The 2022 ESMO Conference will be held in Paris, France, from September 9 to 13, 2022, and ESMO has published 1835 accepted abstracts. Among them, there are many recent research advances in clinical trials of hepatobiliary tumors, and some of them are particularly eye-catching in the study of targeted immune drugs.
Cholangiocarcinoma
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The effectiveness of the triple regimen of duvalliumab combined with tremelImumab + chemotherapy in the treatment of cholangiocarcinoma has not been achieved compared with the use of I alone
IMMUCHEC is a prospective, randomized, multicenter Phase II study. ECOG0-1 and histology confirmed that adult patients with metastatic BTC/gallbladder carcinoma were eligible. The primary endpoint was the objective response rate (ORR) in patients who had not previously received systemic palliative CTx according to the RECIST 1.1 criteria. Secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Exploratory analyses included a comprehensive efficacy and safety analysis of the experimental treatment group.
Trial interventions:
A组D 1.5 g Q3W+4x T75mg Q3W+gem 1000mg/m2；
B组D 1.5g Q3W+4x T75mg Q3W+Gem 1000mg/m2+ 顺式25mg/m2；
Group C
Controlled therapy Gem + Cis;
Group D
D 1.5g，Q3W+1x bolus T 300mg+Gem+Cis；
Group E
D1.5g Q3W+Gem+Cis.
In total, 138 patients were randomly assigned to 16 German centers. Relative distribution of anatomical subgroups (extrahepatic/intrahepatic/gallbladder): A–21.7%/47.8%/30.4%; B–25.0%/70.0%/5.0%； C–26.7%/73.3%/0%； D–13.8%/69.0%/17.2%； E–11.1%/88.9%/0%。
The groups of ORR, mOS, mPFS, and AEs are as follows.
The results showed no clear evidence that tremelImumab improved significantly compared with degrees of valliyumab and CTx alone in first-line BTC. The omission of Cis is associated with poorer results. There are no new safety signals.
Second-line treatment for cholangiocarcinoma, the combination of Nal-IRI and 5-FU/LV failed
NALIRICC is a prospective, randomized, bilateral, Phase II study. Patients > 18 years of age, ECOGPS 0/1, histologically confirmed progression to metastatic BTC and first-line gemcitabine are eligible. Trial interventions were ArmAnal-IRI (80 mg/m2) plus 5-FU (2400 mg/m2)/LV (400 mg/m2), q2w or ArmB5-FU/LV, q2w. Patients are stratified according to the primary tumor site and efficacy is evaluated every 6 weeks according to RECISTv1.1. The primary endpoint (EP) was progression-free survival (PFS). Secondary EPs are overall survival (OS), overall response rate (ORR), safety, and quality of life (EORTCQLQC30). The objective of this study was to increase the median PFS from 1.5 months (P0) to 3 months (P1; HR0.5), with a 2-sided α of 0.05 and a efficacy of 90.3%.; A total of 99 points are required.
A total of 100 patients were randomly assigned to 17 centers (49 patients: nal-IRI/5-FU/LV arm/51 patients: 5-FU/LV arm). 64/19/17pts had intrahepatic/extrahepatic/gallbladder cancer. The Pt characteristics between the arms are well balanced. The test results are shown in the table. The most common ≥ grade 3 adverse events in the nal-IRI/5-FU/LV group were decreased neutrophil count (16.6%), diarrhea (14.6%), and nausea (8.3%). 27.5% of patients in the 5-FU/LV group received irinotecan-based therapy after progression. The quality of life was similar between the two groups.
The NALIRICC test did not reach its primary EP. The addition of nal-IRI to 5-FU/LV did not improve PFS or OS compared to 5-FU/LV alone and was associated with higher toxicity. 5FU/LV can be seen as a reasonable alternative to 2-wire premium BTC.
hepatocellular carcinoma
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A small sample study of the "double ai" combination of perioperative treatment showed success
In a multicenter randomized controlled trial (NCT04930315), patients with excisable HCC were enrolled and randomly assigned to the perioperative phase (four cycles of neoadjuvant therapy followed by eight cycles of adjuvant therapy) and the postoperative group (12 adjuvant cycles) at a 1:1 ratio. Each two-week cycle consists of 200 mg of intravenous carrelizumab on day 1 and 250 mg of apatinib orally daily. The primary endpoint was one-year progression-free survival (EFS).
At the end of the data (23 April 2022), a total of 24 patients were enrolled, including 13 in the perioperative group and 11 in the postoperative group. One year's EFS data is immature. Eight patients in the perioperative period have completed neoadjuvant therapy and were evaluated according to the mRECIST criteria. There were 5 patients in partial remission and 3 cases were stable, with an overall response rate of 62.5% and a disease control rate of 100%. Six of the 8 patients underwent surgery (1 partially relieved patient refused surgery and 1 stable patient underwent transarterial chemoembolization). The R0 resection rate was 100%, and 2 of these 6 patients reported major pathological reactions. One patient is now receiving adjuvant therapy. All 11 patients in the postoperative group underwent surgery, and the R0 resection rate was 100%. Seven patients are receiving adjuvant therapy and no efficacy data are available. Eight patients in both groups experienced grade 3/4 adverse events, including 3 patients with liver dysfunction, 2 patients with thrombocytopenia, and 3 patients with hand-foot syndrome.
