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ESMO 2018 HEPATOBILIARY TRACK
SPOTLIGHT ON LIVER CANCER
By: Anita Shree Jacob, MBBS and Stijn van den Borne, MSc | Last updated: 3rd November 2018 | In: Conferences, ESMO 2018 Annual Meeting, Gastrointestinal Cancer, ImmunoOncology, Immunotherapy, Oncology, Targeted Therapies, Translational Research
Whereas this year’s American Society of Clinical Oncology Annual Meeting (ASCO 2018) boasted two Phase III studies and four Phase II studies with notable results in hepatocellular carcinoma (HCC), the trend did not continue to the European Society for Medical Oncology Conference (ESMO 2018), held in Münich, Germany between October 19-23, 2018. The focus for this years ESMO was mostly on biliary-tract cancers (BTC). Welcome to the hepatobiliary track of ESMO 2018.
ESMO 2018 HCC and BTC Keywords
ANG2, Bayer, BGJ398, BTC, cabozantinib, cholangiocarcinoma, cMET, CPS, erdafitinib, FGF19, FGF21, FGF23, FGFR1, FGFR2, FGFR3, FGFR4, HCC, infigratinib, irAE, KIT, levantinib, MSC2156119J, MSI-H, Nexavar, PD-1, PD-L1, PDGFRα, ramucirumab, RET, sorafenib, tepotinib, VEGF, VEGFR, VEGFR1, VEGFR2, VEGFR3
Hepatocellular Carcinoma
One Phase II study reported the efficacy and safety of the potent and highly selective MET-inhibitor tepotinib vs sorafenib in the first-line treatment of Asian patients with advanced MET-positive HCC (NCT01988493).1Ryoo BY, et al. Ann Oncol 2018;29(8):mdy282.005 Inclusion criteria included Barcelona clinic liver cancer (BCLC) Stage B/C disease; Child-Pugh Class A cirrhosis without encephalopathy, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and a 2+ or 3+ MET stain by immunohistochemistry.
In total 90 patients were randomised; and 38 patients on tepotinib and 37 patients on sorafenib were included in the efficacy analysis (Table 1). The time-to-progression (TTP) by independent review committee (IRC) favoured tepotinib with 2.8 months vs 1.4 months with sorafenib (hazard ratio [HR]=0.42; 90% confidence interval [CI], 0.26-0.70; P=0.0043). The median progression-free survival (PFS) by IRC was significantly longer in the tepotinib-group vs the sorafenib-group; 2.8 vs 1.4 months, respectively (HR=0.53; 90% CI, 0.33-0.84; P=0.0229). The median overall survival (OS) was similar (HR=0.73; 90% CI, 0.43-1.12; P=0.3039) for tepotinib (9.3 months) and sorafenib (8.6 months). Four partial responses were observed in patients treated with tepotinib alone resulting in an objective response rate (ORR) by IRC of 10.5% with tepotinib vs 0% with sorafenib (P=0.0438). Grade ≥3 treatment-related and emergent adverse events were more commen in patients treated with sorafenib 20/44 (46%) than in patients treated with tepotinib 37/45 (82%). The investigators did not report new safety signals.
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Table 1. Data of selected ESMO 2018 HCC studies
AFP=alphafeto protein; BCLC=Barcelona Clinic Liver Cancer staging; Cabo=cabozantinib; CI=confidence interval; ECOG PS=Eastern Collaborative Oncology Group performance status; HCC=hepatocellular carcinoma; HR=hazard ratio; IHC=immunohistochemistry; MET=hepatocyte growth factor receptor; mo=months; NE=not evaluated; NS=not significant; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; S=significant.
Previously, 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 sorafenib in the first-line treatment of 954 unresectable HCC patients.
The study included a biomarker analysis, assaying VEGF, ANG2, FGF19, FGF21, and FGF23 by ELISA in serum samples (N=407) collected at baseline and during treatment and correlated these (Wilcoxon rank-sum test) with tumour response (mRECIST) by IRC.2Finn RS, et al. Ann Oncol 2018;29(8):mdy269.057
Both levantinib and sorafenib increased VEGF levels. However, FGF19 and FGF23 levels were only increased in patients treated with levantinib and was more profound in patients with a complete response or a partial response (PR) than in non-responders; FGF19: 55.2% vs 18.3%, P=0.0140; FGF23: 48.4% vs 16.4%; P=0.0022, respectively. Higher baseline-levels of VEGF, ANG2, and FGF21 correlated with a worse OS outcome for both sorafenib and levantinib, though patients with increased baseline FGF21 receiving levantinib (N=70) had longer OS compared to those patients receiving sorafenib (N=27); median OS 10.9 vs 6.8 months, respectively (HR=0.528; 95% CI, 0.328–0.849; P=0.0075).
