Combination Regimens Make Their Mark in Frontline HCC

Combination Regimens in Frontline HCC

| Image Credit: © Sebastian Kaulitzki

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In recent years, combination regimens have reshaped the hepatocellular carcinoma (HCC) treatment landscape, offering options to better personalize frontline treatments. Specifically, single tremelimumab (Imjudo) and regular-interval durvalumab (Imfinzi; STRIDE) is the most recent regimen to gain FDA approval in treatment-naive HCC, with other combination regimens showing promise as they progress through the development pipeline.¹

“In liver cancer, 20 years ago we were still giving [only] chemotherapy; now we have targeted therapy, immunotherapy, and combinations of different modalities,” Steven Chan, MD, said. “Now, we [are discussing treatment] sequencing because we have so many different agents. I foresee liver cancer being one of the cancers with the best prognosis and a higher cure population. This is our dream and is a goal that we need to move toward.”

During the 2024 European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain, OncologyLive was onsite and filmed a Peer Exchange with leading experts in the field of HCC. The panelists discussed how new data presented during the meeting could be used to optimize treatment in the frontline setting, touching on updates from the phase 3 HIMALAYA (NCT03298451), LEAP-012 (NCT04246177), EMERALD-1 (NCT03778957), and IMbrave050 (NCT04102098) trials. They also discussed findings from the phase 4 STELLAR study (NCT04763408) and looked ahead to the future of HCC treatment.

New Data With Combination Regimens Emerge in Frontline HCC

A regimen that has moved to the forefront of the first-line treatment landscape of unresectable HCC in recent years is STRIDE. In October 2022, STRIDE was approved by the FDA for the treatment of adult patients with unresectable HCC based on data from HIMALAYA. HIMALAYA was an open-label, multicenter study for patients who had no prior systemic treatment for HCC and were randomly assigned 1:1 to receive STRIDE, durvalumab monotherapy, or sorafenib (Nexavar) monotherapy.¹

Findings from the 5-year overall survival (OS) update of HIMALAYA presented during the 2024 ESMO Congress demonstrated that patients who were treated with the STRIDE regimen (n = 393) achieved a median OS of 16.43 months (95% CI, 14.16-19.58) compared with 13.77 months (95% CI, 12.25-16.13) among patients treated with sorafenib (HR, 0.76; 95% CI, 0.65- 0.89; 2-sided P = .0008). STRIDE also produced superior OS rates vs sorafenib, respectively, at 18 months (48.7% vs 41.5%), 24 months (40.5% vs 32.6%), 36 months (30.7% vs 19.9%), 48 months (25.2% vs 15.1%), and 60 months (19.6% vs 9.4%). Study authors noted that these data had the longest follow-up to date in phase 3 studies of treatments for unresectable HCC.²

“Where in the Child-Pugh B [score range you] can give doublets vs a single [agent] is subjective at the moment,” Anthony B. El-Khoueiry, MD, commented. ”I worry about giving a doublet either [when a patient’s] liver function is not great, [due to their] performance status, or other worries. It has become a minority of patients who get single-agent IO [immuno-oncology], but it still does exist in my practice.”

Another combination regimen, lenvatinib (Lenvima) plus pembrolizumab (Keytruda) and transarterial chemoembolization (TACE), is under investigation in LEAP-012. The coprimary end points of the study are OS and progression-free survival (PFS). TACE is considered the standard of care for patients with intermediate-stage HCC, and lenvatinib monotherapy is an FDA-approved option for the first-line treatment of patients with unresectable HCC.^3,4

Data from LEAP-012 presented during the 2024 ESMO Congress showed that patients who received lenvatinib, pembrolizumab, and TACE (n = 237) achieved a median PFS of 14.6 months (95% CI, 12.6- 16.7) vs 10.0 months (95% CI, 8.1-12.2) among patients who received dual placebo with TACE (HR, 0.66; 95% CI, 0.51-0.84; P = .0002). The 12-month PFS rates were 62.2% vs 43.4%, respectively, and the 18-month rates were 39.1% vs 27.9%,respectively. The addition of lenvatinib and pembrolizumab to TACE also led to an OS benefit (HR, 0.80; 95% CI, 0.57-1.11; P = .0867). The 12-month OS rates were 89.0% vs 83.1%, respectively, and the 24-month rates were 74.6% vs 68.6%, respectively.³

