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Spotlight

This roundtable series reviews immunotherapy in patients with unresectable hepatocellular carcinoma as first-line treatment, as discussed by key opinion leaders and participants at virtual live events.

Using Immunotherapy Combinations in Hepatocellular Carcinoma

Targeted Oncology: What did the subgroup analyses of the HIMALAYA study of atezolizumab (Tecentriq) plus bevacizumab (Avastin) show for patients with hepatocellular carcinoma (HCC)?

Looking at the forest plot in the initial report, it was more or less similar across all subgroups in terms of benefit with the STRIDE [Single Tremelimumab Regular Interval Durvalumab (Imfinzi)] regimen compared with sorafenib [Nexavar].

 But women and patients with hepatitis C [etiology] did not appear to get the benefit from the combination arm, at least in this initial analysis. Subsequently, when they looked at ALBI [Albumin-Bilirubin] scores and they looked at extrahepatic spread and adjusted for that, these changes did not seem significant.

Because some of these subgroups are slightly different in their biology and their outcomes, as has been noted in other studies, they specifically looked at overall survival [OS] and ORR [objective response rate] versus sorafenib in the Hong Kong or Taiwan subgroup. What they saw was much higher median OS in this group, 29.4 months in the STRIDE regimen and with sorafenib, 19 months—much higher than what we would see in most clinical trials—with an HR of 0.44 [95% CI, 0.26-0.77].

 The ORR as well, at 33.9%, was a bit higher in this group of patients, but the median duration of this benefit lasted for close to 2 years, 20.5 months [IQR, 3.8–not reached].

The HIMALAYA investigators also brought up the point of the best Child-Pugh class. Class B is the kind of patients we all see in our clinical practices. In these patients who might have just albumin or bilirubin issues, the 2 that concern us when we’re treating people with immunotherapy, their [performance] as well as their tolerability of the agents that we want to give. [They] looked at patients with ALBI grade 1, and [those with] grades 2 and 3. These were originally developed for a post-hepatectomy analyses of prediction of survival, but it has been used more and more now. What they saw was the ORR was still higher in the STRIDE regimen, as well as the durvalumab arm, compared with sorafenib in both of these subgroups.

 The median time to treatment response was short in both the [immunotherapy-containing] arms compared with sorafenib, and the duration of response was longer with the STRIDE regimen than durvalumab or sorafenib in the ALBI subgroup of grades 2/3. The slightly sicker patients did get benefit and continued to tolerate it and stay on it for longer than if they had had the durvalumab or the sorafenib in those groups.

What was the safety and tolerability observed in the HIMALAYA trial?

In terms of safety, [the regimens were] reasonably well tolerated in terms of grade 3 or 4 toxicities, although 50% of patients experienced these toxicities in the STRIDE arm, 37% in the durvalumab arm, and approximately 50% in the sorafenib arm.

 Only about 13% of patients in the STRIDE arm and 16% in the sorafenib arm discontinued because of these toxicities. In terms of [grade 3 or 4] immune-mediated toxicities, only about 12% of patients [in the STRIDE arm] had very significant immune-mediated adverse events [AEs].

They also looked at the same safety information in the Hong Kong and Taiwan group and very similarly did see any-grade AEs in pretty much all of the patients, but grade 3 and 4 AEs were only seen in about 40%, with discontinuation secondary to toxicities in only about 5% of patients on the STRIDE regimen, compared with almost a 12% [discontinuation rate with sorafenib].

[Looking at] the onset of the toxicities so we are aware in practice when we expect these toxicities to occur, it looks like the majority occurred less than 90 days from the first dose.

 If they’re going to have these toxicities, they happen relatively early, and most of these toxicities did resolve, with the resolution time being less than 60 days. I know from a practice perspective, [when] we have to follow patients and bring them back, this is relevant to know when these toxicities occur and how to manage them. [There were] diarrhea, poor appetite, fatigue, and blood pressure issues, although both the IMbrave150 study [NCT03434379]as well as the HIMALAYA study did exclude patients with uncontrolled hypertension.

 Investigators saw some of that while patients were on therapy, and some of the other skin reactions: pruritus, rash, hand-foot skin reaction, alopecia AEs.

What additional data are there for frontline immunotherapy-based regimens in HCC?

