Approximately 3-5 % patients with non-small cell lung cancer patients (NSCLC) harbor abnormal rearrangements of the ALK (Anaplastic Lymphoma Kinase) gene, whereby the ALK gene abnormally fuses with another gene, EML4, resulting in a fusion oncogene, EML4-ALK. This gene rearrangement causes aberrant downstream signaling leading to the development of cancer.
Though these percentages of ALK-driven lung cancer patients seem small, given the total number of patients diagnosed with lung cancer each year, these percentages actually translate into a sizable number of NSCLC patients.
Testing for the ALK rearrangement is critical because highly active, targeted therapies exist for this subset of patients. One of the most common ALK rearrangement-targeted inhibitors is crizotinib (Xalkori), which was approved by the FDA on November 20, 2013 for the treatment of patients with locally advanced or metastatic ALK+ NSCLC. Crizotinib is a highly effective, orally active, ALK inhibitor demonstrating response rates in the 60-70% range and median progression-free survival of ~8-11 months.
Unfortunately, despite initial responses most patients on crizotinib invariably develop resistance during the first year on treatment with this therapy and their disease relapses. This acquired resistance is one of the major challenges in treating ALK+ lung cancer patients. Most often in these crizotinib-resistant NSCLC patients, new tumors emerge in the central nervous system (CNS), typically the brain, which is a difficult area to reach with current medications. Multiple mechanisms have been identified for crizotinib resistance, several of which involve the development of unique new mutations in the ALK gene.
Till very recently, treatment options for patients who failed crizotinib were limited to toxic chemotherapy, palliative radiotherapy or supportive care. However, things are rapidly changing in this space and there are currently over 10 new next-generation inhibitors under preclinical and clinical development for ALK+ NSCLC patients that have developed resistance to crizotinib. Since the CNS (brain) is a frequent site of progression in ALK+ NSCLC treated with crizotinib, CNS efficacy is a critical point to look for in the new ALK inhibitors.
Ceritinib (Zykadia, LDK378) is one of the first next generation ALK- targeted inhibitors that has been granted an accelerated approval by the FDA for the treatment of ALK+ metastatic NSCLC patients who experienced disease progression on, or who are intolerant to crizotinib.
Data on 3 promising ALK inhibitors was presented at the recently concluded 16th World Conference on Lung Cancer (WCLC) in Denver, CO in which the Addario Lung Cancer Foundation participated- Alectinib, Brigatinib and Loralitinib.
Alectinib is a highly-selective, orally available, ALK inhibitor with 10-fold greater potency than crizotinib, and has shown activity in both crizotinib-naïve and crizotinib-resistant patients. Alectinib has been shown to cross the blood-brain barrier and is very effective against central nervous system (brain) metastases that are commonly seen in patients that progress on crizotinib.
This CNS penetrable ALK inhibitor has been approved in Japan and has received breakthrough therapy designation in United States for patients who have failed crizotinib.
Pooled efficacy data from two phase 2 studies evaluating alectinib in ALK+ NSCLC patients previously treated with crizotinib was presented at the WCLC meeting. These findings showed that alectinib has promising efficacy against CNS metastases in ALK+ NSCLC patients previously treated with crizotinib, irrespective of whether these patients received any prior radiotherapy. Interestingly, this CNS activity was sustained for an equivalent duration of time as that seen for systemic response. Therefore, this inhibitor is capable of inducing very durable response rates in this subset of patients. Alectinib was also well tolerated overall, with mild side effects such as constipation, fatigue, myalgia, edema, etc.
Ongoing, randomized phase 3 clinical studies, such as ALEX, will assess the systemic and CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.
Brigatinib is an investigational, oral, ALK-targeted inhibitor that has demonstrated promising antitumor activity in ALK+ NSCLC patients with or without prior treatment with crizotinib, including patients with brain metastases.
Brigatinib has received a Breakthrough Therapy designation by the U.S. FDA for the treatment of patients with ALK+ metastatic NSCLC whose tumors are resistant to crizotinib. This designation is based on results from the ongoing Phase 1/2 trial that show anti-tumor activity of brigatinib in patients with ALK+ NSCLC, including patients with active brain metastases.
Updated analyses of data from this ongoing trial were presented at the WCLC meeting in Denver, demonstrating a median progression-free survival (PFS) of 13.4 months in patients with prior crizotinib therapy, and a median PFS not reached so far for crizotinib-naïve patients. Brigatinib demonstrated excellent intracranial activity with a median intracranial PFS of 15.6 months and a median duration of intracranial response of 18.9 months.
In summary, based on data presented on brigatinib so far, this experimental agent has a high activity against brain metastases typically seen in ALK+ NSCLC patients, and durable intracranial responses.
A global, phase 2 trial (ALTA) of brigatinib in crizotinib-resistant ALK+ NSCLC patients is ongoing and results from this trial are eagerly awaited to get a complete picture of brigatinib’s CNS activity as well as systemic efficacy.
Lorlatinib, which mostly goes as ‘3922’, is a highly potent, selective, brain-penetrant ALK inhibitor that is active against not just ALK rearrangements but also the resistance mutations that arise in the ALK gene driving resistance to current clinical ALK inhibitors such as crizotinib. One of these mutations is G1202R and Lorlatinib is currently the only ALK-targeted inhibitor that is active against this resistance mutation in the ALK gene. Based on preclinical studies, Lorlatinib is believed to be the one ALK inhibitor that covers the broadest spectrum of ALK resistance mutations.
Early data from the ongoing phase 1 study evaluating Lorlatinib in NSCLC patients shows that this experimental agent is active against both crizotinib-naïve as well as crizotinib-resistant non-small cell lung cancers.
In this Ph 1 study, Lorlatinib has demonstrated robust clinical activity in ALK+ NSCLC patients who have been previously treated with other ALK-directed inhibitors. In this heavily pretreated population of ALK+ NSCLC patients, Lorlatinib demonstrated high activity against brain metastases.
Other agents under development: There are several other ALK-targeted inhibitors currently in early stages of development, such as X-396, TSR-011, CEP-37440 and RXDX-101 (entrectinib).
In summary, there’s a currently a lot of activity in the drug development arena for ALK targeted agents. For ALK+ NSCLC patients that relapse on crizotinib, there are several CNS- and extra-CNS active next-generation ALK inhibitors currently under development. Each of these agents have variable side effect profiles, and may have varying levels of activity against brain metastases in ALK+ patients. There is currently no data available on a head-to-head comparison of these agents to identify which ones patients must go on after they stop responding to crizotinib. It will also be very interesting to see how these agents perform in the front-line setting; studies to this effect are currently underway for ceritinib and alectinib, while those for brigatinib are planned.