“[These findings] go to the question of, ‘should we be using the combination strategy up front or waiting until a later time to introduce systemic therapy following initial liver-directed therapy?’” Daneng Li, MD, said. “I believe toxicity matters here. In terms of grade 3 or higher treatment-related adverse effects [AEs], in the combination arm, it was [approximately] 71% and in the TACE alone arm, it was approximately 31%, so essentially a doubling of toxicity. Some of those toxicities are easier to manage but we have to see more data. What wasn’t presented were the quality- of-life [QOL] data, and those can potentially help us determine whether this up-front combination strategy is the way to go going forward.”

“I was excited with the results of LEAP-012 because they solidify some of the current direction in the community about not waiting until the patient develops metastatic disease or progression [to use a regimen such as this]. I believe we are going to see more and more IO/tyrosine kinase inhibitor [TKI] combinations in different lines of treatment,” Olatunji B. Alese, MD, added.

The EMERALD-1 study is also evaluating a TACEbased regimen in frontline unresectable HCC, combining it with durvalumab with or without bevacizumab (Avastin) in patients who are eligible for embolization. The primary end point of the study is PFS by blinded independent central review per RECIST 1.1; OS and QOL represent key secondary end points.⁵

Findings from EMERALD-1 presented during the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium revealed that patients who received TACE with durvalumab and bevacizumab (n = 204) achieved a median PFS of 15.0 months (95% CI, 11.1-18.9) compared with 8.2 months (95% CI, 6.9-11.1) among patients treated with TACE alone (HR, 0.77; 95% CI, 0.61-0.98; log-rank P = .032), meeting the study’s primary end point. Additionally, the objective response rates (ORRs) were 43.6% vs 29.6%, respectively, (OR, 1.87; 95% CI, 1.24- 2.84), including respective complete response (CR) rates of 3.0% vs 2.5%.

Then, during the 2024 ESMO Congress, investigators presented findings from an analysis of EMERALD-1 that examined outcomes with TACE plus durvalumab with or without bevacizumab by baseline tumor burden. Investigators stratified patients using the up-to-7 criterion, which was defined as the sum of the number of tumors and their size in cm. Data from the analysis showed that the addition of durvalumab and bevacizumab to TACE improved PFS regardless of tumor burden; there was a significant PFS benefit in both the up-to-7 criterion (HR, 0.72; 95% CI, 0.51-1.03) and beyond the up-to-7 criterion (HR, 0.79; 95% CI, 0.57-1.09) subgroups.⁶

“We checked the efficacy outcome—PFS within up-to-7 criteria—and the PFS HR was very similar to the PFS of [those with] beyond up-to-7 criteria, [as was] the time to progression,” Masatoshi Kudo, MD, PhD, who was a coauthor of the analysis, noted. “Even though the tumor burden is very high, beyond the up-to-7 criteria, durvalumab plus bevacizumab and TACE showed better efficacy compared with TACE alone.”

The final study the panelists discussed in the frontline setting was IMbrave050, which examined the combination of atezolizumab (Tecentriq) and bevacizumab vs active surveillance in patients with resected or ablated high-risk HCC. The primary end point of the study was recurrence-free survival (RFS); secondary end points included OS and safety.⁷

Updated findings from IMbrave050 presented during the 2024 ESMO Congress showed that the initial RFS benefit that was previously observed with atezolizumab plus bevacizumab did not persist with additional follow-up. At a median follow-up of 35.1 months, the median RFS in the investigational arm (n = 334) was 33.2 months (24.3-not estimable [NE]) vs 36.0 months (95% CI, 22.7-NE) in the active surveillance arm (n = 334; HR, 0.90; 95% CI, 0.72-1.12). OS data were immature at the time of the presentation, with both arms having a median OS of NE (95% CI, NE-NE; HR, 1.26; 95% CI, 0.85-1.87; P =.250).

