Association of early recurrence within one year of liver transplant for hepatocellular carcinoma with poor survival.

296 Background: Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant is challenging. All the clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. Here we review outcome, and the safety and efficacy of the application of systemic medical therapies in this clinical setting. Methods: This is a retrospective cross-sectional study of consecutive adult patients with recurrence of HCC following liver transplant for the indication of treatment of HCC in Queen Mary Hospital from January 2005 to January 2018. Results: Forty-three consecutive patients with a recurrence of HCC following liver transplant were identified from 2005 to 2018. Median survival from diagnosis of recurrence was 17 months (CI 11.3, 22.7). Early recurrence within 12 months of transplant was associated with a significantly worse median survival of 10 months CI 8.5, 11.4) compared to 26 months (CI 18.8, 33.2) when recurrences occurred after 12 months from transplant (p< 0.001) after adjustment with peritumoural vascular invasion, first line therapy with sorafenib, any second line therapy and use of mTOR inhibitors as immunosuppressants, with a hazard ratio of 0.104 (log-rank test, p<0.001). 41 patients who received medical systemic therapies, 34 (79.1% ) received sorafenib as the first line systemic therapy. 47.1% (N= 16) received subsequent lines of systemic therapies (ranging from 1 to 4 lines). Hand-foot syndrome was most common among the adverse events and it was observed in 34.7% patients treated with sorafenib. It led to dose interruptions in 8.8 % of patients who were given sorafenib. 26.7% had grade 1 diarrhoea. 14.3% had grade 1 transaminase rise. Conclusions: Early recurrence within one year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.

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Safety and Efficacy of amplitude-modulated radiofrequency electromagnetic fields in advanced hepatocellular carcinoma

4open ◽

10.1051/fopen/2021003 ◽

2021 ◽

Vol 4 ◽

pp. 3

Author(s):

Arthur W. Blackstock ◽

Al B. Benson ◽

Masatoshi Kudo ◽

Hugo Jimenez ◽

Preeya F. Achari ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Adverse Events ◽

Electromagnetic Fields ◽

Continuous Treatment ◽

First Line ◽

Advanced Hcc ◽

First Line Therapy ◽

Line Therapy ◽

Historical Controls

Importance: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Despite the recent approval of several new agents, long-term disease control remains elusive for most patients. Administration of 27.12 MHz radiofrequency (RF) electromagnetic fields (EMF) by means of a spoon-shaped antenna (TheraBionic P1 device) placed on the anterior part of the tongue results in systemic delivery of low and safe levels of RF EMF from head to toe. Objective: To report treatment outcomes and adverse events associated with treatment with the TheraBionic P1 device in comparison to suitable historical placebo and actively treated controls. Design: Pooled case series with comparison to historical controls. Participants: Patients with advanced HCC receiving this treatment, 18 real-world patients and 41 patients from a previously reported phase II study. Historical controls from previously conducted clinical trials. Interventions: Three hours daily treatment with the TheraBionic P1 device compared with standard of care as received by historical controls in the previously conducted trials. Main outcomes and measures: Overall survival (OS), time to progression, response rate, and adverse events in the combined pooled patients and in appropriate subgroups comparable to the historical control groups. Results: In the pooled treatment group, median OS of patients with Child-Pugh A disease (n = 32) was 10.36 (95% CI 5.42–14.07) months, 4.44 (95% CI 1.64–7.13) months for patients with Child-Pugh B disease (n = 25), and 1.99 (95% CI 0.76–3.22) months for patients with Child-Pugh C disease (n = 2). Median OS for Child-Pugh A patients was 2.62 (33.9%) months longer than the 7.74 months OS of comparable historical controls (p = 0.036). The 4.73 (95% CI 1.18–8.28) months median OS for Child-Pugh B patients receiving TheraBionic P1 device as first line therapy is slightly higher than the 4.6 months median OS of historical controls receiving Sorafenib as first line therapy. Only grade 1 mucositis and fatigue were reported by patients using the device, even among Child-Pugh B and C patients. No patients discontinued treatment because of adverse events. Conclusions and Relevance: Treatment of advanced HCC with the TheraBionic P1 device is well tolerated, even in patients with severely impaired liver function, and results in improved overall survival compared to historical controls without any significant adverse events, even after many years of continuous treatment. This treatment modality appears to be well suited for patients who have failed or are intolerant to currently approved therapies.