The results suggest that perioperative treatment with carellizumab plus apatinib shows controllable safety and potential efficacy in patients with resectable HCC.
The TALENT PHASE II trial went well, with tirelizumab performing well
TALENT is an ongoing Phase 2 trial enrolling resectable patients with rHCC who received two non-randomized independent treatment groups (group 1: neoadjuvant terelizumab; Group 2: Therapeutic treatment of neoadjuvant tiralizumab and lenvatinib). When Group 1 completes registration, Group 2 starts. In arm1, patients receive two cycles of neoadjuvant terelizumab 200 mg intravenously every 3 weeks, followed by hepatic resection, followed by up to 17 cycles of adjuvant terelizumab over a year. The primary endpoint was 1-year disease-free survival, and the secondary endpoints were recist 1.1 assessed objective response rate (ORR), primary pathological response (> 90% tumor necrosis), and safety.
Between January 2021 and September 2021, 11 patients were enrolled in Group 1 and we report results for Group 1 here. All patients received neoadjuvant terelizumab and underwent hepatic resection. No serious adverse events were observed during neoadjuvant therapy, and adverse events of any magnitude occurred in 4 patients. The most common adverse events of any level were pruritus (two patients), rash (two), and fatigue (one). No patients delayed surgery due to treatment-related adverse events. The ORR is 18.2% (2/11), with one achieving full mitigation and one achieving partial mitigation. One patient progresses to enlarged liver lesions and new lung and bone metastases. And all other patients remained stable. In terms of pathological remission, 2 cases of tumor necrosis were more than 70%, 1 case was completely in remission, and the other had 85% necrosis. Pathological reactions in other patients are 5-35%. Until March 20, 2022, 2 patients experienced relapse.
This is the first trial to demonstrate good safety and moderate efficacy in patients with neoadjuvant therapy rHCC, and researchers are anticipating the efficacy of terelizumab in combination with lenvatinib in ongoing group 2.
CalEra study: Carellizumab combined with remvatinib and RALOX-HAIC in the treatment of BCLB and C hepatocellular carcinoma showed benefit
The single-arm Phase II study included untreated adult (≥18 years) with untreated adults (NCT05003700) with STAGE BB and C BCLC with a Child-Pugh score of less than or equal to 7. Patients received RALOX-HAIC (oxaliplatin 100 mg/m2, raltetrexed 3 mg/m2 every 3 weeks) in combination with carellizulizumab (200 mg intravenously every 3 weeks) and rumvatinib (8 mg orally once daily) for a total of 6 cycles, followed by maintenance therapy with carellizumab and renvatinib until disease progression or unacceptable toxicity developed. The primary endpoint was the objective response rate (ORR).
Between March 2021 and February 2022, a total of 26 patients (23 males and 3 females) were recruited. Median age, 53.5 years). The median tumor size was 11.3 cm, with portal vein invasion in 88.5% and extrahepatic metastases in 23% of patients. As of 20 April 2022, the median follow-up was 8.4 months, and all patients underwent at least one post-baseline tumor evaluation. The ORRs confirmed according to RECISTv1.1 and mRECIST were 57.7% (95% CI, 37.3-78.0) and 80.8% (95% CI, 64.5-97.0), respectively, including 2 (7.7%) patients who achieved a complete radiological response. Grade 3-4 treatment-related adverse events (AE) occurred in 61.5% of patients, most commonly thrombocytopenia (23.1%), elevated aspartate aminotransferase (23.1%), leukopenia (15.4%), and abdominal pain (15.4%).
The results showed that the combination therapy with carellizumab and lenvatinib RALOX-HAIC showed promising antitumor activity and acceptable toxicity in patients with advanced HCC.
EMERALD-3 Phase III study: tremelimumab + dovalibumab plus or without renvatinib plus TACE efficacy to be disclosed
525 patients will be randomly assigned to group A (STRIDE gallonvatinib [8 mg or 12 mg] once a day) on a 1:1:1 basis, group B (STRIDE plus TACE), or group C (TACE only). In groups A and B, the first TACE procedure will be performed no earlier than 7 days after T and the first dose of D (and rumpvatinib in group A); In group C, the first TACE procedure will be performed within 7 days after randomization. Eligible patients must confirm that HCC (by imaging or histopathology) is not suitable for radical therapy but is suitable for embolism, Child-Pugh score A, the eastern tumor collaboration group has a presenting state of 0 to 1, disease can be measured by modified solid tumor response evaluation criteria (mRECIST) and adequate organ and bone marrow function. Patients with primary portal vein violation (Vp3/Vp4) or uncontrolled hypertension are excluded. The primary endpoint was a blinded independent review of groups A versus C (PFS) in a blinded independent review conducted by using RECISTv1.1. Other endpoints included PFS, OS, health-related quality of life, and safety in groups B and C.
The latest developments in the experiment may be disclosed at the poster meeting on September 10.
