ASCO GI Updates Provide Window Into Evolving HCC Treatment Paradigm

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the fourth leading cause of global cancer-related mortality.¹ Despite its prevalence, many patients historically have faced a poor prognosis and a lack of effective treatment options beyond surgery. However, that is beginning to change with the development of new therapeutic approaches.¹

During a recent OncLive Peer Exchange, a panel of oncologists discussed updated findings from key clinical trials presented during the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI), which was held in January. They highlighted key data across the spectrum of HCC management, the use of frontline systemic treatment for advanced HCC, and sequencing considerations in the second line and beyond.

Initial Therapies for HCC

The panel started by reviewing updates on initial treatment options for patients with HCC. For patients with HCC who are eligible for embolization, the standard of care is transarterial chemoembolization (TACE). However, the median progression-free survival (PFS) for patients following TACE is only 7 to 8 months, underscoring the need for more effective therapies for patients with embolization-eligible HCC. Additionally, due to the heterogeneity of HCC in terms of tumor burden, liver function, and comorbidities, the efficacy of TACE can vary greatly.^2,3

During ASCO GI, investigators presented findings from the phase 3 EMERALD-1 trial (NCT03778957), which evaluated TACE plus durvalumab (Imfinzi) with or without bevacizumab (Avastin) in patients with embolization- eligible, unresectable HCC. Patients were randomly assigned 1:1:1 to receive durvalumab, bevacizumab, and TACE (n = 204); durvalumab plus TACE (n = 207); or placebo plus TACE (n = 205). The primary end point was PFS for the durvalumab, bevacizumab, and TACE arm vs the placebo plus TACE arm. Secondary end points included PFS for durvalumab plus TACE vs TACE alone, overall survival (OS), objective response rate (ORR), time to progression (TTP), and safety.²

“[These data from] ASCO GI showed us that there is probably a new era in terms of multimodality approaches and integrating our liver-directed approaches with systemic therapy as it gets better and better,” Rachna T. Shroff, MD, MS, FASCO, said. “The short story is that there were not necessarily any positive trials in this space leading up to EMERALD-1 and that’s why it made such a splash.”

At the final PFS analysis, the median PFS was 15.0 months (95% CI, 11.1-18.9) in the durvalumab, bevacizumab, and TACE arm vs 8.2 months (95% CI, 6.9-11.1) with placebo plus TACE (HR, 0.77; 95% CI, 0.61-0.98; P = .032). The 12- and 18-month PFS rates were 55.5% and 43.1% with durvalumab and bevacizumab vs 39.8% and 28.3%, respectively, with TACE alone.

Additionally, the median TTP was 22.0 months (95% CI, 16.6-24.9) vs 10.0 months (95% CI, 7.1-13.6) in the durvalumab and bevacizumab arm vs the placebo arm, respectively (HR, 0.63; EL-95% CI, 0.48-0.82). The confirmed ORR was 43.6% vs 29.6%, respectively (OR, 1.87; 95% CI, 1.24- 2.84), including complete response (CR) rates of 3.0% vs 2.5%.

However, the durvalumab plus TACE arm did not display a significant benefit in terms of PFS vs the placebo arm; the median PFS was 10.0 months (95% CI, 9.0-12.7) compared with 8.2 months (95% CI, 6.9-11.1), respectively (HR, 0.94; 95% CI, 0.75-1.19; P = .638). The median TTP in the durvalumab plus TACE arm was 11.5 months (95% CI, 9.2-13.9), and the confirmed ORR was 41.0% with a 1.5% CR rate.

“This [trial] is potentially practice-changing, [however], we’re not sure how to extrapolate this with institutions that tend to use more transarterial radioembolization [TARE] than TACE in terms of how we can combine the systemic approach with that approach,” Jun Gong, MD, said. “[Additionally], the durvalumab plus TACE arm didn’t do better than placebo plus TACE, which raises the [question of] whether there is a VEGF benefit. There have been a lot of negative trials with VEGF inhibition plus local regional therapy, so I wonder if the addition of VEGF inhibition is important for modulating the immunotherapy component with local regional therapy and that’s why this combination did better.”