“One of the challenges is defining high-risk [disease],” Richard S. Finn, MD, said. “We’re seeing a [median] RFS of [approximately] 3 years in a control arm. That’s not the estimate we would assume with this study population. That relates somewhat to the statistical assumptions in this population, which we’re still learning about. But, at this point, there’s no reason to offer patients adjuvant treatment after surgery outside of a clinical trial.”

Real-World Data Inform Future HCC Research Directions

The panelists concluded their session by discussing real-world findings in HCC and highlighted what could become the latest FDA-approved regimen in frontline HCC: nivolumab (Opdivo) plus ipilimumab (Yervoy). “[In terms of] the knowledge gaps that have resulted from the rapid accumulation of new drugs and studies in the management of our patients with unresectable liver cancer, real-world evidence is supplementing some of those gaps,” Finn said.

The real-world STELLAR trial was an open-label, observational study that enrolled patients with advanced or unresectable HCC who received lenvatinib or sorafenib according to local prescribing practices. The study enrolled patients in Australia, Europe, and the US. The primary end point was to further elucidate the hepatotoxicity and overall safety profile of lenvatinib.⁸ “The purpose of [this study] was to evaluate the tolerance and effectiveness of the therapy in [additional], less restricted populations, which may be different from the clinical trial populations,” Chan added.

Findings from STELLAR presented during the 2024 ESMO Congress showed that, at a median follow-up of 9.5 months (95% CI, 8.3-11.4) among patients who received lenvatinib (n = 149), the median OS was 16.3 months (95% CI, 11.8-NE). Comparatively, at a median follow-up of 7.4 months (95% CI, 6.5-8.5), the median OS was 13.6 months (95% CI, 8.4-NE) in the sorafenib group (n = 93). Lenvatinib also offered a benefit vs sorafenib regarding 6-month (83.9% vs 79.2%) and 12-month (59.2% vs 54.3%) OS rates.

In terms of safety, no new signals were identified with lenvatinib, and AEs were able to be managed via standard clinical practice. Any-grade treatment-emergent AEs (TEAEs) occurred at a rate of 79.9% vs 81.7% in the lenvatinib and sorafenib arms, respectively; patients in both arms experienced treatmentrelated TEAEs (58.4% vs 66.7%), grade 3 or higher TEAEs (40.3% vs 37.6%), grade 3 or higher treatment- related TEAEs (20.8% vs 18.3%), serious TEAEs (30.2% vs 31.2%), and fatal serious TEAEs (9.4% vs 4.3%).

Any-grade hepatotoxicity occurred in 22.8% of patients who received lenvatinib compared with 33.3% of patients treated with sorafenib. Grade 3 or higher hepatotoxicity was reported at rates of 8.1% vs 15.1%, respectively. Other common any-grade TEAEs occurring in both arms included decreased appetite (24.8% vs 23.7%), fatigue (21.5% vs 21.5%), and diarrhea (19.5% vs 28.0%).

“In terms of the tolerance and the AE profile, they’re very similar to what we have observed from previous clinical trials,” Chan said. “Although we are using more immunotherapy nowadays, TKIs are still used frequently for those patients who are not eligible for immunotherapy or don’t have access to immunotherapy. Sometimes [we also use TKIs] for patients who have failed immunotherapy. I consider this study to be potentially impactful and meaningful for our practice.”

Table. TEAEs in at Least 10% of Patients in the Phase 4 STELLAR Trial⁸

The panelists concluded their discussion by providing their view of updated findings from the phase 3 CheckMate 9DW trial (NCT04039607), which is comparing nivolumab plus ipilimumab vs standard-of-care lenvatinib or sorafenib in frontline unresectable HCC. The primary end point of the study is OS; secondary end points include ORR and duration of response (DOR).⁹

At a median follow-up of 35.2 months (range, 26.8-48.9), the median OS in the combination arm (n = 335) was 23.7 months (95% CI, 18.8-29.4) vs 20.6 months (95% CI, 17.5-22.5) in the lenvatinib/ sorafenib arm (n = 333; HR, 0.79; 95% CI, 0.65- 0.96; P =.018). The 24-month OS rates were 49% vs 39%, respectively, and the 36-month OS rates were 38% vs 24%, respectively. The ORR in the combination arm was 36% (95% CI, 31%-42%), with a CR rate of 7%, vs 13% (95% CI, 10%-17%), with a 2% CR rate, in the control arm (P < .0001). The median DOR was 30.4 months (95% CI, 21.2-NE) vs 12.9 months (95% CI, 10.2-31.2), respectively.

