Novel Therapies Show Promise as Subsequent-Line Treatments for Hepatocellular Carcinoma, ASCO Conference Reveals

From June 2 to June 6, 2023, oncologists from around the world convened at the American Society of Clinical Oncology (ASCO) Annual Meeting to share the latest research and insights on treating hepatocellular carcinoma in the subsequent-line therapy setting. This year’s program included presentations and publications on novel targets and real-world comparisons of treatment strategies. Mohamad B. Sonbol, MD, a gastrointestinal oncologist, consultant, and assistant professor of medicine at the Mayo Clinic in Phoenix, Arizona, shares his perspective on the most important research from the 2023 ASCO Annual Meeting.

A range of studies focusing on subsequent-line treatment for advanced HCC were presented at this year’s ASCO Annual Meeting. Can you review agents targeting novel pathways that have the potential to fill unmet needs in this population? Which of the studies seemed to be the most clinically important?

The standard of care for patients with HCC in the frontline setting is atezolizumab and bevacizumab, and all patients should receive an upfront ICI unless they have a contraindication. The big question facing us now is: what should we use in the second-line setting? Treatment options for patients who develop resistance to frontline atezolizumab and bevacizumab are generally TKIs or the combination of ipilimumab plus nivolumab, which is what I use in this setting. The authors of abstract 4091 presented data from a retrospective review that support the ICI combination; out of 32 patients who had received 1 to 8 prior lines of treatment, including prior PD-1/PD-L1 inhibitor — half of them had received atezolizumab and bevacizumab — 22% achieved an objective response and 25% had stable disease from ipilimumab plus nivolumab. It is worth noting that none of the patients who responded to this treatment had a response to prior PD-1 or PD-L1 inhibitors.¹
 
As much as ICI-based treatments have improved outcomes for patients with HCC, it is important to look beyond ICIs to other strategies. Early clinical research on T cell-based therapies, such as chimeric antigen receptor (CAR) T cells, in the subsequent-line setting for HCC has shown some exciting results. Many of these studies are testing therapies that target GPC3, a heparan sulfate proteoglycan involved in cell growth and regulation that is overexpressed in 70% to 80% of HCCs.^2-4
 
The authors of abstract 4095 reported on a phase 1 study of T cells that were engineered to express anti-GPC3 single-chain fragment variable (scFv) linked to CD3ε (CT0180). In that study, 7 patients with hepatitis B virus (HBV)-related HCC who had had at least 2 prior lines of systemic therapy received up to 3 cycles of CT0180. It was very interesting to see that even in this heavily pretreated group, 2 patients had partial response, 3 had stable disease, and the responses were fairly durable. There were also no major toxicities — 6 patients had the expected cytokine release syndrome, but it was grade 1.⁴ Clinicians are generally getting more familiar with how to manage these types of toxicities with the approval of such therapeutic methods in hematological malignancies and the growing research on using T cell-based therapies for solid tumors.
 
We are still in the very early stages of this research. It should be noted that the study behind abstract 4095 was performed on patients in China with HBV-related HCC, whereas in the United States, HCC is more commonly related to hepatitis C virus (HCV) and nonalcoholic steatohepatitis (NASH). These differences may affect how patients respond to T cell-based therapies.

It is still unclear what the most appropriate second-line therapies are for patients who progress on, or do not tolerate, atezolizumab and bevacizumab. Does abstract e16195, a real-world analysis of patient data from the Veterans Health Administration, add support to the possibility that sorafenib or lenvatinib may be a good option in this setting?⁵

TKIs such as sorafenib and lenvatinib can be used for patients who progress on atezolizumab and bevacizumab, and this study provides more reassurance that these agents are safe and can provide some benefit. The survival data were similar between the 52 patients who received lenvatinib and the 29 who received sorafenib, with a 1-year overall survival of 70.2% and 75%, respectively. The rate of toxicity was 28.9% and 34.5% for the lenvatinib and sorafenib groups, respectively.⁵
 
There is debate about which TKI is most appropriate for patients who are resistant to frontline atezolizumab and bevacizumab — whether it be cabozantinib, sorafenib, lenvatinib, or regorafenib. Data suggest that all of these agents are safe and have some activity in this setting, but they generally come from retrospective studies such as this abstract, and are therefore not level 1 evidence from randomized studies. As a result, clinicians will probably continue to rely on their biases and use whichever TKI they feel is best until more prospective data emerges in this setting.

Patient-reported outcomes (PROs) were analyzed from the phase 3 IMbrave050 trial (ClinicalTrials.gov identifier: NCT04102098), revealing similar health-related quality of life (HRQOL) between atezolizumab/bevacizumab and active surveillance in high-risk HCC.⁶ Can you comment on the clinical importance of quantifying PROs and HRQOL as part of phase 3 trials?

