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LARTRUVO (olaratumab) injection

2016-11-03 07:58:14 来源: 作者: 【大中小】浏览:447次评论:0条

2016年10月20日，美国FDA加快批准了Lartruvo（olaratumab）与多柔比星（doxorubicin）联合治疗某些类型的成人软组织肉瘤（STS），适用人群为不能用放疗或手术治愈的STS患者，但他们可以接受经FDA批准的蒽环类化疗方案。Lartruvo由礼来公司生产上市。
据美国国家癌症研究所（The National Cancer Institute）估计，2016年将约有1.2万例STS新增病例以及近5千例死亡人数。经手术治疗后，针对STS的最常见的方案是接受多柔比星单药治疗或与其他药物联合治疗。STS能在人体内众多组织部位产生病灶，包括肌肉、脂肪、血管、神经、肌腱或关节内衬。
Lartruvo是血小板衍生生长因子（PDGF）受体-α的阻截型抗体。当PDGF受体被相关配体刺激之后，下游信号通路可引起肿瘤生长。于是，Lartruvo通过阻断这些受体来有效减缓或终止肿瘤生长。
在一项涉及133人数、25多种不同亚型的转移性STS患者的随机临床试验中，Lartruvo的安全性和有效性得以评估，其中，患者接受Lartruvo加上多柔比星联合用药或多柔比星单一治疗。
该试验测量了治疗后患者存活的时间长度（总生存率，OS），治疗后肿瘤无增长时间（无进展生存期，PFS）以及肿瘤收缩患者的百分比（总反应率，ORR）。接受多柔比星加上Lartruvo治疗的患者，他们的总生存率有统计学上的显著改善：中位生存期为26.5个月，而单独接受多柔比星的患者为14.7个月。接受Lartruvo+多柔比星的患者的中位无进展生存期为8.2个月，而单独接受多柔比星的患者为4.4个月。接受Lartruvo+多柔比星治疗患者的总反应率为18.2％，单独接受多柔比星的患者的总反应率只有7.5％。
FDA曾授予Lartruvo快速通道地位、突破性疗法认定和优先审查资格，Lartruvo也获得了孤儿药资格认定。目前一项更大的研究正在进行中，进一步探讨Lartruvo在STS多种亚型中的有效性。
“增加Lartruvo到多柔比星治疗方案之中，为这些STS患者的提供了一种新的治疗选择，”FDA药物评价和研究中心血液和肿瘤产品办公室主任兼FDA肿瘤中心代理主任Richard Pazdur博士说道：“在40多年前，多柔比星获FDA批准之后，Lartruvo是FDA批准的首个初治软组织肉瘤的新疗法。”

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LARTRUVO safely and effectively. See full prescribing information for LARTRUVO.
LARTRUVO (olaratumab) injection, for intravenous use
Initial U.S. Approval: 2016

INDICATIONS AND USAGE
LARTRUVO™ is a platelet-derived growth factor receptor alpha (PDGFR-α) blocking antibody indicated, in combination with doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. (1)

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. (14)
DOSAGE AND ADMINISTRATION

Administer LARTRUVO at 15 mg/kg as an intravenous infusion over 60 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. (2.1)
For the first 8 cycles, LARTRUVO is administered with doxorubicin. (2.1)
Premedicate with diphenhydramine and dexamethasone intravenously, prior to LARTRUVO on Day 1 of cycle 1. (2.2)
For intravenous infusion only. Do not administer as an intravenous push or bolus. (2.4)

DOSAGE FORMS AND STRENGTHS

Injection: 500 mg/50 mL (10 mg/mL) solution in a single-dose vial (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS

Infusion-Related Reactions: Monitor for signs and symptoms during and following infusion. Discontinue LARTRUVO for Grade 3 or 4 infusion-related reactions. (2.2, 2.3, 5.1)
Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose. (5.2, 8.1, 8.3)

ADVERSE REACTIONS

The most common (≥20%) adverse reactions of LARTRUVO plus doxorubicin are nausea, fatigue, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache. (6.1)

The most common (≥20%) laboratory abnormalities were lymphopenia, neutropenia, thrombocytopenia, hyperglycemia, elevated aPTT, hypokalemia, and hypophosphatemia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 10/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

2.2 Premedication

2.3 Dosing Modifications

2.4 Preparation and Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Infusion-Related Reactions

5.2 Embryo-Fetal Toxicity

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Immunogenicity

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*: Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

LARTRUVO™ is indicated, in combination with doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery.

This indication is approved under accelerated approval [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dose of LARTRUVO is 15 mg/kg administered as an intravenous infusion over 60 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. For the first 8 cycles, LARTRUVO is administered with doxorubicin, [see Clinical Studies (14)].

Refer to doxorubicin prescribing information for dosing, and dose modifications.

2.2 Premedication

Premedicate with diphenhydramine (25 to 50 mg intravenously) and dexamethasone (10 to 20 mg intravenously) prior to LARTRUVO on Day 1 of cycle 1.

2.3 Dosing Modifications

Infusion-Related Reactions

Permanently discontinue LARTRUVO for Grade 3 or 4 infusion-related reactions [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

Interrupt infusion of LARTRUVO for Grade 1 or 2 infusion-related reactions (IRR). After resolution, resume LARTRUVO infusion at 50% of the initial infusion rate. [see Warnings and Precautions (5.

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