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A phase I/II trial to evaluate cabozantinib in patients with advanced hepatocellular carcinoma with Child-Pugh class B cirrhosis after first-line therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps357 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS357-TPS357

Author(s):

Thomas Enzler ◽

Neehar Parikh ◽

Chih-Yi Liao ◽

Aparna Kalyan ◽

David Hsieh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Phase I ◽

Systemic Treatment ◽

Advanced Hepatocellular Carcinoma ◽

First Line ◽

Early Stage Disease ◽

Advanced Hcc ◽

Line Therapy ◽

Class B ◽

Pugh Class

TPS357 Background: Hepatocellular carcinoma (HCC) is the 4th leading cause of cancer related death worldwide. HCC typically develops in patients with cirrhosis and has a 5-year survival estimate of 20%. Only patients with early stage disease may be eligible for a curative approach using local treatment and/or transplant. The majority of patient present with advanced HCC and will require systemic treatment for disease control. Several systemic therapies are FDA-approved for the treatment of HCC; however, they are only approved for patients with Child-Pugh class A cirrhosis. There are limited data and no approved second-line therapy for HCC with more advanced cirrhosis, including Child-Pugh class B, which represents a significant proportion of patients. The aim of this trial is to determine the safety and efficacy of cabozantinib, a multi-kinase inhibitor, in patients with HCC with Child-Pugh class B cirrhosis. Methods: This investigator-initiated, phase I/II study is enrolling 32 patients with advanced HCC, Child-Pugh B7 or B8, who have previously received first-line systemic treatment. Patients receive cabozantinib at one of 3 dose levels (20 mg, 40 mg, and 60 mg) with a starting dose level of 40 mg to evaluate the safety profile and obtain the recommended phase 2 dose (RP2D). The primary endpoint is assessment of dose-limiting toxicity with a null hypothesis greater than 35%. Secondary endpoints include ORR per RECIST v1.1, PFS, OS, and PK profile. Exploratory endpoints include whole exome/RNAseq analysis (including MET, VEGF, AXL, and immune signature), spatial profiling of immune markers by multiplex immunofluorescence, and specimen banking (tissue, blood and imaging). The trial design is based on the Time-To-Event modification of the Continual Reassessment Method (TiTE-CRM), which allows for continued monitoring of toxicity as a function of a dose-over-time, and is flexible with regard to the number of patients treated at a certain dose. The trial is open at University of Michigan as lead and coordinating site, and due to open at 3 additional high-volume centers. Clinical trial information: 04497038.

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Personalized DNA neoantigen vaccine in combination with plasmid IL-12 and pembrolizumab for the treatment of patients with advanced hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps2680 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS2680-TPS2680

Author(s):