It is very important to look at PROs and HRQOL in clinical trials of new treatments, especially when the standard of care is no treatment, as it was in the IMbrave050 trial, which included patients with HCC who had undergone resection or ablation with curative intent and who were at high risk for recurrence. Half of the patients were randomly assigned to receive atezolizumab and bevacizumab, while the other half had active surveillance. The adjuvant treatment was associated with a statistically significant improvement in 12-month recurrence-free survival compared with active surveillance.⁷
 
The findings of IMbrave050 trial will hopefully lead to the approval of atezolizumab and bevacizumab for this indication. If so, it will be critical to have a careful discussion with patients about the potential benefits and risks, including the very small chance of dying from this regimen. It is interesting that the study found that improvements in HRQOL after resection or ablation appeared to be more gradual for the adjuvant treatment arm, although the difference was not significant. This could be due to fatigue and other adverse events associated with atezolizumab, and this is another point that may be worth bringing up with patients.

The role of atezolizumab and bevacizumab in the second-line setting for patients who are refractory to lenvatinib and other therapies has not been well studied. Does anything presented at this year’s ASCO Annual Meeting suggest that atezolizumab and bevacizumab may be safe and effective in this setting?

Abstract e16189 is helpful to address this question because the authors suggest, based on the 4 studies reviewed, that atezolizumab and bevacizumab has activity and is safe to use in the second-line setting for patients who received a first-line TKI.⁸ However, we see that this regimen is less active in the second-line setting than in the first-line, which is expected because patients have been exposed to lenvatinib, which is a vascular endothelial growth factor (VEGF) inhibitor similar to bevacizumab.
 
Even though atezolizumab and bevacizumab is the standard of care in the frontline setting, there are groups of patients, such as those who received a solid organ transplant or those who have an autoimmune disease, who cannot receive ICIs. These patients tend to receive a frontline TKI, and it is important to continue to study subsequent-line treatments for patients who progress.

Locoregional therapy, such as TACE, is the standard of care for patients with intermediate-stage HCC and may also offer benefit in combination with targeted therapy for patients with advanced disease.^9,10 A pair of small, retrospective studies of patients with advanced HCC who received subsequent-line TACE or cryoablation along with regorafenib and PD-1 inhibition suggest that these treatments may be safe and effective.^11,12 Do you think these early findings may lead to more clinical research on the role of combining TACE with targeted therapy and immunotherapy as subsequent-line treatment for patients with advanced HCC?

This is a very interesting space right now. The authors of abstract e16159 found an objective response rate of 23.5% in the group of 17 patients who received TACE along with regorafenib and PD-1 inhibition compared with 7.1% among the 14 patients who received only regorafenib and PD-1 inhibition.¹¹ Even though there was no improvement in progression-free survival associated with TACE, the objective response benefit may be helpful because, for example, it might reduce symptoms for patients with bulky disease. The authors of abstract e16151 reported improvements in both response and survival rates for patients in the cryoablation group. The objective response rate was 31% among 29 patients in the cryoablation group compared with 4.8% for the 21 patients in the regorafenib and PD-1 inhibition alone group, and the 6-month progression-free survival was 53.6% and 14.3%, respectively.¹² The caveat is that both of these abstracts are small, retrospective studies and we do not know whether there were important differences between the patient groups that may have accounted for the differences in outcomes.
 
The data in these abstracts, as well as previous studies, suggest that combining locoregional therapy with TKIs and ICIs may potentially be an effective strategy in the second-line setting. However, more prospective randomized studies are needed in this space. In addition, it is important to note that both of these abstracts were from studies performed in China that looked at TACE and cryoablation, respectively, whereas many centers in the US tend to use transarterial radioembolization (TARE), as opposed to TACE.

A new phase 2 trial was described at the ASCO Annual Meeting of a novel inhibitor of monopolar spindle 1 (MPS1), which is overexpressed in HCC and correlates with poor survival.¹³ Do you think MPS1 could become an important addition to the arsenal of second-line treatments for HCC?

This abstract presented a protocol for a phase 2 trial of NMS-01940153E that is currently in progress. The earlier phase 1 trial, which was a first-in-human study, found that 2 out of 11 patients had a partial response, and that the main adverse event was neutropenia, but it was manageable, and the agent was well tolerated overall.¹⁴
 
We are always looking for therapeutic targets for HCC. Unlike other gastrointestinal and many other solid cancers, the mutations and aberrations found in HCC have not yet led to the development of effective new treatment options. I am looking forward to seeing the results of this phase 2 trial.

Researchers presented findings that suggest that patients with HCC who were long-term aspirin users had improved in-hospital outcomes.¹⁵ What is the role of long-term aspirin use in those with HCC?

Earlier research has suggested that the use of aspirin might be associated with lower risk of developing HCC, at least in some patients.¹⁶ The authors of abstract e16162 searched an inpatient database and found that among more than 200,000 patients with HCC, those with long-term aspirin use had lower rates of sepsis, death, and other poor in-hospital outcomes.¹⁵ But the caveat with this type of research is that there are many unknowns for each individual patient, such as their liver function, stage of HCC, and reason for hospitalization. As a result, it is unclear whether aspirin use can protect patients with HCC, or whether it can reduce the risk of developing HCC.
 
This Q&A was edited for clarity and length.

Disclosures

Mohamad B. Sonbol, MD, reported affiliations with Eli Lilly and Company; Taiho Oncology, Inc; and Novartis Pharmaceuticals Corporation.

References

1. Alden SL, Lim M, Kao C, et al. Salvage ipilimumab plus nivolumab in advanced hepatocellular carcinoma after prior anti-PD-(L)1 blockade. Poster presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 4091.
 
2. Hendrickson PG, Olson M, Luetkens T, et al. The promise of adoptive cellular immunotherapies in hepatocellular carcinoma. Oncoimmunology. 2019;9(1):e1673129. doi:10.1080/2162402X.2019.1673129
 
3. Rochigneux P, Chanez B, De Rauglaudre B, Mitry E, Chabannon C, Gilabert M. Adoptive cell therapy in hepatocellular carcinoma: biological rationale and first results in early phase clinical trials. Cancers (Basel). 2021;13(2):271. doi:10.3390/cancers13020271
 
4. Zheng Y, Fu Q, Zhao Q, et al. Phase I trial of chimeric anti-GPC3 scFv-CD3ε engineered T cells (CT0180) in patients with advanced hepatocellular carcinoma. Poster presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 4095.
 
5. Aldawoodi T, Alkadimi M, Lucero K, et al. Treatment patterns post atezolizumab plus bevacizumab for advanced hepatocellular carcinoma: Real-world analysis at Veterans Health Administration comparing lenvatinib vs. sorafenib. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract e16195.
 
6. Kudo M, Chen M, Chow PKH, et al. Efficacy, safety and patient reported outcomes (PROs) from the phase III IMbrave050 trial of adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 4002.
 
7. Chow P, Chen M, Cheng AL, et al. IMbrave050: phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma at high risk of disease recurrence following resection or ablation. Abstract presented at: American Association for Cancer Research (AACR) 2023 Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT003.
 
8. Devarkonda V, Byreddi LY, Balmuri S, et al. Real-world experience with atezolizumab plus bevacizumab in the management of non-resectable hepatocellular carcinoma refractory to first-line systemic therapy: review of literature.Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract e16189.
 
9. Prince D, Liu K, Xu W, et al. Management of patients with intermediate stage hepatocellular carcinoma. Ther Adv Med Oncol. 2020;12:e1758835920970840. doi:10.1177/1758835920970840
 
10. Zheng L, Fang S, Wu F, et al. Efficacy and safety of TACE combined with sorafenib plus immune checkpoint inhibitors for the treatment of intermediate and advanced TACE-refractory hepatocellular carcinoma: a retrospective study. Front Mol Biosci. 2021;7:e609322. doi:10.3389/fmolb.2020.609322
 
11. Fu X, Mu M, Qi H, Jiang W, Chen Z, Gao F. Efficacy and safety of regorafenib + PD-1 inhibitor combined with local therapy as second-line treatment in patients with advanced hepatocellular carcinoma: a multicenter retrospective real-world study. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract e16159.
 
12. Chen Y, Kong H, Wang S, et al. Efficacy and safety of regorafenib and PD-1 combined with cryoablation in the treatment of advanced hepatocellular carcinoma after second-line targeted therapy. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract e16151.
 
13. Rimassa L, Reig M, Damian S, et al. Phase II study on safety and efficacy of NMS-01940153E, an MPS1 inhibitor with first-in-class potential, in adult patients with unresectable hepatocellular carcinoma (HCC) previously treated with systemic therapy. Poster presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract TPS4185.
 
14. Reig, M, Damian S, Roberti D, et al. NMS-01940153E, an MPS1 inhibitor with anti-tumor activity in relapsed or refractory unresectable hepatocellular carcinoma. Eur. J. Cancer. 2022;174(suppl 1). doi:10.1016/S0959-8049(22)00813-9
 
15. Dhaliwal A, Sohal A, Chaudhry H, et al. Effect on in-hospital outcomes of patients with hepatocellular carcinoma on aspirin. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract e16162.
 
16. Hui VW, Yip TC, Wong VW, et al. Aspirin reduces the incidence of hepatocellular carcinoma in patients with chronic hepatitis B receiving oral nucleos(t)ide analog. Clin Transl Gastroenterol. 2021;12(3):e00324. doi: 10.14309/ctg.0000000000000324
 
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