Investigators Test Immunotherapy Combo in HCC

Stacey Stein, MD

Investigators hope to expand frontline treatment options for patients with hepatocellular carcinoma (HCC) via the phase III IMbrave150 study (NCT03434379), which is exploring the synergistic potential of immunotherapy and the immunomodulatory potential of a VEGF inhibitor in locally advanced, metastatic or unresectable HCC. In IMbrave150, patients are being randomized 2:1 to receive either a doublet of atezolizumab (Tecentriq) and bevacizumab (Avastin) or standard-of-care single-agent sorafenib (Nexavar; Figure).¹

Investigators believe atezolizumab and bevacizumab could be clinically beneficial in this patient population due to the pair’s complementary mechanisms of action. Atezolizumab promotes T-cell activation by binding to PD-L1 and inhibiting interaction with PD-1 and B7-1 receptors.² Bevacizumab is an antiangiogenic therapy that targets the VEGF protein. Investigators hope to capitalize on bevacizumab’s immunomodulatory effects in the tumor microenvironment, such as enhanced T-cell infiltration, influence on dendritic cell maturation, and downregulation of myeloid-derived suppressor cells that promote tumor growth.

Breakthrough Combination

In July 2018, the FDA granted a breakthrough therapy designation to the combination in frontline advanced or metastatic HCC.³ The decision was based on promising results from a phase IB study (NCT02715531) that assessed the safety and clinical activity of atezolizumab and bevacizumab as a first-line treatment for patients with unresectable or metastatic HCC who were naïve to systemic therapy. According to findings presented at the 2018 American Society of Clinical Oncology Annual Meeting, investigators observed responses in all subgroups, regardless of disease etiology, region, baseline alpha-fetoprotein levels, or spread of the tumor beyond the liver. Among 21 evaluable patients, confirmed partial responses were seen in 13 (62%). In addition, the doublet regimen was well tolerated. In 26 evaluable patients in the safety population, treatment-related grade 3/4 adverse events (AEs) were seen in 9 (35%), the most common being hypertension (n = 5). No grade 5 AEs were observed.⁴

Investigators of the phase IB study continue to collect progression-free survival (PFS) and overall survival (OS) data. The updated response rate is now 32%, which investigator Stacey Stein, MD, described as “still significantly high” in an interview with OncologyLive^®.

In addition, in response to an FDA request, investigators have expanded the phase IB study to include an option for atezolizumab monotherapy in patients with advanced, metastatic or unresectable HCC with no prior systemic treatment, according to Stein, assistant professor of medicine (medical oncology) at Smilow Cancer Hospital in New Haven, Connecticut.

Informing Future Study

The phase IB study paved the way for IMbrave150, which completed enrollment in January 2019 and has accrued more than 500 patients. The anticipation that surrounds the frontline synergistic potential of the atezolizumab and bevacizumab combination is partly due to HCC’s rising incidence and mortality. HCC is the most common primary malignancy of the liver and has the highest mortality- to-incidence ratio of any solid tumor.^2,5 In the United States each year, there are an estimated 6 new cases per 100,000 individuals, up from 1.4 new cases in the 1970s, and more than 29,000 deaths. The rising incidence is believed to be due to an aging population of patients with hepatitis C infection who have developed liver injury in recent decades.⁵

Figure. Atezolizumab Plus Bevacizumab in Metastatic HCC¹

A series of unfruitful attempts to expand the first-line therapies available to patients with HCC also accounts for much of the enthusiasm about the combination. In frontline unresectable HCC, sorafenib was notably the sole treatment until the August 2018 indication of lenvatinib (Lenvima).⁶ The FDA’s acceptance of the multiple-receptor tyrosine kinase inhibitor followed the phase III REFLECT trial (NCT01761266), the results of which showed that lenvatinib was noninferior but not statistically superior to sorafenib in OS (HR 0.92; 95% CI, 0.79-1.06); the median OS was 13.6 months with lenvatinib and 12.3 months with sorafenib. Median PFS was 7.3 versus 3.6 months, respectively. Lenvatinib’s approval constituted rare success in the ongoing effort to broaden the portfolio of first-line treatment options. Investigators have evaluated several agents for the treatment of HCC, but none led to new approvals or indications.

For example, investigators of the phase III CheckMate-459 trial (NCT02576509) compared nivolumab (Opdivo) with sorafenib in the frontline treatment of advanced HCC. Although the data from the phase III study have not been presented, Bristol-Myers Squibb announced in June that the nivolumab findings did not achieve statistical significance for improved OS, the trial’s primary endpoint.⁷

The phase III KEYNOTE-240 trial (NCT02702401) examined the efficacy of second-line or later pembrolizumab (Keytruda) in patients with advanced disease who completed prior systemic therapy.⁸ Patients were randomized to receive pembrolizumab plus best supportive care (BSC; n = 278) or placebo plus BSC (n = 135). Those treated with the anti—PD-1 therapy achieved longer OS (HR, 0.78; 95% CI, 0.611-0.998; P = .0238) and PFS (HR, 0.78; 95% CI, 0.61-0.99; P = .0219) versus those treated with BSC. However, neither the OS nor the PFS was statistically significant in the context of the study’s predetermined statistical plan.