Mark Yarchoan ◽

Edward Gane ◽

Thomas Urban Marron ◽

Sarah Rochestie ◽

Neil Cooch ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trial ◽

T Cell ◽

Disease Progression ◽

T Cell Responses ◽

First Line ◽

Advanced Hcc ◽

Cell Responses ◽

First Line Therapy ◽

Line Therapy

TPS2680 Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death. Immune checkpoint inhibitors targeting PD-1 have limited activity in HCC as monotherapy, with response rates ranging from 14-17%. Tumor neoantigens derived from tumor-specific mutations can be incorporated into personalized therapeutic cancer vaccines to prime T cell responses, potentially enhancing responses to anti-PD1 therapy. DNA vaccines have been shown to elicit strong CD8 and CD4 T cell responses in preclinical and clinical trials. In preclinical studies, DNA-encoded neoantigen vaccines have shown induction of CD8 T cells against 50% of predicted high affinity epitopes with the ability to impact tumor growth. GNOS-PV02 is a personalized DNA vaccine, encoding up to 40 patient-specific neoantigens. In the GT-30 trial, it is used in combination with INO-9012 (plasmid-encoded IL-12) and pembrolizumab for the treatment of advanced HCC. Methods: The GT-30 trial (NCT04251117) is a single-arm phase I/II clinical trial to assess the safety, immunogenicity, and preliminary efficacy of GNOS-PV02 in combination with INO-9012 and pembrolizumab in patients with advanced HCC. Twenty-four patients are anticipated to be enrolled. Patients are recruited upon diagnosis or during first-line treatment with tyrosine kinase inhibitors (TKI). Tumors are biopsied for exome and transcriptome sequencing. The tumor specific vaccine is designed, optimized and manufactured during first-line therapy. Each vaccine encodes up to 40 neoantigens, which includes all detected neoantigens for the majority of HCC patients. After progression or intolerance with first-line therapy, patients can commence trial therapy with concurrent personalized vaccine and pembrolizumab. GNOS-PV02 + INO-9012 are administered Q3w for the first 4 doses and Q9w thereafter until disease progression. Pembrolizumab is delivered Q3w until disease progression. Immunogenicity of each of the vaccine epitopes will be determined by ex vivo ELISpot and flow cytometry. Clinical activity is assessed by RECIST1.1 at baseline and every 9 weeks. Serial biopsies will be obtained at 9 weeks and upon disease progression to evaluate changes in the exome, transcriptome and changes to the tumor microenvironment. Clinical trial information: NCT04251117.

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453 Personalized DNA neoantigen vaccine (GNOS-PV02) in combination with plasmid IL-12 and pembrolizumab for the treatment of patients with advanced hepatocellular carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.453 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A481-A481

Author(s):

Mark Yarchoan ◽

Edward Gane ◽

Thomas Marron ◽

Sarah Rochestie ◽

Neil Cooch ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trial ◽

T Cell ◽

Peripheral Blood ◽

First Line ◽

T Cell Clones ◽

Advanced Hcc ◽

First Line Therapy ◽

Line Therapy ◽

Cell Clones

BackgroundHepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death. Immune checkpoint inhibitors targeting PD-1 have limited activity in HCC as monotherapy, with response rates ranging from 14–17%. Tumor neoantigens derived from tumor-specific mutations can be incorporated into personalized therapeutic cancer vaccines to generate tumor-specific T cell immunity, potentially priming the immune system for anti-PD1 therapy. DNA vaccines have been shown to elicit strong CD8 and CD4 T cell responses in preclinical and clinical trials. GNOS-PV02 is a personalized DNA vaccine, encoding up to 40 patient-specific neoantigens. In the GT-30 trial, it is used in combination with INO-9012 (plasmid-encoded IL-12) and pembrolizumab for the treatment of advanced HCC.MethodsGT-30 is a single-arm phase I/II clinical trial to assess the safety, immunogenicity, and preliminary efficacy of GNOS-PV02 in combination with INO-9012 and pembrolizumab in patients with advanced HCC. Twenty-four patients are anticipated to be enrolled. Patients are recruited upon diagnosis or during first-line treatment with tyrosine kinase inhibitors (TKI). Tumors are biopsied for exome and transcriptome sequencing, and peripheral blood collected for germline sequencing and histogenetics. The tumor specific vaccine is designed, optimized and manufactured during first-line therapy. Each vaccine encodes up to 40 neoantigens. After progression or intolerance with first-line therapy, patients commence concurrent personalized vaccine and pembrolizumab. GNOS-PV02 + INO-9012 are administered Q3w for the first 4 doses and Q9w thereafter. Pembrolizumab is delivered Q3w.ResultsWe performed a data cut-off on the first 12 patients. The median age was 66 years (range 55–75 years). GNOS-PV02 + INO-9012 with pembrolizumab has had no reported DLTs or drug related SAEs. The most common treatment-related AE were grade 1 fatigue (25%) and grade 1 injection site reactions (17%). By including up to 40 epitopes in the vaccine we were able to target all neoantigens present in 83% of the patients. The objective response rate was 25% (3/12 partial response, 5/12 stable disease, 4/12 progressive disease). Analysis of the TCR repertoire in peripheral blood and tumor tissue identified novel and significantly expanded T cell clones post-vaccination in all patients analyzed. Many of the novel peripheral T cell clones were also identified to have trafficked to the TME at week 9, potentially mediating the observed tumor regressions.ConclusionsThese data demonstrate the potential of GNOS-PV02 + INO-9012 with pembrolizumab to target multiple neoepitopes, and provide initial support for the safety and efficacy of this regimen in patients with advanced HCC.Trial RegistrationNCT04251117Ethics ApprovalThe study obtained IRB approval (IRB) and all patients signed informed consent prior to taking part in the clinical trial. NZCR EC: 20/NTA/6; JHU: IRB00227771; Mount Sinai: HS#: 20–00076

