VI) First Line Combination Therapy or Sequential Therapy for HCC

Symposium (VI)

FIRST LINE COMBINATION THERAPY OR SEQUENTIAL THERAPY FOR HCC

EXPANDING THE LANDSCAPE OF SYSTEMIC THERAPY FOR HCC: 2021 AND 2022

Ann-Lii Cheng Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan

The combination of atezolizumab and bevacizumab (atezo-bev) has revolutionized the treatment of advanced HCC, for which prolonged tumor remission has now become commonplace. Atezo-bev also bring in unprecedented improvement of the quality of life for the patients. With the success of atezo-bev, systemic therapy is now being explored in early and intermediate stages of HCC.

Contemporary guidelines for systemic therapy of HCC largely belong to two schools. The first school, including of ASCO and ESMO, indicates a preference for the use of atezo-bev for 1L therapy, and leaves sorafenib and lenvatinib for those who are unsuitable for atezo-bev. The second school, which consists of most of the other guidelines, depicts no preference of either sorafenib, lenvatinib, or atezo-bev for 1L therapy, and thus leaves room for physicians to make decision based on their individual real-world environments. Second-line treatment after atezo-bev or lenvatinib is becoming a predicament. At this point, a rational approach based on individualized treatment goals, as well as real world evidence is advised.

Future landscape of development of systemic therapy includes combinations of multiple immune checkpoint inhibitors (CPI), novel CPIs, and combinations of CPI and multi-target tyrosine kinase inhibitors (TKI). Exploratory studies on triplet (e.g. double CPIs + TKI) are ongoing. We are truely in a new era of pursuing highly efficacious systemic therapy for HCC.

Symposium (VI)

FIRST LINE COMBINATION THERAPY OR SEQUENTIAL THERAPY FOR HCC

COMBINATION THERAPY IN JAPAN: FIRST LINE SETTING

Masatoshi Kudo Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan

A phase III IMbrave 150 trial was conducted using the combination atezolizumab plus bevacizumab with sorafenib as the active comparator. The first interim analysis revealed combination atezolizumab plus bevacizumab was statistically far superior in both co-primary endpoints (PFS and OS). After this landmark result, from 2007 onwards, drug treatment for HCC changed substantially, including with respect to the long-prevailing standard first-line treatment of sorafenib. OS data in the atezolizumab plus bevacizumab group was not fully mature, but OS in the sorafenib group was 13.2 months (95% CI: 10.4–NE) (HR = 0.58; 95% CI: 0.42−0.79; p < 0.001). PFS in the atezolizumab plus bevacizumab group was 6.8 months (95% CI: 5.7–8.3) and in the sorafenib group was 4.3 months (95% CI: 4.0–5.6) (HR = 0.59; 95% CI: 0.47–0.76; p < 0.001). Adverse events were also less frequent in the atezolizumab plus bevacizumab group, and based on patient-reported QOL, the time to QOL deterioration was far better in the atezolizumab plus bevacizumab group at 11.2 months than the 3.6 months in the sorafenib group (HR = 0.63; 95% CI: 0.46−0.85). With these results, concomitant atezolizumab plus bevacizumab firmly established its position as the first choice first-line treatment unless immunotherapy was contraindicated owing to autoimmune disease. At the 2021 Gastrointestinal Cancers Symposium (ASCO-GI) in January, updated OS data was published up to the final follow-up period of 15.6 months (compared to 8.6 months at interim analysis). OS in the sorafenib group was 13.4 months (95% CI: 11.4−16.9) and in the atezolizumab plus bevacizumab group was 19.2 months (95% CI: 17.0−23.7) (HR = 0.66; 95% CI: 0.52−0.85; p = 0.0009). Updated PFS data also showed PFS in the sorafenib group was 4.3 months (95% CI: 4.0–5.6) and in the atezolizumab plus bevacizumab group was 6.9 months (95% CI: 5.7−8.6) (HR = 0.65; 95% CI: 0.53−0.81; p = 0.0001), results that were consistent with OS data. By final analysis, ORR in the atezolizumab plus bevacizumab group was 30% (95% CI: 25−35), an improvement over ORR at interim analysis. In the sorafenib group, ORR at final analysis (11%; 95% CI: 7−17) was almost unchanged from interim analysis. Duration of response in the atezolizumab plus bevacizumab group was 18.1 months compared to 14.9 months in the sorafenib group (95% CI: 4.9−17.0). In addition, in high risk patients, defined as patients with Vp4, tumor burden >50% or bile duct invasion clearly showed fairy good efficacy results COs 7.6 M, PFS 5.4 M, ORR 25%), resulting in paradigm change in treatment strategy in advanced HCC in Japan.

Symposium (VI)

FIRST LINE COMBINATION THERAPY OR SEQUENTIAL THERAPY FOR HCC

SEQUENTIAL THERAPY: TKI OR ANTI-VEGF MONOCLONAL ANTIBODY FOR ADVANCED HEPATOCELLULAR CARCINOMA

Chia-Jui Yen Department of Oncology, National Cheng Kung University, Tainan, Taiwan

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor, and it is a worldwide leading cause of morbidity and mortality. During the last decades, further knowledge of HCC molecular mechanisms has led to the development of effective systemic treatment including tyrosine kinase inhibitors (TKIs) and immunotherapy. Three potential scenarios can develop during first line systemic treatment, which determine the subsequent patients’ management: (1) Tolerance or intolerance; (2) Radiological progression; and (3) Symptomatic progression. Several advances have been made especially in pretreated patients; phase III trials of regorafenib, cabozantinib, and ramucirumab in patients with elevated α-fetoprotein have demonstrated efficacy in patients progressing after or intolerant to sorafenib. In this review, we describe the second line systemic treatment options for advanced HCC focusing on sequencing therapy (sorafenib-based treatment) and comparison of different second line options. We will discuss the evidence on secondline options for advanced HCC, focusing on the latest results of phase III RESORCE, CELESTIAL, and REACH-2 trials that are currently refining the treatment scenario.

Symposium (VI)

FIRST LINE COMBINATION THERAPY OR SEQUENTIAL THERAPY FOR HCC

ROLE OF LOCOREGIONAL THERAPY IN THE ERA OF SYSTEMIC THERAPY

Chen-Chun Lin Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, LinKuo Chang Gung Memorial Hospital, Taoyuan, Taiwan Chang Gung University, Taoyuan, Taiwan

Hepatocellular carcinoma (HCC) is the fifth common cancer and the second cancer death in the world. Locoregional therapies, such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), are the mainstay measures for treating the early and intermediate stages of HCC by guideline recommendations worldwide. In recent years, systemic therapy has advanced significantly, especially on immune checkpoint inhibitor (ICI)-based combination therapy. The landscape of systemic therapy, including tyrosine kinase inhibitors (TKI) and ICI, has approval for treating the HCC in the advanced stage. Systemic therapies may provide opportunities to eradicate the circulating tumor cells or micrometastasis in the adjuvant therapy after curative therapies and may combine with TACE to extend the therapeutic target. The rationale of the combination of TKI and ICI is sound. Local therapies induce antigen and proinflammatory cytokine release, whereas VEGF inhibitor and TKI booster immunity and prime tumors for checkpoint inhibition. These combinations may also provide a new chance to reduce recurrence after curative therapy by adjuvant therapy or to improve resectability after downstage by neoadjuvant therapy. Radiotherapy is another kind of locoregional therapy to directly treat liver tumors and also has the abscopal effect of extending the systemic tumor control by releasing antigen and proinflammatory cytokine in combination with ICI. The ongoing phase III studies may result in a paradigm shift, changing the current treatment algorithms of HCC therapy.