In Light of Recently Approved Regimens, Sequencing Strategies Are Under Discussion in HCC

Laura Goff, MD

Following FDA approval of the first systemic therapy combination to demonstrate improved survival and greater response rates versus sorafenib (Nexavar) in frontline hepatocellular carcinoma (HCC), clinicians treating this disease continue to have more treatment options than ever before. This newfound advantage in a disease that once had limited opportunities for treatment leaves clinicians feeling optimistic for the future.

The regimen, which comprises the immunotherapy agent atezolizumab (Tecentriq) plus the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin), was discussed at the 17th Annual Meeting of the International Society of Gastrointestinal Oncologyâ (ISGIO), hosted by Physicians’ Education Resource, LLC (PERâ) by Laura Goff, MD, who is an associate professor of Medicine (Hematology/Oncology), medical director of the Division of Hematology and Oncology, and co-chair of the Data and Safety Monitoring Committee at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. In the presentation, she detailed this recent advancement in relation to its effect on the treatment paradigm of HCC.¹

The FDA handed down approval for the combination of atezolizumab and bevacizumab in May of this year for the treatment of patients with unresectable or metastatic HCC who had not received prior therapies for their disease.² The data that led to the approval of the combination were from the phase 3 IMbrave150 clinical trial (NCT03434379), which showed a 42% reduction in the risk of death versus standard-of-care sorafenib (HR, 0.58; 95% CI, 0.42-0.79; P <.001).³

“Atezolizumab/bevacizumab demonstrates striking response rates,” Goff said. By RECIST 1.1, the response rate with the PD-1/VEGF inhibitor combination was 27.3% versus 11.9% with sorafenib.³ These rates also compare favorably with response rates reported for other first- and second-line agents, she said.

Based on these data, Goff said that the combination of atezolizumab and bevacizumab is clearly the preferred frontline agent for metastatic HCC, but not all are eligible for its administration. Therefore, clinicians need to assess patients’ individual characteristics to determine what therapies are appropriate in each clinical situation.

To Use Frontline Atezolizumab/Bevacizumab or Not

Patients who may not be eligible for the combination include those who have contraindications for regimens containing an immunotherapeutic, most notably those who have received a liver transplant. For patients who are not candidates for treatment with immunotherapy, Goff attempted to clarify what is the next optimal therapy choice.

“I think it’s safe to say that lenvatinib [Lenvima] or sorafenib in patients who cannot tolerate immunotherapy would be appropriate first-line standard [agents],” said Goff, as both agents have been approved by the FDA and are supported by level 1 evidence.

The tyrosine kinase inhibitor TKI donafenib, an investigational agent with a chemical structure similar to that of the established agent regorafenib (Stivarga), is also under evaluation in a phase 2/3 randomized noninferiority trial versus sorafenib (NCT02645981). Data presented at the American Society for Medical Oncology 2020 Virtual Scientific Program showed that donafenib therapy resulted in modest overall survival (OS) benefit versus the comparator (12.1 vs 10.3; HR, 0.831; 95% CI, 0.699-0.988; P = .0363).⁴

Although the investigators concluded that these data support the use of single-agent donafenib in frontline HCC, Goff took a more measured approach to the results. “I think it remains to be seen if the role for this agent in the already crowded landscape of TKIs targeting VEGF, but I’m never sad to see additional drugs demonstrating activity in HCC,” Goff said of these data.

Troubling adverse effects of therapy related to bevacizumab may also preclude certain patients from receipt of the combination, including the incidence of esophageal varices. Even with screening, there was 7% rate of upper gastrointestinal tract bleeding in the atezolizumab/bevacizumab arm of IMbrave150 versus 4.5% with sorafenib.³

In the United States, nonalcoholic steatohepatitis tracks closely with cardiovascular disease and is an increasingly more common risk factor for HCC. Bevacizumab administered at doses of 10 to 15 mg/kg, such as the dose used in the approved regimen in HCC therapy, has been known to increase the relative risk of cardiac events and cerebral ischemia.

In these patients who are not suitable for therapy with bevacizumab, Goff considered single-agent immune checkpoint inhibitors such as nivolumab (Opdivo) or pembrolizumab (Keytruda). Both agents had previously received accelerated approvals from the FDA for use following sorafenib based on phase 2 trials that showed promising and durable response rates.^5,6

Regarding the phase 3 CheckMate 459 (NCT02576509) trial of single-agent nivolumab versus sorafenib in frontline disease, Goff said results were less impressive than expected. “While the response rates still looked better, the median overall survival did not demonstrate improvement. Still, [the agent induced] longer survival times than historically seen.” Despite this lack of level 1 evidence to support use of immunotherapy in the frontline setting, she said it is clear these agents have activity against HCC tumors, and there may still be a place for them in treatment sequencing.