Study authors concluded that EMERALD-1 met its primary end point and noted that it was the first global phase 3 trial to display a significant and clinically meaningful PFS benefit with immunotherapy plus TACE in this population of patients with HCC. They concluded that the regimen could potentially represent a new standard of care in unresectable HCC eligible for embolization.

“We also are waiting to see a lot more details in relation to the tumor burden of these patients— what was it exactly and is there a specific subgroup that had more benefit than others, [etc]. It’s also unclear if we would get the same outcome if we did TACE followed [immediately] by systemic therapy rather than delayed systemic therapy. But as a proof of concept, that an effective immunotherapy combination could be combined with liver-directed therapy and potentially could be beneficial, that’s what we’ve learned from EMERALD-1. How we incorporate it into practice is going to have to evolve with more data,” Anthony B. El-Khoueiry, MD, added.

The panel also briefly discussed findings from the phase 2 REPLACEMENT study (jRCTs071200051), which were presented during the 2023 ASCO Annual Meeting.

REPLACEMENT was a trial in Japan that evaluated the combination of atezolizumab (Tecentriq) plus bevacizumab in patients with intermediate-stage HCC who were eligible for TACE. The primary end point was PFS; secondary end points included ORR, OS, duration of response, and safety.³

At the August 15, 2022, data cutoff, patients who received the combination (n = 74) had achieved a median PFS of 9.1 months (95% CI, 7.1-10.2) with a 6-month PFS rate of 66.8% (95% CI, 54.7%-76.4%) and a median OS of not reached (NR; 95% CI, NR-NR) with a 6-month OS rate of 94.5% (95% CI, 86.0%-97.9%). The ORR by HCC mRECIST was 45.9% (95% CI, 34.3%-57.9%), including a CR rate of 16.2%.

“[Investigators] used an existing control group of patients who received TACE [with] propensity matching for those patients,” Michael Morse, MD, MHS, FACP, said. “It was interesting in that if you do that comparison, PFS was better with systemic therapy and the response rate was better. The OS hadn’t been reached with this early data, but it certainly suggests that patients who are not ideal candidates for local regional therapy like TACE certainly could benefit quite a bit from the systemic therapy with atezolizumab plus bevacizumab.”

Frontline Systemic Therapy for Advanced HCC

The panelists opened their conversation on frontline therapy in the advanced setting by discussing the regimen most recently approved by the FDA, tremelimumab (Imjudo) plus durvalumab. The combination was approved for the treatment of adult patients with unresectable HCC on October 21, 2022.⁴

The approval was supported by findings from the phase 3 HIMALAYA trial (NCT03298451), which compared the safety and efficacy of the STRIDE regimen (single tremelimumab regular interval durvalumab) with sorafenib (Nexavar) in patients with unresectable HCC who had no prior systemic therapies. The primary end point was OS; secondary end points included PFS, TTP, ORR, and safety.⁵

Updated findings from HIMALAYA, which were presented during the European Society for Medical Oncology Asia Congress 2023 in December, showed that at a median follow-up of 49.12 months (95% CI, 46.95-50.17) in the STRIDE arm (n = 393) and 47.31 months (95% CI, 45.08- 49.15) in the sorafenib arm (n = 389), treatment with STRIDE led to a 22% reduction in the risk of death compared with sorafenib (HR, 0.78; 95% CI, 0.67-0.92). The 36-month OS rates were 30.7% (95% CI, 26.1%-35.3%) vs 19.8% (95% CI, 15.9%- 24.1%), respectively, and the 48-month OS rates were 25.2% (95% CI, 20.8%-29.7%) vs 15.1% (95% CI, 11.5%-19.2%), respectively.

The panelists then discussed the current role of atezolizumab plus bevacizumab, which is considered the standard of care in frontline unresectable HCC. On May 29, 2020, atezolizumab plus bevacizumab was approved by the FDA for the frontline treatment of patients with unresectable or metastatic HCC based on findings from the phase 3 IMbrave150 trial (NCT03434379).⁶

IMbrave150 randomly assigned patients 2:1 to receive atezolizumab plus bevacizumab (n = 336) or sorafenib (n = 165); the coprimary end points were OS and PFS. The median OS was NR in the combination arm compared with 13.2 months (95% CI, 10.4-not estimable) in the sorafenib arm (HR, 0.58; 95% CI, 0.42-0.79; P = .0006). The estimated median PFS was 6.8 months (95% CI, 5.8-8.3) vs 4.3 months (95% CI, 4.0-5.6), respectively (HR, 0.59; 95% CI, 0.47-0.76; P < .0001).

