Blog
About

28
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Phase 2 prospective analysis of alectinib in ALK-positive, crizotinib-resistant non-small-cell lung cancer

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Background

          Alectinib, a highly selective, central nervous system (CNS)-active anaplastic lymphoma kinase (ALK) inhibitor, demonstrated promising clinical activity in crizotinib-naïve and crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC). This phase 2 study evaluated the safety and efficacy of alectinib in ALK-positive NSCLC patients who progressed on previous crizotinib.

          Methods

          This ongoing North American study (NCT01871805) enrolled patients with stage IIIB/IV ALK-positive NSCLC, who had progressed following crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death or withdrawal. Primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), intracranial ORR and DOR, safety, and patient-reported outcomes. The intent-to-treat population was used for efficacy and safety analyses, with the response evaluable population used for response endpoints.

          Findings

          A total of 87 patients were enrolled in the intent-to-treat population. All patients had received prior crizotinib therapy, and 64 patients (74%) had also received prior chemotherapy. Fifty-two patients (60%) had baseline CNS metastases, of whom 18 (35%) had received no prior brain radiation therapy. At the time of primary analysis (median follow-up 4.8 months), ORR by IRC was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation, fatigue, myalgia and peripheral edema. The most common grade ≥3 AEs were changes in laboratory values, including increased blood creatine phosphokinase (in 8%, n=7), increased alanine aminotransferase (in 6% n=5), and increased aspartate aminotransferase (in 5% n=4).

          Interpretation

          Alectinib demonstrated clinical efficacy and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Alectinib was active in the CNS, as demonstrated by durable responses in the majority of crizotinib-resistant patients with CNS disease. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.

          Related collections

          Most cited references 18

          • Record: found
          • Abstract: found
          • Article: not found

          Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.

          Patients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small-molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those who do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in patients with ALK(+) non-small cell lung cancer (NSCLC). We analyzed tissue obtained from 14 patients with ALK(+) NSCLC showing evidence of radiologic progression while on crizotinib to define mechanisms of intrinsic and acquired resistance to crizotinib. Eleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient showed outgrowth of epidermal growth factor receptor (EGFR) mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient showed the emergence of an ALK gene fusion-negative tumor compared with the baseline sample but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism. Crizotinib resistance in ALK(+) NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Patient-derived models of acquired resistance can identify effective drug combinations for cancer.

            Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.

              Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib.
                Bookmark

                Author and article information

                Journal
                100957246
                27004
                Lancet Oncol
                Lancet Oncol.
                The Lancet. Oncology
                1470-2045
                1474-5488
                12 January 2016
                19 December 2015
                February 2016
                01 February 2017
                : 17
                : 2
                : 234-242
                Affiliations
                [1 ]Massachusetts General Hospital, Boston, MA, USA
                [2 ]Dana-Farber Cancer Institute, Boston, MA, USA
                [3 ]Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA
                [4 ]Memorial Sloan Kettering Cancer Center, New York, NY
                [5 ]Oregon Health and Sciences University, Portland, OR, USA
                [6 ]Swedish Cancer Center, Seattle, WA, USA
                [7 ]University of Colorado, Boulder, CO, USA
                [8 ]University of Pittsburgh Medical Center, Pittsburgh, USA
                [9 ]Moffitt Cancer Center, Tampa, FL, USA
                [10 ]Florida Hospital Cancer Institute, Orlando, USA
                [11 ]Ohio State University, Columbus, OH, USA
                [12 ]Fox Chase Cancer Center, Philadelphia, PA, USA
                [13 ]MD Anderson Cancer Center, Houston, TX, USA
                [14 ]F. Hoffmann-La Roche, Basel, Switzerland
                [15 ]Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange, CA, USA
                Author notes
                Correspondence to: Alice T. Shaw, Massachusetts General Hospital, Boston, MA, USA. Tel: 617-724-4000; ASHAW1@ 123456mgh.harvard.edu
                Article
                NIHMS750484
                10.1016/S1470-2045(15)00488-X
                4752892
                26708155

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.

                Categories
                Article

                Oncology & Radiotherapy

                Comments

                Comment on this article