Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced ...hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher.
REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433.
Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0–12·5), median overall survival (8·5 months 95% CI 7·0–10·6 vs 7·3 months 5·4–9·1; hazard ratio HR 0·710 95% CI 0·531–0·949; p=0·0199) and progression-free survival (2·8 months 2·8–4·1 vs 1·6 months 1·5–2·7; 0·452 0·339–0·603; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine 5% of 197 vs one 1% of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months 95% CI 2·8–4·4 vs 2·8 months 1·6–2·9; HR 0·799 95% CI 0·545–1·171; p=0·238) and ECOG performance statuses (HR 1·082 95% CI 0·639–1·832; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 13% in the ramucirumab group vs five 5% in the placebo group), hyponatraemia (11 6% vs 0) and increased aspartate aminotransferase (six 3% vs five 5%). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure).
REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma.
Eli Lilly.
Reactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with ...patient response, which presents a clinical challenge to stratify patients. Because PD-L1 is heavily glycosylated, we developed a method to resolve this by removing the glycan moieties from cell surface antigens via enzymatic digestion, a process termed sample deglycosylation. Notably, deglycosylation significantly improves anti-PD-L1 antibody binding affinity and signal intensity, resulting in more accurate PD-L1 quantification and prediction of clinical outcome. This proposed method of PD-L1 antigen retrieval may provide a practical and timely approach to reduce false-negative patient stratification for guiding anti-PD-1/PD-L1 therapy.
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•N-linked glycosylation of PD-L1 hinders its recognition by PD-L1 antibodies•Removal of glycosylation enhances anti-PD-L1 signal in a variety of bioassays•Patient sample deglycosylation prevents false-negative detection of PD-L1•Deglycosylated PD-L1 is a more reliable biomarker to guide immunotherapy
Histological detection of PD-L1 may guide therapy with anti-PD-1/PD-L1 antibodies but some PD-L1-negative tumors respond to these treatments. Lee et al. show that enzymatic deglycosylation of tissue sections improves PD-L1 detection and its predictive value, and could potentially impact patient stratification.
The global, randomized NAPOLI‐1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal‐IRI) plus 5‐fluorouracil/leucovorin (nal‐IRI+5‐FU/LV) in patients with metastatic pancreatic ...ductal adenocarcinoma (mPDAC) after previous gemcitabine‐based therapy. Median overall survival (OS) with nal‐IRI+5‐FU/LV was 6.1 vs 4.2 months with 5‐FU/LV alone (unstratified hazard ratio HR = 0.67, P = .012). Herein, we report efficacy and safety results from a post‐hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal‐IRI+5‐FU/LV (n = 34) had significantly longer median OS versus 5‐FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal‐IRI+5‐FU/LV versus 5‐FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal‐IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5‐FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal‐IRI+5‐FU/LV versus 5‐FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal‐IRI+5‐FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine‐based therapy, with a safety profile agreeing with previous findings. The nal‐IRI+5‐FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506)
The global NAPOLI‐1 phase 3 trial (NCT01494506) evaluated the safety and efficacy of liposomal irinotecan (nal‐IRI) and 5‐fluorouracil/leucovorin (5‐FU/LV) compared with 5‐FU/LV in patients with metastatic pancreatic adenocarcinoma that progressed following gemcitabine‐based therapy. We report data from a post‐hoc subgroup analysis focusing on Asian patients at centers in South Korea and Taiwan. Our findings are consistent with those from the primary analysis and show that, despite association with higher incidence of manageable grade 3‐4 neutropenia, the nal‐IRI+5‐FU/LV regimen is an effective treatment option in Asian patients with gemcitabine‐failed metastatic pancreatic cancer.
Background and Aim
The Albumin‐Bilirubin (ALBI) grade is a new index to assess objectively liver function and prognosis in patients with hepatocellular carcinoma (HCC). This study aimed to elucidate ...the application of ALBI grade in baseline and sorafenib‐end in advanced HCC patients who received sorafenib.