Based on data from CheckMate 9DW, the FDA accepted the supplemental biologics license application seeking the approval of nivolumab plus ipilimumab in frontline unresectable HCC in August 2024. The Prescription Drug User Fee Act goal date is April 21, 2025.¹⁰ The regimen previously earned accelerated approval from the FDA in March 2020 for the treatment of patients with HCC who were previously treated with sorafenib; the regulatory decision was supported by findings from the phase 1/2 CheckMate 040 trial (NCT01658878).¹¹

“[I believe this regimen] will be approved by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency [of Japan],” Kudo said. “An important point is that in patients who [went on to receive] second-line treatment, the PFS and PFS2 were much longer than in the control arm. That is a very good message, if the [patient received] nivolumab/ipilimumab, the second-line treatment will be better.”

References

1. FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma. FDA. Updated October 24, 2022. Accessed October 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-unresectable-hepatocellular-carcinoma
2. Rimassa L, Chan SL, Sangro B, et al. Five-year overall survival (OS) and OS by tumour response measures from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma (uHCC). Ann Oncol. 2024;35(suppl 2):S656. doi:10.1016/j.annonc.2024.08.1007
3. Llovet J, Finn RS, Ren Z, et al. Transarterial chemoembolization (TACE) with or without lenvatinib (len) + pembrolizumab (pembro) for intermediate-stage hepatocellular carcinoma (HCC): phase III LEAP-012 study. Ann Oncol. 2024;35(suppl 2):S1229. doi:10.1016/j.annonc.2024.08.2277
4. FDA approves lenvatinib for unresectable hepatocellular carcinoma. FDA. August 16, 2018. Accessed October 24, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-unresectable-hepatocellular-carcinoma
5. Lencioni R, Kudo M, Erinjeri J, et al. EMERALD-1: a phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. J Clin Oncol. 2024;42(suppl 3):LBA432. doi:10.1200/JCO.2024.42.3_suppl.LBA432
6. Kudo M, Lencioni R, Erinjeri JP, et al. Outcomes by baseline tumour burden in EMERALD-1: a phase III, randomised, placebo (PBO)-controlled study of durvalumab (D) ± bevacizumab (B) with transarterial chemoembolisation (TACE) in participants (pts) with embolisation-eligible unresectable hepatocellular carcinoma (uHCC). Ann Oncol. 2024;35(suppl 2):S658-S659. doi:10.1016/j.annonc.2024.08.1010
7. Yopp A, Kudo M, Chen M, et al. Updated efficacy and safety data from IMbrave050: phase III study of adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in patients (pts) with resected or ablated high-risk hepatocellular carcinoma (HCC). Ann Oncol. 2024;35(suppl 2):S1230. doi:10.1016/j. annonc.2024.08.2279
8. Peck Radosavljevic M, Abdelgafur AM, Granito A, et al. Lenvatinib (L) and sorafenib (S) in patients (pts) with advanced or unresectable hepatocellular carcinoma (uHCC): an international, multicenter, phase IV study (STELLAR). Ann Oncol. 2024;35(suppl 2):S664. doi:10.1016/j.annonc.2024.08.1024
9. Decaens T, Yau T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as firstline (1L) treatment for unresectable hepatocellular carcinoma (uHCC): expanded analyses from CheckMate 9DW. Ann Oncol. 2024;35(suppl 2):S657. doi:10.1016/j.annonc.2024.08.1025
10. Bristol Myers Squibb receives US Food and Drug Administration sBLA acceptance for first-line treatment of unresectable hepatocellular carcinoma. News release. Bristol Myers Squibb. August 21, 2024. Accessed October 25, 2024. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Receives-U.S.-Food-and-Drug-Administration-sBLA-Acceptance-for-First-Line-Treatment-of-Unresectable-Hepatocellular-Carcinoma/default.aspx
11. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA. Updated March 11, 2020. Accessed October 25, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma