Singal Speaks to ASCO Highlights in Rapidly Evolving HCC Paradigm

Amit G. Singal, MD, MS

The treatment landscape of advanced hepatocellular carcinoma (HCC) has been subject to rapid development in the last few years, said Amit G. Singal, MD, MS, who added that the introduction of novel agents is particularly encouraging given the “dark decade” of stagnation in this space following the 2007 approval of sorafenib (Nexavar).

However, as HCC-related patient deaths continue to rise, developing novel therapies and combination regimens to improve patient outcomes is of paramount importance, explained Singal.

During the 2020 ASCO Direct Highlights^TMwebcast, a program developed by Physicians’ Education Resource® (PER®), LLC, Singal, an associate professor of medicine, the David Bruton Jr. Professor in Clinical Cancer Research, and medical director of the Liver Tumor Program at UT Southwestern Medical Center, discussed pivotal data in HCC presented at the 2020 ASCO Virtual Scientific Program.

An FDA Approval Reshapes Frontline Treatment of HCC

On May 29, 2020, the FDA approved the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) for the first-line treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy.¹

The approval was based on findings from the pivotal phase 3 IMbrave150 study in which the combination elicited a 41% reduction in the risk of disease progression or death compared with sorafenib (HR, 0.58; 95% CI, 0.42-0.79; P = .0006).

At the 2020 ASCO Virtual Scientific Program, analyses from the IMbrave150 study were presented during a poster session.^2-3 One analysis focused on the time to response (TTR) with the combination versus sorafenib and the characteristics of patients who achieved complete responses (CRs) while enrolled on the trial.³

Per RECIST 1.1 criteria, the median TTR was 2.8 months with the combination versus 3.3 months with sorafenib. Although the TTR was similar between arms, a significantly higher overall response rate (ORR) was noted in the combination arm (27%) versus the sorafenib arm (12%).

Additionally, 6% of patients achieved a CR with the combination compared with 0% with sorafenib per RECIST v1.1 criteria. These findings were particularly encouraging as HCC is typically associated with very low CR rates, explained Singal.

Notably, the majority of patients who derived a CR from the combination had an ongoing CR at 6 months of follow up. Moreover, the median duration of CR has not yet been reached.

Another poster presentation described a meta-analysis that evaluated the clinical value of frontline atezolizumab/bevacizumab in unresectable HCC.3 While head-to-head comparisons of atezolizumab/bevacizumab and lenvatinib (Lenvima) and nivolumab (Opdivo) monotherapy do not exist, cross-trial comparison from the analysis indicated that atezolizumab/bevacizumab led to improved overall survival (OS) and progression-free survival (PFS) compared with lenvatinib, nivolumab, and sorafenib.

Indirect OS comparisons showed that atezolizumab plus bevacizumab had a 93.7% probability of superiority versus lenvatinib (HR, 0.63; 95% CrI, 0.32-1.25), 90.3% probability versus nivolumab (HR, 0.68; 95% CrI, 0.35-1.38), and 97.6% probability versus sorafenib (HR, 0.58; 95% CrI, 0.35-0.99).

Similarly, indirect PFS comparisons revealed that the probability of atezolizumab/bevacizumab superiority was 61.5% versus lenvatinib (HR, 0.91; 95% CrI, 0.23-3.65), 85.5% versus nivolumab (HR, 0.63; 95% CrI, 0.16-2.59), and 92.3% versus sorafenib (HR, 0.59; 95% CrI, 0.23-1.58).

Finally, the safety profiles appeared to be similar between regimens, but multiple factors were not taken into account in this analysis.

Overall, the consensus is that atezolizumab/bevacizumab is a new standard of care for the frontline treatment of patients with unresectable HCC.

Novel Combinations Poised to Continue the Paradigm Shift

Two abstracts demonstrated promising clinical activity with novel combinations that are currently being evaluated in phase 3 clinical trials.

The combination of tremelimumab and durvalumab (Imfinzi) demonstrated promising clinical activity with a manageable safety profile in a phase 2 trial.⁴ Eligible patients had to have unresectable HCC and progressed on, were intolerant to, or refused prior sorafenib. Additionally, patients had to have Child Pugh A liver function.

In part 2A of the trial, patients were randomized to receive 1500 mg of durvalumab monotherapy every 4 weeks (n = 40), 750 mg of tremelimumab monotherapy every 4 weeks for 7 doses and then every 12 weeks thereafter (n = 69), or 75 mg of low-dose tremelimumab for 4 doses in combination with 1500 mg of durvalumab every 4 weeks (n = 39). Part 2B allocated patients to receive 300 mg of tremelimumab plus 1500 mg of durvalumab every 4 weeks (n = 10).

An additional 64, 33, 45, and 65 patients were included in each cohort, respectively, in part 3 of the trial.

The longest median OS was observed in patients who received 300 mg of tremelimumab. The median OS was 18.73 months in the 300-mg cohort (95% CI, 10.78-27.27) compared with 13.57 months with durvalumab alone (95% CI, 8.74-17.64), 15.11 months with tremelimumab alone (95% CI, 11.33-20.50), and 11.30 months with low-dose tremelimumab (95% CI, 8.38-14.95).

The 12-month survival rates were 60.3%, 51.2%, 60.2%, and 49.2%, respectively. At 18 months, the rates were 52%, 35.3%, 45.7%, and 34.7%. Notably, responses were observed irrespective of PD-L1 or viral status.

The median treatment duration for the durvalumab monotherapy arm, tremelimumab-alone arm, and 300-mg tremelimumab arm was 3.7 months. The low-dose tremelimumab arm reported a median treatment duration of 2.4 months.

Regarding secondary end points, the ORR was 24% with 300 mg of tremelimumab, 10.6% with durvalumab alone, 7.2% with tremelimumab alone, and 9.5% with low-dose tremelimumab. Notably, 1 patient in the 300 mg tremelimumab arm and 2 patients in the low-dose tremelimumab arm achieved a CR.

The disease control rates were 45.3%, 37.5%, 49.3%, and 36.9%, respectively. The median duration of response was not reached, 11.17 months, 23.95 months, and 13.21 months, respectively. Finally, the median PFS was 2.17 months, 2.07 months, 2.69 months, and 1.87 months, respectively.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) were observed in 82.4% of patients in the 300-mg tremelimumab arm (n = 74), 60.4% with durvalumab alone (n = 101), 84.1% with tremelimumab alone (n = 69), and 69.5% with low-dose tremelimumab (n = 82). Of these reported TRAEs, 35.1%, 17.8%, 43.5%, and 23.2% were grade 3/4 TRAEs, respectively.

TRAEs that led to treatment discontinuation occurred in 10.8%, 7.9%, 13%, and 6.1% of patients, respectively. TRAEs that required additional intervention with systemic steroids occurred in 24.3%, 9.9%, 26.1%, and 24.4% of patients, respectively.

Additionally, one patient each in the tremelimumab combination arms and 3 patients in the durvalumab monotherapy arm had a TRAE that led to patient death.

Findings from part 3 of the study were updated at the 2020 ESMO World Congress on Gastrointestinal Cancer, confirming that the higher dose of tremelimumab demonstrated the most clinical activity among the 4 evaluated regimens.⁵

The higher-dose combination regimen and durvalumab monotherapy are being evaluated as first-line treatment regimens versus sorafenib in the ongoing phase 3 HIMALAYA study, for which results are anticipated, explained Singal.

Another abstract presented at the 2020 ASCO Virtual Scientific Program reported the findings of a phase 1b study (NCT03006926) of lenvatinib in combination with pembrolizumab (Keytruda) in patients with unresectable HCC.⁶

The combination demonstrated promising antitumor activity with a high ORR and disease control rate (DCR) at a median follow-up of 10.6 months. Per RECIST 1.1 criteria, the ORR was 36% and the DCR was 88%.