“I believe both of those regimens are viable in the frontline space considering the different populations that went on both studies, which might [also] explain why we’ve seen different median OS between the two studies,” Anwaar Saeed, MD, said. “But in real-world practice, the patients that I would avoid using durvalumab/ tremelimumab in would be those [who] have issues with getting a timely esophagogastroduodenoscopy [EGD] to rule out high-risk viruses, variceal bleeding, and other issues. That’s a big issue in busy clinical practices in the community as well as in some of the larger cancer centers where the endoscopy suites are busy with a high volume of patients. [We know] getting a timely EGD for a patient who needs to start therapy is important.”

During ASCO GI, investigators presented findings from a retrospective observational study that examined 374 patients who initiated first-line therapy with atezolizumab plus bevacizumab between January 2019 and August 2022 within the US Oncology Network. The median real-world OS was 13.2 months (95% CI, 9.5-15.9) and the median real-world PFS was 6.4 months (95% CI, 5.1-7.7). The estimated 6- and 12-month real-world PFS rates were 52.2% (95% CI, 46.7%-57.5%) and 33.4% (95% CI, 27.8%-39.1%), respectively, and the estimated 6- and 12-month real-world OS rates were 68.6% (95% CI, 63.2%-73.3%) and 53.5% (95% CI, 47.4%-59.2%).⁷

Findings from an exploratory subgroup analysis revealed that patients with Child-Pugh class A (n = 229), B (n = 91), or C (n = 12) disease had a median real-world PFS of 7.3 months (95% CI, 5.4-9.4), 5.7 months (95% CI, 3.1-7.0), and 4.5 months (95% CI, 1.3-9.2), respectively. The median real-world OS in these groups was 16.5 months (95% CI, 12.6-NR), 7.5 months (95% CI, 4.7-9.9), and 4.5 months (95% CI, 1.3-NR), respectively. Investigators noted that outcomes with atezolizumab plus bevacizumab did not differ significantly across etiology and race/ ethnicity subgroups. “In community oncology settings, first-line atezolizumab plus bevacizumab demonstrates effectiveness in diverse patient cohorts, including those with impaired liver function, nonviral liver disease, and racial/ ethnic minorities,” they conclude.

“For now, the National Comprehensive Cancer Network guidelines place a category 1 [recommendation] for atezolizumab plus bevacizumab [for patients] with Child-Pugh A disease,” Gong said. “This is where the [real-]world evidence really shares some more insight into [outcomes in] the real world. For the most part, the retrospective real-world studies have mirrored the trial data in terms of efficacy and safety, but [this analysis also] provided more insight into [one-fourth] to one-third of the study population that was Child-Pugh B. The OS, not surprisingly, was a little bit inferior to [that of] the Child- Pugh A population. There have been some mixed results [in terms of adverse effects (AEs)], where the AEs may be comparable to [those seen in] the Child-Pugh A population. But this is where some more granularity [could be beneficial]. [Indicating] whether they’re including those with Child-Pugh B 7 vs 8 vs 9 could really separate out who gets the more toxic results with this combination.”

Added El-Khoueiry, “A prospective trial into Child-Pugh B 7 and 8 populations is launching imminently with atezolizumab plus bevacizumab to provide data in the space. There’s also a trial launching into the Child-Pugh B space with durvalumab and tremelimumab. This is very important that we will have prospective, phase 2 data with these regimens in that space. So currently, we’re using [the combination] cautiously [in the Child-Pugh B population]; we all extrapolate to different extents.”

Options in Second-Line Advanced HCC and Beyond

After treatment with standard-of-care atezolizumab plus bevacizumab, there is no globally established subsequent therapy for patients with unresectable HCC who experience failure with this regimen.8 However, there are multiple regimens under clinical evaluation that have been showing promise for patients with advanced HCC in the second line and beyond.

