Summary Heat shock protein 90 (HSP90) is a molecular chaperone that is crucial for the stability and function of many proteins essential for cell survival. Many oncogenes, including tyrosine kinases, ...transcription factors, and cell-cycle regulatory proteins, are client proteins of HSP90. Inhibition of HSP90 causes client protein degradation via the ubiquitin–proteasome pathway, and is a mechanism that might simultaneously downregulate several redundant pathways crucial for cell viability and tumour development. HSP90 inhibitors are currently being developed as anticancer agents, and have shown early promising results in molecularly defined subgroups of solid tumours (eg, ALK-rearranged non-small-cell lung cancer and HER2-amplified breast cancer) and some haematological malignancies (eg, multiple myeloma). Here, we review the current status of HSP90 inhibitors in clinical development, including geldanamycin derivatives, resorcinol derivatives, purine analogues, and other synthetic inhibitors. We also discuss novel strategies and future perspectives on how to optimise the therapeutic potential of this exciting new class of drugs.
Summary Background Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. ...We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Methods Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01183780 .ld Findings We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4–14·5) for patients in the ramucirumab group versus 11·7 months (10·8–12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730–0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 38% of 529 patients in the ramucirumab group vs 123 23% of 528 in the placebo group, with febrile neutropenia incidence of 18 3% vs 13 2%), hypertension (59 11% vs 15 3%), diarrhoea (57 11% vs 51 10%), and fatigue (61 12% vs 41 8%). Interpretation Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable. Funding Eli Lilly.
This ENETS guidance paper, developed by a multidisciplinary working group, provides an update on the previous colorectal guidance paper in a different format. Guided by key clinical questions ...practical advice on the diagnosis and management of neuroendocrine tumours (NET) of the caecum, colon, and rectum is provided. Although covered in one guidance paper colorectal NET comprises a heterogeneous group of neoplasms. The most common rectal NET are often small G1 tumours that can be treated by adequate endoscopic resection techniques. Evidence from prospective clinical trials on the treatment of metastatic colorectal NET is limited and discussion of patients in experienced multidisciplinary tumour boards strongly recommended. Neuroendocrine carcinomas (NEC) and mixed neuroendocrine non‐neuroendocrine neoplasms (MiNEN) are discussed in a separate guidance paper.
Background
Gastroenteropancreatic neuroendocrine neoplasms (GEP‐NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification ...provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki‐67 cutoff values in GEP‐NENs.
Subjects, Materials, and Methods
A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors well differentiated) or NECs (neuroendocrine carcinomas poorly differentiated), and by Ki‐67 index as G1 (Ki‐67 <2%), G2 (Ki‐67 3%–20%), or G3 (Ki‐67 >20%). Patients were stratified into five cohorts: NET‐G1, NET‐G2, NET‐G3, NEC‐G2, and NEC‐G3.
Results
Five‐year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5‐year survival: 81% Ki‐67 3%–5%, 72% Ki‐67 6%–10%, 52% Ki‐67 11%–20%) and G3 NENs (5‐year survival: 35% Ki‐67 21%–50%, 22% Ki‐67 51%–100%). Five‐year survival was significantly greater for NET‐G2 versus NEC‐G2 (75.5% vs. 58.2%) and NET‐G3 versus NEC‐G3 (43.7% vs. 25.4%).
Conclusion
Substantial clinical heterogeneity is observed within G2 and G3 GEP‐NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index.
Implications for Practice
Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real‐world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.
This article evaluates the prognostic impact of histological differentiation within the WHO 2010 grading classifications and explores additional Ki‐67 cut‐off values for gastroenteropancreatic neuroendocrine neoplasms.
Background
In the phase III CORRECT trial, regorafenib significantly improved survival in treatment‐refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further ...characterize regorafenib safety and allow patients access to regorafenib before market authorization.
Methods
This prospective, single‐arm study enrolled patients in 25 countries at 186 sites. Patients with treatment‐refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4‐week cycle. The primary endpoint was safety. Progression‐free survival (PFS) per investigator assessment was the only efficacy evaluation.
Results
In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment‐emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib‐related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib‐related TEAEs occurred in <1%. The most common grade ≥3 regorafenib‐related TEAEs were hypertension (15%), hand–foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment‐emergent grade 3–4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib‐related severe drug‐induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval CI) was 2.7 months (2.6–2.7).
Conclusion
In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680.
Implications for Practice
Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment‐refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.
