As part of our coverage of the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 1–5 in Chicago, we spoke with Alice Shaw, MD, PhD, about the development of ALK inhibitors for lung cancer. Dr. Shaw, a professor of medicine at Harvard Medical School and a medical oncologist specializing in lung cancer at the Massachusetts General Hospital in Boston, gave a pre-meeting “New Drugs in Oncology” educational seminar at ASCO on ALK inhibitors and the relatively rapid path from phase I clinical trials to FDA approval of selected agents.
—Interviewed by Anna Azvolinsky
Cancer Network: First, can you tell us what ALK inhibitors target, and the rationale for their use in lung cancer?
Dr. Shaw: ALK inhibitors are a class of small-molecule tyrosine kinase inhibitors, or TKIs, that specifically target and inhibit the ALK tyrosine kinase. Over the past decade, three generations of ALK inhibitors have been developed—including first-generation (crizotinib), second-generation (ceritinib, alectinib, brigatinib, and ensartinib), and third-generation inhibitors (lorlatinib). In general, each generation of ALK inhibitors is more potent, more selective, and more brain-penetrant compared with the prior generation.
ALK inhibitors are highly effective in patients whose lung cancers harbor chromosomal rearrangements of ALK. These rearrangements lead to aberrant expression of oncogenic ALK fusions and dependency on ALK signaling for survival. As a result, ALK inhibitors which block ALK signaling often induce rapid and dramatic responses in patients with ALK-rearranged (or ALK-positive) lung cancer. In head-to-head comparisons, ALK inhibitors have been shown to be much more effective than standard chemotherapy, and have become the standard of care for all patients with advanced ALK-positive lung cancer.
Cancer Network: Can you tell us about the path to approval by the US Food and Drug Administration of the first ALK inhibitor, crizotinib? Is there anything unique about how this drug went from being tested in clinical trials to being an approved drug in the clinic?
Dr. Shaw: The first-generation ALK inhibitor, crizotinib, is actually a multitargeted TKI, inhibiting not only ALK but also ROS1 and MET. Crizotinib was initially designed by medicinal chemists at Pfizer to be a potent and selective MET inhibitor, but in subsequent studies [conducted] to characterize its biochemical and cellular activity, it was found to inhibit ALK in addition to MET. The phase I study of crizotinib opened in mid 2006 and enrolled patients with advanced solid tumors. In 2007, about 1 year into the dose-escalation portion of the study, ALK rearrangements were discovered in a subset of NSCLC [non–small-cell lung cancer] patients, and preclinical studies suggested that ALK could represent a new molecular target.
At this point, Dr. John Iafrate at MGH set out to develop and validate a diagnostic assay for ALK rearrangement in NSCLC. Within a few months of the initial report of ALK in NSCLC, patients with ALK-rearranged lung cancer were identified and enrolled onto the phase I study of crizotinib. The first few ALK-positive patients treated with crizotinib showed dramatic responses, leading to modification of the protocol to include an expansion cohort for ALK-positive NSCLC. The efficacy results in this expansion cohort were marked, with significant and durable responses. Together with the results from a single-arm phase II study, this phase I study led to accelerated approval of crizotinib for advanced ALK-positive NSCLC, roughly 4 years after the initial discovery of ALK.
Several factors contributed to crizotinib’s rapid approval, including the early development of a robust diagnostic assay which enabled identification of the target population, and close collaboration between investigators and the Pfizer study team, which facilitated rapid enrollment and treatment of patients in need. There was also a large component of fortuitous timing—almost serendipity—in that the target was identified just when a highly effective targeted therapy was being tested in a phase I study.
Cancer Network: There are other ALK inhibitors now approved in lung cancer. Did these have a rapid path to approval, similar to crizotinib?