During ASCO GI, investigators presented updated findings from the phase 2 REGONEXT study (NCT05134532), which evaluated the safety and efficacy of second-line treatment with the kinase inhibitor regorafenib (Stivarga) in patients with unresectable HCC. Eligible patients had received at least 2 prior cycles of atezolizumab plus bevacizumab, have Child-Pugh A disease, and have an ECOG performance status of 1 or 0. The primary end point was PFS; secondary end points included ORR, OS, and safety.

At the August 15, 2023, data cutoff, the median PFS among patients who received regorafenib (n = 40) was 3.5 months (95% CI, 3.0-4.0) and the median OS was 9.7 months (95% CI, 8.3-11.1), including a 6-month OS rate of 55.0%. Additionally, the ORR was 10.0% and the disease control rate was 82.5%. Study authors concluded that regorafenib was an effective second-line atezolizumab plus bevacizumab. Results from REGONEXT were consistent with those in the pivotal phase 3 RESORCE trial (NCT01774344), which evaluated the efficacy and safety of regorafenib in patients who had progressed on sorafenib. Based on the results, in April 2017, the FDA approved regorafenib in patients with HCC who previously received sorafenib.⁹

In the phase 3 CELESTIAL trial (NCT01908426), patients were randomly assigned 2:1 to receive either the tyrosine kinase inhibitor cabozantinib (Cabometyx; n = 470) or placebo (n = 237). Eligible patients had received prior treatment with sorafenib and experienced disease progression after at least 1 line of treatment for HCC. Patients were permitted to have received up to 2 previous systemic regimens for advanced HCC. The primary end point was OS; secondary end points included PFS and ORR.¹⁰

Data from CELESTIAL, which were published in The New England Journal of Medicine in 2018, showed that patients treated with cabozantinib achieved a median OS of 10.2 months (95% CI, 9.1-12.0) vs 8.0 months (95% CI, 6.8-9.4) in patients who received placebo (HR, 0.76; 95% CI, 0.63-0.92; P = .005). Additionally, the median PFS was 5.2 months (95% CI, 4.0-5.5) vs 1.9 months (95% CI, 1.9-1.9), respectively (HR, 0.44; 95% CI, 0.36-0.52; P < .001).

The FDA approved cabozantinib on January 14, 2019, for patients with HCC who had previously undergone treatment with sorafenib. The approval was supported by findings from CELESTIAL.¹¹ “It’s certainly an exciting time in the HCC space, we’ve gone from just 1 drug [that was available] for a long time, sorafenib, until about 2017, when nivolumab opened the door to immunotherapy in the space. Since then, the field has really exploded,” El-Khoueiry commented.

“Combinations are really exciting,” Anne Covey, MD, said. “TACE has been the standard local regional therapy worldwide but, at least in this country, it’s shifting toward radioembolization. Two exciting studies for me are going to be [the phase 2] ROWAN trial [NCT05063565], looking at radioembolization plus durvalumab and tremelimumab, and [the phase 2] EMERALD-Y90 trial [NCT06040099], which is going to look at radioembolization with durvalumab and bevacizumab. I’m very excited to see what the future holds.”

References

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7. Cosgrove D, Tan A, Osterland A, et al. Atezolizumab plus bevacizumab (A+B) in patients with unresectable hepatocellular carcinoma (uHCC): real-world experience from a US community oncology network. J Clin Oncol. 2024;42(suppl 3):447. doi:10.1200/JCO.2024.42.3_suppl.447
8. Yoo C, Cheon J, Ryoo BY, et al. Second-line regorafenib in patients (pts) with unresectable hepatocellular carcinoma (uHCC) after progression on first-line atezolizumab plus bevacizumab (atezo-bev): phase 2 REGONEXT trial. J Clin Oncol. 2024;42(suppl 3):477. doi:10.1200/ JCO.2024.42.3_suppl.47
9. FDA expands approved use of Stivarga to treat liver cancer. FDA. April 27, 2017. Accessed February 14, 2024. https://www.fda.gov/news-events/ press-announcements/fda-expands-approved-use-stivargatreat- liver-cancer
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11. FDA approves cabozantinib for hepatocellular carcinoma. FDA. Updated March 12, 2019. Accessed February 14, 2024. https://www.fda.gov/drugs/fda-approves-cabozantinib- hepatocellular-carcinoma