Date: 2017-02-16
Type of information: Granting of a Market Authorisation in the EU
Product name: Alecensa®
Compound: alectinib hydrochloride
Therapeutic area: Cancer - Oncology
Action mechanism: kinase inhibitor/tyrosine kinase inhibitor/ALK inhibitor. Alecensa® (alectinib hydrochloride) is an oral ALK inhibitor created by Chugai Kamakura Research Laboratories. It has been reported that ALK fusion genes are expressed in two to five percent of the patients with NSCLC. It is considered that the ALK kinase activity is constantly increased in the cells with this fusion gene, and transforms the cells into tumor cells. Alectinib hydrochloride demonstrates its anti-tumor effect by selectively inhibiting the kinase activity, and inhibiting the proliferation of tumor cells and inducing apoptosis. The rights to Alecensa® in overseas countries including Europe and the US were out-licensed to Roche in 2012, and clinical trials of Alecensa® (Roche Development Code: RG7853) are currently ongoing in the US, Europe and other countries.
ALK-positive NSCLC occurs in approximately five percent of people with advanced NSCLC, translating to about 75,000 people globally being diagnosed with the disease per year. ALK-positive disease is more common in light or non-smokers.
Company: Chugai (Japan) Roche (Switzerland) Genentech (USA - CA)
Disease: ALK fusion gene positive non-small cell lung cancer (NSCLC)
Latest news:
- • On February 16, 2017, the European Commission has approved Alecensa® (alectinib) for the treatment of of adult patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) whose disease has progressed following treatment with crizotinib.
- • On December 15, 2016, the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for the use of Alecensa® (alectinib) for the treatment of adult patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) whose disease has progressed following treatment with crizotinib. The EMA’s recommendation is based primarily on data from the pivotal studies NP28673 and NP28761. The studies showed that Alecensa® shrank tumours in people with advanced ALK-positive NSCLC whose disease had progressed following treatment with crizotinib, overall response rate; ORR: 50.8 percent, (95% CI: 41.6%, 59.9%) and 52.2 percent (95% CI 39.7%, 64.6%) in NP28673 and NP28761, respectively. Alecensa extended the time that people lived without their disease worsening or death (progression-free survival, PFS) by 8.9 months, [5.6, 12.8] in the NP28673 study and 8.2 months, [6.3, 12.6] in the NP28761 study. In a pooled analysis of Central Nervous System (CNS) endpoints from studies NP28673 and NP28761 Alecensa shrank CNS tumours that were measurable in 64.0 percent of people [95% CI: 49.2%, 77.1%]. In addition, the people whose CNS tumours shrank in response to Alecensa continued to respond for a median of 11.1 months, CNS duration of response (DOR) [95% CI: 7.6, NE]. Twenty two percent (n=11) of people achieved a complete response of their measurable CNS tumours.
- • On October 4, 2016, Chugai Pharmaceutical announced that the FDA has granted Breakthrough Therapy Designation for the first-line treatment of ALK positive non-small cell lung cancer (NSCLC) to Alecensa®, a highly selective ALK inhibitor created by Chugai. Alecensa® is approved in Japan and in the United States, and filed in Europe by Roche.
- This designation is based on the J-ALEX study, conducted by Chugai, which is an open-label, randomized phase III study that compares the efficacy and safety between Alecensa and crizotinib. The J-ALEX study enrolled 207 ALK-inhibitor naïve patients with ALK fusion gene positive advanced or recurrent NSCLC, who had not undergone chemotherapy or had undergone one chemotherapy regimen. The subjects were allocated to either the Alecensa arm or the crizotinib arm in a one to one ratio. The primary endpoint of the J-ALEX study was progression free survival (PFS) as assessed by a blinded independent review board. The secondary endpoints included overall survival, objective response rate and safety. In February 2016, an independent data monitoring committee recommended to discontinue the J-ALEX study early for benefit based on the results of the predetermined interim analysis which was examined by the committee.
- The PFS hazard ratio of the Alecensa arm to the crizotinib arm was 0.34, and Alecensa demonstrated significantly prolonged PFS (99.6826% CI: 0.17-0.70, stratified log-rank p<0.0001). Median PFS was not reached (95% CI: 20.3-Not reached) in the Alecensa arm while it was 10.2 months (95%CI: 8.2-12.0) in the crizotinib arm. In the Alecensa arm, constipation was an adverse event (AE) with >30% frequency, while in the crizotinib arm nausea, diarrhea, vomiting, visual disturbance, dysgeusia, constipation, ALT elevation and AST elevation were observed in >30% patients. Grade 3-4 AEs occurred in 27% of the Alecensa arm and in 51% of the crizotinib arm, with no treatment-related deaths in both arms.
