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

English

Reporter: J. Nicholas Lukens, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 6 de junio del 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:

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.

Dosed at 250 mg BID, the steady state plasma concentration was above the predicted efficacious concentration from preclinical models (120 ng/mL).
The median t_1/2 was ~53 hours.

The median duration of time that patients remained on the study drug was 6 months.
Endpoints:

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.

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.

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.

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.

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.