ASCO 2018 HCC: The ASCO18 hepatocellular cancer track summarised

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ASCO 2018 HCC TRACK

SPOTLIGHT ON HEPATOCELLULAR CARCINOMA

By: Anne John Michael | Last updated: 10th June 2018 | In: ASCO 2018 Annual Meeting, Chemotherapy, Conferences, Gastrointestinal Cancer, ImmunoOncology, Immunotherapy, Oncology, Targeted Therapies, Translational Research

ASCO 2018 HCC Keywords

#ASCO18, apatinib, atezolizumab, Avastin, AXL, Bayer, bevacizumab, cabozantinib, CELESTIAL, cMET, Cometriq, Cyramza, doxorubicin, Eisai, Eli Lilly, Exelixis, Genentech, icaritin, Imclone, Keytruda, lenvatinib, Lenvima, Merck, MSD, Nexavar, PD-1, PD-L1, pembrolizumab, ramucirumab, REACH-2, Roche, SHR-1210, sorafenib, TACE, Tecentriq, TMB, VEGF, VEGFR

Hepatocellular carcinoma (HCC) is a rapidly deteriorating malignancy with poor prognosis. Since the introduction of sorafenib (SHARP and the Asia Pacific studies) a decade ago, successes with novel agents have been scarce. This year’s American Society of Clinical Oncology (ASCO) annual meeting included two Phase III studies in the second-line treatment of the disease. Moreover, data with several immune-checkpoint inhibitors were presented, including the KEYNOTE-224 with pembrolizumab. Welcome to the summary of the ASCO 2018 HCC track.

NEW EVIDENCE FOR SECOND-LINE TARGETED THERAPIES IN ADVANCED HCC

In the randomised Phase III REACH-2 study (NCT02435433), ramucirumab significantly improved median overall survival (OS) (8.5 months) of patients with advanced HCC and elevated alpha-fetoprotein when compared to placebo (7.3 months) in the second-line treatment of HCC (P=0.0199).¹ The VEGFR2-directed monoclonal antibody (MAb) also significantly improved median progression-free survival (PFS) (2.8 months vs 1.6 months for placebo); P<0.0001), as well as increased the objective response rate (ORR) (4.6% vs 1.1% for placebo; P=0.1156) and disease control rate (DCR) (59.9% vs 38.9% for placebo; P=0.0006).¹

CELESTIAL (NCT01908426), another Phase III randomised trial in the second-line treatment of HCC, revealed that cabozantinib, a small molecule inhibitor of MET, the VEGF receptors, and AXL, significantly improved median OS (10.2 months vs 8.0 months for placebo; P=0.0049) and median PFS (5.2 months vs 1.9 months for placebo; P<0.0001) for previously treated patients with advanced HCC.² Subgroup analysis showed improved efficacy of cabozantinib, in both patients younger than 65 years as well as patients 65 years and older.³ Hepatitis B virus (HBV) was associated with HCC in patients younger than 65 years. The distribution of hepatitis C virus (HCV) was evenly distributed over the two age groups. Another subgroup analysis looked at CELESTIAL patients who received sorafenib as the only prior systemic therapy; cabozantinib improved the OS and PFS, an effect irrespective of the duration of sorafenib treatment.⁴

ADVANCES IN IMMUNOTHERAPY

The ASCO 2018 HCC track contained two studies that independently showed anti-tumour activity of pembrolizumab in the second-line for advanced liver cancer. Preliminary data from the open-label, Phase II KEYNOTE-224 trial (NCT02702414) indicated an ORR of 16.3% to pembrolizumab, an immunotherapy medication.⁵ The trial also revealed that at 12 months, pembrolizumab had a PFS rate of 25.4% and OS rate of 53.6%.⁵ Notably, in the KEYNOTE-224, 21% were HBV carrier and 26% were HCV carrier. Another Phase II trial showed a median time to tumour progression of 3 months and median OS of 14 months.⁶

Japanese investigators of the SCRUM-Japan GI-SCREEN study (UMIN000016343) looked at tumour mutation burden (TMB) in advanced gastrointestinal (GI) malignant tissue samples (N=1,759) in the Cancer Genome Atlas (TCGA) to determine which patients may confer benefit from immunotherapy.⁷ Twenty-seven (1.5%) HCC samples were included of which 7% were found to be TMB-high.⁷

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Figure 1. Data of selected Phase II and III ASCO 2018 HCC studies

AFP=alpha-fetoprotein; BCLC=Barcelona Clinic Liver Cancer staging; DCR=disease control rate; ECOG PS=Eastern Collaborative Oncology Group performance status; EHS=extrahepatic spread; HCC=hepatocellular carcinoma; mo=months; NE=not evaluated; NR=not reported; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; TTP=time to progression; VI=vascular invasion.

