If the abstracts presented at ESMO were any indication, the US Food and Drug Administration approval of crizotinib only opened the door to a virtual roomful of next-generation ALK inhibitors. While crizotinib targets only the 5% of non–small cell lung cancer (NSCLC) patients with the ALK genetic translocation, it makes a huge impact on this subset, doubling the time that patients with advanced disease spend in remission.
“Crizotinib is the poster child for precision medicine,” according to Mace Rosenberg, MD, Senior Vice President of Clinical Development and Medical Affairs at Pfizer Oncology. At a press briefing, he noted that the robust responses observed in phase 1 trials of ALK-positive patients led to a “rapid reduction of our clinical development program.”
At ESMO, data from phase 1 and 2 trials suggest that the following next-generation ALK inhibitors may follow in the footsteps of crizotinib:
- AP26113 is an oral agent that also targets mutations in the epidermal growth factor receptor (EGFR). A study of 29 patients with NSCLC showed activity in both the first-line and resistant cohorts.
- LDK378, a potent oral small molecule ALK inhibitor, showed a high level of activity in patients who progressed after crizotinib.
- CH5424802, an oral agent, produced 3 complete responses and 36 partial responses among 46 NSCLC patients with no prior ALK therapy; 40 patients remain on treatment.
- AUY922, a heat shock protein 90 inhibitor that is delivered by weekly infusion, was highly active in 121 patients with previously treated NSCLC who had ALK or EGFR mutations. Responses were observed in 32% of ALK-positive patients and 20% of EGFR-mutated patients.
NSCLC investigators at the meeting emphasized that new ALK inhibitors will be needed for treating patients, who inevitably become resistant to crizotinib, in spite of its initial efficacy. They also said that next-generation ALK inhibitors appear to be even better tolerated than crizotinib.