First-Line Systemic Strategies Continue to Evolve in HCC

Anthony B. El-Khoueiry, MD

The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) is likely to become the new frontline standard in unresectable hepatocellular carcinoma (HCC) in the near future, according to Anthony B. El-Khoueiry, MD, associate professor of clinical medicine at University of Southern California Norris Comprehensive Cancer Center in Los Angeles. For the time being, however, sorafenib (Nexavar) and lenvatinib (Lenvima) remain the current standard of care.

El-Khoueiry reviewed sequencing in first-line therapy for HCC as part of the virtual platform for the 5th Annual School of Gastrointestinal Oncology™ (SOGO®), hosted by Physicians’ Education Resource®, LLC (PER®).

“We have multiple systemic therapy options now available in this disease, which is fantastic for patients,” he said. “This all happened within the span of 2 to 3 years. It’s becoming critical to transition patients from liver-directed therapy to systemic therapy at the right time.” (Timeline)

In January, Roche submitted a supplemental biologics license application to the FDA for the combination of atezolizumab and bevacizumab for the treatment of patients with unresectable HCC who have not received prior systemic therapy based on findings from the phase 3 IMbrave150 study (NCT03434379). Ann-Lii Cheng, MD, director of the National Taiwan University Cancer Center, presented the data in November at the European Society for Medical Oncology Asia 2019 Congress.¹

The combination induced a 42% reduction in the risk for death (HR, 0.58; 95% CI, 0.42-0.79; P = .0006) and a 41% reduction in the risk for disease progression or death versus sorafenib (HR, 0.59; 95% CI, 0.47- 0.76; P <.0001).

After a median follow-up of 8.6 months, the median overall survival (OS) was not reached in the combination arm compared with 13.2 months in the sorafenib arm. The 6-month OS rate also favored the combination, 85% versus 72%, respectively.

The combination arm also significantly improved median progression-free survival (6.8 vs 4.3 months; HR, 0.59; 95% CI, 0.47, 0.76; P <.0001). The 6-month progression-free survival rate was 55% in the experimental arm versus 37% in the sorafenib arm.

Atezolizumab plus bevacizumab induced an overall response rate (ORR) more than twice as high as sorafenib (27% vs 12%, P <.0001) based on independent assessment using RECIST 1.1 guidelines.

Per IMbrave150 protocol, 501 patients were randomly assigned to atezolizumab plus bevacizumab or sorafenib alone. Investigators administered 1200 mg of IV atezolizumab on day 1 of each 21-day cycle; IV bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. Oral sorafenib was administered at 400 mg twice daily on days 1 to 21 of each 21-day cycle. In both arms, treatment was given until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

“This is the first study in 11 years to show an improvement in survival with a new firstline treatment option compared to sorafenib, which has been the standard of care throughout this time,” Cheng said in a news release. “Atezolizumab plus bevacizumab has the potential to be a practice-changing treatment option in hepatocellular carcinoma.”

El-Khoueiry had some caveats about the combination. Mature data are not yet available, and he noted that all patients in the IMbrave150 study were required to have an endoscopy within the previous 6 months and varices had to be treated. He added that physicians should avoid extrapolating the data and treating patients beyond Child-Pugh A liver function because of an increased risk for portal hypertension and variceal bleeding.

“We can’t just take everyone to this without the appropriate caution,” he said, adding that sorafenib or lenvatinib will remain the best choice for patients with contraindications to bevacizumab or atezolizumab.

Shaking Up the Standard Proves Difficult

The FDA approved lenvatinib for use in this patient population based on findings from the phase 3 REFLECT trial, which were first presented at the 2017 American Society of Clinical Oncology Annual Meeting and later published in the Lancet. Findings from REFLECT demonstrated that the primary end point of OS was noninferior for lenvatinib versus sorafenib (13.6 vs 12.3 months; HR, 0.92; 95% CI, 0.79-1.06).^2,3

The ORR was 24.1% with lenvatinib (n = 478) versus 9.2% with sorafenib (n = 476; OR, 3.13; 95% CI, 2.15-4.56; P <.00001). The complete response rate was 1.3% in the lenvatinib group and 0.4% with sorafenib.

“They’re noninferior. Both are valid options,” El-Khoueiry said of lenvatinib and sorafenib. “But if we have patients who are symptomatic, who need a response, we may gravitate toward lenvatinib.”

In a post hoc analysis of the REFLECT trial presented at the 2020 Gastrointestinal Cancers Symposium, patients with unresectable HCC treated with lenvatinib demonstrated a median OS of 23.0 months, compared with 9.6 months in those randomized to first-line sorafenib. The HR was 0.71, although this difference fell just short of statistical significance (95% CI, 0.51-1.01).⁴

Investigators had hoped that nivolumab (Opdivo), which is active in secondline therapy, would become another treatment option in the first line. They compared the anti–PD-1 monoclonal antibody versus sorafenib in the phase 3 CheckMate 459 trial (NCT02576509). Patients with advanced HCC were assigned to 240-mg IV nivolumab every 2 weeks (n = 371) or 400-mg twice-daily oral sorafenib (n = 372).⁵

The median OS was 16.4 months for nivolumab and 14.7 months for sorafenib (HR, 0.85; 95% CI, 0.72-1.02; P = .0752), which did not meet the predefined threshold for statistical significance.

However, nivolumab induced an ORR of 15% versus 7% for sorafenib, and nivolumab produced superior health-related quality of life and reduced treatment burden, leading investigators to consider a role for the immune checkpoint inhibitor in patients with unresectable HCC.

Emerging Options

El-Khoueiry said investigators are exploring a variety of drug combinations for first-line treatment in ongoing trials, noting that the use of these will likely be decided on a case-by-case basis by evaluating the risk-benefit ratio for each individual patient. with a survival benefit as compared with neoadjuvant radiation therapy for the treatment of patients with type II GEJ cancer.⁵

Timeline. Approvals for the Treatment of Hepatocellular Carcinoma

A total of 1497 patients with resectable GEJ cancer were identified, with 746 receiving adjuvant radiation therapy and 751 receiving neoadjuvant radiation therapy. Adjuvant radiation had a significantly lower death risk (HR, 0.84; 95% CI, 0.73-0.97; P = .0168) as well as a significantly lower disease-specific death risk (HR, 0.84; 95% CI, 0.72-0.97; P = .0211).⁵

“The individualized surgical approach remains critical not only preoperatively but also intraoperatively for decision making,” Yang said.

References

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2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Esophageal and esophagogastric junction cancers (version 1.2020). Accessed April 20, 2020. https:// www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
3. Nagaraja A, Kikuchi O, Bass A. Genomics and targeted therapies in gastroesophageal adenocarcinoma. Cancer Discov. 2019;9(12):1656-1672. doi:10.1158/2159-8290.CD-19-0487
4. Parry K, Haverkamp L, Bruijnen R, et al. Surgical treatment of adenocarcinomas of the gastro-esophageal junction. Ann Surg Oncol. 2015;22(2):597-603. doi:10.1245/s10434-014-4047-1
5. Miccio J, Oladeru O, Yang J. et al. Neoadjuvant vs. adjuvant treatment of Siewert type II gastroesophageal junction cancer: an analysis of data from the surveillance, epidemiology, and end results (SEER) registry. J Gastrointest Oncol. 2016;7(3):403- 410. doi:10.21037/jgo.2015.10.06