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Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211031141 ◽

2021 ◽

Vol 13 ◽

pp. 175883592110311

Author(s):

Chiun Hsu ◽

Lorenza Rimassa ◽

Hui-Chuan Sun ◽

Arndt Vogel ◽

Ahmed O. Kaseb

Keyword(s):

Hepatocellular Carcinoma ◽

Adverse Events ◽

Kinase Inhibitor ◽

Treatment Options ◽

Healthcare Providers ◽

Safety Data ◽

Standard Of Care ◽

Antiangiogenic Agents ◽

Efficacy And Safety ◽

First Line

In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.

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191 Association of immune related adverse events with the efficacy of immune checkpoint inhibitors in metastatic renal cell carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0191 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A205-A206

Author(s):

Vasilii Bushunow ◽

Leonard Appleman ◽

Roby Thomas

Keyword(s):

Renal Cell Carcinoma ◽

Adverse Events ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Checkpoint Inhibitors ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Kaplan Meier

BackgroundImmune checkpoint inhibitors (ICI) are first-line therapy for tumors including metastatic renal cell carcinoma (mRCC). Use of ICI is complicated by diverse immune-related adverse events (irAEs), which can add significant morbidity but are also associated with improved efficacy of therapy.1 2 Risk factors for development of irAE are still poorly understood. We hypothesized that patients with mRCC treated with ICI as first-line therapy have higher rates of developing irAE’s than patients previously treated with other therapies.MethodsWe conducted a single-institution, retrospective medical record review of patients with mRCC treated with immune-checkpoint inhibitors from March 2011 through April 15, 2020. We identified therapy duration, and presence, severity, and treatment of adverse events. We defined overall survival as time elapsed from date of diagnosis until death or until completion of study. We classified severity of adverse events according to CTCAE guidelines. Statistical methods included univariate Cox proportional hazards and logistic regression models, and Kaplan-Meier curves were plotted for subgroups.ResultsA total of 64 unique charts were reviewed. 18 patients (28%) of patients were treated with ICI as first-line therapy. 28 patients (44%) experienced immune-related adverse events with a total of 40 irAE’s identified. Most irAE were grade I-II (78%), with 7 (17%) grade III and 1 (2.4%) grade IV irAE’s. Most common sites were skin (29%), thyroid (20%) and gastrointestinal (15%). Patients with irAE had increased survival compared to those who did not have irAE (median survival not reached, vs 139 weeks, p=0.0004) (figure 1). This finding remained after excluding patients who had only experienced dermatologic irAE (median survival not reached in non-derm irAE subgroup, vs 144 weeks for dermatologic or no irAE, p=0.01) (figure 2). Patients treated with ICI as first line therapy had greater rates of developing irAE (72%) than those who had prior therapies (32%) (OR 5.4; p = 0.006). There was no association between histology type and rate of irAE.Abstract 191 Figure 1Kaplan-Meier survival plot of OS between patients with any irAE and those without any irAEAbstract 191 Figure 2Kaplan-Meier survival plot of OS between patients with non-dermatologic irAE and those without any irAE or only dermatologic irAEConclusionsThe development of irAE’s in patients with mRCC treated with ICI is associated with longer survival. This study joins the growing body of evidence showing that presence of irAE’s is associated with increased treatment efficacy. Use of ICI as first-line therapy is associated with higher risk of irAE. Given growing use of ICI as first-line therapy, further study to predict onset and severity of irAE’s is required.AcknowledgementsHong Wang, PhD, for statistical support.Ethics ApprovalThis study was approved by the University of Pittsburgh Institutional Review Board. Approval number STUDY19100386.ReferencesElias R, Yan N, Singla N, Levonyack N, Formella J, Christie A, et al. Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients. J Clin Oncol 2019;37(7):S645.Verzoni E, Cartenì G, Cortesi E, et al. Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program. J Immunother Cancer 2019;7(1):99.

