On November 13, 2015, the FDA granted accelerated approval to osimertinib (TAGRISSO; AstraZeneca), a breakthrough therapy-designated drug for the treatment of patients with metastatic EGFR T790M ...mutation-positive non-small cell lung cancer, as detected by an FDA-approved test, with progression on or after EGFR tyrosine kinase inhibitor therapy. Approval was based on durable tumor response rates in two single-arm, multicenter trials: the dose extension cohort of a first-in-human trial (FIH; AURA extension;
= 201) and a fixed-dose, activity-estimating trial (AURA2;
= 210). Osimertinib was administered at 80 mg orally once daily. The objective response rates (ORR) per blinded independent committee review were 57% 95% confidence interval (CI), 50-64) in AURA extension and 61% (95% CI, 54-68) in AURA2. Median duration of response (DOR) could not be estimated. Supportive efficacy data from 63 patients in the dose-finding part of the FIH trial demonstrated an ORR of 51% (95% CI, 38-64), with a median DOR of 12.4 months. Common adverse events (AE) evaluated in 411 patients included diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). Grade 3 to 4 AEs occurred in 28% of patients, and 5.6% discontinued treatment due to AEs.
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On March 11, 2016, after an expedited 5‐month review, the U.S. Food and Drug Administration expanded the crizotinib metastatic non‐small cell lung cancer (mNSCLC) indication to include the treatment ...of patients whose tumors harbor a ROS1 rearrangement. The approval was based on a clinically meaningful, durable objective response rate (ORR) in a multicenter, single‐arm clinical trial (ROS1 cohort of Trial PROFILE 1001) in patients with ROS1‐positive mNSCLC. The trial enrolled 50 patients (age range: 25–77 years) whose tumors were prospectively determined to have a ROS1 gene rearrangement by break‐apart fluorescence in situ hybridization (96%) or reverse transcriptase polymerase chain reaction (4%) clinical trial assays. Crizotinib demonstrated an ORR of 66% (95% confidence interval CI: 51%–79%) with a median duration of response of 18.3 months by independent radiology review and 72% (95% CI: 58%–84%) by investigator review. Patients received crizotinib 250 mg twice daily and had a median duration of exposure of 34.4 months. The toxicity profile in ROS1‐positive patients was generally consistent with the randomized safety data in the U.S. Product Insert from two ALK‐positive mNSCLC trials. The most common (≥25%) adverse reactions and laboratory test abnormalities included vision disorders, elevation of alanine transaminase and aspartate transaminase levels, nausea, hypophosphatemia, diarrhea, edema, vomiting, constipation, neutropenia, and fatigue. There were no treatment‐related deaths. A favorable benefit‐to‐risk evaluation led to the traditional approval of crizotinib for this new supplemental indication.
Implications for Practice:
Given the results from the ROS1 cohort of the clinical trial PROFILE 1001, crizotinib represents a new treatment option and the first approved therapy for patients with metastatic non‐small cell lung cancer whose tumors are ROS1 positive. Crizotinib demonstrated efficacy irrespective of prior treatment status.
The FDA has expanded the crizotinib metastatic non‐small cell lung cancer indication to include treatment of patients whose tumors harbor a ROS1 rearrangement. The approval was based on a clinically meaningful, durable objective response rate (66%) in a multicenter, single‐arm clinical trial. Patients received crizotinib 250 mg twice daily; the median duration of exposure and of response was 34.4 and 18.3 months, respectively.
With the Breakthrough Therapy Designation program adding to the tools that the U.S. Food and Drug Administration (FDA) has for expediting drug development, the FDA reassessed the endpoints needed for ...approval of transformative therapies. Although the demonstration of an improvement in overall survival remains the gold standard for drug approval, innovation in cancer research has led to use of other endpoints in regulatory decision‐making. These endpoints include substantially delaying tumor progression or extending progression‐free survival, substantially reducing tumor size for a prolonged time, improving objective response rate and duration of response, or improving cancer‐related symptoms and patient function.
On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or ...metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥1% of the tumor area, as determined by an FDA-approved test. Approval was based on data from IMpassion130, which randomized patients to receive atezolizumab or placebo in combination with paclitaxel protein-bound. Investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) and PD-L1-positive populations were coprimary endpoints. After 13-month median follow-up, the estimated median PFS in the PD-L1-positive population was 7.4 months in the atezolizumab arm and 4.8 months in the placebo arm HR = 0.60; 95% confidence interval (CI), 0.48-0.77. Overall survival (OS) results were immature with 43% deaths in the ITT population, representing 59% of the OS events required to perform the final OS analysis. Adverse reactions occurring in ≥20% of patients receiving atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. Accelerated approval was appropriate taking into account the unmet medical need along with the immaturity of the OS results and potential for PFS in the PD-L1-expressing population to predict clinical benefit.