TACE: UPDATES ON COMBINATION THERAPY AND REAL-WORLD USE

The Barcelona Clinic Liver Cancer (BCLC) criteria consider intermediate stage (B) HCC patients with multinodular disease and preserved liver function and good performance status (ECOG PS 0) candidates for TACE.⁸ BCLC intermediate stage (C) patients are those with extrahepatic spread (EHS) or vascular invasion (VI) and have a reduction in performance status of (ECOG PS 1 or 2); they are considered candidates for systemic treatment.⁸

The prospective, observational OPTIMIS trial (NCT01933945) included 1650 patients with unresectable HCC planned for TACE.⁹ The study found that 32% (N=529) had BCLC stage C disease at study entry. Moreover, 7% (N=118) had EHS and 7% (N=123) had VI.⁹ In total, 39% of patients receiving TACE at study entry were ineligible for the procedure by international and regional treatment guidelines.⁹ Additionally, the trial found that the rate of disease progression increased with multiple TACE procedures.⁹ The majority of the patients (91%) who became TACE ineligible during the course of the study (N=507) were either not prescribed sorafenib or received it late.⁹

Another study by Professor Kudo and colleagues investigated the combination of transarterial chemoembolisation (TACE) and sorafenib for patients with unresectable HCC in the randomised, open-label TACTICS trial (NCT01217034).¹⁰ In total 156 patients with Child-Pugh score ≤7, ECOG performance status ≤1, no VI, no EHS, a maximum lesion size ≤10 cm and with ≤10 nodules were randomised to sorafenib plus conventional TACE (cTACE) vs cTACE alone. ).¹⁰ Kudo et al. reported a significantly increased median PFS (25.2 months) when compared to cTACE alone (13.5 months) (p=0.006), the number of OS events had not been reached and the median time to unTACEable progression (TTUP) was 26.7 months (sorafenib plus cTACE) vs 20.6 (cTACE).¹⁰ There were no unexpected toxicities.¹⁰

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Figure 2. Data of selected Phase I ASCO 2018 HCC studies

BCLC=Barcelona Clinic Liver Cancer staging; CR=complete response; DCR=disease control rate; ECOG PS=Eastern Collaborative Oncology Group performance status; HCC=hepatocellular carcinoma; mo=months; NE=not evaluated; ORR= objective response rate; PD-1=Programmed Death 1; pts=patients; TRAE=treatment-related adverse events.

ASCO 2018 HCC: IN THE PIPELINE

A single arm Phase II trial of icaritin, a highly selective oestrogen receptor a 36 (ERa36) modulator, in advanced HCC (N=70) found the drug to be safe (NCT01972672).¹¹ No Grade 3 or higher drug-related adverse events were reported.¹¹ Median OS was 254 days and disease control was achieved in 34.4% of patients.¹¹ The study included subgroup analysis: the presence of high PD-L1 expression, interleukin (IL)-6 advantage, or a neutrophil-lymphocyte ratio (NLR)-advantage all showed better OS outcomes.¹¹

A Phase Ib study of patients with unresectable or metastatic HCC who were naive to systemic treatment revealed that atezolizumab plus bevacizumab was well tolerated and had no new safety signals (NCT02715531).¹² The combination therapy was associated with a 62% confirmed response rate in the selected study population.¹²

Another Phase I study investigated the combination of SHR-1210, a fully human IgG4 monoclonal antibody against PD-1, and VEGFR2 inhibitor apatinib in patients with several advanced GI cancers, including HCC refractory to standard therapy (NCT02942329).¹³ The investigators concluded the novel combination therapy had a manageable toxicity profile and showed early signs of clinical activity. Fourteen patients with HBV-related HCC were treated at different dosing levels and evaluable. The ORR and DCR were 50.0% and 85.7%, respectively.¹³

Finally, initial results from a Phase Ib trial combining the multikinase inhibitor lenvatinib with PD-1 MAb pembrolizumab in patients (N=13) with BCLC stage B (not amenable for TACE) or C, Child-Pugh class A, and ECOG PS ≤ 1 unresectable HCC (NCT03006926).¹⁴ The study revealed good safety profile and potential anti-tumour activity; with 6 partial responses and 6 stable diseases, the disease control rate (DCR) was 93%. The response assessment of 1 patient could not be evaluated.¹⁴

UNSUCCESSFUL CLINICAL DRUG CANDIDATES

Some ASCO 2018 HCC studies were not successful.