“The newest kid on the block that is an alternative to VEGF targeting altogether is the combination of nivolumab and ipilimumab [Yervoy],” Goff said. She detailed data that were published in The Lancet in 2017 from the phase 1/2 CheckMate 040 trial (NCT01658878), which demonstrated a durable response rate and no new safety signals with the administration of the PD-1 plus CTLA-4 inhibitor combination in patients following progression on sorafenib.⁷ Based on these data, the combination was granted accelerated approval in this patient population.⁸

“We await randomized data to determine where this doublet may fit, especially in light of the [approval of] frontline atezolizumab/bevacizumab,” Goff said. “But if patients are not candidates for VEGF-targeting drugs, could this combination be better than single-agent nivolumab, pembrolizumab, or atezolizumab? These are questions that need to be addressed in trials.”

Choices in the Second-Line Setting

If atezolizumab/bevacizumab is indeed used in the frontline setting, Goff said many clinicians are insisting that sorafenib is the best choice as second-line therapy, given its long-established track record of efficacy. In addition, the TKI structure may have better activity following an immunotherapy-plus-VEGF-inhibitor combination versus other types of agents.

Other questions remain, such as whether or not ramucirumab (Cyramza) should be used in patients with a-fetoprotein levels of greater than 400 ng/mL following bevacizumab. Some evidence exists showing that the anti-VEGF agent sequence has activity in colorectal cancer.⁹ However, the trial she discussed used ramucirumab in combination with other drugs, so the activity may not translate to use of the single agent.

Additionally, it needs to be determined whether the escalation of immunotherapy with the nivolumab/ipilimumab combination would be efficacious following frontline atezolizumab plus bevacizumab. Goff said it is possible that these patients may be insensitive to immunotherapy and moving on to TKIs could be the best option.

In patients who received sorafenib in the frontline, Goff said these questions regarding the new frontline combination can also be extrapolated as there are no data to support or contradict the use of atezolizumab and bevacizumab in the second-line setting. “[The combination’s] striking activity in the frontline argues for at least a consideration of this sequence,” Goff said.

Furthermore, phase 3 data supporting the use of the TKI regorafenib following sorafenib demonstrate long OS times, and Goff questions whether it makes sense to employ other sequencing strategies at this time that are only supported by uncontrolled data.

Looking Ahead

Goff concluded by outlining other potentially practice-changing regimens under investigation, such as lenvatinib plus pembrolizumab that is being explored in the phase 3 LEAP-002 trial (NCT03713593), as evidence that the HCC systemic therapy picture is rapidly evolving.

“[These data taken together] leads us to many exciting questions as to how best to use our options and where we can go next,” Goff concluded. “Ongoing studies are likely to continue to make headlines and improve care for our patients.”

References

1. Goff L. Optimizing treatment in advanced hepatocellular carcinoma. Presented at: 17th Annual Meeting of the International Society of Gastrointestinal Oncologyâ, hosted by Physicians’ Education Resource, LLC (PERâ). October 2-3, 2020. Virtual.
2. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. FDA. May 29, 2020. Accessed October 2, 2020. https://bit.ly/2HMdXRD
3. Finn RS, Qin S, Ikeda M, et 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
4. Bi F, Qin S, Gu S, et al. Donafenib versus sorafenib as first-line therapy in advanced hepatocellular carcinoma: An open-label, randomized, multicenter phase II/III trial. J Clin Oncol. 2020;38(suppl 15):4506. doi: 10.1200/JCO.2020.38.15_suppl.4506
5. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. September 27, 2017. Accessed October 2, 2020. https://bit.ly/2HJrYj0
6. FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. FDA. November 9, 2018. Accessed October 2, 2020. https://bit.ly/3lcXsN7
7. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2
8. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA. March 10, 2020. Accessed October 5, 2020. https://bit.ly/2GDrryM
9. Hochster HS, Catalano PJ, O’Dwyer PJ, et al. Randomized trial of irinotecan and cetuximab (IC) versus irinotecan, cetuximab and ramucirumab (ICR) as 2nd line therapy of advanced colorectal cancer (CRC) following oxaliplatin and bevacizumb based therapy: Result of E7208. J Clin Oncol. 2018;36(suppl 15):3504. doi:10/1200/JCO.2018.36.15_suppl.3504