Larotrectinib Among 20 New Drugs Granted Clinical Trial Implicit Approval in China

Recently, the Center for Drug Evaluation (CDE) of the National Medical Products Administration announced another batch of drugs granted implied approval for clinical trials. According to the list, a total of 20 drugs received implied approval for clinical trials, all of which are from Hengrui Pharma.Pharmaceuticals, Baxter Healthcare, Bristol-Myers Squibb, Pfizer, Bayer, and other pharmaceutical companies.

Notably, Bayer’s “broad-spectrum anticancer drug” Larotrectinib was also included in this list. Developed jointly by Loxo Oncology and Bayer, Larotrectinib is a next-generation, highly specific oral TRK inhibitor. It is also a broad-spectrum oncology drug that, from the early stages of development, has targeted specific genetic mutations rather than specific cancer types. It is indicated for all patients with tumors expressing tropomyosin receptor kinase (TRK), regardless of the tumor’s anatomical location.

On November 26, 2018, the FDA granted accelerated approval for the marketing of Larotrectinib for the treatment of adult and pediatric patients with solid tumors harboring NTRK gene fusions, who have no known resistance mutations, present with widely metastatic disease or locally advanced disease where surgical resection is not feasible, and have experienced disease progression on existing therapies or have no satisfactory alternative treatment options. (NTRK gene fusions are chromosomal alterations that result in the production of constitutively activated abnormal TRK fusion proteins, which act as tumor drivers and promote tumor cell proliferation and survival in tumor cell lines.)

In previous clinical trials conducted abroad, larotrectinib demonstrated clinical benefits across a variety of distinct tumor types, including lung cancer, thyroid cancer, melanoma, gastrointestinal stromal tumors (GIST), colorectal cancer, soft tissue sarcoma, salivary gland tumors, and infantile fibrosarcoma. Upon its initial approval for market launch, larotrectinib was even hailed in media reports as a “miracle drug capable of curing many cancers.”

In a previous in-depth article on larotrectinib published by Arterial Network, industry experts stated that larotrectinib cannot achieve a cure for cancer; the current treatment goal is to prolong patients' overall survival. The term "response" can be understood as tumor cells reacting to the medication being administered.

First, larotrectinib is indeed applicable to a variety of solid tumors; however, as a targeted therapy, it is effective only when specific gene fusions—namely, NTRK gene fusions—are detected. According to Josh Bilenker, CEO of Loxo Oncology, in an interview with The Washington Post, NTRK fusions occur in less than 1% of most solid tumor types but are common in certain malignancies, such as adult salivary gland cancers and infantile fibrosarcoma. In the United States, it is estimated that only 2,000 to 3,000 people are diagnosed with NTRK-related cancers each year.

Secondly, regarding the "cure rate," the correct term should be response rate. Clinical trial data supporting the approval of larotrectinib showed that in a trial with a sample size of 55 patients, the overall response rate (ORR) was 75% (95% CI, 61%-85%) [22% complete response (CR) and 53% partial response (PR)] across various types of solid tumors in adults and children.

Regarding pricing, Bayer’s official list price for a 30-day supply of adult capsules is $32,800 at wholesale acquisition cost. The cost for the pediatric oral solution will be based on the patient’s body surface area, with a starting monthly price of $11,000.

However, it is currently expected that most insurance companies will set the out-of-pocket costs for drugs and patients at $20 or less per month. Bayer stated that it will provide payment assistance to patients in need, and if the drug does not provide clinical benefits within the first three months, they will refund the drug costs to payers and patients.

As with many drugs, long-term use of larotrectinib can lead to drug resistance. Currently, Bayer and Loxo are developing second-generation drugs targeting new mutations.

It is also worth noting that in addition to larotrectinib, BLU-667 capsules, jointly submitted by CStone Pharmaceuticals and its partners, have also received implied clinical trial approval. This drug was previously granted Breakthrough Therapy Designation by the U.S. FDA for the treatment of RET-mutant medullary thyroid cancer (MTC) in patients requiring systemic therapy who have no alternative treatment options.

On November 5, 2018, the Center for Drug Evaluation (CDE) officially announced that the approval system for new drug clinical trials had been reformed to an implied permission system.

In recent years, accelerating reforms in clinical trial management and adjusting and optimizing the review and approval procedures for drug clinical trials have become one of the key priorities in the reform of the drug review and approval system. In July this year, the National Medical Products Administration issued the "Announcement on Adjusting the Review and Approval Procedures for Drug Clinical Trials (No. 50 of 2018)," which has made adjustments to the review and approval of drug clinical trials: For those applying for drug clinical trials in China, if the applicant does not receive any negative or questioning opinions from the Center for Drug Evaluation (CDE) within 60 days from the date of application acceptance and payment, they may proceed with the drug clinical trial according to the submitted protocol.

From the perspective of industry insiders, the shift from an approval-based system to a default-approval mechanism signifies new progress in the reform of clinical trial management in China. This change will also break the existing bottlenecks that have slowed down drug clinical trials, effectively accelerating the clinical trial process and enabling domestic patients to access global innovative and high-quality medicines more rapidly.

Since the CDE published the first list of drugs subject to the implied approval system, a total of 448 drug products have obtained clinical trial approval through implied licensure for clinical registration.

Appendix: List of Drugs Granted Default Approval for Clinical Trials