- • On December 11, 2015, the FDA approved Alecensa® (alectinib) to treat people with advanced (metastatic) ALK-positive non-small cell lung cancer (NSCLC) whose disease has worsened after, or who could not tolerate treatment with, another therapy called Xalkori® (crizotinib). The safety and efficacy of Alecensa® were studied in two single-arm clinical trials of patients with metastatic ALK-positive NSCLC whose disease was no longer controlled by treatment with Xalkori®. Study participants received Alecensa® twice daily to measure the drug’s effect on their lung cancer tumors. In the first study, 38 percent of participants experienced a partial shrinkage of their NSCLC tumors, an effect that lasted for an average of 7.5 months. In the second study, 44 percent of participants experienced a partial shrinkage of their NSCLC tumors, lasting for an average of 11.2 months. The trials also examined Alecensa®’s effect on individuals’ brain metastases, a common occurrence in this population. Sixty-one percent of participants in the two trials who had measurable brain metastases experienced a complete or partial reduction in their brain tumors, lasting an average of 9.1 months. The most common side effects of Alecensa® are fatigue, constipation, swelling (edema) and muscle pain (myalgia). Alecensa® may cause serious side effects, including liver problems, severe or life-threatening inflammation of the lungs, very slow heartbeats and severe muscle problems. Treatment with Alecensa® may cause sunburn when patients are exposed to sunlight.
- Alecensa® was approved using the accelerated approval regulatory pathway, which allows the FDA to approve products for serious or life-threatening diseases based on evidence that the product has an effect on an outcome that is reasonably likely to predict clinical benefit. In the case of Alecensa®, the tumor response to treatment, along with the duration of response, provided this evidence. Under the accelerated approval requirements, a confirmatory study is required to verify and describe the clinical benefit of Alecensa. Alecensa® will be available to people in the United States within two weeks.
- • On January 27, 2015, the FDA has granted orphan drug designation for alectinib for the treatment of ALK-positive non-small cell lung cancer. In the US, the sponsor is Genentech.
- • On September 5, 2014, Chugai Pharmaceutical announced that it has launched the ALK inhibitor Alecensa® capsule 20mg and 40mg” (alectinib hydrochloride) for the indication of “ALK fusion gene positive unresectable, recurrent / advanced non-small cell lung cancer” on September 5. Alecensa® received a manufacturing and marketing approval on July 4, 2014 and was listed on the National Health Insurance (NHI) reimbursement price list on September 2, 2014. It has been reported that in 2 to 5 percent of patients with non-small cell lung cancer, a chromosomal rearrangement results in fusion of the ALK gene with another gene. ALK kinase signaling is constantly active in cells with such fusion genes, resulting in uncontrolled growth and transforming the cells into tumor cells. Alecensa® exerts its anti-tumor effect by selectively inhibiting ALK kinase activity, resulting in inhibition of tumor cell proliferation and induction of cell death.
- • On July 4, 2014, Roche and Chugai announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved alectinib for the treatment of people living with non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase fusion gene-positive (ALK+). The approval was based on results from a Japanese Phase I/II clinical study (AF-001JP) for people whose tumours were advanced, recurrent or could not be removed completely through surgery (unresectable).This trial was conducted in 13 medical institutions in ALK fusion gene positive recurrent or advanced non-small cell lung cancer patients with a treatment history of one or more chemotherapy regimens. The trial consisted of two phases: Phase I that evaluated safety, tolerability, pharmacokinetic parameters and recommended dose (24 patients), and a Phase II part that evaluated the efficacy and safety of the recommended dose (46 patients). The primary endpoint was response rate.
- The Phase I part of the study determined a recommended dose of 300 mg twice daily. No dose limiting toxicity was observed.
- The Phase II portion of the study was conducted using the recommended dose, and demonstrated a response rate of 93.5% (43/46 patients; 95%CI: 82.1-98.6%).
- - 14 patients entered the study with Central Nervous System (CNS) metastases
- - 9 of the 14 patients remained in the study without CNS or systemic progression for more than 12 months
- Progression Free Survival (PFS) at 12 months was measured as 83% (95% CI: 68-92%)
- There were no treatment-related deaths and/or grade 4 or higher serious adverse reactions assessed according to CTCAE (Common Terminology Criteria for Adverse Events) defined by the Japan Clinical Oncology Group. The most frequently observed grade 3 or higher adverse reaction was neutropenia, and the incidence of the adverse event was 4 out of 58 patients (6.9%) who were treated with 300 mg twice daily, the approved dose.
- Alectinib is expected to be made available in Japan later this year. Alectinib was also granted Breakthrough Therapy Designation (BTD) by the FDA in June 2013 for patients with ALK+ NSCLC who progressed on crizotinib.
- • On October 8, 2013, Chugai Pharmaceutical, a member of Roche group, has announced that it has filed a new drug application to the Ministry of Health, Labour and Welfare (MHLW) on October 7, 2013, for ALK (Anaplastic Lymphoma Kinase) inhibitor alectinib hydrochloride for the treatment of ALK fusion gene positive non-small cell lung cancer (NSCLC). On September 13, 2013, alectinib hydrochloride for the treatment of “ALK fusion gene positive unresectable, recurrent / advanced non-small cell lung cancer” was designated as orphan drug by MHLW.
- • On September 23, 2013, Roche has announced that the FDA has granted breakthrough therapy designation for Roche’s alectinib based on data that will be presented at the European Cancer Congress (ECC) in Amsterdam between September 27 to October 1, 2013. At ECC, encouraging efficacy and safety data in patients with metastatic NSCLC that has progressed on crizotinib will be presented for alectinib, a promising investigational 2nd generation ALK inhibitor, in a late breaking report.
Patents:
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2015-12-11
UE authorization: 2017-02-16
Favourable opinion UE: 2016-12-15
Favourable opinion USA:
Orphan status USA: 2015-01-27
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
OTC status:
Other news:
Is general: Yes