PTEN hamartoma tumor syndromes BLUMENTHAL, Gideon M; DENNIS, Phillip A
European journal of human genetics : EJHG,
11/2008, Volume:
16, Issue:
11
Journal Article
Peer reviewed
Open access
The PTEN hamartoma tumor syndromes (PHTS) are a collection of rare clinical syndromes characterized by germline mutations of the tumor suppressor PTEN. These syndromes are driven by cellular ...overgrowth, leading to benign hamartomas in virtually any organ. Cowden syndrome (CS), the prototypic PHTS syndrome, is associated with increased susceptibility to breast, thyroid, and endometrial cancer. PTEN is located on chromosome 10q22-23 and negatively regulates the prosurvival PI3K/Akt/mTOR pathway through its lipid phosphatase activity. Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival. Clinical management of patients with PHTS, particularly those with CS, should include early and frequent screening, surveillance, and preventive care for associated malignancies. Concomitant with improved understanding of the biology of PTEN and the PI3K/Akt/mTOR pathway, inhibitors of this pathway are being developed as anticancer agents. These medications could have applications for patients with PHTS, for whom no medical options currently exist.
Patients who receive immunotherapeutic drugs might develop an atypical response pattern, wherein they initially meet conventional response criteria for progressive disease but later have decreases in ...tumour burden. Such responses warrant further investigation into the potential benefits and risks for patients who continue immunotherapy beyond disease progression defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
For this pooled analysis, we included all submissions of trial reports and data to the US Food and Drug Administration (FDA) in support of marketing applications for anti-programmed death receptor-1 (PD-1) antibodies (alone or in combination) for the treatment of patients with unresectable or metastatic melanoma that allowed for continuation of the antibody beyond RECIST-defined progression in the anti-PD-1 group and were approved by FDA before Jan 1, 2017. To investigate the effect of treatment beyond progression in patients with metastatic melanoma and to better characterise which of these patients would benefit from extended treatment, we pooled individual patient data from patients who received at least one dose of an anti-PD-1 antibody in the included trials. We included any patient receiving the anti-PD-1 antibody after their RECIST-defined progression date in the treatment beyond progression cohort and analysed them descriptively at baseline and at time of progression versus the cohort not receiving treatment beyond progression. We analysed the target lesion response after progression in patients in the treatment beyond progression cohort relative to progressive disease and baseline target lesion burden. We defined a treatment beyond progression response as a decrease in target lesion tumour burden (sum of the reference diameters) of at least 30% from the burden at the time of RECIST-defined progression that did not require confirmation at a subsequent assessment. We also compared individual timepoint responses, overall survival, and adverse events in the treatment beyond progression versus no treatment beyond progression cohorts.
Among the eight multicentre clinical trials meeting this study's inclusion criteria, we pooled the data from 2624 patients receiving immunotherapy. 1361 (52%) had progressive disease, of whom 692 (51%) received continued anti-PD-1 antibody treatment beyond RECIST-defined progression and 669 (49%) did not. 95 (19%) of 500 patients in the treatment beyond progresssion cohort with evaluable assessments had a 30% or more decrease in tumour burden, when considering burden at RECIST-defined progression as the reference point, representing 14% of the 692 patients treated beyond progression and 4% of all 2624 patients treated with immunotherapy. Median overall survival in patients with RECIST-defined progressive disease given anti-PD-1 antibody was longer in the treatment beyond progression cohort (24·4 months, 95% CI 21·2–26·3) than in the cohort of patients who did not receive treatment beyond progression (11·2 months, 10·1–12·9). 362 (54%) of 669 patients in the no treatment beyond progression cohort had a serious adverse event up to 90 days after treatment discontinuation compared with 295 (43%) of 692 patients in the treatment beyond progression cohort. Immune-related adverse events that occurred up to 90 days from discontinuation were similar between the treatment beyond progression cohort (78 11% of 692 patients) and the no treatment beyond progression cohort (106 16% of 669).
Continuation of treatment beyond progression in the product labelling of these immunotherapies has not been recommended because the clinical benefit remains to be proven. Treatment beyond progression with anti-PD-1 antibody therapy might be appropriate for selected patients with unresectable or metastatic melanoma, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile.
None.
