Advances Continue With Targeted Agents in ALK+ NSCLC

Paul K. Paik, MD

Alectinib (Alecensa) is the preferred frontline treatment for patients with ALK-positive metastatic non—small cell lung cancer (NSCLC), but the potential FDA approval of lorlatinib may shift the landscape once again. The problem, says Paul K. Paik, MD, is that physicians are unable to pinpoint exactly how.

In February 2018, the FDA granted a priority review for lorlatinib for use in patients with ALK-positive metastatic NSCLC who have progressed on 1 or more ALK tyrosine kinases inhibitors (TKIs). Phase II data submitted by Pfizer showed an overall response rate (ORR) of 69% in ALK-positive patients who had received crizotinib (Xalkori), then the frontline standard of care, with or without chemotherapy.

ALK-positive patients who were treated with a non-crizotinib ALK inhibitor with or without chemotherapy had an ORR of 33%. ALK-positive patients who had received 2 or 3 ALK inhibitors with or without chemotherapy showed an ORR of 39%. The efficacy also extended to treatment-naïve patients with ALK-positive NSCLC; results reflected an ORR of 90%.

“How lorlatinib’s [potential] approval shifts the landscape is still unclear, not because of the lack of efficacy, but because the data just aren't consolidated enough in terms of sequencing in trial data,” says Paik. He adds that navigating from treatment to treatment is a dynamic process that can be best guided by a rational application of preclinical data and tolerability.

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Is there a typical sequence of therapies for these patients?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Paik, who is clinical director of Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, discussed treatment advances and sequencing strategies for patients with ALK-positive NSCLC.Paik: There has been a shift in the treatment landscape of patients with ALK-positive lung cancer, specifically how we go about moving from 1 treatment to another treatment over time. At the end of the day, the old paradigm no longer holds. We're in a bit of a data gap as we await the results of other trials and endeavors to move forward. The problem is that patients are sick now, and they need to be treated now.A report published in the New England Journal of Medicine at the end of 2016 showed that a patient with ALK-positive NSCLC who had received crizotinib (Xalkori) developed disease progression. As is recommended, the tumor was biopsied and physicians found a particular alteration that should have predicted sensitivity to lorlatinib. The patient was treated with lorlatinib and had a very good response. Over time, the patient developed another resistance mutation. The particular mutation predicted sensitivity to crizotinib, which was the drug the patient had originally progressed on. The patient received the drug and showed a dramatic response in their liver metastases.

How will the potential approval of lorlatinib alter the landscape?

The use of preclinical data and importing it directly into clinical practice does work. The biology sorts out as we would predict. We can have some confidence that we should be able do this in practice—without any other better data that tells us what to do. Additionally, the case example shows that this is a dynamic process; there's a “push and pull” [situation]. We can't be too dogmatic about this. We have to move along with how the cancer progresses to figure out what to do. We don’t yet know whether going from 1 agent to another agent is better than going from a different drug. We're not there yet. It does, however, give us a new tool to use. As long as there is a rational approach to this—based on how the patient is doing and what the molecular biology is with additional testing—it is certainly a reasonable approach in the post-alectinib setting.

How important have TKIs been in treating patients with ALK rearrangements?

Do the dosing schedules differ across these agents?

Other things should and can be considered. Those things would be other ALK inhibitors, particularly if the mutation-specific data tell you that you should not use lorlatinib. The other would be chemotherapy. Chemotherapy is still a very good option for these patients and should definitely be considered as something, particularly if we need something reliable to get patients over their symptoms.TKIs were really earth shattering and certainly a “sea change” in the management of patients with ALK-positive NSCLC. There was a very low frequency event that we detected, and we didn't think that we would be able to do much because it was so uncommon. However, in a relatively short period of time, we were able to develop—through sponsors and clinical trials—a great slew of different drugs to use. Now, we arguably have the best treatment option for any [patient with] lung cancer in terms of reliable, durable, and dramatic responses. This would be through the use of alectinib in the first-line setting. It has been a wonderful development for these patients. There are differences in dosing schedules between these different drugs. There are also differences in the adverse event (AE) profiles of these drugs and the magnitude of the (AEs). This is one of the reasons why there has been some preference in the pre-alectinib first-line era for agents that we have used. One of the agents that we preferred to use was alectinib because it was a well-tolerated drug. There were some tolerability issues with ceritinib (Zykadia) that seemed to be ameliorated with food consumption. At the time though, it was not as well of a tolerated drug. As we go forward, these will continue to be issues that may help to guide patients to specific therapies. AE profiles is another way to rationally structure therapy for patients.

Solomon BJ, Shaw A, Ignatius Ou S-H, et al. Phase 2 study of lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer. In: Proceedings from the IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract 8573.