Methods
A total of 415 consecutive advanced HCC patients in Child–Pugh A received sorafenib in our hospital. Sorafenib was terminated when radiologic tumor progression or clinical liver function deterioration (LD) occurred in the reassessment bimonthly. Patients who failed with sorafenib monotherapy were retrospectively analyzed.
Results
A total of 260 (62.6%) patients were enrolled, including 98 (37.7%) ALBI grade I and 162 (62.3%) grade II in baseline. More patients in ALBI grade II stopped sorafenib because of LD than in grade I (33.3% vs 14.3%, P < 0.001). Those who in baseline ALBI grade I had a superior overall survival than in grade II (8.5 months vs 4.4 months, P = 0.003). Cox regression analysis confirmed that baseline ALBI grade II (P < 0.001) and ALBI grade increase during treatment (P < 0.001) strongly contributed to the mortality of HCC patients who received sorafenib. After sorafenib failure, those with post‐sorafenib treatment had a better post‐sorafenib survival than those without (9.3 vs 1.6 months, P < 0.001). Logistic regression analysis indicated that sorafenib‐end ALBI grade and LD occurrence were the only two predictors of post‐sorafenib treatment after sorafenib failure.
Conclusions
In clinical practice, we firstly demonstrated that not only ALBI grade in baseline but also ALBI grade change during treatment could predict the prognosis of advanced HCC patients who received sorafenib.
Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in ...advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma.
This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293).
Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab–rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1–10·6). Median progression-free survival was significantly improved with camrelizumab–rivoceranib versus sorafenib (5·6 months 95% CI 5·5–6·3 vs 3·7 months 2·8–3·7; hazard ratio HR 0·52 95% CI 0·41–0·65; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1–18·7). Median overall survival was significantly extended with camrelizumab–rivoceranib versus sorafenib (22·1 months 95% CI 19·1–27·2 vs 15·2 months 13·0–18·5; HR 0·62 95% CI 0·49–0·80; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 38% of 272 patients in the camrelizumab–rivoceranib group vs 40 15% of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 12% vs 41 15%), increased aspartate aminotransferase (45 17% vs 14 5%), and increased alanine aminotransferase (35 13% vs eight 3%). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab–rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab–rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse).
Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population.
Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.
This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) ...with MET overexpression.
In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose RP2D) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP).
In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26-0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib.
Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression.
ClinicalTrials.gov NCT01988493.
BackgroundThe programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade ...the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.MethodsPatients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.ResultsBetween May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity; anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.ConclusionsTislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.Trial registration number NCT02407990.
Background.
The EACH study assessed the efficacy of oxaliplatin, 5‐fluorouracil, and leucovorin (the FOLFOX4 regimen) compared with doxorubicin alone in terms of overall survival (OS), ...progression‐free survival (PFS), and safety in patients with advanced hepatocellular carcinoma (HCC). We present the results of this study in Chinese patients.
Methods.
In a multicenter, open‐label, randomized, phase III study (00471965), 371 patients (279 patients from the People's Republic of China) were randomized 1:1 to receive either FOLFOX4 or doxorubicin until disease progression, intolerable toxicity, death, or surgical resection.
Results.
Baseline characteristics of the Chinese patients enrolled in the study were similar for the 2 treatment groups and in comparison with the whole EACH cohort. Median OS at the prespecified time point of treatment was 5.7 months with FOLFOX4 and 4.3 months with doxorubicin (hazard ratio HR: 0.74; 95% confidence interval CI: 0.55–0.98; p = .03). At the end of the follow‐up period, median OS was 5.9 months with FOLFOX4 and 4.3 months with doxorubicin (HR: 0.75; 95% CI: 0.58–0.98; p = .03). Median PFS was 2.4 months and 1.7 months in the FOLFOX4 and doxorubicin groups, respectively (HR: 0.55; 95% CI: 0.45–0.78; p = .0002). The response rate (RR) and disease control rate (DCR) were significantly higher in the FOLFOX4 group than in the doxorubicin group (RR: 8.6% vs. 1.4%, p = .006; DCR: 47.1% vs. 26.6%, p = .0004). Hematological toxicity was more frequently reported in the FOLFOX4 group.
