Adjuvant therapy with atezolizumab (Tecentriq®; Genentech/Roche) and bevacizumab (Avastin®; Genentech/Roche) increased recurrence-free survival of patients with hepatocellular carcinoma (HCC), a primary tumor of the liver, following surgical resection or ablation.*

This conclusion is based on the results from the phase 3 IMbrave050 clinical trial, which were presented at the American Association for Cancer Research (AACR) 2023 Annual Meeting, being held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida.[1]

The study was funded by F. Hoffmann-La Roche.

Hepatocellular carcinoma (HCC) is the seventh most common cancer and the second leading cause of cancer-related mortality in the world, with an estimated 841,080 new cancer cases and accounts for 781,631 deaths worldwide.[2]

“The mainstays of curative therapies for early-stage HCC include surgical resection and thermal ablation, a treatment that destroys the cancer cells with heat or cold. However, the risk of recurrence reaches 70–80% five years after resection or ablation with curative intent,” explained presenting author Pierce Chow, FRCS(E), Ph.D., senior consultant surgeon at National Cancer Centre Singapore and Singapore General Hospital, and professor and program director at Duke-NUS Medical School, Singapore.

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Today, there is no standard of care in the adjuvant setting for hepatocellular carcinoma following resection or ablation with curative intent. Furthermore, the risk of postoperative recurrence is high, and this rate is even higher in patients with high-risk features including large tumor size, multiple tumors, poor tumor differentiation, or vascular invasion. [1]

Pierce Chow, FRCS(E), Ph.D., senior consultant surgeon at National Cancer Centre Singapore and Singapore General Hospital, and professor and program director at Duke-NUS Medical School, Singapore.

“Due to the lack of proven adjuvant therapy strategies for HCC, patients who are treated with surgical resection or thermal ablation with curative intent tend to have significantly higher recurrence rates and shorter overall survival than patients with other types of cancer, for example, colorectal and breast cancer treated with similar curative intent,” said Chow.

“The positive results of IMBrave050 address this huge and urgent unmet clinical need in HCC,” Chow added.

The efficacy of an adjuvant treatment
The randomized, controlled phase 3 IMbrave050 trial was designed to investigate the efficacy of an adjuvant treatment combination of the checkpoint inhibitor atezolizumab and the targeted therapy bevacizumab in delaying or preventing recurrence compared with active surveillance, which represents the current standard of care after complete surgical resection or ablation.

The trial enrolled 668 patients with HCC who were at high risk of recurrence following tumor resection or ablation, based on criteria such as size and number of tumors, presence of cancer cells within the lumen of blood and/or lymphatic vessels, and tumor grade. Study participants were randomly assigned (1:1) to receive atezolizumab (1200 mg) plus bevacizumab (15 mg/kg IV) every three weeks (q3w)  for a period of one year or 17 cycles or undergo active surveillance for one year.

Patients in the control arm were eligible to switch to the experimental arm in case of recurrence. The primary endpoint was independent review facility-assessed recurrence-free survival (IRF-RFS).

Stratification factors included geographic region (Asia-Pacific excluding Japan vs rest of world) and a composite factor encompassing the number of high-risk features, curative procedure, and use of optional adjuvant TACE (allowed for one cycle following resection).

Interim analysis
In this study, the primary endpoint was independent review facility (IRF-) assessed recurrencefree survival (RFS). Secondary efficacy endpoints included Overall Survival (OS); investigatorassessed (INV) recurrence-free survival (RFS); RFS and OS according to PDL1 status; and time to extrahepatic spread and/or macrovascular invasion.

According to the results of an interim analysis in the intent to treat population, conducted after a median follow-up of 17.4 months, the trial met its primary endpoint, and the combination of atezolizumab and bevacizumab significantly increased IRF-RFS with an HR of 0.72 (95% CI, 0.56, 0.93; P=0.0120), and results were generally consistent across clinical subgroups, when used as adjuvant therapy following surgical resection or ablation. INVRFS was similar (HR, 0.70; 95% CI, 0.54, 0.91).

Patients who received the combination treatment had their risk of recurrence or death reduced by 28% compared with patients in the active surveillance arm. At this time-point, the median IRF-RFS was not reached for either arm.

Chow noted that the patients stayed on treatment longer than in the previous IMbrave150 trial that evaluated the same combination of drugs for unresectable HCC (median duration of treatment for atezolizumab and bevacizumab, respectively, was 11.07 and 11.02 months in IMbrave050 and 7.4 and 6.9 months in IMbrave150).

“Despite the longer duration of treatment, the incidence of serious therapy-related adverse events was comparable to that in the IMbrave150 trial, indicating tolerability of this regimen when used as adjuvant therapy,” he said.

“IMbrave050 is a landmark study and the first to demonstrate an efficacious adjuvant therapy for patients with HCC who have undergone surgical resection or ablation,” Chow said.

“These results have established a benchmark in adjuvant therapy for HCC and have the potential to be practice-changing,” he noted.

Chow added that better clinical outcomes following treatment with this adjuvant regimen might also have an impact on the clinical indications for surgical resection and ablation in HCC.

“Currently, surgery is not offered to many patients with potentially resectable disease if rapid recurrence is expected based on tumor burden or the presence of vascular invasion,” said Chow.

“The availability of an efficacious adjuvant therapy may lead to a reassessment of which patients may benefit from surgical resection,” he added.

Study limitations
According to the author, the limitations of the study include that, since the trial met its primary endpoint earlier than expected, the data were not mature enough to allow the researchers to determine the outcomes of the trial’s secondary endpoints, including overall survival.

“For these results, we will have to wait for subsequent analyses,” Chow concluded.

Note: *The Phase 3 IMbrave150 study has previously demonstrated statistically significant and clinically meaningful improvement in progressionfree survival, overall survival and objective response rate with the combination of atezolizumab + bevacizumab compared with sorafenib in the firstline unresectable hepatocellular carcinoma setting. As a result, atezolizumab + bevacizumab is an established standard of care for advanced, unresectable disease. [3]

Clinical trials
A Study of Atezolizumab Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation (IMbrave050) – NCT04102098
A Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma (IMbrave150) – NCT03434379

Highlights of prescribing information
Atezolizumab (Tecentriq® Genentecg/Roche) [Prescribing Information]
Bevacizumab (Avastin®; Genentech/Roche)[Prescribing Information]
Sorafenib (Nexavar®; Bayer)[Prescribing Information]

[1] Chow P, Chen M, Cheng AL, Kaseb AO, Kudo M, Lee HC, Yopp A, Zhou J, Wang L, Wen X, Heo J, Tak YW, Nakamura S, Numata K, Uguen T, Hsiehchen D, Cha E, Hack SP, Lian Q, Spahn J, Wu C, Qin S. IMbrave050: Phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr CT003.
[2] Wang L, Wang W, Rong W, Li Z, Wu F, Liu Y, Zheng Y, Zhang K, Siqin T, Liu M, Chen B, Wu J. Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study. BMC Cancer. 2020 Jul 1;20(1):614. doi: 10.1186/s12885-020-07087-7. PMID: 32611327; PMCID: PMC7329435.
[3] Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745. PMID: 32402160.

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