Hepatocellular carcinoma (HCC) accounts for about 90% of all primary liver cancers and is the second leading cause of cancer-related deaths worldwide. The hypervascular nature of most HCC tumors ...underlines the importance of angiogenesis in the pathobiology of these tumors. Several angiogenic pathways have been identified as being dysregulated in HCC, suggesting they may be involved in the development and pathogenesis of HCC. These data provide practical targets for systemic treatments such as those targeting the vascular endothelial growth factor receptor and its ligand. However, the clinical relevance of other more recently identified angiogenic pathways in HCC pathogenesis or treatment remains unclear. Research into molecular profiles and validation of prognostic or predictive biomarkers will be required to identify the patient subsets most likely to experience meaningful benefit from this important class of agents.
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor and remains a fatal malignancy in the majority of patients. Approximately 20%–30% of patients are eligible for ...resection, which is considered the only potentially curative treatment; and, after resection, a median survival of 53 months has been reported when sequenced with adjuvant capecitabine. For the 70%–80% of patients who present with locally unresectable or distant metastatic disease, systemic therapy may delay progression, but survival remains limited to approximately 1 year. For the past decade, doublet chemotherapy with gemcitabine and cisplatin has been considered the most effective first‐line regimen, but results from the recent use of triplet regimens and even immunotherapy may shift the paradigm. More effective treatment strategies, including those that combine systemic therapy with locoregional therapies like radioembolization or hepatic artery infusion, have also been developed. Molecular therapies, including those that target fibroblast growth factor receptor and isocitrate dehydrogenase, have recently received US Food and Drug Administration approval for a defined role as second‐line treatment for up to 40% of patients harboring these actionable genomic alterations, and whether they should be considered in the first‐line setting is under investigation. Furthermore, as the oncology field seeks to expand indications for immunotherapy, recent data demonstrated that combining durvalumab with standard cytotoxic therapy improved survival in patients with ICC. This review focuses on the current and future strategies for ICC treatment, including a summary of the primary literature for each treatment modality and an algorithm that can be used to drive a personalized and multidisciplinary approach for patients with this challenging malignancy.
Despite lengthening survival, death rates from metastatic colorectal cancer (CRC) remain unacceptably high, with a bright spot being the demonstration of durable responses in patients with CRC who ...have mismatch repair‐deficient (dMMR) and/or microsatellite instability‐high (MSI‐H) tumors and are treated with immune checkpoint inhibitor therapy. Nivolumab and pembrolizumab, as well as nivolumab in combination with low‐dose ipilimumab—all checkpoint inhibitors—are currently approved by the U.S. Food and Drug Administration (FDA) for patients with MSI‐H/dMMR metastatic CRC that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Nonetheless, there are a number of questions and considerations in the use of these checkpoint inhibitor therapies. Using a question‐and‐answer format, this review summarizes the scientific rationale for immune checkpoint inhibitor therapy in CRC, including the effects of tumor factors such as genetic aberrations and mutational load on the immune response, particularly in patients with MSI‐H/dMMR disease. We discuss response patterns, response criteria, and immune‐related adverse events using findings from published efficacy and safety data of immune checkpoint inhibitor therapy in metastatic CRC. We also discuss issues surrounding treatment sequencing, incorporating approved checkpoint inhibitors into the current treatment paradigm, and the multiple investigational strategies that may optimize immunotherapy for advanced CRC in the future, including novel combination therapies.
Implications for Practice
Colorectal cancer (CRC) is the third most common cancer in the U.S. Despite advances in chemotherapy, survival remains poor for patients with metastatic CRC. Certain immunotherapy agents have demonstrated long‐lasting responses in previously treated patients with immune‐responsive microsatellite instability‐high/mismatch repair‐deficient metastatic CRC, leading to U.S. Food and Drug Administration approval of the immune checkpoint inhibitors nivolumab (with or without low‐dose ipilimumab) and pembrolizumab in this population. Combination therapy (e.g., nivolumab with low‐dose ipilimumab) has demonstrated numerically higher response rates and improved long‐term clinical benefit relative to anti‐programmed death‐1 monotherapy. Ongoing trials are evaluating immunotherapy in the broader CRC population and novel combinations to optimize immunotherapy for advanced CRC.
