Abstract
Data from a phase I study indicate that the investigational ALK inhibitor lorlatinib is active in patients with ALK- or ROS1-positive non–small cell lung cancer, including those with brain metastases. Objective responses were seen among patients with known ALK resistance mutations who had relapsed following treatment with other tyrosine kinase inhibitors.
Data from a phase I study indicate that lorlatinib (Pfizer), an investigational next-generation ALK inhibitor, is active in patients with ALK- or ROS1-positive non–small cell lung cancer (NSCLC) whose tumors have become resistant to other tyrosine kinase inhibitors (TKI), and who have brain metastases. The results were presented during the American Society of Clinical Oncology's annual meeting in Chicago, IL, June 3–7.
For patients with ALK-positive NSCLC, crizotinib (Xalkori; Pfizer) is currently the standard first-line therapy. However, most patients relapse within a year of treatment due to a variety of resistance mechanisms. Approved second-line options include the next-generation ALK inhibitors ceritinib (Zykadia; Novartis) and alectinib (Alecensa; Genentech). Both have shown efficacy in patients whose cancer has progressed on crizotinib—and alectinib has also been effective in patients with brain metastases—but all patients eventually relapse.
In this study, 41 patients with ALK-positive NSCLC and 12 whose disease was ROS1-positive were treated with lorlatinib across 10 dose levels to establish the recommended daily dose of 100 mg. The majority (87%) had relapsed after at least one prior TKI; 72% also had brain metastases. Among those with ALK rearrangements, the confirmed objective response rate (ORR) to lorlatinib was 46%, with three complete responses. Median progression-free survival was 11.4 months. Significant tumor shrinkage was also seen in six ROS1-positive patients.
Among 18 patients with measurable brain metastases, the confirmed intracranial ORR, assessed through MRI, was 39%, including five complete responses. Lorlatinib was well tolerated overall. The most frequent side effect, hypercholesterolemia, was asymptomatic and readily managed with statin therapy.
“We are continuing to see positive responses to this drug, which is remarkable given most of these patients relapsed on several prior ALK inhibitors,” says the study's lead investigator, Alice Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital (MGH) in Boston. “Lorlatinib is different from other ALK inhibitors because it was specifically designed to penetrate the brain and to overcome all known resistance mutations in ALK” such as the G1202R mutation, which is commonly seen after treatment with ceritinib and alectinib. At MGH, one patient who had progressed on both inhibitors, as well as crizotinib, achieved a partial response to lorlatinib that is ongoing after a year of treatment.
“The few drugs approved for ALK-positive NSCLC have shown exciting activity, but they're not helping all patients,” says Gregory Masters, MD, a lung cancer specialist at the Helen Graham Cancer Center in Newark, DE. “Lorlatinib looks like it could be an option for heavily pretreated patients, but we still need to determine what the sequencing of these new agents should be.”
Shaw says lorlatinib may not be effective for all patients because some who relapse on second-generation inhibitors do not harbor secondary ALK mutations and are not ALK-dependent. Combination approaches targeting other pathways that mediate ALK resistance, such as EGFR, SRC, and MAPK, may be needed for these patients. Through the Lung Master Protocol, a basket study that matches patients to new therapies based on their mutation status, Shaw and her colleagues are “working on defining more resistance mechanisms, including those independent of ALK.” –Janet Colwell
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