Conclusion.
For Chinese HCC patients enrolled in the EACH study, FOLFOX4 significantly improved the RR and DCR and prolonged survival compared with doxorubicin. Systemic chemotherapy with oxaliplatin‐based regimens may play an important role in the treatment of Chinese patients with advanced HCC.
摘要
背景. EACH 研究评估了 FOLFOX4 方案（奥沙利铂、5‐氟尿嘧啶和亚叶酸）与多柔比星单药治疗进展期肝细胞癌（HCC）患者的有效性 包括总生存（OS）和无进展生存（PFS）和安全性。本文介绍了 EACH 研究的中国患者结果。
方法. EACH 研究是一项多中心、开放标签的 III 期随机临床试验（ 00471965），371 例患者（其中 279 例来自中国大陆）按 1:1 比例随机分配，接受 FOLFOX4 方案或多柔比星单药治疗，直至疾病进展、发生不可耐受的毒性事件、死亡或接受手术切除。
结果. 中国招募的患者中两个治疗组的基线特征相似，中国患者人群的基线特征与 EACH 研究总队列也相似。在计划的治疗时间内，FOLFOX4 方案与多柔比星的中位 OS 分别为 5.7 个月和 4.3 个月 风险比（HR）：0.74；95% 可信区间（CI）：0.55 ∼ 0.98，P = 0.03。随访结束时，FOLFOX4 方案与多柔比星的中位 OS 分别为 5.9 个月和 4.3 个月（HR：0.75，95%CI ：0.58 ∼ 0.98；P = 0.03）。FOLFOX4 组和多柔比星组的中位 PFS 分别为 2.4 个月和 1.7 个月（HR：0.55；95%CI ：0.45 ∼ 0.78；P = 0.0002）。FOLFOX4 组的缓解率（RR）和疾病控制率（DCR）显著高于多柔比星组（RR：8.6% vs. 1.4%，P = 0.006 ；DCR：47.1% vs. 26.6%，P = 0.0004）。FOLFOX4 方案组中血液学毒性更常见。
结论. 与多柔比星相比，FOLFOX4 方案显著提高 EACH 研究入组的中国 HCC 患者的 RR 和 DCR，并延长了生存期。以奥沙利铂为基础的全身化疗方案在中国进展期 HCC 患者的治疗方面可能具有重要作用。The Oncologist 2014;19: 1169‐1178
The authors report the results of the EACH study for the subgroup of Chinese patients with advanced hepatocellular carcinoma (HCC) who are ineligible for curative resection or local treatment. FOLFOX4 significantly improved response and disease‐control rates and prolonged survival compared with doxorubicin. Systemic chemotherapy with oxaliplatin‐based regimens may play an important role in the treatment of Chinese patients with advanced HCC.
FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with ...activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours.
The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1–4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0–1 (or equivalent for adolescents aged 12–17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976.
Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6–23·9), an objective response was observed in 64 (30% 95% CI 24–36) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 12%), palmar-plantar erythrodysaesthesia syndrome (12 6%), and hyperphosphataemia (11 5%). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths.
RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours.
Janssen Research & Development.
We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain ...metastases of breast cancer (BMBC).
A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m(2)/day; days 2-4) and cisplatin (70 mg/m(2); day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)-objective response rate according to volumetric response criteria.
A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33-75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients 77.1%; 95% confidence interval (CI), 59.9-89.6 achieved a CNS-objective response, including 13 patients (37.1%) with a ≥80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5-8.1) and 10.5 months (95% CI, 7.8-13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%).
By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted.
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