A Phase IB study showed that enzalutamide was not efficacious for patients with either androgen receptor (AR)-positive or AR-negative HCC.¹⁵ The trial also investigated the combination of enzalutamide plus sorafenib, but this combination was limited by drug-drug interactions (NCT02642913).¹⁵

A Phase II trial in the second-line setting for advanced HCC found that sorafenib plus doxorubicin after first-line failure on sorafenib did improve OS but was not well-tolerated.¹⁶ The investigators do not recommend further investigations of the combination therapy (NCT01840592).¹⁶

REFERENCES

Zhu AX et al. J Clin Oncol 2018;36(suppl):Abstr 4003

Abou-Alfa GK et al. J Clin Oncol 2018;36(suppl):Abstr 4019

Rimassa L et al. J Clin Oncol 2018;36(suppl):Abstr 4090

Kelley RK et al. J Clin Oncol 2018;36(suppl):Abstr 4088

Zhu AX et al. J Clin Oncol 2018;36(suppl):Abstr 4020

Feun LG et al. J Clin Oncol 2018;36(suppl):Abstr 4086

Nakamura Y et al. J Clin Oncol 2018;36(suppl):Abstr 12094

Forner A et al. Lancet 2018;391(10127):1301–14

Peck-Radosavljevic M et al. J Clin Oncol 2018;36(suppl):Abstr 4018

Kudo M et al. J Clin Oncol 2018;36(suppl):Abstr 4017

Sun Y et al. J Clin Oncol 2018;36(suppl):Abstr 4077

Stein S et al. J Clin Oncol 2018;36(suppl):Abstr 4074

Xu JM et al. J Clin Oncol 2018;36(suppl):Abstr 4075

Ikeda M et al. J Clin Oncol 2018;36(suppl):Abstr 4076

Harding JJ et al. J Clin Oncol 2018;36(suppl):Abstr 4083

El Dika IH et al. J Clin Oncol 2018;36(suppl):Abstr 4080

Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).

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Ramucirumab FDA approved for hepatocellular carcinoma | MediPaper says:

23rd May 2019 at 11:58 AM

[…] FDA approval was based on data of the multinational, double-blind, placebo-controlled, multicentre REACH‑2 (NCT02435433) study that randomised 292 advanced HCC patients with AFP ≥400 ng/mL and disease […]

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Ramucirumab FDA approved for hepatocellular carcinoma | MediNews Asia says:

23rd May 2019 at 11:50 AM

[…] FDA approval was based on data of the multinational, double-blind, placebo-controlled, multicentre REACH‑2 (NCT02435433) study that randomised 292 advanced HCC patients with AFP ≥400 ng/mL and disease […]

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Cabozantinib FDA approved in HCC patients failing sorafenib says:

17th January 2019 at 10:35 AM

[…] randomised, double-blind, placebo-controlled, multicentre CELESTIAL trial randomised 707 HCC patients with Child-Pugh Class A liver impairment and previously treated […]

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ESMO 2018 HCC: The ESMO18 hepatobiliary cancer track summarised says:

5th November 2018 at 1:03 PM

[…] the Phase III, open-label, randomised REFCLECT (NCT01761266) study showed non-inferiority for levantinib -a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT- when compared to […]

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ESMO 2018 HCC: The ESMO18 hepatobiliary cancer track summarised says:

3rd November 2018 at 10:35 PM

[…] sorafenib treatment in patients with advanced HCC from the Phase III REACH (NCT01140347) and REACH-2 studies (NCT02435433).2Zhu AX, et al. Ann Oncol 2018;29(8):mdy282.006 Patients in the REACH-2 were […]

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SPOTLIGHT ON HEPATOCELLULAR CARCINOMA

ASCO 2018 HCC Keywords

NEW EVIDENCE FOR SECOND-LINE TARGETED THERAPIES IN ADVANCED HCC

ADVANCES IN IMMUNOTHERAPY

Newsletter Sign-Up

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REFERENCES

Disclaimer

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