The trial data from IMbrave150 showed us a very impressive median OS of around 19 months,1 but in terms of real life, we always have slightly different patient populations and outcomes in these patients. The real-life study [AB-Real] that was reported showed slightly lower median OS, as is expected in real life, at 15.7 months, and median PFS was 6.9 months, which was similar to the IMbrave150-reported PFS.

Looking at all the studies that have led to approvals prior to the HIMALAYA study—nivolumab [Opdivo] versus sorafenib [CheckMate-459; NCT02576509], atezolizumab/bevacizumab versus sorafenib, and KEYNOTE-240 [NCT02702401], which was pembrolizumab [Keytruda]—looking at the HR for [OS in] the non-viral etiologies, generally it appears that the treatment with immunotherapies didn’t have as much benefit. It has led us all to wonder whether that is the best approach, and if there are other approaches we should be taking with tyrosine kinase inhibitor combinations in this group.

However, in the patients with viral etiology, the HRs have generally been lower, with the best being for IMbrave150 at 0.48. In hepatitis C virus [HCV]­–related HCC, we’re also seeing significant benefit across the board with all 3 of the immunotherapy trials I listed, a little bit more so with atezolizumab and bevacizumab. In the patients with hepatitis B virus etiology, as well, we see significant benefit.

In the HIMALAYA study, looking across the board, it appears that at least in the initial report that the patients with HCV didn’t get quite the benefit.4,9 But when they did the subsequent analysis and adjusting for distant spread, as well as the ALBI score, it didn’t look like there was much of a difference in terms of benefit across etiologies.

1. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. 

. 2022;40(4_suppl):379. doi:10.1200/JCO.2022.40.4_suppl.379

2. Chan SL, Kudo M, Sangro B, et al. Outcomes in the Asian subgroup of the phase III HIMALAYA study of tremelimumab (T) plus durvalumab (D) in unresectable hepatocellular carcinoma (uHCC). 

. 2022;33(suppl_9):S1454-S1484. doi: 10.1016/annonc/annonc1123

3. Vogel A, Chan SL, Furuse J, et al. Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the phase 3 HIMALAYA study. 

. 2022;33(suppl_4):S380-S381. doi:10.1016/j.annonc.2022.04.446

4. Abou-Alfa GK, Lau G, Kudo M, et al; HIMALAYA Investigators. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. 

. 2022;1(8). Published online June 6, 2022. doi:10.1056/EVIDoa2100070​

5. Lau G, Sangro B, Crysler OV, et al. Temporal patterns of immune-mediated adverse events (imAEs) with tremelimumab (T) plus durvalumab (D) in the phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (uHCC). 

. 2023;41(16_suppl):4073. doi: 10.1200/JCO.2023.41.16_suppl.4073

6. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. 

 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

7. Fulgenzi CAM, Cheon J, D'Alessio A, et al. Reproducible safety and efficacy of atezolizumab plus bevacizumab for HCC in clinical practice: Results of the AB-real study.

. 2022;175:204-213. doi:10.1016/j.ejca.2022.08.024

8. Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. 

. 2021;592(7854):450-456. doi:10.1038/s41586-021-03362-0

9. Chan LS, Kudo M, Sangro B, et al. Impact of viral aetiology in the phase III HIMALAYA study of tremelimumab (T) plus durvalumab (D) in unresectable hepatocellular carcinoma (uHCC).

. 2022;33(suppl_7):S323-S330. doi: 10.1016/annonc/annonc1057

During a Targeted Oncology™ Case-Based Roundtable™ event, Renuka Iyer, MD, discussed subgroup analyses of the HIMALAYA trial of frontline durvalumab plus tremelimumab for patients with hepatocellular carcinoma. This is the second of 2 articles based on this event.



Analyses Show Subgroup-Dependent Benefits of Immunotherapy in HCC

Targeted Oncology: What was the design and goals of the IMbrave150 trial (NCT03434379) for patients with hepatocellular carcinoma (HCC)?

The IMbrave150 study [enrolled] patients with locally advanced or metastatic and unresectable HCC who were not previously treated. It was an international study with patients from all over the world…with ECOG [performance status of] 0 or 1. They allowed macrovascular invasion and/or extrahepatic spread but stratified for it, as well as for the AFP [α-fetoprotein] levels, and there was a 2:1 randomization to atezolizumab [Tecentriq] and bevacizumab [Avastin] versus sorafenib [Nexavar] done every 3 weeks at the standard approved dosing. The study was open label, something to remember [since] everyone knew what they were getting.

