Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial

Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study

TPS649 Background: Despite advances in unresectable HCC treatment, long-term survival rates remain poor. The combination of atezolizumab (Atezo) plus bevacizumab (Bev) is approved as frontline therapy for advanced HCC, but only a minority of patients (pts) respond, and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment (TME) mediated by the expression of immune checkpoint signals and angiogenesis pathways, which may contribute to therapeutic resistance. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 (HSV-1) that expresses GM-CSF, a fusogenic glycoprotein (GALV-GP-R–), and an anti–CTLA-4 antibody-like molecule. RP2 showed preliminary clinical activity alone or combined with anti–PD-1 in a phase 1 study in pts with advanced solid tumors. The direct oncolytic effect coupled with immune stimulation by RP2 in the TME is intended to provide systemic antitumor activity and synergize with anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors when administered with Bev, supporting the clinical combination of RP2 with Bev. This study will evaluate the safety and efficacy of RP2 combined with Atezo plus Bev as second-line systemic therapy for unresectable advanced HCC (NCT05733598). Methods: This is an open-label, single arm, phase 2 trial. Up to 30 pts will be enrolled and receive RP2 in combination with Atezo plus Bev. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh class A, an Eastern Cooperative Oncology Group performance status of 0 to 1, and progression on 1 prior systemic treatment, which must have included a PD-1/PD-L1–directed agent. Key exclusion criteria include untreated/incompletely treated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of the tumor into any major blood vessel(s) and/or main bile ducts. Pts will receive intratumoral RP2 Q2W for 4 doses, then Q3W for up to 4 doses. Bev will be given at 10 mg/kg Q2W starting with the first dose of RP2, then at 15 mg/kg Q3W starting with cycle 4; Atezo will be given at 840 mg Q2W for cycles 2 and 3, then at 1200 mg Q3W starting with cycle 4. Pts will receive treatment until confirmed progressive disease, loss of clinical benefit, or unacceptable toxicity. The primary endpoint is overall response rate (ORR), defined as the proportion of pts achieving a best overall response of complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as modified for this study. Secondary endpoints include safety, ORR using HCC-modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

TPS4191 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of atezolizumab (Atezo) plus bevacizumab (Bev) is approved as frontline therapy for advanced HCC, but only a minority of patients (pts) respond and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment (TME), mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), GM-CSF, and an anti–CTLA-4 antibody-like molecule. The direct oncolytic effect coupled with immune stimulation by RP2 in the TME is intended to provide systemic antitumor activity and synergize with anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP2 with Bev. This study will evaluate the safety and efficacy of RP2 combined with Atezo plus Bev as second-line systemic therapy for unresectable and advanced HCC (NCT05733598). Methods: This is an open-label, single arm, phase 2 trial. Up to 30 pts will be enrolled and receive RP2 in combination with Atezo plus Bev. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh class A, an Eastern Cooperative Oncology Group performance status of 0 to 1, and progression on 1 prior systemic treatment, which must have included a PD-1/PD-L1–directed agent. Key exclusion criteria include untreated/incompletely treated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of the tumor into any major blood vessel(s) and/or main bile ducts. Pts will receive intratumoral RP2 Q2W for 4 doses, then Q3W for up to 4 doses. Bev will be given at 10 mg/kg Q2W starting with the first dose of RP2 then at 15 mg/kg Q3W starting with cycle 4; Atezo will be given at 840 mg Q2W for cycles 2 and 3, then at 1200 mg Q3W starting with cycle 4. Pts will receive treatment until confirmed progressive disease, loss of clinical benefit, or unacceptable toxicity. The primary endpoint is overall response rate (ORR), defined as the proportion of pts achieving a best overall response of complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as modified for this study. Secondary endpoints are safety, ORR using HCC-modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

