Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer (NSCLC)

Reporter: J. Nicholas Lukens, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2010

Presenter: Y. Bang, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.


  • Efficacy of conventional chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC) appeared to reach a plateau in the mid-1990s, at the same time that targeted therapeutics began to enter clinical trials.
  • Early trials with targeted therapeutics were initially disappointing, until subset analysis revealed a subset of patients with EGFR mutations who were responsive to tyrosine kinase inhibitors (TKIs) (Lynch, NEJM 2004).
  • EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs. (Shaw JCO 2009)
    • EML4-ALK fusion oncogenes have been reported in approximately 4% of patients with NSCLC;
    • These are mutually exclusive with activating EGFR and KRAS mutations, and represent a potential target for novel therapeutics.
  • PF-02341066 (PF-1066, or crizotinib) is a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases.
    • This compound leads to cell growth inhibition and apoptosis in ALK+ cell lines in vitro.
  • This is the first in-patient monotherapy trial of crizotinib. It established an appropriate dose, and then began recruiting patients with NSCLC harboring the ALK fusion.
  • The present study reports initial data from this expanded cohort at the recommended phase II dose.


  • Patients with ALK fusion + NSCLC, as determined by FISH analysis, were enrolled into the expanded cohort at the Phase II dose level of 250 mg BID.
  • Patients were enrolled irrespective of prior therapy:
    • Treated brain metastases were allowed.
  • Responses were determined using radiographic studies every 8 weeks, as determined by RECIST criteria.
  • Endpoints:
    • Disease control rate (DCR): the frequency of patients with evidence of complete response (CR), partial response (PR) and stable disease at 8 weeks.
    • Additional endpoints were objective response rate (CR+PR), progression-free survival (PFS), and toxicity.


  • 82 ALK+ NSCLC patients have been enrolled to date, 76 have been treated, and 50 patients are evaluable for response.
  • Patient characteristics:
    • The median number of prior treatments for NSCLC was 3 (range, 0-7).
    • Most patients (96%) had adenocarcinoma and were never smokers (76%) or former smokers.
    • The mean age was 51.
  • Pharmacokinetics:
    • Dosed at 250 mg BID, the steady state plasma concentration was above the predicted efficacious concentration from preclinical models (120 ng/mL).
    • The median t1/2 was ~53 hours.
  • The median duration of time that patients remained on the study drug was 6 months.
  • Endpoints:
    • Disease control rate (DCR) was 87%
    • Objective response rate (ORR = PR and CR) was 57%;
      • This did not appear to vary by the number of prior treatment regimens received.
      • Radiologic responses typically were observed at the first or second restaging CT scan.
  • The median progression-free survival is not yet mature; however,
    • The progression-free survival (PFS) at 6 months is 72%.
  • Toxicity:
    • Gastrointestinal toxicities, including mild (Grade 1) nausea (55%) and vomiting (39%), were the most frequent adverse events.
    • One interesting side effect observed in several patients was a change in their ability to visually accommodate between light and dark.

Author’s Conclusions

  • The oral ALK inhibitor, PF-1066, demonstrated a high response rate in patients who tested positive for the ALK fusion, and was associated with a good safety profile.
    • The observed response rates were especially impressive in light of the heavily pre-treated population of NSCLC patients who were enrolled.
  • A phase III study has been initiated and is currently enrolling (PROFILE 1007), with the following inclusion criteria:
    • NSCLC patients who test positive for the ALK fusion gene, and have had progression of disease after one platinum-based chemotherapy regimen.
    • PF-1066 will be compared to pemetrexed or docetaxel.
  • The rapid clinical development of this compound from target identification to clinical validation supports the concept of molecular selection of NSCLC patients for appropriately designed treatment.

Clinical Implications

  • The excellent radiographic response rates observed in this subset of ALK-positive patients is very impressive, especially in light of how heavily pre-treated these patients were.
  • While ALK-positive patients represent only 4% of NSCLC patients, given the high prevalence of NSCLC, this correlates to approximately 40,000 patients worldwide per year who may benefit from this drug.
  • This study supports routine genetic testing of NSCLC patients to guide therapy;
    • Algorithms are being developed to test for the following mutations: KRAS® EGFR® ALK ® additional mutations.
  • A Phase III study is underway to determine if the impressive response rates observed in this trial are durable over time, and if this translates into a survival benefit.
    • Given the poor prognosis of ALK+ patients treated with conventional cisplatin-based chemotherapy, the excellent response rates in this trial raise the question of whether a Phase III trial is necessary or ethical.
  • Future directions include:
    • The need to determine the optimal clinical setting for this compound: as first line monotherapy, as first line therapy in combination with chemotherapy, or upon relapse only?
    • The need to discover additional biomarkers in adenocarcinoma (besides EGFR, KRAS and ALK) to guide future drug development for the 50% of patients with adenocarcinoma who do not harbor one of these mutations.
  • In summary, this study represents a very exciting development in the treatment of a subset of patients with NSCLC, and is a promising proof of principle study in the development of targeted therapeutics for NSCLC, a disease in which progress is difficult to achieve.