“These were the first randomized studies in HCC with immunotherapy, and both were negative, which is disappointing,” Stein said. “Especially given the negative data of the single immunotherapy [agents] that have come out recently, everyone is looking forward to seeing the combination data…. I think we’re going to see more positive data with the combination than with the single agents.”

Richard Finn, MD, director of the Signal Transduction and Therapeutics Program at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, echoes Stein’s sentiment. “The combination responses are higher than with atezolizumab alone or with bevacizumab alone, or for that matter with lenvatinib or pembrolizumab alone, so there’s a lot of interest in this,” Finn told OncologyLive^®. Finn is also the principal investigator of the IMbrave150 trial, which includes the coprimary endpoints of OS and PFS.

Finn said that response rates for combinations of VEGF inhibitors and PD-1/PD-L1 inhibitors in HCC tend to fall between 30% and 40%, whereas rates for PD-1/PD-L1 inhibitors alone are about 15% to 20%. “When you use either agent alone, you get a certain response rate, but when you use the agents together, you increase the response rate, because more patients will derive benefit,” he said.

Elevating response rates is of paramount importance for IMbrave150 investigators, because there is no biomarker for HCC. IMbrave150 investigators and those of other HCC-focused studies cannot predict which patients will respond to treatment. “You either develop a biomarker for patients who respond or you increase the number of patients who benefit. With the checkpoint agents, there are subsets of patients who have dramatic responses, and I think that the real hope is that you’ll increase the number of patients who respond when you combine these drugs with VEGF inhibitors,” Finn said.

Although the lack of a definitive biomarker that predicts for response poses a difficulty at present, Finn and Stein agree that the identification of a biomarker is possible and will eventually improve the process by which patients are selected for treatment. “What will be important with the blood samples and pathology specimens that we have for patients in these combination studies will be trying to elucidate some marker or patient group who is more likely to respond,” Stein said. “We really have no way of selecting patients for treatments right now, so we’re just offering the same treatments to everyone.”

Moving Forward

Reported studies of frontline agents and their effects on patient survival show that existent first-line treatment options can extend survival in HCC for about a year, but a more effective armamentarium is essential, Finn said. “Although we think that [survival] is getting better, it’s not even a question. We need more options.”

References

1. A Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma [IMbrave150] (IMbrave150). clinicaltrials.gov/ct2/show/NCT03434379. Updated July 22, 2019. Accessed July 23, 2019.
2. Finn RS, Ducreux M, Qin S, et al. IMbrave150: a randomized phase III study of 1L atezolizumab plus bevacizumab vs sorafenib in locally advanced or metastatic hepatocellular carcinoma. Presented at: 2018 American Society of Clinical Oncology Genitourinary Cancers Symposium; June 1-5, 2018; Chicago, IL. Abstract TPS4141. meetinglibrary.asco.org/ record/165293/abstract.
3. FDA grants breakthrough designation for atezolizumab/bevacizumab combination as first-line treatment for advanced or metastatic HCC. The ASCO Post. July 24, 2018. ascopost.com/News/59089. Updated September 14, 2018. Accessed July 11, 2019.
4. Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study of hepatocellular carcinoma (HCC). Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 4074. meetinglibrary.asco.org/record/160179/abstract.
5. Schwartz JM. Hepatocellular carcinoma (HCC). National Organization for Rare Disorders website. rarediseases.org/physician-guide/ hepatocellular-carcinoma-hcc/. Accessed July 18, 2019.
6. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi: 10.1016/S0140- 6736(18)30207-1.
7. Bristol-Myers Squibb announces results from CheckMate-459 study evaluating Opdivo (nivolumab) as a first-line treatment for patients with unresectable hepatocellular carcinoma [press release]. Princeton, NJ: Bristol-Myers Squibb; June 24, 2019. news.bms.com/press-release/bmy/bristol-myers-squibb-announces- results-checkmate-459-study-evaluating-opdivo- nivol. Accessed July 11, 2019.
8. Merck provides update on KEYNOTE-240, a phase 3 study of KEYTRUDA (pembrolizumab) in previously treated patients with advanced hepatocellular carcinoma [press release]. Kenilworth, NJ: Merck; February 19, 2019. mrknewsroom. com/news-release/oncology/merck-provides-update-keynote- 240-phase-3-study-keytruda-pembrolizumab-previou. Accessed July 19, 2019.