Another presentation reported the patient-reported outcome (PRO) of second-line treatment with ramucirumab following sorafenib treatment in patients with advanced HCC from the Phase III REACH (NCT01140347) and REACH-2 studies (NCT02435433).3Zhu AX, et al. Ann Oncol 2018;29(8):mdy282.006 Patients in the REACH-2 were selected based on alpha-fetoprotein levels (AFP) ≥400 ng/mL, the study met its primary OS endpoint, consistent with what was observed in patients from the REACH-study who had AFP-levels ≥400 ng/mL .
Zhu and colleagues assessed the PRO of ramucirumab vs placebo in REACH-2 patients and in REACH patients with an AFP≥400 ng/mL by Functional Assessment of Cancer Therapy (FACT) and Hepatobiliary Symptom Index (FHSI)-8 and concluded that ramucirumab-treatment lead to a consistent trend in benefit for disease-related symptoms.
Table 2. Data of selected ESMO 2018 Cholangiocarcioma studies
BTC=biliary-tract carcinoma; CCA=cholangiocarcinoma; cORR=confirmed objective response rate; CPS=programmed death ligand 1 combined positive score; CR=complete response; DCR=disease control rate; ECOG PS=Eastern Collaborative Oncology Group performance status; FGFR2=fibroblast growth factor receptor 2; IHC=intrahepatic cholangiocarcinomas; mo=months; NE=not evaluated; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; PR=partial response; SD=stable disease; uCR=unconfirmed complete response; uPR=unconfirmed partial response.
Biliary-Tract Cancer
Several Phase II studies reported the outcome of novel therapies for biliary-tract cancer (BTC). One open-label Phase II study investigated pan-fibroblast growth factor receptor (FGFR) kinase inhibitor infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in 71 patients with previously treated advanced, intrahepatic cholangiocarcinoma (IHC) harbouring FGFR2 fusions or translocations (NCT02150967).4Javle M, et al. Ann Oncol 2018;29(8):mdy424.030 The investigators found that infigratinib had clinically meaningful activity after chemotherapy in patients with IHC with FGFR2 fusions and that the associated toxicity was manageable.
At a median duration of treatment of 5.5 months the investigator-assessed ORR by RECIST 1.1 was 31.0% (95% CI, 20.5–43.1%) and the confirmed ORR was 26.9% (95% CI, 16.8–39.1%). The confirmed ORR in patients (n=28) who had received ≤1 prior lines of treatment was 39.3%, compared to 17.9% in patients (n=39) who had received ≥2 lines of prior treatment. The disease control rate DCR was 83.6% (95% CI, 72.5–91.5%) and the median duration of response measured 5.4 months (95% CI, 3.7–7.4) with a median PFS of 6.8 months (95% CI, 5.3–7.6). The median OS was 12.5 months (95% CI, 9.9–16.6). Most common Grade 3/4 treatment emergent adverse events (TEAEs) in 47 pts (66.2%) were hypophosphatemia (14.1%), hyperphosphatemia (12.7%), and hyponatremia (11.3%).
Preliminary results of another open-label multicentre Phase IIa study (LUC2001, NCT02699606) in 11 out of 150 Asian patients with advanced cholangiocarcinoma (CCA) harbouring FGFR 2 or 3 alterations evaluated the efficacy and safety of erdafitinib after failing first-line treatment.5Chen YY, et al. Ann Oncol 2018;29(8):mdy282.008 In this study, erdafitinib showed encouraging clinical activity with 3 confirmed PR, 2 unconfirmed PR (uPR), 4 stable disease (SD), and 2 progression disease (PD, [both FGFR3 mutations]). The unconfirmed ORR measured 45.5% and the unconfirmed DCR 81.8%. Common adverse events (AEs) in >30% of patients included are hyperphosphatemia, dry mouth, stomatitis, diarrhea, nail disorder, and palmar-plantar erythrodysaesthesia syndrome. Grade ≥3 AEs occured in 7 patients, 3 subjects required dose reductions, but treatment-discontinuation or Grade 5 toxicities were not reported. Non-drug related serious AEs (SAEs) occurred in 3 patients.
The multicohort, Phase 2 KEYNOTE-158 (NCT02628067) study investigated pembrolizumab in 104 patients with advanced BTC and prior progression/intolerance on standard chemotherapy, measurable disease per RECIST 1.1, ECOG PS ≤1, and sufficient tumour tissues sample available for biomarker evaluation including programmed death ligand 1 (PD-L1) by the immunohistochemistry 22C3 antibody.6Ueno M, et al. Ann Oncol 2018;29(8):mdy282.009 In this study, pembrolizumab showed durable antitumour activity in a subset of advanced BTC patients regardless of the PD-L1 expression by combined positive score (CPS) and with a manageable toxicity-profile.