Prior to enrollment, because of the concern of bleeding varices within the last 6 months, all patients had to have a screening endoscopy and have treated, completely controlled varices before enrollment. They were treated until the loss of clinical benefit or unacceptable toxicity. The coprimary end points [of overall survival (OS) and progression-free survival (PFS) by independent review] were investigated as well as independent reviewer–assessed objective response rate [ORR] using RECIST 1.1. They did an initial report and then did a follow-up report with updates on the survival.

The patient characteristic profile...[included] median age of about 64 to 66 in both arms, very well balanced, and about 40% of patients were in Asia [excluding Japan].

 The majority were Child-Pugh class A, and they even gave subclassifications of A5 and A6. The patients with macrovascular invasion were about 38% to 40% of patients and patients with [hepatitis B etiology] made up 45% to 50% in this group. Nonviral etiology was seen in approximately 30%; I bring this up so that we keep that in mind as we look at some of the other data.

What were the updated efficacy data for this trial?

When they updated the efficacy and safety data, they reported the difference in median OS was statistically significant with 19.2 months for the study arm versus 13.4 months for the sorafenib arm with an HR of 0.66 [95% CI, 0.52-0.85; log-rank 

 The median PFS was 6.9 months versus 4.3 months with an HR of 0.65 [95% CI, 0.53-0.81; log-rank 

They also looked at ORR and these were pretty impressive response rates for this disease group. In the update they saw 30% ORR [for the study arm], a little bit more than they had initially reported. Eight percent of these were complete responses compared with less than 1% with sorafenib, and also only about 19% had disease progression [with atezolizumab and bevacizumab. Forty-four percent had stable disease [SD] with atezolizumab and bevacizumab and another 22% had partial responses [PR], meaning 74% of patients had disease control [versus 43% SD, 11% PR, and 55% disease control rate for sorafenib]. The duration of response [DOR] continued for about 18 months [versus 14.9 months with sorafenib].

What was the purpose of the phase 3 HIMALAYA trial (NCT03298451) of durvalumab (Imfinzi) plus tremelimumab (Imjudo) and how does it compare with IMbrave150?

The HIMALAYA study was initiated around the same time or slightly before the IMbrave150 study but was completed later and was reported with 3 years of follow-up. The phase 3 study initially was launched as a 4-arm study, with the fourth arm using 4 doses of priming tremelimumab. But, after they saw some initial results from their phase 2 data, they decided to close that arm. The final study was in patients with confirmed unresectable HCC and had similar [requirements to IMbrave150, including] Child-Pugh class A, ECOG performance status of 0 or 1, but no main portal vein thrombosis, and esophagogastroduodenoscopy was not required of this group of patients; it had similar stratification factors. In the first arm, patients got tremelimumab as…just 1 priming dose followed by durvalumab in that cycle and subsequent cycles, once [every 4 weeks] at 1500 mg intravenously. The other 2 arms were durvalumab [monotherapy] and sorafenib [monotherapy], and the plan for the primary objective was to look for superiority in OS with the durvalumab/tremelimumab arm compared with sorafenib and also to look at noninferiority between durvalumab [monotherapy] and sorafenib. The other additional secondary objectives [included PFS, ORR, DOR, and safety].

The patient characteristics [were] very similar to the IMbrave150 study in terms of the median age of patients and in terms of the groupings of where the patients were, a little bit fewer patients from Asia, about 39% compared with IMbrave150.

 Because of that, they had slightly fewer patients with hepatitis B [etiology] and a little bit more in terms of non-viral etiology; in the IMbrave150 study it was about 30% and here it was approximately 41% in each of the 3 arms.

 They also reported their PD-L1 status in the patients who were enrolled. About 37% of patients were PD-L1–positive and they were also stratified by AFP and macrovascular invasion.

What were the key efficacy outcomes in this trial?

They met the primary objective of superiority in OS with the durvalumab/tremelimumab arm compared with sorafenib after the prespecified number of OS events had occurred, with a difference between the 2 groups of 16.4 months versus 13.8 months, with an HR of 0.78 [95% CI, 0.65-0.92; 2-sided 

 What was interesting and exciting about this report was that they had a 36-month OS rate of 30.7% [for durvalumab/tremelimumab] and 20% in the sorafenib-alone arm, keeping in mind that 17% of the sorafenib patients eventually, at progression, did get IO [immunotherapy] subsequently versus patients [receiving] further IO therapies in the durvalumab/tremelimumab arm [being] only single digits, 1% to 3%. Keeping that in mind, these were great results for us to see.

