AMG 510 approved

FDA批准Lumakras (sotorasib) 成为首个用于携带KRAS G12C突变的、接受过至少一次系统治疗的NSCLC，也是首个批准用于KRAS突变肿瘤的靶向治疗，KRAS突变占了NSCLC的25%，其中KRAS G12C约12%

获批基于一项纳入124例经免疫治疗and/or含铂化疗后进展的NSCLC例患者的研究，主要终点ORR 36%，其中58%的患者持续缓解≥6mo，获批的960mg QD剂量基于现有的临床数据，同样也被PK/PD模型支持，作为加速审批的一部分，监管机构要求上市后临床研究探索低剂量是否也有类似的临床效果——4-28更新时提到  接受FDA的建议，在上市后开展一项比较960mg QD和每日低剂量的多中心随机对照研究，基于临床前、PK及临床数据，计划比较960mg QD 和 240mg QD，这项研究将在22年晚些时候开始不会影响LUMAKRAS™ (sotorasib) 的优先审评

好快，之前提到治疗KRAS pG12Cm NACLC的PDUFA Date是8月16日，

R&D 更新

CodeBreak 100

81%的患者在含铂化疗和免疫治疗后进展

ORR 37.1% ，DCR  80.6%

缓解深度相比ESMO20已经提升不少，也出现了3例CR

DoR 10.0mo，TTR 1.4mo，至数据截止日期获得缓解的患者中仍有43%(20/46)持续缓解

PFS  6.8mo

安全性比较好：TRAE大部分都是G人1-2，无致死的TRAE，分别7.1%和22.2%的患者因TRAE引起治疗终止或剂量调整

探索性的biomarker分析，有的样本量太小，结论不好得

SILVER SPRING, Md., May 28, 2021 /PRNewswire/ -- Today, the U.S. Food and Drug Administration approved Lumakras (sotorasib) as the first treatment for adult patients with non-small cell lung cancer whose tumors have a specific type of genetic mutation called KRAS G12C and who have received at least one prior systemic therapy. This is the first approved targeted therapy for tumors with any KRAS mutation, which accounts for approximately 25% of mutations in non-small cell lung cancers. KRAS G12C mutations represent about 13% of mutations in non-small cell lung cancers.

"KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer," said Richard Pazdur, M.D., director of the FDA's Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research. "Today's approval represents a significant step towards a future where more patients will have a personalized treatment approach."

Lung cancer, the most common cancer type with the highest mortality, can largely be categorized by the genetic mutations that cause it. KRAS is a type of mutation in a group of genes that help regulate cell growth and division.

Researchers evaluated the efficacy of Lumakras in a study of 124 patients with locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy. The major outcomes measured were objective response rate (proportion of patients whose tumor is destroyed or reduced) and duration of response. The objective response rate was 36% and 58% of those patients had a duration of response of six months or longer.

The approved 960 milligram dose is based on available clinical data, as well as pharmacokinetic and pharmacodynamic modeling that support the approved dose. As part of the evaluation for this accelerated approval, the agency is requiring a postmarketing trial to investigate whether a lower dose will have a similar clinical effect.

The most common side effects of Lumakras include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough. Lumakras should be withheld if patients develop symptoms of interstitial lung disease and permanently discontinued if interstitial lung disease is confirmed. Health care professionals should monitor a patient's liver function tests prior to starting and when taking Lumakras. If a patient develops liver damage, Lumakras should be withheld, dose reduced or permanently discontinued. Patients should avoid taking acid-reducing agents, drugs that induce or are substrates for certain enzymes in the liver and drugs that are substrates of the P-glycoprotein while taking Lumakras.

Lumakras was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study is required to verify and describe anticipated clinical benefits of Lumakras.

The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations.

Lumakras also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada and Medicines and Healthcare products Regulatory Agency (MHRA; United Kingdom). The application reviews are ongoing at the other regulatory agencies.

The FDA granted approval of Lumakras to Amgen Inc.

Along with Lumakras, the FDA also approved the QIAGEN therascreen KRAS RGQ PCR kit (approval granted to QIAGEN GmbH) and the Guardant360 CDx (approval granted to Guardant Health, Inc.) as companion diagnostics for Lumakras today. The QIAGEN GmbH test analyzes tumor tissue and the Guardant Health, Inc. test analyzes plasma specimens to determine if Lumakras is an appropriate treatment for patients. If no mutation is detected in a plasma specimen, the patient's tumor should be tested.