Second-Generation ALK Inhibitors Show Promise in Early-Stage NSCLC Trials

Oncology & Biotech News, July 2013, Volume 7, Issue 7

Although crizotinib (Xalkori) is highly effective in treating patients with advanced ALK-positive non–small cell lung cancer (NSCLC), most patients develop resistance to the drug.

Alice T. Shaw, MD, PhD


Although crizotinib (Xalkori) is highly effective in treating patients with advanced ALK-positive non—small cell lung cancer (NSCLC), most patients develop resistance to the drug. Several second-generation ALK-inhibitors are being developed for patients with crizotinib- resistant disease. Promising early-stage research on two of these drugs, LDK378 and AP26113, was highlighted at the 2013 ASCO Annual Meeting.LDK378 is an oral, highly potent, and selective small-molecule, second-generation ALK tyrosine kinase inhibitor (TKI). A phase I study presented at ASCO 2013 identified the maximum-tolerated dose (MTD) of the drug, and showed high response rates in both crizotinib-naïve and crizotinib-resistant patients with advanced NSCLC.1 A molecular analysis in crizotinib-resistant patients also showed that tumor responses were not dependent on developing a secondary ALK mutation or amplification.

“LDK induces responses in the majority of crizotinib- resistant patients, not just the one-third who have acquired a new ALK mutation or amplification. This suggests that the majority of crizotinib-resistant patients remain ALK dependent, and that an important factor contributing to crizotinib resistance may be subtherapeutic inhibition of the target—perhaps due to pharmacokinetic or pharmacodynamic issues,” said Alice T. Shaw, MD, PhD, who is the lead researcher on the study and presented the data in an oral abstract session.

An MTD of 750 mg/day was determined in the dose-escalation phase of the study, according to Shaw, an attending physician at the Massachusetts General Hospital Center for Thoracic Cancers, an assistant professor of Medicine at the affiliated Harvard Medical School, and a clinical investigator at MIT’s David H. Koch Institute for Integrative Cancer Research. Shaw presented data on 114 ALK-positive NSCLC patients in the dose-expansion phase of the study who received daily doses of 400 mg to 750 mg of LDK378. The median patient age in the study overall was 53 years and 88% of patients had an ECOG score of 0 or 1.

Response rates were high in both crizotinib-resistant and crizotinib-naïve patients. The overall response rate (ORR; confirmed per RECIST) with LDK378 was 57% for patients with prior crizotinib (45/79) and 60% in crizotinib-naïve patients (21/35). Similar rates were observed in patients receiving the MTD.

The median progression-free survival (PFS) was 8.6 months in patients receiving ≥400 mg/day of LDK378. The data were similar among the 79 crizotinib-resistant patients, in whom the median PFS was 8.3 months. Among the 66 patients who achieved a confirmed response, the median duration of response was 8.2 months. The median PFS has not yet been reached in the MTD group, but the 6-month PFS and duration of response for these patients were both slightly over 60%, said Shaw.

Importantly, Shaw also noted, “LDK is active in the CNS [central nervous system], with durable responses observed. CNS relapses are a major source of morbidity and mortality in ALK-positive patients treated with crizotinib, so establishing the CNS activity of LDK will be extremely important.”

Regarding toxicity, Shaw said, “Overall, LDK378 was generally well-tolerated, with mostly grade 1 or 2 nausea, diarrhea, vomiting, and fatigue.”

Grade 3/4 events reported in ≥5% of patients included elevated transaminases, diarrhea, increased lipase, hypokalemia, and nausea. “There were four cases of pneumonitis, three of which were possibly drug related. There were also three patients who discontinued LDK due to adverse events, only one of which—bilateral leg pain—was considered to be possibly study-drug related. And to date, there have no treatment-related deaths,” said Shaw.

Based on the results of this phase I study, LDK378 received the Breakthrough Designation from the FDA in March, according to Novartis, which is developing the drug.


Two single-arm phase II LDK378 studies are now recruiting ALK-positive NSCLC patients previously treated with chemotherapy who are either crizotinibnaïve (NCT01685138) or progressed on crizotinib (NCT01685060). There are also two phase III LDK378 studies launching that will compare LDK378 with chemotherapy; one study involves patients who are chemotherapy- and crizotinib-naïve (NCT01828099), and the other will enroll patients previously treated with both (NCT01828112).Phase I/II data were also presented at ASCO 2013 for Ariad’s AP26113, a second-generation ALK TKI that may also be active in patients with EGFR-mutant (EGFRm) advanced NSCLC.2

In the phase I part of the study, patients with ALK-positive NSCLC received one of seven oral doses of AP26113 ranging from 30 mg to 300 mg per day. Although the MTD has not been determined, a recommended dose of 180 mg/daily was established for phase II, according to a statement released by Ariad during ASCO 2013.

Partial responses were observed in 75% of crizotinib- resistant ALK-positive patients (12/16), and one of the two crizotinib-naïve patients had a complete response. The duration of response ranged from 3 to 9 months.

Notably, signs of radiographic improvement in CNS were observed in four out of five ALK-positive patients with pre-existing brain metastases, including one patient resistant to both crizotinib and LDK378. In patients who become crizotinib-resistant, the CNS is a common site of disease progression.

Of 18 evaluable patients with a history of EGFRm, one patient had a partial response and seven had stable disease (SD). Of the 10 patients with a history of the T790M secondary EGFR mutation, four had SD (duration, 2 to 9 months) and one has SD that is ongoing (duration thus far, 4 months).

The most common treatment-related adverse events (≥10% of patients) were nausea (33%), fatigue (22%), and diarrhea (20%). Serious toxicities of any origin experienced by ≥2 patients included pneumonia (7%), cough (4%), dyspnea (4%), hypoxia (4%), and pleural effusion (4%). Investigators did not observe rash that is common with other EGFR TKIs. Two deaths occurred (sudden death, hypoxia) that were considered to possibly be treatmentrelated.

The phase II part of the study includes five expansion cohorts and is now enrolling patients in nine locations in the United States and Europe.


  1. Shaw AT, Mehra R, Kim D-W, et al. Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC. J Clin Oncol. 2013;31(suppl; abstr 8010).
  2. Camidge DR, Bazhenova L, Salgia R, et al. First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: updated results. J Clin Oncol. 2013;31(suppl; abstr 8031).