Combination of Immunotherapy and VEGF Inhibitor Improves Survival in Hepatocellular Carcinoma [ESMO Asia 2019 Press Release]

SINGAPORE – Combination therapy with the PD-L1 inhibitor atezolizumab and the VEGF inhibitor bevacizumab significantly improves overall survival and progression-free survival in patients with unresectable hepatocellular carcinoma (HCC) compared to standard of care, showed results from a phase 3 study to be reported at the ESMO Asia 2019 Congress. (1)

“This is the first study in 11 years to show an improvement in survival with a new fist-line treatment option compared to sorafenib, which has been the standard of care throughout this time,” said study first author Ann-Lii Cheng, Director of the National Taiwan University Cancer Center, Taipei, Taiwan. He added, “Atezolizumab plus bevacizumab has the potential to be a practice-changing treatment option in hepatocellular carcinoma.”

Unresectable HCC is currently a major challenge in countries with a high prevalence of this cancer. Most patients in countries without screening programmes present with unresectable or advanced HCC because of the late appearance of symptoms, resulting in a very high mortality rate (almost 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 3 IMbrave150 study randomised patients with unresectable HCC to a combination of atezolizumab plus bevacizumab or sorafenib. Atezolizumab reactivates the immune response to tumour cells while bevacizumab stops tumours 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.

Commenting on the findings, Ian Chau, Consultant Medical Oncologist at the Royal Marsden Hospital, London, UK, said: “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.”

Angela Lamarca, Consultant Medical Oncologist at the Christie NHS Foundation Trust, Manchester, UK, agreed: “I think this is a breakthrough and based on the results, the combination of atezolizumab plus bevacizumab could become the new standard of care.”

Lamarca added, “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.”

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.

Looking to the future, Chau said, “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.”

Study results

The phase 3 IMbrave150 study randomised 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.

Notes to Editors

Official Congress Hashtag:  #ESMOAsia19

References

1. Abstract 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)’ 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

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)

A-L. Cheng¹, S. Qin², M. Ikeda³, P. Galle⁴, M. Ducreux⁵, A. Zhu⁶, T-Y. Kim⁷, M. Kudo⁸, V. Breder⁹, P. Merle¹⁰, A. Kaseb¹¹, D. Li¹², W. Verret¹³, Z. Xu¹⁴, S. Hernandez¹⁵, J. Liu¹⁶, C. Huang¹⁷, S. Mulla¹⁸, H.Y. Lim¹⁹, R. Finn²⁰

¹Department of Oncology, National Taiwan University Cancer Center and National Taiwan University Hospital, Taipei, Taiwan, ²Cancer Center, People’s Liberation Army Cancer Center, Nanjing, China, ³Hepatobiliary & Pancreatic Oncology Dept., National Cancer Center Hospital East, Kashiwa, Japan, ⁴I. Medical Department, University Medical Center Mainz, Mainz, Germany, ⁵Medical Oncology, Gustave Roussy Cancer Center, Villejuif, France, ⁶Cancer Center, Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, MA, USA, ⁷Medical Oncology Center, Seoul National University College of Medicine, Seoul, Republic of Korea, ⁸Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan, ⁹Chemotherapy Dept No17, N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, ¹⁰Hepatology and Gastroenterology Unit, Hopital de la Croix-

Rousse, Lyon, France, ¹¹GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, ¹²Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA, USA, ¹³Product Development - Oncology, Genentech, Inc., San Francisco,

CA, USA, ¹⁴Product Development, Roche, Beijing, China, ¹⁵Product Development Oncology Department, Genentech, Inc. - Member of the Roche Group, South San Francisco, CA, USA, ¹⁶Product Development, Shanghai Roche Pharmaceuticals Ltd., Shanghai, China, ¹⁷Safety Science Oncology, Roche Product Development, Shanghai, China, ¹⁸Product Development, F. Hoffmann-La Roche, Ltd., Mississauga, ON, Canada, ¹⁹Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, ²⁰Jonsson Comprehensive Cancer Center, Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Introduction: Ph 1b data has shown promising efficacy and safety for atezo + bev in unresectable HCC pts who have not received prior systemic therapy. Here, we report the primary analysis data from the Ph 3 IMbrave150 trial comparing atezo + bev vs sor in this pt population.
Methods: IMbrave150 enrolled systemic treatment (tx)-naïve pts with unresectable HCC. Pts were randomised 2:1 to receive either atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg BID until unacceptable toxicity or loss of clinical benefit per investigator. Coprimary endpoints were OS and PFS by independent review facility (IRF)-assessed RECIST 1.1. The key secondary endpoints IRF-ORR per RECIST 1.1 and IRF-ORR per HCC mRECIST were also part of the study statistical testing hierarchy.
Results: The ITT population included 336 pts randomised to atezo + bev and 165 randomised to sor. Baseline demographics were well balanced between arms. With a median follow up of 8.6 mo, OS HR was 0.58 (95% CI, 0.42, 0.79; P = 0.0006) and PFS HR was 0.59 (95% CI, 0.47, 0.76; P < 0.0001; see table) for atezo + bev vs sor. ORR was 27% vs 12% (P < 0.0001) per IRF RECIST 1.1 and 33% vs 13% (P < 0.0001) per IRF HCC mRECIST for atezo + bev vs sor, respectively. Results were generally consistent across clinical subgroups. Atezo + bev delayed deterioration of quality of life vs sor.Median tx duration was 7.4 mo for atezo, 6.9 for bev and 2.8 for sor. Gr 3-4 AEs occurred in 57% of pts receiving atezo + bev and 55% of pts receiving sor. Gr 5 AEs were seen in 5% and 6% of pts, respectively.
Conclusions: IMbrave150 demonstrated statistically significant and clinically meaningful improvement in both OS and PFS for atezo + bev vs sor in pts with unresectable HCC who have not received prior systemic therapy. The safety of atezo + bev is consistent with the known safety profile of each agent, and no new safety signals were identified. Atezo + bev has the potential to be a practice changing tx in HCC.