PFS, however, was very similar in the 2 arms and I’d be curious to see what responses people have seen in their practices if they’ve had experience using the STRIDE [Single Tremelimumab Regular Interval Durvalumab] regimen.

 They saw a median PFS of 3.78 months [95% CI, 3.68-5.32] with the STRIDE regimen; with sorafenib, it was 4.07 months [95% CI, 3.75-5.49]; and with the durvalumab alone, it was 3.65 months [95% CI, 3.19-3.75].

1. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. 

2. Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. 

. 2022;76(4):862-873. doi:10.1016/j.jhep.2021.11.030

3. Abou-Alfa GK, Lau G, Kudo M, et al; HIMALAYA Investigators. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. 

4. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. 

During a Targeted Oncology™ Case-Based Roundtable™ event, Renuka Iyer, MD, discussed the study designs, patient populations, and efficacy outcomes of the IMbrave150 and HIMALAYA trials of frontline immunotherapy-containing regimens for patients with hepatocellular carcinoma. This is the first of 2 articles based on this event. 

Comparing IMbrave150 and HIMALAYA Outcomes in Frontline HCC

Milind Javle, MD, professor in the department of gastrointestinal medical oncology, division of cancer medicine at The University of Texas MD Anderson Cancer Center, discusses the phase 3 HIMALAYA study (NCT03298451) of durvalumab (Imfinzi) and tremelimumab (Imjudo) in patients with locally advanced or metastatic hepatocellular cancer (HCC).

The open-label, multicenter, global phase 3 HIMALAYA trial randomly assigned 1171 patients on a 1:1:1 basis to receive durvalumab plus tremelimumab (STRIDE), durvalumab alone, or sorafenib (Nexavar). The primary end point was overall survival (OS) improvement of STRIDE over sorafenib, and a secondary end point was noninferiority of OS of durvalumab versus sorafenib.

At a median follow-up of approximately 32 months, the median OS was 16.43 months for STRIDE, 16.56 months for durvalumab, and 13.77 months for sorafenib. The HR for superiority of STRIDE versus sorafenib was 0.78 [96.02% CI, 0.65-0.93; 

 = .0035] and the HR for noninferiority of durvalumab versus sorafenib was 0.86 [95.67% CI, 0.73-1.03; noninferiority margin, 1.08]. The objective response rate (ORR) was 20.1% for STRIDE, 17.0% for durvalumab, and 5.1% for sorafenib. According to Javle, the improvement in OS appeared to increase with time.

Javle says this trial was significant because it showed efficacy for an immune checkpoint inhibitor combination without VEGF-targeted agents, as patients with portal vein thrombosis or portal hypertension cannot receive the VEGF inhibitor bevacizumab (Avastin).

 The [HIMALAYA] study very remarkably achieved its aim with an improvement in OS demonstrable in the study arm, that is durvalumab and tremelimumab versus sorafenib. The survival improvement was around 13 months in the sorafenib arm as compared with 16 months in the STRIDE arm with a hazard ratio of 0.78. In the other 2 arms, that is the other arm durvalumab single-agent versus sorafenib, it was a noninferiority study design and that goal was achieved with the hazard ratio 0.86. Also interestingly, the response rate was higher with the STRIDE regimen over 20% versus 5% with sorafenib. The improvement in survival...appeared to increase with time. So, when you look at survival results at, say, 30 months, this difference was even greater.

So, I think this was a very important trial because it included a unique regimen of a combination of checkpoint inhibitors and did not include VEGF inhibitor–targeted therapy, because this is often a problem with systemic therapy for HCC as patients have portal vein thrombosis or portal hypertension and viruses and cannot get VEGF-directed therapies like bevacizumab. So [this is] certainly a very remarkable advance in HCC management. And I'm happy now that we have another tool in our toolbox for this cancer.

Milind Javle, MD, discusses the phase 3 HIMALAYA study of durvalumab and tremelimumab in patients with locally advanced or metastatic hepatocellular cancer. 