The trial enrolled 104 patients (dose-limiting toxicity [DLT] phase, n = 6; expansion phase, n = 98) with unresectable HCC. Patients had to have stage B or C disease as defined by the Barcelona Clinic Liver Cancer (BCLC) criteria, have Child-Pugh class A disease, and have an ECOG performance status of 0 or 1. Additionally, eligible patients were required to have at least 1 measurable target lesion as determined by modified RECIST.

In the DLT phase of the study, patients were ineligible for other therapies. The expansion phase enrolled patients with no history of prior systemic therapy.

Patients were given 8 mg or 12 mg of daily oral lenvatinib as determined by their body weight and 200 mg of intravenous pembrolizumab administered on day 1 of a 21-day cycle.

Of the 100 evaluable patients, the median age was 66.5 years and the majority of patients were male (81%). Most patients (81%) had a bodyweight of greater than or equal to 60 kg.

Sixty-two percent of patients had an ECOG performance status of 0, and the remainder had a score of 1. Additionally, 29% of patients were BCLC stage B and 71% were stage C. Similarly, 71% of patients had a Child-Pugh score of 5 and 27% had a score of 6. Two patients had a Child-Pugh score of 7 and had protocol deviations.

Finally, 67% of patients’ serum alpha fetoprotein levels were less than 400 ng/mL and 62% of patients had macroscopic portal vein invasion, extrahepatic spread, or both.

Tumor size reductions were observed in 83% of patients by RECIST 1.1 criteria.

Of the patients who responded to the combination, 1% achieved a CR and 35% achieved a partial response per RECIST 1.1. Additionally, 52% of patients experienced stable disease, and 7% of patients had progressive disease.

Regarding safety, the median duration of treatment with the combination was 7.9 months.

The most common TRAEs that occurred at any grade included hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), hypothyroidism (25%), palmar-plantar erythrodysesthesia syndrome (23%), weight decrease (22%), dysphonia (21%), aspartate aminotransferase increase (20%), and proteinuria (20%).

Grade 3 or higher AEs occurred in 67 patients. The only grade 4 event was an incidence of leukopenia/neutropenia.

Three grade 5 TRAEs included 1 case of acute respiratory failure/acute respiratory distress syndrome, 1 case of abnormal hepatic function, and 1 case of intestinal perforation. Each TRAE was found to be a potential drug class effect. 

The ongoing phase 3 LEAP-002 study (NCT03713593) is evaluating the combination of lenvatinib/pembrolizumab versus lenvatinib alone in the frontline setting for patients with unresectable HCC.

References

1. FDA approves Genentech’s Tecentriq in combination with Avastin for people with the most common form of liver cancer. News release. Genentech. May 29, 2020. Accessed May 29, 2020. bit.ly/2Aneztc.
2. Finn RS, Qin S, Ikeda M, et al. Complete responses (CR) in patients receiving atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in IMbrave150: a phase III clinical trial for unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2020;38(15 suppl):4596. doi:10.1200/JCO.2020.38.15_suppl.4596
3. Vogel A, Rimassa L, Sun HC, et al. Clinical value of atezolizumab + bevacizumab for first-line unresectable hepatocellular carcinoma (HCC): a network meta-analysis. J Clin Oncol. 2020;38(15 suppl):4585. doi:10.1200/JCO.2020.38.15_suppl.4585
4. Kelley RK, Sangro B, Harris WP, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J Clin Oncol. 2020;38(15 suppl):4508. doi:10.1200/JCO.2020.38.15_suppl.4508[CS4]
5. Kelley RK, Kudo M, Harris W, et al. The novel regimen of tremelimumab in combination with durvalumab provides a favorable safety profile and clinical activity for patients with advanced hepatocellular carcinoma (aHCC). Presented at: ESMO World Congress on Gastrointestinal Cancer 2020. July 1-4, 2020; Virtual. Abstract O-6.
6. Zhu AX, Finn RS, Ikeda M, et al. A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2020;38(15 suppl):4519. doi:10.1200/JCO.2020.38.15_suppl.4519