Clinical Trial Identifier: NCT03434379
Editorial acknowledgement: Medical writing assistance for this abstract was provided by Jessica Bessler, PhD, of Health Interactions, Ltd. and funded by F. Hoffmann-La Roche, Ltd.
Legal entity responsible for the study: F. Hoffmann-La Roche, Ltd.
Funding: F. Hoffmann-La Roche, Ltd.           
Disclosure: A-L. Cheng: Advisory / Consultancy: Bayer Schering Pharma; Advisory / Consultancy:
Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony,
Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy: Merck Serono; Honoraria (self),
Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses:
Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel /
Accommodation / Expenses: Ono Pharmaceutical; Advisory / Consultancy: Exelixis; Advisory /
Consultancy: Nucleix Ltd.; Honoraria (self), Advisory / Consultancy, Travel / Accommodation /
Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation /
Expenses: IQVIA; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer
Yakuhin, Ltd; Speaker Bureau / Expert testimony: Amgen Taiwan; Honoraria (self): Bayer; Honoraria
(self): Merck Sharp Dohme; Honoraria (self): Merck Serono. M. Ikeda: Honoraria (self): Abbott
Japan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer
Yakuhin; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb;
Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self), Research grant / Funding (institution):
Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo;
Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Eisai; Honoraria
(self), Advisory / Consultancy, Research grant / Funding (institution): Lilly Japan; Honoraria (self):
Nippon Kayaku; Honoraria (self): Novartis; Honoraria (self), Research grant / Funding (institution):
Taiho Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): Kyowa Hakko
Kirin; Advisory / Consultancy, Research grant / Funding (institution): NanoCarrier; Research grant /
Funding (self): ASLAN Pharmaceuticals; Research grant / Funding (self): AstraZeneca; Research grant
/ Funding (self): Baxter; Research grant / Funding (self): Boehringer Ingelheim; Research grant /
Funding (self): Kowa; Research grant / Funding (self): Merck Serono; Research grant / Funding (self):
Ono Pharmaceutical, Yakult, Zeria Pharmaceutical. P.R. Galle: Honoraria (self), Research grant /
Funding (institution): Bayer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD;
Honoraria (self): AstraZeneca; Honoraria (self): SIRTEX; Honoraria (self): Merck; Honoraria (self):
Lilly; Honoraria (self): Blueprint; Honoraria (self): AdaptImmune; Honoraria (self): Eisai; Honoraria
(self): Roche; Honoraria (self): Ipsen. M.P. Ducreux: Honoraria (self), Advisory / Consultancy: Lilly;
Honoraria (self), Advisory / Consultancy: Servier; Advisory / Consultancy: Amgen; Advisory /
Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene;
Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses:
Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Advisory /
Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant /
Funding (self), Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony:
Bayer; Speaker Bureau / Expert testimony: Merck KGaA; Research grant / Funding (self): Pfizer;
Spouse / Financial dependant: Sandoz. A.X. Zhu: Advisory / Consultancy: AstraZeneca; Advisory /
Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant /
Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy:
Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory /
Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant /
Funding (institution): Novartis; Advisory / Consultancy: Roche/Genentech. M. Kudo: Honoraria
(self), Research grant / Funding (institution): AbbVie; Honoraria (self), Advisory / Consultancy:
Bayer; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Japan;
Honoraria (self): EA Pharma; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self):
Gilead Sciences; Honoraria (self): Merck Serono; Honoraria (self), Advisory / Consultancy: MSD;
Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (institution):
Taiho Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Research grant /
Funding (institution): Astellas Pharma; Research grant / Funding (institution): Chugai Pharma;
Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution):
Otsuka. V. Breder: Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation /
Expenses: Bayer; Honoraria (self), Advisory / Consultancy: BioCad; Honoraria (self), Advisory /
Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel /
Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Eisai;
Honoraria (self), Advisory / Consultancy: MSD Oncology; Honoraria (self), Advisory / Consultancy,
Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses:
Takeda. P. Merle: Research grant / Funding (self): ONXEO; Advisory / Consultancy, Travel /
Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses:
Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses:
Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation
/ Expenses: Bristol-Myers Squibb. A. Kaseb: Shareholder / Stockholder / Stock options: Gilead
Sciences; Honoraria (self), Advisory / Consultancy: Bayer Health; Honoraria (self), Advisory /
Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers
Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Exelixis;
Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation /
Expenses: Merck; Research grant / Funding (self): Genentech; Research grant / Funding (self), Travel /
Accommodation / Expenses: Bayer/Onyx. D. Li: Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Exelixis; Advisory / Consultancy, Speaker Bureau /
Expert testimony: Ipsen; Honoraria (institution), Speaker Bureau / Expert testimony: Lexicon;
Advisory / Consultancy: Novartis; Speaker Bureau / Expert testimony: Advanced Accelerator
Applications. W. Verret: Full / Part-time employment: Genentech. Z.D. Xu: Full / Part-time employment:
Roche. S. Hernandez: Shareholder / Stockholder / Stock options, Full / Part-time employment:
Genentech. J. Liu: Full / Part-time employment: Roche. C. Huang: Full / Part-time employment:
Roche. S. Mulla: Full / Part-time employment: Roche. R. Finn: Advisory / Consultancy: AstraZeneca;
Advisory / Consultancy: Bayer; Advisory / Consultancy: BristolMyersSquibb; Advisory / Consultancy:
Eisai; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy:
Pfizer; Advisory / Consultancy: Roche/Genentech; Speaker Bureau / Expert testimony: Novartis.