Emerging Combos Lead to More Questions, Research Efforts in Advanced HCC

James J. Harding, MD

After years of little advancement, novel agents and combination strategies are now introducing paradigm-shifting options for the treatment patients with advanced or metastatic hepatocellular carcinoma (HCC), said James J. Harding, MD.

"It is fascinating that for over a decade, we had 1 active drug—sorafenib (Nexavar)," said Harding. "It has been difficult to find new drugs [to treat these patients]. They are not candidates for surgical transplant and have failed regional therapies. Now, they are looking at systemic therapies to control their disease and improve their quality of life (QoL). We have had multiple positive studies in the first- and second-line settings that show similar or better activity [with a novel therapy] than sorafenib.”

For example, results of the phase III IMbrave150 study demonstrated a 42% reduction in the risk of progression or death with the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) versus sorafenib in patients with unresectable HCC (HR, 0.58; 95% CI, 0.42-0.79; P = .0006).¹ The median overall survival (OS) was not reached compared with 13.2 months (95% CI, 10.4—not estimable), respectively (HR, 0.58; 95% CI, 0.42-0.79; P = .0006).

At the 2020 Gastrointestinal Cancers Symposium, an analysis of patient-reported outcomes from the IMbrave150 trial showed meaningful QoL and functioning benefit with the combination compared with sorafenib.² Atezolizumab/bevacizumab also extended the median time to key symptoms including appetite loss, fatigue, pain, jaundice, and diarrhea.

Additionally, time to deterioration of QoL was 11.2 months versus 3.6 months with the combination and sorafenib, respectively (HR, 0.63; 95% CI, 0.46-0.85).

Based on the efficacy findings from IMbrave150, a supplemental biologics license application was submitted to the FDA in January 2020 for the combination of atezolizumab and bevacizumab as a treatment for patients with unresectable HCC who have not received prior systemic therapy.

Furthermore, investigators are exploring additional combination regimens and conducting biomarker analyses, which could determine predictive or prognostic factors that may be associated with response to available and emerging therapies.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Harding, the regional director of Early Drug Development at Memorial Sloan Kettering Cancer Center, discussed the evolving treatment landscape in frontline HCC and ongoing trials that may revolutionize the space.

OncLive: The IMbrave150 trial has garnered a lot of interest. What are your thoughts on the data?

Harding: The IMbrave150 data are really exciting. It was a frontline study that randomized patients 2:1 to receive atezolizumab and bevacizumab versus sorafenib. The primary objective was OS. IMbrave150 was statistically designed to prove that the intravenous combination [of atezolizumab and bevacizumab] was superior to sorafenib and, indeed, it met its primary endpoint. In fact, the median OS with atezolizumab/bevacizumab has not been reached. The improvement in [hazard ratio] was dramatic and statistically significant.

Importantly, secondary endpoints favored atezolizumab/bevacizumab. Namely, there was longer PFS and higher ORR [with the combination]. In the study, 30% of patients who received atezolizumab/bevacizumab had tumor shrinkage versus about 12% with sorafenib.

Additionally, the safety profile is compelling in that we saw less overall severe toxicities with atezolizumab/bevacizumab; [it is consistent with what we would expect with this combination].

We also saw a delayed deterioration of QoL [with the combination]. That is particularly important because we want patients to not only have responses and live longer, but [for the regimen] to be tolerable.

How would you define the impact of the phase III REFLECT study in HCC?

Harding: The REFLECT study looked at sorafenib compared with lenvatinib (Lenvima), which is another multikinase inhibitor. The study showed that lenvatinib was noninferior to sorafenib; however, lenvatinib was superior [to sorafenib] in terms of secondary endpoints. Namely, lenvatinib offered a higher objective response rate (ORR), progression-free survival (PFS), and time-to-progression.

Toxicities were essentially equivalent between the 2 arms, with slight differences in the types of adverse events. [Lenvatinib] represents a reasonable option outside of sorafenib.

What else in HCC is coming down the pipeline?

There are several ongoing, randomized phase III trials that [may be] pivotal in the vein of combining PD-L1 inhibitors with antiangiogenic [agents] or TKIs.

We are waiting for the results of the LEAP-002 trial, which is a randomized study of frontline lenvatinib versus lenvatinib plus pembrolizumab (Keytruda). This study was prompted by some promising phase I/II data in HCC and in all solid tumors.

There is also the COSMIC-312 study, which looks at sorafenib versus atezolizumab with cabozantinib (Cabometyx). Again, that study focuses on the same idea that if we block key disease receptors—particularly those involved with angiogenesis—and pair that with immunotherapy, we may get synergistic activity based on the biology.

Combination immunotherapy is also an important set of studies. We know that CTLA-4 antibodies have single-agent activity in HCC. We also know that we see improved outcomes across solid tumors when we combine anti—CTLA-4 with anti–PD-1.

The HIMALAYA and CheckMate-9DW trials are 2 ongoing studies. HIMALAYA is looking at sorafenib versus single-agent durvalumab (Imfinzi) versus durvalumab plus tremelimumab. CheckMate-9DW looks at the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) versus dealer's choice of sorafenib or lenvatinib. These studies may help define further options, and potentially a new standard of care, as they read out.

With these potential therapeutic additions, will determining an optimal sequencing strategy be a challenge?

More options are always better. Even though these data are positive, there is a long way to go. Ultimately, the degree of response followed by toxicity and improvement in QoL will define what [therapy] is used first.

We don't know how these studies are going to read out. It will be great if a majority of them are positive. Our choices would then be based on those metrics. If they are not positive, it will at least inform us on which way to go. In terms of sequencing, that will be important to define over the next several years.

It is hard to predict how the field of HCC will evolve, but it is certainly changing very rapidly. It is hard to keep track of all the approvals [in this space] since 2017. We are actively trying to conduct studies that will define the best course of action.

What biomarker work is being conducted in HCC?

The hypothesis is that the reason why people may respond to these therapies is that some tumors are immunologically active. They elicit an immune response. By using these antibodies, we unleash their immune system to attack the tumor.

However, defining what immunologic activity is in the tumor is difficult. There are simplistic ways of measuring PD-1/PD-L1 expression in the tumor microenvironment, and then there are more sophisticated measures looking at the tissue in regard to RNA signatures and the distribution of lymphoid cells. A more inflamed tumor may respond better [to treatment].

There is also a genomic measure commonly thought of as tumor mutational burden (TMB). Our work suggests that high TMB is not as prevalent in HCC. That was observed in a "hypothesis-generating way" in preliminary data. If you have alterations in Wnt/β-catenin, that may suggest a worse outcome. Other groups have done experimental models and showed similar results that are not yet defined.

Other factors [for response to therapies] include host. Could it be the viral infections, the immune human leukocyte antigen types, or the microbiome? There are many potential pathways that may become important over the next several years to isolate who responds well and who does not.

[In HCC], we don't have a clear biomarker for immunotherapy yet. Although physicians are doing next-generation sequencing on tumors and staining for PD-L1, we do not know what the results mean from a clinical perspective. It will require the research community to push through and define that.

References

1. Cheng A-L, Qin S, Ikeda M, et al. IMbrave150: efficacy and safety results from a ph 3 study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol. 2019;30(suppl_9):mdz446.002. doi: 10.1093/annonc/mdz446.002.
2. Galle P, Finn RS, Qin S, et al. Patient-reported outcomes (PROs) from the Phase III IMbrave150 trial of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-line treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2020;38(suppl; abstr 476). doi: 10.1200/JCO.2020.38.4_suppl.476.