Despite advances in treatment, survival remains poor for patients with colorectal cancer. This article considers the use of immune checkpoint inhibitors, summarizing the rationale for immune checkpoint inhibitor therapy in colorectal cancer.
Purpose Nivolumab provides clinical benefit (objective response rate ORR, 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival OS, 73%) in previously treated patients with ...DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported. Patients and Methods Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Results Of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of patients and were manageable. Patients (13%) who discontinued treatment because of study drug-related AEs had an ORR (63%) consistent with that of the overall population. Conclusion Nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC.
Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels ...of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer.
In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged ≥18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188.
Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12·0 months (IQR 8·6–18·0), 23 (31·1%, 95% CI 20·8–42·9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57–79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62–95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six 8%) and amylase (two 3%). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator.
Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients.
Bristol-Myers Squibb.
Summary Background Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in ...patients with SCLC who progressed after one or more previous regimens. Methods The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov , number NCT01928394. Findings Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0–464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0–470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0–288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 8% vs none) and diarrhoea (none vs 3 5% vs 1 2%). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Interpretation Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. Funding Bristol-Myers Squibb.
Parkinson's disease (PD) progresses relentlessly and affects five million people worldwide. Laboratory tests for PD are critically needed for developing treatments designed to slow or prevent ...progression of the disease. We performed a transcriptome-wide scan in 105 individuals to interrogate the molecular processes perturbed in cellular blood of patients with early-stage PD. The molecular multigene marker here identified is associated with risk of PD in 66 samples of the training set comprising healthy and disease controls third tertile cross-validated odds ratio of 5.7 (P for trend 0.005). It is further validated in 39 independent test samples third tertile odds ratio of 5.1 (P for trend 0.04). Insights into disease-linked processes detectable in peripheral blood are offered by 22 unique genes differentially expressed in patients with PD versus healthy individuals. These include the cochaperone ST13, which stabilizes heat-shock protein 70, a modifier of α-synuclein misfolding and toxicity. ST13 messenger RNA copies are lower in patients with PD (mean ± SE 0.59 ± 0.05) than in controls (0.96 ± 0.09) (P = 0.002) in two independent populations. Thus, gene expression signals measured in blood can facilitate the development of biomarkers for PD.
Background
Early detection and management of treatment‐related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) ...plus low‐dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate ORR 55%, median duration of response not reached, 12‐month overall survival OS rate 85%) and manageable safety for previously treated microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) metastatic colorectal cancer (mCRC). In‐depth safety and additional efficacy outcomes from CheckMate 142 are presented.
Materials and Methods
Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune‐mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune‐modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs.
Results
Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2–12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5–9.0 weeks). IMMs were used to manage sTRAEs in 22%–56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12‐month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%).
Conclusion
The benefit‐risk profile of nivolumab plus low‐dose ipilimumab provides a promising treatment option for patients with previously treated MSI‐H/dMMR mCRC.
Implications for Practice
Nivolumab (NIVO) plus low‐dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment‐related adverse events (sTRAEs) occurred early, were managed using evidence‐based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune‐modulating medications. The benefit‐risk profile of NIVO + low‐dose IPI provides a promising treatment option for MSI‐H/dMMR mCRC.
