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.
Targeted Oncology: What was the design and goals of the IMbrave150 trial (NCT03434379) for patients with hepatocellular carcinoma (HCC)?
RENUKA IYER, MD: 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].1 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 P <.001].2 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 P <.001].
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 IMbrave150.3 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.1,3 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 P = .0035].4 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.3 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. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745
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. J Hepatol. 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. NEJM Evidence. 2022;1(8). Published online June 6, 2022. doi:10.1056/EVIDoa2100070
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. J Clin Oncol. 2022;40(4_suppl):379. doi:10.1200/JCO.2022.40.4_suppl.379