On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva, Astellas Pharma Inc., Northbrook, IL, http://www.us.astellas.com/) for the first‐line treatment of patients with ...metastatic non‐small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. This indication for erlotinib was approved concurrently with the cobas EGFR Mutation Test (Roche Molecular Systems, Inc., Basel, Switzerland, http://www.molecular.roche.com), a companion diagnostic test for patient selection. The approval was based on clinically important improvements in progression‐free survival (PFS) and objective response rate (ORR) and an acceptable toxicity profile demonstrated in a multicenter, open label trial enrolling 174 patients with metastatic NSCLC whose tumors had EGFR mutations as determined by a laboratory‐developed test. Patients were randomized (1:1) to receive erlotinib (150 mg/day) or platinum‐based doublet chemotherapy. The primary endpoint was investigator‐assessed PFS. Secondary endpoints included overall survival (OS) and ORR. Superior PFS (hazard ratio HR 0.34; 95% confidence interval CI: 0.23, 0.49; p < .001) and ORR (65% vs. 16%) were observed in the erlotinib arm. Median PFS was 10.4 months and 5.2 months in the erlotinib and chemotherapy arms, respectively. There was no difference in OS (HR 0.93; 95% CI: 0.64, 1.35) with median OS of 22.9 months and 19.5 months in the erlotinib and chemotherapy arms, respectively. The most frequent (≥30%) adverse reactions in the erlotinib‐treated patients were rash, diarrhea, asthenia, cough, dyspnea, and decreased appetite. The most frequent (≥5%) grade 3 and 4 adverse reactions were rash and diarrhea.
仅摘要 摘要
2013 年 5 月 14 日，美国食品药品监督管理局批准将厄洛替尼（特罗凯，安斯泰来制药公司，伊利诺伊州诺斯布鲁克市，http://www.us.astellas.com/）作为一线药物用于治疗表皮生长因子受体 (EGFR) 外显子 19 缺失或外显子 21 (L858R)替换突变的转移性非小细胞肺癌 (NSCLC) 患者。在厄洛替尼获准用于这一适应症的同时，与厄洛替尼伴随使用的诊断性患者筛查试剂盒——cobas EGFR 突变检测试剂盒（罗氏分子系统公司，瑞士巴塞尔，http://www.molecular.roche.com）——也获得了批准。FDA 的这一批准基于一项多中心、开放标签研究的结果。这项研究共纳入了 174 名被实验室开发的试剂盒判定为存在 EGFR 突变的 NSCLC 患者，其结果表明，厄洛替尼可显著提高患者的无进展生存期 (PFS) 和客观缓解率 (ORR)，且毒性谱处在容许范围之内。研究中，患者被随机分入两组 (1:1)，分别接受厄洛替尼（150 mg/天）或含铂两药化疗。研究的主要终点为研究者评定的 PFS。次要终点包括总生存期 (OS) 和 ORR。厄洛替尼组的 PFS 风险比（HR）：0.34；95% 置信区间（CI）：0.23，0.49；p < 0.001和 ORR（两组分别为 65% vs. 16%）均优于化疗组。厄洛替尼组和化疗组的中位 PFS 分别为 10.4 和 5.2 个月。两组的 OS 并不存在显著差异 (HR 0.93; 95% CI: 0.64, 1.35)，其中厄洛替尼组的中位 OS 为 22.9 个月，化疗组为 19.5 个月。厄洛替尼组患者的最常见 (≥30%) 不良反应为皮疹、腹泻、虚弱、咳嗽、呼吸困难和食欲下降。最常见 (≥5%) 的 3 和 4 级不良反应为皮疹和腹泻。The Oncologist 2014;19:774–779
Erlotinib was approved for the first‐line treatment of patients with metastatic non‐small cell lung cancer whose tumors have epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. The approval was based on demonstration of clinically important improvements in progression‐free survival and objective response rate and an acceptable toxicity profile in a multicenter, open label trial comparing erlotinib with platinum‐based doublet chemotherapy.
In January 2017, the U.S. Food and Drug Administration (FDA) formally established the Oncology Center of Excellence (OCE) to streamline the development of cancer therapies by uniting experts from FDA ...product centers to conduct expedited review of drugs, biologics, and devices. In May 2017, the FDA approved a cancer treatment based on a biomarker, without regard to the tumor’s site, by granting accelerated approval to pembrolizumab for patients with solid tumors that have the microsatellite instability-high or mismatch repair deficient biomarker. We describe here the OCE’s role in this first site-agnostic approval and OCE programs for further advancement of oncology-related regulatory science and policy. In addition, the FDA’s four expedited review programs that enable transformative therapies to reach patients with life-threatening malignancies earlier in the development process are key to the continued rapid development of safe and effective therapies for patients with few or no other treatment options. These changes at FDA are taking place in the context of recent progress in the understanding of the genetic and immunologic foundations of cancer, resulting in the development of targeted therapies and immunotherapies. The traditional system of phased clinical trials has evolved as early trials of breakthrough therapies use expansion cohorts in a process known as seamless drug development. Increasingly, FDA approvals of targeted therapies are likely to have contemporaneous approvals of companion diagnostics to identify patients whose cancers harbor actionable abnormalities.
Impact statement
This publication describes the U.S. Food and Drug Administration’s (FDA) first site-agnostic oncology drug approval, a landmark event in the history of cancer drug development. The role of the FDA’s newly established Oncology Center of Excellence (OCE) in this approval is described, as are several OCE programs to advance excellence in regulatory science in the era of precision medicine. Also provided is an overview of FDA’s expedited drug review programs, which are important to the continued acceleration of therapeutics development for patients with life-threatening diseases and few or no other treatment options.
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