摘要
背景。在接受免疫检查点抑制剂治疗的患者中，早期发现和管理治疗相关不良事件 (TRAE) 可改善预后。在 CheckMate 142 研究中，纳武单抗 (3 mg/kg) 联合低剂量易普利姆玛单抗 (1 mg/kg) 可提供持久的临床疗效 客观反应率 (ORR)为 55%，未达到中位反应持续时间，12 个月的总生存(OS)率为 85%，且对于既往已接受微卫星不稳定性高/错配修复缺陷(MSI‐H/dMMR)转移性结直肠癌 (mCRC) 治疗的患者具有可控的安全特性。此外，还介绍了 CheckMate 142 的深度安全性及其他疗效。
材料和方法。安全性评估包括TRAE发生频率、选择性TRAE (sTRAE) 及免疫介导型不良事件的发生率；发生时间 (TTO)；消退时间 (TTR)；免疫调节药物 (IMM) 的使用；剂量延迟；恢复治疗后出现sTRAE。疗效评估包括对sTRAE伴有或不伴IMM的患者及不伴sTRAE的患者的ORR和生存率进行分析。
结果。在 119 名患者中，25%、23%、19%、5%、5% 及 29% 的患者分别出现了内分泌系统、胃肠、肝脏、肺、肾脏或皮肤方面的sTRAE；多数 (57%) 属于 1/2 级。sTRAE发生于早期(中位TTO，5.2–12.6 周)。多数(超过 71%)患者的非内分泌系统sTRAE消退(中位TTR，1.5–9.0 周)。22%–56% 的患者使用IMM治疗sTRAE(多数均消退)。在由于sTRAE而导致剂量延迟的患者中，29 例中有 25 例恢复了治疗。对于伴有或不伴sTRAE的患者，在ORR(57% vs. 52%)和 12 个月的OS率(93% vs. 75%)方面相差无几。经观察发现，无论IMM使用与否，伴有或不伴sTRAE的患者均取得了类似的疗效(ORR 52% vs. 57%；OS率 87% vs. 82%)。
结论。根据对纳武单抗联合低剂量易普利姆玛单抗的疗效‐风险分析，此种疗法将有望成为既往已接受MSI‐H/dMMR mCRC治疗者的首选治疗方案。
实践意义:纳武单抗 (NIVO) 联合低剂量 (1 mg/kg) 易普利姆玛单抗 (IPI) 疗法获得了美国食品和药品管理局的批准，可用于患微卫星不稳定高/错配修复缺陷 (MSI‐H/dMMR) 转移性结直肠癌 (mCRC) 且在接受氟尿嘧啶、奥沙利铂及伊立替康的治疗后病情恶化(基于 CheckMate 142 研究的结果)的患者。在此项安全性分析中，大多数选择性治疗相关不良事件 (sTRAE) 均发生于早期，在采用循证治疗方法进行治疗后消退。无论是否同时使用免疫调节药物，伴有或不伴sTRAE的患者均取得了类似的疗效。根据对NIVO联合低剂量IPI的疗效‐风险分析，此种疗法将有望成为MSI‐H/dMMR mCRC的首选治疗方案
Because of unique mechanisms of action, immune checkpoint inhibitor use is associated with adverse events that differ from chemotherapy‐related adverse events. This article analyzes the safety profile of nivolumab plus low‐dose ipilimumab in previously treated patients with microsatellite instability‐high and/or mismatch repair‐deficient metastatic colorectal cancer.
The safety of simultaneous resections of colorectal cancer and synchronous liver metastases (SCRLM) is not established. This multi-institutional retrospective study compared postoperative outcomes ...after simultaneous and staged colorectal and hepatic resections.
Clinicopathologic data, treatments, and postoperative outcomes from patients who underwent simultaneous or staged colorectal and hepatic resections at three hepatobiliary centers from 1985-2006 were reviewed.
610 patients underwent simultaneous (n = 135) or staged (n = 475) resections of colorectal cancer and SCRLM. Seventy staged patients underwent colorectal and hepatic resections at the same institution. Simultaneous patients had fewer (median 1 versus 2) and smaller (median 2.5 versus 3.5 cm) metastases and less often underwent major (> or = three segments) hepatectomy (26.7% versus 61.3%, p < 0.05). Combined hospital stay was lower after simultaneous resections (median 8.5 versus 14 days, p < 0.0001). Mortality (1.0% versus 0.5%) and severe morbidity (14.1% versus 12.5%) were similar after simultaneous colorectal resection and minor hepatectomy compared with isolated minor hepatectomy (both p > 0.05). For major hepatectomy, simultaneous colorectal resection increased mortality (8.3% versus 1.4%, p < 0.05) and severe morbidity (36.1% versus 15.1%, p < 0.05). Combined severe morbidity after staged resections was lower compared to simultaneous resections (36.1% versus 17.6%, p = 0.05) for major hepatectomy but similar for minor hepatectomy (14.1% versus 10.5%, p > 0.05). Major hepatectomy independently predicted severe morbidity after simultaneous resections hazard ratio (HR) = 3.4, p = 0.008.
Simultaneous colorectal and minor hepatic resections are safe and should be performed for most patients with SCRLM. Due to increased risk of severe morbidity, caution should be exercised before performing simultaneous colorectal and major hepatic resections.
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