TPS576 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of atezolizumab (Atezo) plus bevacizumab (Bev) is approved frontline therapy for advanced HCC, but a minority of patients (pts) respond and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment (TME), mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the TME is intended to provide systemic antitumor activity and synergize with anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP3 with Bev. This study will evaluate the safety and efficacy of RP3 combined with Atezo plus Bev as first- (1L) and second-line (2L) systemic therapies for unresectable and advanced HCC (NCT05733598). Methods: The 1L and 2L cohorts will each enroll up to 30 pts. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following 1 prior line of systemic therapy, which must have included a PD-1/PD-L1–directed agent. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh class A, and an Eastern Cooperative Oncology Group performance status of 0 to 1. Key exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of the tumor into any major blood vessel(s) and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in the 1L cohort will receive Atezo 1200 mg and Bev 15 mg/kg every 3 weeks (Q3W) together with RP3 intratumorally Q3W for a total of up to 8 doses. Pts in the 2L cohort will receive RP3 every 2 weeks for 4 doses with Bev Q3W starting on cycle (C)1 day (D)1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint is the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints are safety, ORR using HCC modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

Sorafenib in Hepatocellular Carcinoma: Separating the Hype From the Hope

Background: SOR is an active agent and has favorable immunomodulatory effects in HCC. Combinations of immune checkpoint inhibitors with SOR may enhance effector T-cell function and lead to improved clinical outcomes for patients with HCC. We tested this hypothesis in an open-label, multicenter study of SOR and PEM in patients with advanced HCC. Methods: Pts with advanced or metastatic HCC, CP Class A, ECOG PS of 0/1 were included. One prior therapy was allowed. Pts were treated with SOR alone for 4 weeks (lead-in) at a stable dose (minimum 200 BID), followed by SOR plus PEM 200mg IV q3 weeks. The phase Ib part included the first 6 pts who completed the SOR lead-in and began SOR+PEM. Treatment continued until disease progression or unacceptable toxicity. Disease assessment was performed q6 weeks using the RECIST 1.1 criteria. The primary endpoint was overall response rate (ORR). The study used an exact one-stage design. With 27 evaluable pts, the study had 80% power to detect an ORR ≥20% with SOR/PEM vs. 5% with SOR alone (a=0.05). Peripheral blood mononuclear cells were collected at baseline and on-treatment for correlative analyses (flow cytometry). Results: Of the 37 total pts enrolled, 27 were evaluable (9 female). Median age was 68 years. Forty-four percent of the pts had viral hepatitis. Four pts were pre-treated with atezolizumab/bevacizumab (n=3) or tivozanib/durvalumab (n=1). The ORR was 33% (95% CI: 18 - 52%) p= 0.08. Best response was PR in 9 patients (33%), 12 patients SD (44%), and 6 (22%) had PD. One patient had a near CR. Median progression-free (PFS) and overall survival (OS) were 4.8 (95% CI: 3.4 - 16.3) and 28.5 (95% CI: 15.2 - 57.7) months respectively. Fifty-two percent of patients had a decrease in AFP >50%. One atezolizumab/bevacizumab pretreated pt with progressive disease as best response had a near-complete response to SOR+PEM. The most common grade ≥3 treatment-related adverse events (AEs) in the safety population (n=37) were hypertension (16%), immune-related AEs (11%), fatigue (8%) and diarrhea (8%). CD8+ T-cells increased by 5.5% (-35.6 - 36.9%; p=0.035) and Tregs decreased by 14.73% (-378.6 - 61%, p=0.049) from baseline to C1D1. The increase in activated Tregs prior to PEM initiation was associated with worse OS (HR: 1.8, p=0.03) while a higher Teff/Treg at C1D1 (prior to PEM initiation) was associated with improved PFS (HR: 0.4, p=0.036). An increase in the percentage of Tregs between baseline and C4D1 was associated with worse PFS (HR: 2; p=0.03). Conclusions: SOR+PEM is a safe and active treatment for pts with advanced HCC. The results of our study confirm the favorable immunomodulatory effects of SOR and support further exploration of this regimen for patients with advanced HCC. Further tissue and blood correlative analyses are ongoing. NCT03211416. Citation Format: Renuka Iyer, Sahithi Sonti, Devalingam Mahalingam, Sarbajit Mukherjee, Sayan Chakraborty, Kristopher Attwood, Anthony George, Orla Maguire, Hans Minderman, Christos Fountzilas. Phase Ib/II study of sorafenib (SOR) and pembrolizumab (PEM) in patients (pts) with advanced hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT210.

Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.

Advanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation. To assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC. The PEACOCC trial is a single-arm multicenter phase 2 trial conducted at 5 UK centers investigating the clinical benefit and safety of pembrolizumab. PD-1 inhibitor-naive patients with histologically confirmed advanced CCGC, radiological disease progression following 1 or more prior courses of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024. Pembrolizumab, 200 mg, intravenously every 21 days up to 2 years until progression, discontinuation due to toxic effects, or patient/clinician decision. Up to 1 year of retreatment on diseases progression, if stable disease, partial response, or complete response at 2 years. The primary end point was progression-free survival (PFS) rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary end points included objective response rate, duration of response, PFS, overall survival, safety, and quality of life. A total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced CCGC. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events. A total of 45 of 46 patients (98%) had mismatch repair-proficient tumors. The 12-week PFS rate was 42% (95% CI, 28-57), and the best objective response rate was 25% (95% CI, 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median PFS was 2.7 months (95% CI, 1.3-5.4), and the median overall survival was 14.8 months (95% CI, 6.7-28.2). The PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had MMR-proficient disease. Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial. ClinicalTrials.gov Identifier: NCT03425565.

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial.

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the landscape of PLC management at all evolutionary stages.1 As an anti-programmed cell death-1 (PD-1) antibody, camrelizumab monotherapy and in combination with apatinib, an...

TPS4190 Background: Most patients with hepatocellular carcinoma (HCC) present with advanced unresectable or metastatic disease and survival rates remain poor. While approved checkpoint inhibitor (CPI)-based combination regimens for HCC have shown improvements in overall survival (OS), not all patients respond to currently available CPI-based therapy, and new strategies to overcome CPI-resistance using novel combination therapies are urgently needed. HCC gene expression profile analysis points to TGF-β signaling as a possible mechanism of immune escape. The first-in-class humanized monoclonal antibody livmoniplimab (ABBV-151) was developed that specifically binds to the glycoprotein-A repetitions predominant-transforming growth factor (GARP–TGF)-β complex, blocking release of active TGF-β1 and promoting immunoreactivity. A phase 1 study in HCC showed an overall response rate (ORR) of 42% (5/12) when combining livmoniplimab with the programmed cell death 1 inhibitor budigalimab (ABBV-181). We describe herein a phase 2/3 study of livmoniplimab + budigalimab in patients with locally advanced or metastatic HCC. Methods: This multicenter, phase 2/3, randomized, open-label study (NCT06109272) will enroll patients (≥18 years) with advanced HCC (aHCC) who have not previously received systemic treatment and have Barcelona Clinic Liver Cancer stage B or C, not eligible for locoregional therapy, Child-Pugh class A or B7, and Eastern Cooperative Oncology Group performance status 0‒1. The study will have 2 stages. Stage 1 is a phase 2 dose-optimization lead-in, during which ~80 patients will be enrolled and randomized 1:1:2 to receive 1 of 2 doses of livmoniplimab in combination with budigalimab Q3W, or investigator’s choice of either atezolizumab + bevacizumab Q3W or single-dose tremelimumab + durvalumab Q4W per STRIDE regimen. The primary objective of stage 1 is to select the optimal livmoniplimab dose to use in combination with budigalimab. Efficacy, safety, pharmacokinetic (PK), and pharmacodynamic data will be combined with prior phase 1/2 study data to select the livmoniplimab dose for stage 2. Stage 2 is a phase 3 study in ~580 patients with aHCC. Patients will be randomized 1:1 to receive the optimized dose of livmoniplimab + budigalimab or single-dose tremelimumab (300 mg) + durvalumab (1500 mg) Q4W (STRIDE). The primary objective for stage 2 is to evaluate the efficacy of livmoniplimab + budigalimab as measured by median OS. Secondary objectives include assessment of safety, tolerability, immunogenicity, and PK, efficacy measured by median progression-free survival, ORR, and duration of response as well as the impact on patient-reported outcomes. Enrollment is planned in Europe, Asia, and USA, and is open as of Dec 2023. Clinical trial information: NCT06109272 .

Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study