Lorlatinib正式获批 / 开普饭

U.S. FDA APPROVES LORBRENA® (LORLATINIB) FOR PREVIOUSLY-TREATED ALK-POSITIVE METASTATIC NSCLC

November 02, 2018

LORBRENA Addresses Unmet Needs for Certain Patients Treated With Prior ALK Therapy

11月2日FDA批准Lorlatinib用于治疗：1）接受过crizotinib及至少其他一种ALK抑制剂后进展的ALK阳性转移性非小细胞；或 2）接受过alectinib或ceritinib作为一线抗ALK治疗后进展的ALK阳性转移性非小细胞（所以称Loratinib为第三代ALK TKI是合理的）。这个适应症的获批之前基于缓解率和持续缓解时间进入了加速审批。

获批的依据基于代号B7461001的研究，评估治疗携带ALK+或者ROS1+的进展型NSCLC，这个数据先前已经披露过，275名患者，分为若干队列，主要终点ORR和颅内ORR(IC-ORR)，当时在17年8月Lorlatinib治疗先前经1种或多种TKI治疗后进展的ALK+ mNSCLC就获得BTD：

1）ALK阳性的先前未接受系统治疗：

ORR 90% (27/30; 95% CI: 74, 98) ;

IC-ORR 75% (6/8; 95% CI: 35, 97)；

2）ALK阳性的先前只接受过crizotinib±化疗；

ORR 69% (41/59; 95% CI: 56, 81)

IC-ORR 68%(25/37; 95% CI: 50, 82)

3）ALK阳性的先前只接受过1种crizotinib以外的ALK TKI±化疗；

ORR 33% (9/27; 95% CI: 16, 54)

IC-ORR 42% (5/12; 95% CI: 15, 72)

4）ALK阳性的先前接受过≥2种ALK TKI±化疗；

ORR 39% (43/111; 95% CI: 30, 49)

IC-ORR 48% (40/83; 95% CI: 37, 59)

5）ROS-1阳性的不考虑先前治疗情况

ORR 36% (17/47; 95% CI: 23, 52)

IC-ORR 56% (14/25; 95% CI: 35, 76)

申报提交的是ALK+NSCLC的数据，患者先前接受1种或多种ALK TKI治疗，一共215人，57%接受过≥1种ALK TKI治疗，69%脑转移史：整体ORR 48%，IC-ORR 60%，其它略

The approval was based on a non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter Phase 1/2 study, B7461001, evaluating LORBRENA for the treatment of patients with ALK-positive metastatic NSCLC, who were previously treated with one or more ALK TKIs. A total of 215 patients with ALK-positive metastatic NSCLC were enrolled across various subgroups based on prior treatment. Among these patients, overall response rate (ORR) was 48 percent (95% CI: 42%, 55%) and importantly, 57 percent had previous treatment with more than one ALK TKI. In the trial, 69 percent of patients had a history of brain metastases and intracranial response rate was 60 percent (95% CI: 49%, 70%).

“Since leading with the first approval of a biomarker-driven treatment for ALK-positive non-small cell lung cancer in 2011, Pfizer scientists and clinicians have remained committed to researching and developing medicines that can further advance the care of these patients,” said Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development. “LORBRENA’s approval is an important milestone for patients, having demonstrated marked activity in a study that included a broad range of individuals with ALK-positive non-small cell lung cancer. This includes patients who were heavily pretreated and facing limited options after receiving first- and second-generation ALK tyrosine kinase inhibitors.”

Among 295 ALK-positive or ROS1-positive metastatic NSCLC patients who received LORBRENA 100 mg once daily in study B7461001, the most common (≥ 20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. The most common (≥20%) laboratory abnormalities were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase. Serious adverse reactions occurred in 32 percent of the 295 patients. The most frequent serious adverse reactions reported were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7 percent of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%). Permanent discontinuation of LORBRENA for adverse reactions occurred in eight percent of patients; approximately 48 percent of patients required dose interruptions and 24 percent required at least one dose reduction. The full prescribing information for LORBRENA can be found here.

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