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Modeling sequential systemic therapy for unresectable hepatocellular carcinoma in the era of immunotherapy: What comes next?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.324 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 324-324

Author(s):

Ciro Celsa ◽

Giuseppe Cabibbo ◽

Marco Enea ◽

Salvatore Battaglia ◽

Giacomo Emanuele Maria Rizzo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Survival Data ◽

Survival Curve ◽

Second Line ◽

First Line ◽

Lifetime Horizon ◽

First Line Therapy ◽

Line Therapy ◽

Unresectable Hepatocellular Carcinoma ◽

Sequential Strategy

324 Background: Atezolizumab plus Bevacizumab represents the new best performing first-line approach for unresectable hepatocellular carcinoma (u-HCC). However, the best sequential strategy after every first-line failure (for progression or intolerance) remains elusive, and options for retreating patients failing Atezolizumab plus Bevacizumab with multi-kinase inhibitors (MKI) or immune checkpoint inhibitor (ICI) are yet undefined. Methods: We developed a Markov model to analyze simulated-Overall Survival (s-OS) of second-line ICIs or MKIs after first-line Atezolizumab plus Bevacizumab over a lifetime horizon. For first-line therapy, PFS of Atezolizumab plus Bevacizumab was extracted from Imbrave 150 trial and it was used as endpoint since it is not influenced by post-progression survival. For second-line retreatment, pooled OS of MKIs (Regorafenib and Cabozantinib), or ICIs (Nivolumab and Pembrolizumab) were adopted. Survival estimates for sequential settings considered the proportion of patients who did not receive second-line therapy due to death during first-line therapy. Individual patient survival data were extracted from PFS and OS Kaplan-Meier curves of RESORCE trial for Regorafenib, CELESTIAL trial for Cabozantinib, CheckMate-040 for Nivolumab and Keynote-240 for Pembrolizumab. Each reconstructed survival curve was inspected for accuracy and was compared with originally published curves. Results: First-line Atezolizumab plus Bevacizumab followed by second-line ICIs turned on from the model as the best sequential strategy (median s-OS 24 months; 95% Confidence Interval (CI) 23-26 months) and extends survival when compared Atezolizumab plus Bevacizumab followed by MKIs (median s-OS 20 months; 95% CI 19-21 months). Conclusions: To our knowledge and given the absence of adequately designed sequential RCTs, this is the first model to date which suggests, with a proper methodological approach, an accurate estimate of outcome of patients with u-HCC treated by sequential systemic therapies. In patients with u-HCC failing first-line treatment, modelling estimates of s-OS for each retreatment strategies may assist in choosing the most promising sequences in order to plan appropriate RCTs.

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