Background

C inhibits tyrosine kinases including MET, VEGFR, and AXL. In the CELESTIAL trial (NCT01908426), C significantly improved overall survival (median OS 10.2 mo vs 8.0 mo; HR 0.76, 95% CI 0.63–0.92; P = 0.0049), progression-free survival (median PFS 5.2 mo vs 1.9 mo; HR 0.44, 95% CI 0.36–0.52; P < 0.0001), and objective response rate (4% vs 0.4%, P = 0.0086) vs P in patients (pts) with previously treated advanced HCC. Here, we report a secondary analysis of tumor response including best percent change in sum of tumor target lesion diameters (SOD), best percent change in AFP levels, and TTP.

Methods

A total of 707 pts, stratified by disease etiology, geographic region, and extent of disease, were randomized 2:1 to C 60 mg once daily (N = 470) or P (N = 237). Eligible pts had a pathologic diagnosis of HCC, Child-Pugh score A, and ECOG performance status ≤1. Pts must have received prior sorafenib; up to 2 lines of prior systemic therapy for HCC were allowed. Tumors were assessed by the investigator at baseline and every 8 wks thereafter; serum AFP levels were measured centrally on the same schedule. Best percent change in SOD or AFP was defined as the maximum reduction from baseline at any timepoint. TTP, determined retrospectively, was defined as the time from randomization to radiological progression or clinical deterioration attributed to cancer progression.

Results

Based on the intent-to-treat population, 222 of 470 pts (47%) in the C arm and 27 of 237 pts (11%) in the P arm had any reduction in SOD from baseline as best response. Thirty-nine of 470 pts in the C arm (8%) and 3 of 237 pts (1%) in the P arm had ≥30% reduction in SOD as best response. In the C arm, 9% (26/278) of pts with baseline AFP <400 ng/mL and 7% (13/192) of pts with AFP ≥400 ng/mL achieved a ≥ 30% reduction in SOD. Overall, 109 of 470 pts (23%) in the C arm and 13 of 237 pts (5%) in the P arm had a ≥ 50% decrease from baseline in AFP levels. Median TTP was 5.4 mo with C vs 1.9 mo with P (HR 0.41, 95% CI 0.34–0.49).

Conclusions

C is associated with improved TTP, greater rates of target lesion regression, and AFP response compared with P in pts with previously treated advanced HCC.

Editorial acknowledgement

Editorial assistance was provided by Vasupradha Vethantham, PhD, of inScience Communications, Springer Healthcare,New York, NY, USA.

Clinical trial identification

NCT01908426.

Legal entity responsible for the study

Exelixis, Inc.

Funding

Exelixis, Inc.

Disclosure

P. Merle: Advisory boards: Exelixis, Ipsen, BMS, Bayer. Consultancy: Onxeo, Bayer. Grants: Onxeo. L. Rimassa: Honoraria: AstraZeneca, Abbvie; Consultant: Lilly, Bayer Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter, Ipsen, Exelixis; Travel, accomodations, expenses: ArQule, Ipsen. W.P. Harris: Advisory boards: BMS, Bayer, Neotherma; Research Funding BMS, Exelixis, Arqule, Halozyme, Medimmune, BTG. D. Sarker: Advisory boards: Eisai, Ipsen, Novartis, Baxalta. Travel: Ipsen, Bayer, MiNA Therapeutics; Honoraria: Ipsen, Pfizer, Bayer. S. Sen, C. Love: Employee: Exelixis. A-L. Cheng: Consultant: Novartis, Merck Serono, Eisai, Merck Sharp & Dohme (I.A.) Corp., Onxeo, Bayer HealthCare Pharmaceuticals Inc., Bristol-Myers Squibb Company, Ono Pharmaceutical Co., Ltd. T. Meyer: Advisory boards: Merck, BMS, Beigene, Eisai, Bayer, Ipsen. R.K. Kelley: Ad board: Agios, AstraZeneca, Bayer, BMS, Debio, Exelixis; Funding Agios, AstraZeneca, Bayer, BMS, Celgene, Eli Lilly, Exelixis, Medimmune, Merck, Novartis, Target Pharma Solutions, Tekmira. Grants: NCI, NCCN. G.K. Abou-Alfa: Consultant/advisory boards including but not limited to: AstraZeneca, Bayer, Blueprint, BMS, Celgene, Gilead, Halozyme, Ipsen, Janssen, Medimmune, Merck, Merrimack, Newlink, Pfizer, Roche, Sanofi, VAXIMM, Vicus, Westhaven. All other authors have declared no conflicts of interest.

Background

Met is a therapeutic target in advanced HCC. We report final results from a phase 2 study evaluating tepotinib, a highly selective Met inhibitor, in pts with sorafenib-treated, advanced Met + (immunohistochemistry [IHC] 2/3+) HCC.

Methods

This single-arm, multicenter study included adults with advanced Met+ HCC, Child-Pugh Class A liver function, ECOG performance status 0–1, and ≥4 weeks of prior sorafenib therapy. MET amplification was assessed by in-situ hybridization (ISH). Pts received tepotinib 500 mg once-daily. Primary endpoint: investigator-assessed progression-free survival (PFS) at 12 weeks (null hypothesis: ≤15% progression-free pts at 12 weeks); secondary endpoints included safety and other efficacy parameters.

Results

Forty-nine pts received treatment (male: 83.7%; median [range] age: 66 [19–82] years). Median (range) duration of therapy was 3.02 (0.03–16.49) months. As 31/49 pts (63.3%) were progression-free at 12 weeks, the study met its primary endpoint. Per RECIST 1.1, 4/49 pts had objective responses (8.2%; 1 CR [ISH+], 3 PR [all ISH-]); 24/49 (49.0%) had SD. Median overall survival was 5.6 months [90% CI: 5.1, 8.2 months]. There were no relevant PFS differences in IHC2 vs 3+ or ISH+ vs - pts; there was a trend toward improved PFS in hepatitis B/C-infected pts, but subgroup numbers were limited (Table). Peripheral edema (38.8%; includes 3 pts with grade 3), asthenia (22.4%), fatigue (18.4%) and diarrhea (16.3%) were the most common treatment-related treatment-emergent adverse events (TEAEs); all were grade 1/2 except where noted. Fourteen pts (28.6%) had treatment-related TEAEs grade ≥3, 8 pts (16.3%) permanently discontinued treatment due to related TEAEs and 1 pt (2.0%) died due to a treatment-related TEAE (hypoglycemic coma). No new safety signals emerged.Table: 152O

Conclusions

Tepotinib has anti-tumor activity in pts with sorafenib-treated Met + (IHC 2/3+) advanced HCC and appears well tolerated.

Editorial acknowledgement

Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Dawn Batty, PhD of Bioscript Science (Macclesfield, UK).

Clinical trial identification

NCT02115373.

Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany.

Funding

Merck KGaA, Darmstadt, Germany.

Disclosure

T. Decaens: Consultant: BMS, Ipsen, AstraZeneca, Sirtex; Advisory board: Bayer, Ipsen, Sirtex, BMS; Research Funding ArQule, Genoscience Pharma, Roche; Travel costs: Bayer, Gillead, MSD, BMS, Abbvie. C. Barone: Advisory board membership and fee: Merck Serono, Servier; Honoraria: Novartis, Bayer, MSD, Eisai; Research Funding Novartis. M. Wermke: Honoraria: BMS, Novartis, Roche, Bayer, Glenmark, AstraZeneca; Travel costs: AstraZeneca, BMS, MSD, Novartis, Glenmark; Research Funding Novartis, Pfizer. P. Merle: Advisory boards: Bayer, Ipsen, BMS. J-F. Blanc: Advisory boards: Bayer, Lilly Oncology, BMS, Onxeo, Esai, Ipsen. R. Bruns: Employee: Merck KGaA, Darmstadt, Germany and owns Merck shares, J. Straub: Employee: Merck KGaA, Darmstadt, Germany, C. Zhao: Employee: EMD Serono, Billerica, MA, USA, S. Faivre: Consultant, clinical trial grants: Blueprint, Bristol-Myers Squibb, Bayer Pharma, Eli Lilly, Ipsen, Merck Serono, MSD, Novartis., All other authors have declared no conflicts of interest.

Background

The etiological factors and management of HCC vary by geographical region¹. REACH-2² and REACH³ showed significant survival benefits of RAM treatment for HCC in patients (pts) with baseline AFP ≥400 ng/mL. We conducted a pooled subgroup analysis to investigate the efficacy and safety of RAM in Asian and non-Asian pts from REACH-2 and REACH (high AFP subpopulation).

Methods

Pts were randomized to receive RAM 8 mg/kg IV or placebo (PL) once every two weeks, plus best supportive care, until disease progression or unacceptable toxicity. Endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Kaplan-Meier analysis and Cox proportional hazards regression were performed for OS and PFS. Efficacy analyses were stratified by study.

Results

Across the two studies, 291 Asian pts were randomized to RAM (168) or PL (123); 251 non-Asian pts were randomized to RAM (148) or PL (103). Baseline characteristics were generally balanced between treatment arms in Asian and non-Asian patients. RAM significantly improved median OS in Asian pts; 8.08 months (m) RAM vs 4.76 m PL (stratified hazard ratio [HR] 0.73, 95% confidence interval [CI]: 0.56, 0.95), and non-Asian pts; 7.98 m RAM vs 5.22 m PL (HR 0.65, 95% CI: 0.49, 0.86). RAM significantly improved median PFS in Asian pts; 2.73 m RAM vs 1.45 m PL (HR 0.58, 95% CI: 0.44, 0.76), and non-Asian pts; 3.06 m RAM vs 1.87 m PL (HR 0.55, 95% CI: 0.41, 0.73). ORR was 4.2% RAM vs 0.8% PL (Asian pts) and 6.8% RAM vs 1.0% PL (non-Asian pts); DCR was 53.6% RAM vs 33.3% PL (Asian pts) and 59.5% RAM vs 41.7% PL (non-Asian pts). The most common grade ≥3 adverse event occurring in the RAM arm of Asian and non-Asian pts was hypertension (7.7% and 16.9%, respectively).

Conclusions

This subgroup analysis demonstrates survival benefits of RAM treatment in Asian and non-Asian patients with advanced HCC and AFP ≥400 ng/mL. Treatment was well tolerated, with similar safety profiles between Asian and non-Asian pts. References: ¹Fong et al. Cancer 2014;120:2824-38. ²Zhu et al. J Clin Oncol 2018;36:suppl. abstr 4003. ³Zhu et al. Lancet Oncol 2015;16:859-70.

Editorial acknowledgement

Medical writing assistance was provided by Lisa Cossens and editorial assistance by Antonia Baldo from Syneos Health.

Clinical trial identification

NCT01140347, NCT02435433.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

Y-K. Kang: Consultant: Eli Lilly and Company, BMS, Ono, Bayer, Blueprint, M. Kudo: Member on an advisory board, board of directors: Eli Lilly Japan KK., H-Y. Lim: Member of the steering committee: Bayer; Advisory board meetings: Bayer, Ipsen, Eisai & Ono., C-H. Hsu: Membership on an advisory board: BMS, Ono, MSD, Merck/Sorono, Novartis Roche; Recipient of research Funding MSD., A. Vogel: Honoraria: Eli Lilly and Company, Bayer, MSD, Roche, Novartis, AstraZeneca, Beigene. R. Cheng, I. Carton: Full time employee, stock holder: Eli Lilly and Company. P. Abada: Full time employee: Eli Lilly and Company. Y. Hsu: Full time employee, stock owner, patent pending: Eli Lilly and Company. A. Zhu: Advisory and consulting roles: BMS, Eisai, Bayer, Merck, Eli Lilly and Company. All other authors have declared no conflicts of interest.

Background

Patients (pts) with advanced HCC have limited treatment (tx) options; the multikinase inhibitor sorafenib is the global standard of care. Inhibition of either PD-L1/PD-1 or VEGF signalling has only limited activity in HCC. However, the additional immunomodulatory effects of bevacizumab (bev; anti-VEGF) may create a favourable tumour microenvironment that can enhance the efficacy of atezolizumab (atezo; anti–PD-L1), leading to an effective anti-tumour immune response. Therefore, atezo + bev may have synergistic effects in HCC.

Methods

In a Phase Ib study cohort, pts with unresectable or metastatic 1L HCC received atezo 1200 mg + bev 15 mg/kg IV q3w until loss of clinical benefit. The primary endpoints were safety and ORR per investigator (INV) assessment. Secondary endpoints included PFS and DOR per RECIST v1.1, and OS.

Results

43 pts were evaluable for safety as of Jan 11, 2018. Tx-related all-grade (Gr) AEs occurred in 81% of pts; Gr 3-4 AEs were seen in 28%, most commonly hypertension (16%). 3 pts (7%) had tx-related SAEs (autoimmune encephalitis and mental status change in 1 pt, intra-abdominal haemorrhage, jugular vein thrombosis; all Gr 3). No tx-related Gr 5 AEs were seen. Immune-related AEs requiring systemic corticosteroid tx occurred in 5 pts (12%). 23 pts were evaluable for clinical activity. Response rates and 6-month PFS and OS rates are presented in the table. Medians for DOR, PFS and OS have not yet been reached. 12 of 14 responses were ongoing as of the data cutoff (≥ 6 mo in 10 pts). Updated data from an expanded pt cohort will be shown.Table: 150O

Efficacy (N = 23; minimum follow-up, 16 wk; median follow-up, 10.3 mo)

Conclusions

Atezo + bev had a tolerable safety profile as well as high and durable objective responses. The ORR of 61% suggests that this combination has synergistic activity in HCC. Atezo + bev may offer a promising 1L tx option for advanced HCC and is being evaluated in the Phase III IMbrave150 study (NCT03434379).

