Positive Phase 2 Study Results Reported for Brigatinib in NSCLC Patients

Positive Phase 2 Study Results Reported for Brigatinib in NSCLC Patients

Ariad Pharmaceuticals reported clinical results from its pivotal ALTA Phase 2 trial that evaluated the safety and effectiveness of brigatinib in ALK-positive non-small cell lung cancer (NSCLC) patients whose disease progressed while being treated with Xalkori (crizotinib).

The ALTA trial (NCT02094573) evaluated dosing regimens of brigatinib, an investigational anaplastic lymphoma kinase (ALK) inhibitor, in 222 patients with ALK-positive NSCLC.

Patients were randomly assigned to either 90 mg of brigatinib once daily (cohort A), or 90 mg a day for seven days followed by 180 mg in a 28-day cycle (cohort B). The study also classified patients according to the presence of brain metastasis at the start of the study, and their response to their earlier Xalkori treatment.

The study’s primary endpoint was the investigator-assessed confirmed objective response rate (IA-ORR). Secondary endpoints were safety and tolerability, progression-free survival (PFS), confirmed ORR assessed by an independent review committee (IRC-ORR), overall survival (OS), central nervous system (CNS) response, and duration of response.

From an analysis conducted in May of the patients on the 180-mg regimen (cohort B) with a median follow-up of 11 months, 55% achieved confirmed objective response. These patients also had a median PFS of 15.6 months after Xalkori treatment.

Also, 67% of patients in cohort B with measurable brain metastases achieved a confirmed intracranial objective response, with an intracranial PFS of 18.4 months.

These findings were presented at the 17th World Conference on Lung Cancer (WCLC) Dec. 4-7 in Vienna, Austria.

“These updated ALTA trial data show that with additional follow-up, median progression-free survival from brigatinib given post-crizotinib is now 15.6 months, and that this is the same whether assessed by the investigators or an independent review committee,” D. Ross Camidge, MD, PhD, director of thoracic oncology at the University of Colorado, said in a press release.

“Whether this is a reflection of broader suppression of potential resistance mutations, or its effects on protecting the central nervous system, or both, requires further investigation, but by itself these progression-free survival data should be very encouraging for physicians and patients alike,” he said.

Camidge said the data supports pursuing brigatinib both post-Xalkori and in the ongoing ALTA 1L study, “which aims to assess its potential in the ALK treatment-naive setting.”

About 8% of NSCLC patients have rearrangements in the ALK gene, which is known to be involved in the development of this cancer. Two ALK inhibitors are currently FDA-approved to treat ALK-positive NSCLC: Xalkori and Zykadia (ceritinib). Brigatinib has emerged as a potential treatment for patients who are resistant to other ALK inhibitors.

Ariad is now conducting a randomized, open-label Phase 3 ALTA-1L clinical trial (NCT02737501), evaluating the safety and effectiveness of brigatinib versus Xalkori in patients with advanced NSCLC. The study is currently recruiting participants.

The U.S. FDA has accepted Ariad’s New Drug application for brigatinib, and has granted the drug Priority Review status, setting an action date of April 29, 2017.

Here is other data from the ALTA trial:

  • The average follow-up was 11 months for patients in cohort B and of 10.2 months for patients in cohort A.
  • Investigator assessed (IA)-confirmed ORR in cohort B was 55%, while the IRC-assessed confirmed ORR in this group was 54%. IA-confirmed ORR in cohort A was 45%, while the IRC-assessed confirmed ORR was 49%.
  • There was no difference in confirmed ORR based on previous chemotherapy compared to no previous chemotherapy, as per a subgroup analysis of confirmed ORR performed at study entry. Results from this analysis indicated that patients who had reached partial or complete responses on previous Xalkori treatment had a significantly greater confirmed ORR compared with patients who did not achieve these responses.
  • In cohort B, the probability of OS at one year was 82%, while in cohort A, this probability was of 71%. Median OS had not been reached in either cohort.
  • Of the 44 evaluable patients with measurable brain metastasis, treatment with brigatinib was associated with an intracranial ORR of 67% of patients in cohort B and 46% in cohort A, while the median intracranial PFS was 18.4 months and 15.6 months, respectively.
  • The most common adverse events considered related to the treatment were nausea, diarrhea, cough, headache, increased blood creatine phosphokinase, hypertension , pneumonia, and increased lipase.

“These data are intended to be submitted to the European Medicines Agency in early 2017 for marketing approval. Pending regulatory review, we expect that brigatinib may become an important therapeutic option for the crizotinib-resistant population,” said Timothy P. Clackson, PhD, president of research and development and chief scientific officer at ARIAD.

 

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