摘要
背景。在 III 期 CORRECT 试验中，瑞戈非尼显著提高了难治性转移性结肠直肠癌 (mCRC) 的生存率。CONSIGN 研究旨在进一步彰显瑞戈非尼的安全性，以及让患者在获得上市许可前使用此药品。
方法。此项前瞻性单臂研究在 25 个国家的 186 个地点招募患者。患有难治性 mCRC 且东部肿瘤协作组体能状态 (ECOG PS) <1 的患者以 160 mg 的剂量服用瑞戈非尼，每天一次，每 4 星期周期中的前 3 周服用。主要疗效指标为安全性。每位研究员的无进展生存期 (PFS) 评估是唯一的疗效评估。
结果。总计有 2,872 名患者被分配治疗，2,864 名患者接受治疗。中值年龄为 62 岁，ECOG PS 0/1 为 47%/53%，有 74% 已收到至少三个转移性疾病的前治疗方案。平均治疗时间为三个周期。治疗突发不良反应事件 (TEAE) 导致 46% 的患者减少剂量。9% 的患者因瑞戈非尼相关 TEAE 而停止治疗。少于 1% 的患者出现 5 级瑞戈非尼相关 TEAE。最常见的 3 级及以上瑞戈非尼相关 TEAE 为高血压 (15%)、手足皮肤反应 (14%)、疲劳 (13%)、腹泻 (5%) 和低磷血症 (5%)。治疗突发 3‐4 级实验室毒性包括丙氨酸转氨酶 (6%)、天冬氨酸转氨酶 (6%) 和胆红素 (6%)。正在进行的监测确定了每个 DILI 工作组标准的瑞戈非尼相关药物所致重度肝损伤的非致命病例。中位 PFS(95% 置信区间 CI)为 2.7 个月 (2.6–2.7)。
结论。在 CONSIGN 中，TEAE 的频率和严重程度与瑞戈非尼已知的安全曲线一致。PFS 与 III 期试验报告相似。ClinicalTrials.gov:NCT01538680。
对实践的启示:采用标准治疗(包括化疗和针对血管内皮生长因子或表皮生长因子受体的单克隆抗体)而未达到治疗效果的转移性结肠直肠癌 (mCRC) 患者所能选择的治疗方案极少。在 III 期 CORRECT (N = 760) 和 CONCUR (N = 204) 试验中，多重激酶抑制剂瑞戈非尼被证明可以提高难治性 mCRC 患者的生存率。但是，无法提供大量患者针对 mCRC 的瑞戈非尼安全数据。在 25 个国家的超过 2,800 名患者中进行的前瞻性 CONSIGN 试验，从 III 期试验中证实了瑞戈非尼的安全性，并加强了使用治疗修改来管理不良反应事件的重要性。
This article reports the results of the CONSIGN study, which was designed to characterize the safety of regorafenib in a large patient population, estimate progression‐free survival, and provide patients with treatment‐refractory metastatic colorectal cancer access to regorafenib before market authorization.
In May 1982, the US Food and Drug Administration (FDA) approved the use of streptozotocin to treat pancreatic neuroendocrine tumors (panNETs). Thus, this year marks 40 years since that landmark date. ...This review of streptozotocin to treat panNETs is intended to commemorate this anniversary. A historical perspective of the chemical structure, pharmacokinetics, and mechanism of action of streptozotocin is followed by data from prospective and retrospective clinical studies. The last section of the review addresses the latest aspects and takes note of the prospects that lie ahead on the future horizon of the use of streptozotocin to treat panNETs, including ongoing clinical trials.
The phase 3 KEYNOTE‐177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite‐instability‐high ...(MSI‐H)/mismatch‐repair‐deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression‐free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE‐177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval CI 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio HR 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment‐related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune‐mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first‐line pembrolizumab as a standard of care for patients from Asia with MSI‐H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.
We report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis of the phase 3 KEYNOTE‐177 study which evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite‐instability‐high(MSI‐H)/mismatch‐repair‐deficient (dMMR) metastatic colorectal cancer (mCRC). Median PFS was not reached (NR) with pembrolizumab versus 10.4 months with chemotherapy (hazard ratio HR 0.56, 95% confidence interval CI 0.26–1.20), median OS was NR versus 30.0 months (HR 0.65, 95% CI 0.27–1.55), ORR was 50% versus 46%, and grade 3/4 treatment‐related adverse events were reported by two patients (9%) versus 20 (80%). These data support first‐line pembrolizumab as a standard of care for patients from Asia with MSI‐H/dMMR mCRC.
Background
Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has ...been reported but not confirmed in prospective trials.
Materials and Methods
This prospective, multicenter, single‐arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well‐differentiated gastrointestinal NETs (GI‐NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression‐free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin‐like growth factor 1 receptor IGF1R and phosphoS6 pS6 expression).
Results
Forty‐three patients were included in the intent‐to‐treat analyses. After 12 months of treatment, 62.3% (95% confidence interval CI 48%–77%) of patients had not progressed or died. The 24‐month PFS rate was 43.6% (95% CI 29%–58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow‐up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS.
Conclusion
The everolimus‐octreotide combination provided clinically relevant efficacy in nonfunctioning GI‐NETs, similar to the results of RADIANT‐2 in functioning setting.
Implications for Practice
The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting.
