Next Generation ALK Inhibitors Poised to Become Standard of Care for Crizotinib-Resistant Patients

Alice T. Shaw, MD, PhD

Crizotinib, a c-MET/ALK/ROS1 tyrosine kinase inhibitor, received accelerated approval from the FDA in 2011 for ALK-positive non-small cell lung cancer (NSCLC) based on two single-arm post-chemotherapy trials. While a phase III trial testing crizotinib versus chemotherapy in the frontline setting is ongoing, “The NCCN recommendation is to use crizotinib as a standard agent even prior to chemotherapy in ALK-positive advanced NSCLC patients,” Alice T. Shaw, MD, PhD, said in a presentation at the 8th Annual New York Lung Cancer Symposium in New York City.

Now, next-generation ALK inhibitors are being developed to address the unmet need of those patients who are becoming resistant to crizotinib. Researchers are also accumulating data on the spectrum of resistance mutations that occur in patients who are treated with the drug.

Shaw, an attending physician at the Massachusetts General Hospital Center for Thoracic Cancers, assistant professor of Medicine at the affiliated Harvard Medical School, and clinical investigator at MIT’s David H. Koch Institute for Integrative Cancer Research, discussed resistance mechanisms and next-generation ALK inhibitors in clinical trials that are poised to be broadly available in the next few years.

Approximately 3% to 5% of NSCLC patients harbor a rearrangement in the ALK gene. Rearrangements in ROS1, a receptor tyrosine kinase structurally related to ALK, have also been identified.

“The data so far show that critotinib is effective for ROS1-positive patients,” Shaw said. “The drug is not yet approved for ROS1-rearranged NSCLC, but both ALK and ROS1 are important molecular targets that oncologists need to be aware of in NSCLC.”

Patients with these two types of oncogene-addicted lung cancer tend to be about 10 years younger than other lung cancer patients, are typically light or never smokers, and are commonly diagnosed with adenocarcinoma of the lung, said Shaw.

Among the 36 ROS1-positive patients treated with crizotinib in early-stage research, all have had some degree of response. The median progression free survival has not yet been reached. While less than 10% of ALK-positive patients have intrinsic resistance to crizotinib, so far, a similar intrinsic resistance has not been documented among ROS1-positive patients.

Dr. Shaw on Monitoring Crizotinib-Related Side Effects

While crizotinib works very well, “at some point patients do develop resistance, typically around 9 to 12 months” after starting treatment, said Shaw.

A spectrum of secondary mutations have been identified in the ALK kinase itself. The most common is the L1196M “gatekeeper” mutation. Amplification of the ALK fusion gene has also been identified. In about two-thirds of resistant cases, no resistance mutations in ALK are identifiable, and activation of other signaling pathways, such as the EGFR pathway, may mediate resistance to crizotinib.

Understanding these mechanisms has helped to accelerate the next wave of ALK inhibitors, said Shaw. The next generation ALK inhibitors entering the clinic have primarily been studied in ALK-positive NSCLC patients who have acquired resistance to crizotinib. Many of these drugs also target ROS1 rearrangements, Shaw noted.

The secondary ALK gene mutations have so far shown different degrees of response to the novel ALK inhibitors. The most advanced of these are LDK378 (Novartis) and alectinib (Roche).

Based on positive phase II data, LDK378 is now being tested in two phase III trials in both treatment-naïve patients and those previously treated with both chemotherapy and crizotinib. The drug has shown activity against both ALK and ROS1.

Alectinib selectively targets ALK—but not ROS1—and has shown a high response rate in crizotinib-naïve Japanese patients.

Both of these agents have been shown to be active on brain metastases.

Going forward, the next questions for researchers are whether using these new ALK inhibitors upfront could prolong the time to resistance and how to overcome resistance that develops even to these new drugs.

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