Brigatinib Shows Promise in ALK-Positive NSCLC After Crizotinib Therapy

Excerpt:

“The investigational tyrosine kinase inhibitor (TKI) brigatinib offered good response rates in a pivotal phase II trial of patients with ALK-positive non–small-cell lung cancer (NSCLC) whose disease progressed on crizotinib. The results were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 9007).

“ ‘Most ALK-positive NSCLC patients treated with crizotinib eventually progress, often due to acquired ALK resistance mutations and/or poor CNS drug penetration,’ said Dong-Wan Kim, MD, PhD, of Seoul National University Hospital in South Korea, who presented the study.

“Brigatinib, a next-generation ALK TKI designed to have broad activity against resistant ALK mutants, showed promising clinical activity in a phase I/II study of crizotinib-treated ALK-positive NSCLC patients. The new open-label phase II ALTA study included 222 patients with locally advanced or metastatic NSCLC who had progressive disease on crizotinib. Patients were randomized to two brigatinib treatment regimens: group A (112 patients) received oral brigatinib 90 mg once per day, and group B (110 patients) received the same dose for 7 days followed by 180 mg once per day.”

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Crizotinib Tops Chemo for ALK-Positive NSCLC With Brain Metastases

Excerpt:

“First-line crizotinib therapy offered better intracranial disease control rate (IC-DCR) than chemotherapy in patients with ALK-positive non–small-cell lung cancer (NSCLC) and stable treated brain metastases, according to results of a phase III study.

“Earlier results from the ongoing PROFILE 1014 trial showed that crizotinib offers better progression-free survival (PFS) and response rates compared with pemetrexed-platinum chemotherapy. ‘Although the development of targeted therapies has improved outcomes for selected patient populations with oncogenic driver mutations, brain metastases are frequent and result in significant morbidity and mortality in patients with lung cancer,’ wrote study authors led by Benjamin J. Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in East Melbourne, Australia.”

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FDA Expands Use of Xalkori to Treat Rare Form of Advanced Non-Small Cell Lung Cancer

“The U.S. Food and Drug Administration today approved Xalkori (crizotinib) to treat people with advanced (metastatic) non-small cell lung cancer (NSCLC) whose tumors have an ROS-1 gene alteration. Xalkori is the first and only FDA approved treatment for patients with ROS-1 positive NSCLC.

“Lung cancer is the leading cause of cancer-related deaths in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, according to the National Cancer Institute.  ROS-1 gene alterations, thought to lead to abnormal cells, have been identified in various cancers, including NSCLC. ROS-1 gene alterations are present in approximately 1 percent of patients with NSCLC. The overall patient and disease characteristics of NSCLC with ROS-1 gene alterations appear similar to NSCLC with anaplastic lymphoma kinase (ALK) gene alterations, for which crizotinib use was previously approved. Xalkori was approved to treat certain patients with late-stage NSCLC that expresses an abnormal ALK gene in 2011.”


Alectinib Highly Active in Advanced ALK-Positive NSCLC

“Alectinib showed promising activity in patients with advanced, crizotinib-refractory, ALK-positive non–small cell lung cancer, according to results of a global phase 2 study.

“The regimen also appeared well tolerated.

“In December, the FDA granted accelerated approval to alectinib (Alecensa, Genentech) — an oral, small molecule, ATP-competitive tyrosine kinase inhibitor of ALK — for treatment of patients with metastatic ALK-positive NSCLC who progressed on or are intolerant to crizotinib (Xalkori, Pfizer).”


Personalizing Cancer Therapies May Combat Resistance to Targeted Therapy Drugs

“The use of drugs that target genetic mutations driving the growth of tumors has revolutionized treatment for several serious forms of cancer, but in almost every case, tumors become resistant to the drugs’ therapeutic effects and resume growth, often through the emergence of new mutations, which has spurred the development of more powerful drugs that can overcome resistance mutations. In the Dec. 24 issue of New England Journal of Medicine, Massachusetts General Hospital (MGH) physicians report their study examining the evolution of drug resistance in a lung cancer patient treated with multiple different targeted therapies. When resistance developed to the third targeted therapy, the new mutation actually restored the cancer’s response to the very first targeted therapy drug used to treat the patient.”


FDA Grants Priority Review to Xalkori for New Indication in NSCLC

“The FDA granted priority review to a supplemental new drug application for crizotinib.

“Crizotinib (Xalkori, Pfizer) — a kinase inhibitor — already is approved for treatment of patients with metastatic ALK-positive non–small cell lung cancer.

“The supplemental application requests that the approval be expanded to allow crizotinib to be used for treatment of patients with metastatic ROS1-positive NSCLC. The FDA granted breakthrough therapy designation to crizotinib for this indication in April.

“ROS1 rearrangement occurs in an estimated 1% of NSCLC cases, according to a Pfizer-issued press release.”


Crizotinib Granted FDA Priority Review for ROS1 mNSCLC

“The FDA has granted a priority review for a supplemental new drug application (sNDA) for crizotinib (Xalkori). The application is for an indication in patients with metastatic non–small cell lung cancer (NSCLC), whose tumors are ROS1-positive, according to a press release posted by Pfizer Inc.

” ‘ROS1 is another gene rearrangement. It is like ALK in that it is structurally related, but rarer. ROS1 occurs in about 1% of [NSCLC] patients, but [it has] also been seen in other types of rare cancers,’ said D. Ross Camidge, MD, PhD, director, Thoracic Oncology Clinical Program, University of Colorado Cancer Center, in an interview with Targeted Oncology. He added that crizotinib, originally an ALK inhibitor, may be even more effective as a ROS1 inhibitor. ‘It’s great for that small population of patients.’ “


Prognostic Factors Identified in Patients With ALK‑Rearranged NSCLC and Brain Metastasis

“In a study reported in the Journal of Clinical Oncology, Johung and colleagues identified factors that distinguished survival rates among patients with ALK-rearranged non–small cell lung cancer (NSCLC) and brain metastasis.

“The study included 90 patients from six institutions. Of them, 84 patients had received radiotherapy to the brain, consisting of stereotactic radiosurgery or whole-brain radiotherapy, and 86 patients had received tyrosine kinase inhibitor therapy (crizotinib [Xalkori] in 84 and a second-generation tyrosine kinase inhibitor in 41).”


Pfizer Reports Positive Topline Results from Phase 3 Trial Comparing XALKORI® (crizotinib) to Chemotherapy in Previously Untreated East Asian Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

“Pfizer Inc. announced today that PROFILE 1029, a Phase 3 study of anaplastic lymphoma kinase (ALK) inhibitor XALKORI® (crizotinib), met its primary objective of significantly prolonging progression-free survival (PFS) in previously untreated East Asian patients with ALK-positive advanced non-small cell lung cancer (NSCLC) when compared to a standard chemotherapy doublet. In this study, XALKORI was used as the first systemic therapy for patients with advanced ALK-positive NSCLC, and patients could have received therapy and/or surgery for early stage disease before they were diagnosed with metastatic disease.

“The adverse events observed with XALKORI in the study were generally consistent with findings from previous trials. No unexpected adverse events were observed. Efficacy and safety data from PROFILE 1029 will be submitted for presentation at a future medical meeting.”