The EVERLAR study was conducted to assess the anti‐tumor activity of the everolimus and the somatostatin analog octreotide combination in progressive nonfunctioning gastrointestinal neuroendocrine tumors and to understand the relationship between the activation of the translation of IGFR‐PI3K‐mTOR signal and response to treatment.
The results of the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)-1402 phase II randomized trial suggested that adding aflibercept to modified fluorouracil, oxaliplatin, and leucovorin ...(mFOLFOX6) induction, followed by chemoradiation and surgery, could increase the pathological complete response (pCR) rate in patients with high-risk, locally advanced rectal cancer. Here we update results up to 3 years of follow-up and evaluate the predictive value of consensus molecular subtypes identified with immunohistochemistry (IHC).
Patients with magnetic resonance imaging-defined T3c-d and/or T4 and/or N2 rectal adenocarcinoma in the middle or distal third were randomly assigned to mFOLFOX6 induction, with aflibercept (mF+A; n = 115) or without aflibercept (mF; n = 65), followed by capecitabine plus radiotherapy and surgery. The risk local relapse, distant metastases, disease-free survival (DFS), and overall survival (OS) were estimated at 3 years. Selected samples were classified via IHC into immune-infiltrate, epithelial, or mesenchymal subtypes.
mF+A and mF had 3-year DFS of 75.2% (95% confidence interval CI = 66.1% to 82.2%) and 81.5% (95% CI = 69.8% to 89.1%), respectively; 3-year OS of 89.3% (95% CI = 82.0% to 93.8%) and 90.7% (95% CI = 80.6% to 95.7%), respectively; 3-year cumulative local relapse incidences of 5.2% (95% CI = 1.9% to 11.0%) and 6.1% (95% CI = 1.7% to 15.0%), respectively; and 3-year cumulative distant metastases rates of 17.3% (95% CI = 10.9% to 25.5%) and 16.9% (95% CI = 8.7% to 28.2%), respectively. pCRs were achieved in 27.5% (n = 22 of 80) and 0% (n = 0 of 10) of patients with epithelial and mesenchymal subtypes, respectively.
Adding aflibercept to mFOLFOX6 induction was not associated with improved DFS or OS. Our findings suggested that consensus molecular subtypes identified with IHC subtypes could be predictive of pCR with this treatment.
Lessons Learned
Treatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.
The hypothesis of dual ...targeting of the phosphatidylinositol 3‐kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents.
Background
This phase II study investigated whether targeting the phosphatidylinositol 3‐kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy.
Methods
Patients with advanced pNET were randomized (1:1) to oral BEZ235 400 mg twice daily or oral everolimus 10 mg once daily on a continuous dosing schedule. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included safety, overall response rate (ORR), overall survival (OS), and time to treatment failure.
Results
Enrollment in this study was terminated early (62 enrolled of the 140 planned). The median PFS was 8.2 months (95% confidence interval CI: 5.3 to not evaluable NE) with BEZ235 versus 10.8 months (95% CI: 8.1–NE) with everolimus (hazard ratio 1.53; 95% CI: 0.72–3.25). The most commonly reported all‐grade adverse events (>50% of patients regardless of study treatment relationship) with BEZ235 were diarrhea (90.3%), stomatitis (74.2%), and nausea (54.8%).
Conclusion
BEZ235 treatment in mTOR inhibitor‐naïve patients with advanced pNET did not demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.
经验总结
• 与依维莫司相比,BEZ235 治疗未显示出疗效增加,可能与耐受性较差相关。
• 晚期胰腺神经内分泌肿瘤患者中磷脂酰肌醇3‐激酶和哺乳动物雷帕霉素靶蛋白通路的双靶向假设可能需要使用其他药物进行进一步研究。
摘要
背景.该II期研究考察的内容是,在未接受过哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂治疗的晚期胰腺神经内分泌肿瘤(pNET)患者中,使用BEZ235靶向通过磷脂酰肌醇3‐激酶(PI3K)、mTOR复合物1(mTORC1)和mTOR复合物2(mTORC2)抑制的PI3K/mTOR通路是否比使用依维莫司的mTORC1抑制效果更好。
方法.晚期pNET患者随机以连续给药方案(1:1)口服BEZ235 400 mg每天两次或口服依维莫司10 mg每天一次。主要终点为无进展生存期(PFS)。次要终点包括安全性、总缓解率(ORR)、总生存期(OS)和至治疗失败的时间。
结果.本研究的入组提前终止(计划入组140名,实际入组62名)。BEZ235组的中位PFS为8.2个月95%置信区间(CI):5.3至无法评估(NE),而依维莫司组为10.8个月(95% CI:8.1‐NE)(风险比 1.53;95% CI:0.72‐3.25)。BEZ235最常报告的所有等级不良事件(>50%的患者,不考虑研究治疗关系)为腹泻(90.3%)、口腔炎(74.2%)和恶心(54.8%)。
结论.未接受过mTOR抑制剂治疗的晚期pNET患者的BEZ235治疗未显示出与依维莫司相比增强的疗效,这可能与耐受性较差相关。
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