Effect of tremelimumab + degrees valliyumab on uHCC of different viral etiology in the phase III HIMALAYA study
In the HILALAYA (NCT03298451) study, tremelimumab (T) plus valliyumab (D) (STRIDE) at a single high initiation dose significantly improved overall survival (OS) compared to sorafenib (S), and moderate valliyumab (S) in uHCC was no inferior to sorafenib. Viral aetiology is associated with impaired liver function during the development of HCC and may affect immunotherapy activity.
This exploratory study analysis evaluated STRIDE, D, and S in patients with HBV, HCV, or nonviral/other (NV) causes. The OS risk ratio (HR) was calculated using the Cox proportional risk model. Because the size of the subset is not suitable for formal comparison, no multiplicity adjustments are made. Post-mortem multivariate analysis is used to identify opportunistic imbalances in key prognostic factors that may affect estimated treatment outcomes.
In the HBV and NV subgroups, the baseline demographics and disease characteristics of the treatment groups were similar. However, in the HCV group, multivariate analysis identified an imbalance in two prognostic variables: extrahepatic diffusion (EHS; STRIDE is more frequent than S) and ALBI (STRIDE and D score more frequently than S≥2). STRIDE and S improved OS and progression-free survival in the HBV and NV groups, but not in the HCV group. Using a hierarchical Cox scale risk model to account for imbalances EHS and ALBI in the HCV subset, OSHR supports STRIDE vs S. OSHR continues to support STRIDE when tuning EHS and ALBI in other groups. The results of D and S show a trend similar to THAT of STRIDE and S.
In HILALAYA, when adjusting a subset of prognostic factor imbalances for prognostic factors in the HCV cohort, for all etiologies, the OS supports STRIDE versus S (HR<1); A similar trend was observed across subsets of D and S. These results confirm the benefits of STREDE and D in patients with uHCC, regardless of the underlying cause.
Renvatinib combined with TACE and PD-1 inhibitors (Len-TAP) showed an advantage over TACE alone
EMERALD-3 is a Phase 3, multicenter, prospective, cohort study. Main eligibility criteria: 18-70 years old; Radiologically or histologically confirmed HCC; No history of systemic therapy; BCLC Phase B/C. Conversion therapies include Len-TAP (lenvatinib, then TACE and carellizumab/sindilisumab) and TACE alone. Their adverse events (AE), response rates, conversion resection rates, and survival outcomes were compared.
From October 2020 to March 2022, a total of 71 patients were enrolled in both groups. Until April 2022, the incidence of grade 3 AE was high (P<0.001) in the Len-TAP group, and neither group had a grade 4 or 5 TRAE. At 16±1 weeks, mRECIST-based ORRs were 78.9% and 16.9% in the Len-TAP and TACE groups (P<0.001, respectively. The transit resection rate in the Len-TAP group (50.7% vs 15.5%, P<0,001) was better than that in the TACE group. The median PFS of the Len-TAP and TACE groups were 531±81.2 and 224±33.3 days (P<0.001), respectively, and the 1-year OSS rate was 93.3% and 64.3% (P=0.002).
This result shows that renvatinib combined with TACE and PD-1 inhibitors is safe and effective, which can improve the resectability rate of patients with uHCC and prolong overall survival.
A phase II study of TACE combined with tiralizumab and renvatinib in the treatment of patients with unresectable hepatocellular carcinoma was successful
The study is a single-center, single-arm, open-label Phase II exploratory clinical study (NCT05131698). Eligible patients are BCLC-C, not candidates for surgical resection or liver transplantation, at least one lesion that can be assessed by the RECIST 1.1 criteria, and a physical fitness status of 0 or 1 in the Eastern Tumor Collaboration Group, Child-pughA grade. Enrolled patients received TACE therapy (loplatin + raltetrexed + iodine oil) and then with TIS (200 mg, IV, on the 1st day of the 21-day cycle) and LEN (body weight≥ 60 kg: 12 mg / day; <60 kg: 8 mg / day) per day. The primary endpoints of this study were the safety and ORR of RECISTv1.1. Secondary endpoints included overall survival (OS), disease control rate (DCR), and progression-free survival (PFS).
As of March 18, 2022, a total of 18 patients were enrolled and received TIS combined with LEN after TACE treatment. Patients had BCLCC phases with a Child-Pugh score of 5 (n=8) or 6 (n=10). The median follow-up was 6.0 months. Overall ORR and DCR were 50% and 66.7%, respectively (1 CR, 5.5%; 8 PR, 44.5%; 3 SDs, 16.7%). All 18 patients are still under study. Adverse events (TEAE) occurring at any level occurred in 44.5% (n=8). The most common TEAEs are liver dysfunction (n=7, 38.8%), thrombocytopenia (n=5, 27.7%), and leukopenia (n=5, 27.7%). Only one patient experienced grade 3 TEAE (pneumonia); Seven patients experienced grade 1 TEAE.
Preliminary analysis shows that TACE in combination with TIS and LEN shows considerable efficiency, relatively high ORR and tolerable safety in the treatment of uHCC.
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Source: Hepatobiliary News International