Key HCC Trial Data Establish the Role of Later-Line Cabozantinib and Raise Further Frontline Questions

Positive findings from the phase 3 CELESTIAL trial (NCT01908426) have made a mark on the hepatocellular carcinoma (HCC) treatment paradigm, whereas outcomes from the phase 3 COSMIC-312 trial (NCT03755791) have illuminated an area where extra research is necessary, according to Gentry King, MD.

In an interview with OncLive®, King discussed the practice-changing data from the CELESTIAL trial evaluating cabozantinib (Cabometyx) vs placebo in patients with pretreated advanced HCC; lessons learned from the negative outcomes of COSMIC-312, which assessed cabozantinib plus atezolizumab (Tecentriq) vs sorafenib (Nexavar) in the frontline advanced HCC setting; current challenges addressing new treatments for HCC; and notable upcoming trials in this field.

He provided insight on the evolution of the HCC treatment paradigm, along with the significance of the phase 3 HIMALAYA trial (NCT03298451), in another article.

King is an assistant professor in the Clinical Research Division at Fred Hutchinson Cancer Center and an assistant professor in the Division of Hematology and Oncology at the University of Washington School of Medicine in Seattle.

OncLive: What were the background of and key findings from the CELESTIAL trial?

King: CELESTIAL is an older study [from] 2018 that investigated cabozantinib—a multi-targeted TKI with anti-VEGF, -AXL, and -MET [properties]—in patients with advanced HCC. [Eligibility criteria included] a liver function criteria [of] Child-Pugh class A, an ECOG performance status of 0 or 1, and receipt of up to 2 prior lines of systemic therapy. The study [evaluated] 60 mg of [once-daily] cabozantinib vs placebo.1 This was a positive study, and because of this study, cabozantinib is now a standard second- and third-line treatment for previously treated HCC.

The distribution of patients on this study was approximately 25% from Asia, approximately 50% from Europe, and approximately 23% to 25% from Canada and the United States. It [included] a more Western study population. The median overall survival [OS] with cabozantinib was 10.2 months [95% CI, 9.1-12.0] vs 8.0 months [95% CI, 6.8-9.4] with placebo.1

[A significant] note here is that this was a study done in 2018 when we didn’t have immune checkpoint inhibitors [ICIs] as first-line therapy [for HCC]. This was a study [evaluating the efficacy of a] TKI after patients had progressed on a prior TKI, sorafenib. Interestingly, cabozantinib, with its other mechanisms of action, is geared towards addressing resistance mechanisms to sorafenib, not necessarily resistance mechanisms to the new standard of care [SOC] that we have now, which is a combination of ICIs.

What were the background of and key findings from the COSMIC-312 trial? How did the Asian population differ from the global population?

COSMIC-312 was a first-line study with dual primary end points of progression-free survival [PFS] and OS, and it was a 3-arm study. The study [assessed] first-line treatment of advanced HCC with the same enrollment criteria [as CELESTIAL], [including] Child-Pugh class A disease and an ECOG performance status of less than 1. [The COSMIC-312 study evaluated] cabozantinib at 2 doses: 40 mg [once daily in combination] with atezolizumab, and monotherapy at 60 mg [once daily].2 The third arm received standard sorafenib at 400 mg [twice daily], which was a SOC at that time.

[COSMIC-312] was significantly affected by COVID-19. The trial was geared to recruit a global population. The expectations were that mainland China was going to add a lot of patients into this study, but then the COVID-19 [pandemic arrived].

In the 2021 presentation [of the data [by R. Katie Kelley, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center], there’s a graph where China only contributed 9 patients to the initial patient population, [and patients from] the rest of the world [comprised most of] the patient population. Eventually, [enrollment rates in China] did pick up, but [the early days of the trial affected] the demographics of its patient population. Instead of reflecting the more global representation of etiologies, [COSMIC-312 enrolled patients across] almost the same type of demographics—similar to the phase 3 SHARP study [NCT00105443] that got sorafenib FDA approved [for patients with inoperable HCC]—a lot more of the Western population with hepatitis C and nonviral HCC.