Editorial acknowledgement

Medical writing assistance for this abstract was provided by Steffen Biechele, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.

Clinical trial identification

NCT02715531.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

C-H. Hsu: Membership on advisory board: BMS, Ono, MSD, Merck/Sorono, Novartis, Roche; Research Funding MSD. M.S. Lee: Consulting/advisory: Bayer; Research Funding EMD Sereno, Genentech/Roche. W. Verret, B. Liu, K. Iizuka: Employment: Genentech. A. Kwan: Employment & stock: Genentech/Roche. S. Stein: Consulting/advisory: Genentech/Roche. All other authors have declared no conflicts of interest.

Background

TACE is commonly used to treat patients (pts) with unresectable HCC (uHCC). However, there is no global consensus on appropriate TACE use.

Methods

OPTIMIS is an international, prospective, non-interventional study of pts with uHCC for whom the decision to treat with TACE was made prior to enrollment. We report practice patterns, radiologic tumor response, liver deterioration, and subsequent treatments from Korea and other regions. TACE ineligibility was analyzed per study protocol-specified criteria.

Results

Globally, 1650 enrolled pts received TACE, including 292 from Korea and 459 from other regions. Of those, 85/292 pts (29%) in Korea and 193/459 (42%) in other regions were TACE ineligible at inclusion (Table). Excluding pts with prior sorafenib use, 109/292 (37%) in Korea and 100/459 (22%) in other regions became TACE ineligible during the study. Of those, 6/109 pts (6%) in Korea and 3/100 (3%) in other regions received sorafenib immediately after TACE ineligibility. In TACE administered pts, complete and partial response rates to first TACE were 24% and 36% versus 8% and 20% in Korea and other regions, respectively. In pts with available laboratory values, chronic liver function deterioration (worsening in CTCAE grade 31–90 days post TACE) after first TACE was noted in Korea and other regions: bilirubin (12% and 25%), albumin (22% and 24%), alanine aminotransferase (4% and 27%), and aspartate transaminase (9% and 31%). Table: 151O

Disease characteristics and TACE ineligibility at inclusion in Korea and other regions

Conclusions

TACE ineligibility criteria appear to be followed to a greater extent in Korea than other regions. After first TACE, liver function deterioration was noted in the chronic period which was lower in Korea than other regions. In addition, radiologic tumor response rates were higher in Korea than other regions. Our data highlight the need to evaluate TACE practice in uHCC to ensure pt eligibility for subsequent effective therapies.

Editorial acknowledgement

Editorial assistance in the preparation of this abstract was provided by Luke Burke of SuccinctChoice Medical Communications (London, UK), with financial support from Bayer.

Clinical trial identification

NCT01933945.

Legal entity responsible for the study

Bayer.

Funding

Bayer.

Disclosure

J. Heo: Grants/research support: Roche; Advisory board membership: AbbVie, Bristol-Myers Squibb, Gilead Sciences, SillaJen and PharmaEssentia. A-L. Cheng: Advisory board membership: Bayer Schering Pharma, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical and Onxeo; Honoraria: Bayer, Eisai and Merck Sharp & Dohme; Consulting: Novartis. J-L. Raoul: Advisory board membership: Genoscience Pharma, Bayer Schering Pharma AG, BTG plc, Bristol-Myers Squibb; Honoraria: Bayer, Merck Serono. M. Peck-Radosavljevic: Grants/research support: AbbVie, ArQule, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, ImClone Systems, Lilly, Merck Sharp & Dohme, Novartis and Roche; Advisory board membership: AbbVie, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eisai, Ipsen, Lilly, Merck Sharp & Dohme, Roche; Honoraria: Bayer; Consulting: Bayer. M. Kudo: Grants/research support: Chugai, Otsuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi Sankyo, Merck Sharp & Dohme, Eisai, Bayer, AbbVie, Medico’s Hirata, Astellas Pharma and Bristol-Myers Squibb; Advisory board membership: Kowa, Merck Sharp & Dohme, Bristol-Myers Squibb, Bayer, Chugai, Taiho, Eisai and Ono Pharmaceutical Co.; Honoraria: Bayer, Eisai, Merck Sharp & Dohme, Ajinomoto. K. Nakajima: Stock ownership: Bayer; Full-time employment: Bayer. I. Bayh: Stock ownership: Fresenius Medical Care Deutschland GmbH; Full-time employment: Bayer. H.C. Lee: Grants/research support: SillaJen, Bayer and Ono Pharmaceutical Co.; Advisory board membership: Bayer. All other authors have declared no conflicts of interest.