【原】Lorlatinib正式獲批

八卦小和尚 2021-02-19

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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批準(zhǔn)Lorlatinib用于治療：1）接受過crizotinib及至少其他一種ALK抑制劑后進(jìn)展的ALK陽性轉(zhuǎn)移性非小細(xì)胞,；或 2）接受過alectinib或ceritinib作為一線抗ALK治療后進(jìn)展的ALK陽性轉(zhuǎn)移性非小細(xì)胞（所以稱Loratinib為第三代ALK TKI是合理的）。這個(gè)適應(yīng)癥的獲批之前基于緩解率和持續(xù)緩解時(shí)間進(jìn)入了加速審批,。

獲批的依據(jù)基于代號B7461001的研究,，評估治療攜帶ALK+或者ROS1+的進(jìn)展型NSCLC，這個(gè)數(shù)據(jù)先前已經(jīng)披露過,，275名患者,，分為若干隊(duì)列，主要終點(diǎn)ORR和顱內(nèi)ORR(IC-ORR),，當(dāng)時(shí)在17年8月Lorlatinib治療先前經(jīng)1種或多種TKI治療后進(jìn)展的ALK+ mNSCLC就獲得BTD：

1）ALK陽性的先前未接受系統(tǒng)治療：

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

IC-ORR 75% (6/8; 95% CI: 35, 97)；

2）ALK陽性的先前只接受過crizotinib±化療,；

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

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

3）ALK陽性的先前只接受過1種crizotinib以外的ALK TKI±化療,；

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

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

4）ALK陽性的先前接受過≥2種ALK TKI±化療,；

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

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

5）ROS-1陽性的不考慮先前治療情況

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

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

申報(bào)提交的是ALK+NSCLC的數(shù)據(jù)，患者先前接受1種或多種ALK TKI治療,，一共215人,，57%接受過≥1種ALK TKI治療，69%腦轉(zhuǎn)移史：整體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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