The primary end point of [COSMIC-312] was PFS, and the final analysis showed that there was a significant improvement in PFS with the cabozantinib and atezolizumab combination—a TKI and an ICI—vs sorafenib. However, [although] the primary end point of PFS was met, the OS was not met.

In the HIMALAYA study [of single tremelimumab (Imjudo), regular interval durvalumab (Imfinzi; STRIDE regimen) in unresectable HCC], a PFS benefit [also wasn’t seen] upfront [compared with sorafenib], but the OS with the tail of the curves was positive. These are 2 interesting studies because they are different in the mechanisms of action [of their investigational treatments], their rationales for treatment, [their patient] demographics, and their results. [In COSMIC-312], there was a positive PFS and negative OS, and then [in HIMALAYA], there was a negative PFS and positive OS. That’s interesting to note because right now, STRIDE is an FDA-approved first-line treatment regimen [for HCC], whereas the COSMIC-312 trial, although it met 1 of its primary end points, did not establish a new SOC here in the West, precisely because it did not meet that OS benefit to beat out sorafenib.

Following the demonstrations of positive and negative data from HCC trials, what are some challenges regarding the further development of the HCC treatment paradigm?

The second-line treatments we have are all post-sorafenib, so there are no prospective, large studies or high-level data to inform oncologists about what the optimal second-line treatment should be after the new SOC has been initiated. There aren’t prospective trials of [1 drug vs another] drug or even placebo in patients who’ve received first-line atezolizumab plus bevacizumab [Avastin], for example, or first-line STRIDE. That leaves a big gap.

There are some proposed studies evaluating [2 drugs head to head] post-atezolizumab/bevacizumab, for example. Atezolizumab plus bevacizumab was FDA approved in 2020 [for frontline HCC], and in 2020, nivolumab [Opdivo] plus ipilimumab [Yervoy] was also FDA approved for patients with HCC who have received prior sorafenib. When you’re trying to develop these second-line trials, it’s difficult because the first-line setting keeps changing. The standards kept changing over the past 5 years.

Beyond the trials that opened doors for first-line treatment, what are some notable upcoming trials in HCC?

Moving forward, there are some interesting combination studies that are trying to add to the first-line strategies. The first group [of studies is] adding novel ICIs [in combination with] the ones we typically use. These are anti–PD-L1 and anti–CTLA-4 agents, such as anti–LAG-1 antibodies and TIM-3 [inhibitors]. The other group is trying to add on a different modality, like radiation or Y90 [radioembolization].

The phase 2 EMERALD-Y90 trial [NCT06040099], for example, [is investigating] an ICI [combination following] Y90 [in patients with unresectable HCC]. That’s an interesting study because the phase 3 NRG/RTOG 1112 trial [NCT01730937] showed the benefits of using radiation upfront in a select population of [patients with] HCC, but [that study used] sorafenib as the old standard. Now that we know radiation [is active] in HCC, the question is: How does it fit with the new first-line paradigm?

The third branch [of studies is evaluating] treatments that are not going to be in the first-line setting anytime soon—adoptive cellular therapies like CAR T-cell therapy and certain bispecific antibodies. Some interesting constructs and encouraging studies have been reported over the past 2 years, mainly from China. The antigens and targets for the CAR T-cell therapies are usually ones we see in HCC, such as glypican-3, [GPC3). There are GPC3 CAR T-cells that many companies and groups are developing with different types of constructs. Those are appealing and encouraging based on the responses we’ve seen.

References

1. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63. doi:10.1056/NEJMoa1717002
2. Yau T, Kaseb A, Cheng AL, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 study. Lancet Gastroenterol Hepatol. 2024;9(4):310-322. doi:10.1016/S2468-1253(23)00454-5