizumab reactivates the immune response to tumour cells while bevacizumab stops tumors growing new blood vessels to obtain nutrients and oxygen but also helps upregulate host immunity to fight against cancer.
Results showed statistically and clinically meaningful improvement in the co-primary endpoints of overall survival and progression-free survival in patients treated with atezolizumab plus bevacizumab compared to those treated with sorafenib.
“This is the first time a novel treatment has shown a survival benefit compared to the current standard of care. The results are very encouraging and there is a strong possibility this drug combination will be approved by regulatory authorities and be incorporated into international guidelines for advanced HCC,” noted Ian Chau, MD, Consultant Medical Oncologist at the Royal Marsden Hospital, London, UK, commenting on the findings presented at ESMO Asia 2019.
“I think this is a breakthrough and based on the results, the combination of atezolizumab plus bevacizumab could become the new standard of care,” agreed Angela Lamarca, MD, Ph.D, Consultant Medical Oncologist at the Christie NHS Foundation Trust, Manchester, UK.
“The results are clinically meaningful in the setting of advanced HCC, as well as statistically significant. The delayed deterioration in quality of life is also important – patients are living longer and their quality of life is better,” Lamarca added.
She considered the study was well-designed, with several strengths including its large sample size, with just over 500 patients, the use of a combination endpoint of PFS and OS, assessment of response/progression by a central reviewer and analysis based on the intention-to-treat population.
Lamarca also noted that the median follow-up of 8.6 months is relatively short, with the median OS for atezolizumab plus bevacizumab not yet reached. Chau agreed, noting that the improvement in OS is currently based on relatively immature data, with longer follow-up needed to confirm the magnitude of the OS benefit.
“The combination of atezolizumab plus bevacizumab will be very useful to patients with advanced HCC as a new systemic therapy but, with the high cost of immunotherapy and anti-angiogenic agents, it will also be important that those drugs are accessible to patients,” Chau said.
The phase III IMbrave150 study randomized 501 patients with unresectable HCC on a 2:1 basis to atezolizumab (1200mg IV every three weeks) plus bevacizumab (15mg/kg IV every three weeks) or sorafenib (400mg twice daily). The patients continued with their assigned treatment until unacceptable toxicity or loss of clinical benefit as judged by study investigators.
Results showed the hazard ratio (HR) for overall survival (OS) was 0.58 (95% CI 0.42, 0.79, p=0.0006) after a median follow-up of 8.6 months. The median OS had not yet been reached for atezolizumab plus bevacizumab compared to 13.2 months for patients randomised to sorafenib. Median progression free survival (PFS) was also significantly increased (median 6.8 vs 4.3 months, HR 0.59, 95% CI 0.47, 0.76, p<0.0001).
Overall response rate was more than twice as high with atezolizumab plus bevacizumab compared to sorafenib (27% vs 12%, p<0.0001) based on independent assessment using RECIST 1.1 criteria and similarly increased using HCC mRECIST criteria (33% vs 13%, p<0.0001). Atezolizumab plus bevacizumab delayed deterioration in quality of life compared to sorafenib.
Grade 3-4 adverse events occurred in 57% of patients treated with Atezolizumab plus bevacizumab and 55% of those receiving sorafenib. Grade 5 adverse events occurred in 5% and 6% of patients, respectively.
A Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma (IMbrave150) – NCT03434379
 IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC)’ will be presented by Ann-Lii Cheng during the Presidential Symposium on Saturday, 23 November 2019, 11:00-12:30 (SGT) in Hall 406. Annals of Oncology, Volume 30, 2019 Supplement 9. Abstract LBA3
 Cheng AL, Qin S, Ikeda M, Galle P, Ducreux M, Zhu A, Kim TY, Kudo M, et al. LBA3 – IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC)
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