Analyses Show Subgroup-Dependent Benefits of Immunotherapy in HCC

Renuka Iyer, MD

Professor of Oncology

Coleader, Liver and Pancreas Tumor Program

Section Chief for Gastrointestinal Oncology, Department of Medicine

Roswell Park Comprehensive Cancer Center

Buffalo, NY

[Continued from Part 1]

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

RENUKA IYER, MD. 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].¹ 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].² 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.³ 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.⁴ 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].²

[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.⁵ 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.^4,6 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.⁷

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.⁸

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.⁹

_References:

_{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. J Clin Oncol. 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). Ann Oncol. 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. Ann Oncol. 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. NEJM Evidence. 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). J Clin Oncol. 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. N Engl J Med. 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. Eur J Cancer. 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. Nature. 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). Ann Oncol. 2022;33(suppl_7):S323-S330. doi: 10.1016/annonc/annonc1057}