Dr. Shaw: There are now multiple next-generation ALK inhibitors in the clinic, and several have followed similar paths from early-phase studies to FDA approval. Ceritinib was the first of the next-generation ALK inhibitors tested in the clinic. At the time the phase I study of ceritinib launched, there was an urgent and growing need for next-line options after crizotinib. Unlike most other phase I studies at the time, the phase I dose-escalation study of ceritinib limited enrollment to patients with ALK-positive malignancies. As a result, not only was safety and dosing established, but we also had an early glimpse into the efficacy of ceritinib in the target population. Once the dose escalation [was] completed, we moved quickly into dose expansion, and confirmed the efficacy of ceritinib in both crizotinib-resistant and crizotinib-naive patients. It took just over 3 years from the first patient dosed with ceritinib to accelerated approval of ceritinib for patients with advanced, crizotinib-pretreated ALK-positive NSCLC.
Since then, two other ALK inhibitors—alectinib and brigatinib—have been approved for ALK-positive patients who have failed prior crizotinib. Alectinib has had a particularly rapid path from phase I to frontline approval. Based on its activity in the post-crizotinib setting in phase I/II studies, alectinib was moved quickly into a phase III head-to-head comparison with crizotinib, the standard first-line agent at the time. In the pivotal ALEX trial, alectinib was shown to be significantly superior to crizotinib, with a median PFS [progression-free survival] more than triple that of crizotinib’s in the latest update presented at ASCO 2018.
Cancer Network: And lastly, how are ALK inhibitors currently used in the clinic, and what questions remain about how they should be used?
Dr. Shaw: In the US, alectinib is now established as the new standard first-line treatment for patients with advanced ALK-positive NSCLC. While most responses to first-line alectinib are durable, essentially all patients will develop resistance leading to clinical relapse. Two other second-generation ALK inhibitors—ceritinib and brigatinib—are FDA-approved, but have only been tested in the crizotinib-naive and/or crizotinib-resistant setting.
The third-generation ALK/ROS1 inhibitor lorlatinib has completed phase I and II testing and has been tested across numerous settings, including in patients who are ALK TKI-naive, crizotinib-resistant, or resistant to one or more second-generation ALK TKIs. Lorlatinib has demonstrated antitumor activity in all of these settings, including in patients who have failed a second-generation ALK inhibitor such as alectinib. Lorlatinib is highly CNS-penetrant and has demonstrated potent intracranial activity, even in patients who have failed a brain-penetrable TKI such as alectinib. Based on the efficacy and safety seen in the phase I/II study, lorlatinib received FDA breakthrough therapy designation last year and is anticipated to gain accelerated approval this year for ALK-positive patients previously treated with 1 or more ALK inhibitors. Thus, the paradigm of sequential therapy with crizotinib followed by a second-generation ALK inhibitor is now being replaced by a new paradigm of alectinib followed by lorlatinib.
Numerous questions remain to be addressed. For example, while alectinib is the new standard first-line agent, will a more potent inhibitor like lorlatinib have even greater efficacy upfront? This question is currently being addressed in the global phase III CROWN study, which is comparing lorlatinib versus crizotinib as first-line therapy for advanced ALK-positive NSCLC. Also, what are treatment options for patients who have failed lorlatinib?
Emerging data from our group suggest that resistance to lorlatinib may be mediated by a variety of mechanisms, including a complex array of compound ALK resistance mutations (for example, the gatekeeper mutation ALK L1196M combined with the solvent front mutation ALK G1202R), as well as numerous different ALK-independent mechanisms. The latter include activation of bypass tracks and histologic changes such as epithelial-mesenchymal transition. To overcome these types of resistance mechanisms, novel strategies are needed beyond just ALK inhibitors. We are currently developing combination strategies that incorporate an ALK inhibitor such as alectinib or lorlatinib combined with a second agent that can overcome specific mechanisms of resistance. These combination studies can be challenging in terms of establishing dosing, safety, and efficacy, but are critical to advancing the field and expanding treatment options for patients with ALK-positive NSCLC.