At median follow-up of 9.3 months (range, 0.6–23.6), 6 partial responses were observed matching an ORR of 5.8% (95% CI, 2.1–12.1). Patients with a CPS ≥1 (N=61) had an ORR of 6.6% (95% CI, 1.8–15.9) compared to 2.9% (95% CI, 0.1–15.3) in patients with a PD-L1 CPS <1 (N=34). Seventeen patients (16%) had SD. The median DOR was not yet reached (range, 6.2–15.7+ months). The median PFS was 2.0 months (95% CI, 1.9–2.1); 1.9 months (95% CI, 1.8–2.0) in CPS ≥1 patients vs 2.1 mo (95% CI, 1.9–2.6) in CPS <1 patients. Likewise, a CPS ≥1 did not correlate with an improved OS outcome. The median OS in all patients was 9.1 months (95% CI, 5.6–10.4), and measured 7.2 mo (95% CI, 5.3–11.0) and 9.6 mo (95% CI, 5.4–12.8) in patients with a CPS ≥1 and CPS <1, respectively. No patients were found to be microsattelite instability-high (MSI-H). Grade ≥3 AEs occurred in 13% of patients, 16% had immune-mediated AEs (irAEs). Six patients discontinued due to treatment-related AEs.
IHC (N=36) | EHBD (N=35) | GP (N=14) | VP (N=7) | |
---|---|---|---|---|
APC mutation | 2 (6%) | 1 (3%) | 0 | 1 (14%) |
ATM mutation | 1 (3%) | 2 (6%) | 1 (7%) | 0 |
CCNE1 mutation | 1 (3%) | 0 | 3 (21%) | 0 |
CDKN2A mutation | 3 (8%) | 0 | 2 (14%) | 0 |
CTNNB1 mutation | 1 (3%) | 1 (3%) | 1 (7%) | 2 (29%) |
ERBB2 mutation | 0 | 2 (6%) | 1 (7%) | 0 |
ERBB2 CNV>7 copies | 0 | 1 (3%) | 1 (7%) | 0 |
ERBB3 mutation | 1 (3%) | 3 (9%) | 1 (7%) | 0 |
FGFR3 mutation | 1 (3%) | 0 | 0 | 0 |
FGFR3 CNV | 0 | 2 (6%) | 1 (7%) | 0 |
IDH1 mutation | 5 (14%) | 1 (3%) | 0 | 0 |
KRAS mutation | 12 (33%) | 11 (31%) | 2 (14%) | 4 (57%) |
MDM2 CNV | 1 (3%) | 1 (3%) | 1 (7%) | 1 (14%) |
PIK3CA mutation | 0 | 0 | 4 (29%) | 1 (14%) |
SMAD4 mutation | 2 (6%) | 1 (3%) | 0 | 1 (14%) |
STK11 mutation | 0 | 2 (6%) | 1 (7%) | 1 (14%) |
TET2 mutation | 0 | 1 (3%) | 2 (14%) | 1 (14%) |
TP53 mutation | 9 (25%) | 11 (31%) | 8 (57%) | 4 (57%) |
Finally, results were presented of a nationwide Japanese cancer genome screening project, the SCRUM Japan GISCREEN, identifying BTC cancer genome alterations by utilising Next Generation Sequencing in 167 patients scheduled for -or undergoing- chemotherapy for advanced BTC at 20 major cancer centres (UMIN000016344).7Morizane C, et al. Ann Oncol 2018;29(8):mdy282.007
In total 140 samples were analysed by the cut-off date of March 31, 2017. A successful sequence was performed in 92 (65.7%) of tumour samples (36 IHC, 35 extrahepatic bile duct (EHBD), 14 gallbladder (GB), and 7 ampulla of Vater (VP)). No gene fusions were detected. Frequently detected gene-alterations are listed in Table 3.
REFERENCES
- Ryoo BY, et al. Ann Oncol 2018;29(8):mdy282.005
- Finn RS, et al. Ann Oncol 2018;29(8):mdy269.057
- Zhu AX, et al. Ann Oncol2018;29(8):mdy282.006
- Javle M, et al. Ann Oncol 2018;29(8):mdy424.030
- Chen YY, et al. Ann Oncol 2018;29(8):mdy282.008
- Ueno M, et al. Ann Oncol 2018;29(8):mdy282.009
- Morizane C, et al. Ann Oncol 2018;29(8):mdy282.007
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).
© Copyright 2018 MediPaper Medical Communications Ltd. – ESMO 2018 HCC and Cholangiocarcinoma Track – #ESMO18 Hepatobiliary Cancer
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© Copyright 2018 MediPaper Medical Communications Ltd. – ESMO 2018 HCC and Cholangiocarcinoma Track – #ASCO18 Hepatobiliary Cancer
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