Progress With ALK Inhibitors: When Will We Consider ALK-Positive Lung Cancer a ‘Chronic Disease’?

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Fred R. Hirsch, MD, PhD

Fred R. Hirsch, MD, PhD

As reported by Solomon et al in The Lancet Oncology1 and reviewed in this issue of The ASCO Post, results from a global phase II study of the third-generation ALK inhibitor lorlatinib showed a high overall response rate and high intracranial response rate for patients with advanced ALK-positive non–small cell lung cancer (NSCLC). ALK-positive NSCLC was identified early on as a very sensitive tumor type for ALK inhibitors, first with crizotinib as a first-generation inhibitor and then with several second-generation inhibitors (eg, alectinib, ceritinib, and brigatinib)—and now with high sensitivity to the third-generation inhibitors, such as lorlatinib.

In large randomized studies, the second-generation agents have demonstrated better activity than first--generation agents and have been approved as a first-line treatment choice for patients with ALK-positive advanced NSCLC. The problem with
first- and second-generation ALK inhibitors has been that many patients develop resistance, particularly central nervous system (CNS) relapse, although second-generation agents have demonstrated clearly better CNS activity than crizotinib.

Lorlatinib (PF-06463922) was particularly developed to better penetrate the blood-brain barrier and to retain potency to acquired resistant mutations that developed during therapy with first- and second-generation agents, including the ALK Gly1202Arg mutations. Based on phase I and preliminary phase II data, lorlatinib received accelerated approval by the U.S. Food and Drug Administration in November 2018 for patients whose disease progressed on crizotinib or at least one other ALK inhibitor (alectinib or ceritinib) as first-line therapy for advanced ALK-positive NSCLC.

‘Indisputable’ Future Role for Lorlatinib

The results presented by Solomon et al are promising, particularly in the category of refractory disease after previous therapy with ALK inhibitors, but also in treatment-naive patients. The CNS activity of lorlatinib was clearly demonstrated in this study; 87% of patients treated with previous crizotinib alone had intracranial responses, and more than half of the patients treated previously with second-generation ALK inhibitors had intracranial responses.

The future role of lorlatinib as a potent ALK inhibitor is indisputable.
— Fred R. Hirsch, MD, PhD

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The future role of lorlatinib as a potent ALK inhibitor is indisputable. The presented results clearly indicate a place for lorlatinib in the treatment of previously treated refractory ALK-positive disease. However, the main question for the future is where in the treatment course does the drug best fit? The role of lorlatinib as first-line therapy is not answered in the first presented studies; comparative studies, such as from randomized trials with first- and second-generation agents, are needed, and results from such studies are awaited.

Optimal Treatment Sequence Remains Unknown

For the ALK-positive patient with NSCLC, there are today several treatment options with several active agents on the “market.” Although one agent might be slightly better than another, the main question remains: how do we sequence the therapies to leverage most optimally the specific targeting differences between the drugs and the differences in clinical effect? The knowledge so far acquired about primary and particularly secondary resistant mutations will ultimately help us design the most optimal treatment sequence. However, we are not yet there for routine clinical practice, although we are getting close.

The recent reports from the studies with the third-generation ALK inhibitors, such as lorlatinib, clearly add to the potential for turning NSCLC ALK-positive disease into a chronic disease and potentially a curable disease.
— Fred R. Hirsch, MD, PhD

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The different ALK inhibitors are “sensitive” and “resistant” to different (sometimes similar) mutations, and mutation-driven sequences will certainly guide the treatment path. Today, ALK-positive NSCLC is a role model for how we eventually will transform molecular subtypes of NSCLC into a chronic disease course, with the potential for cure for some patients and most likely “chronic therapy” for most patients. With the current treatment options for a patient with ALK-positive advanced NSCLC, the median survival can be expected to be more than 6 years (6.8 years in a recent publication by Pacheco et al2).

To study the most optimal sequence of the different ALK inhibitors, the U.S. National Cancer Institute is developing a “Master Protocol” for treatment of patients with advanced NSCLC who have ALK-positive tumors, in which the different mutations will direct the given therapy and sequence. It is hoped that such a study concept will lead us to the most optimal treatment strategies by taking molecular biology and new drug development into account.

Awaiting Answers From Future Studies

Although our enthusiasm for the new ALK inhibitors is high and the recent reported lorlatinib results significantly contribute to that, we still need to know more about the resistant mechanisms to the different ALK inhibitors; we also need to know why in some patients, activation of other “druggable” molecular pathways seems to occur during therapy with a single ALK inhibitor. Thus, the potential of eventually combining an ALK inhibitor with another targeted agent(s) might also be relevant in the future. However, while we are awaiting the future studies, we have to conclude that the recent reports from the studies with the third-generation ALK inhibitors, such as lorlatinib, clearly add to the potential for turning NSCLC ALK-positive disease into a chronic disease and potentially a curable disease. 

Dr. Hirsch is Executive Director, Clinical Institute for Lung Cancer, Mount Sinai Cancer, Mount Sinai Health System and Professor of Medicine, Icahn School of Medicine, New York.

DISCLOSURE: Dr. Hirsh is a consultant/advisor for Novartis, Bristol-Myers Squibb, AstraZeneca, Merck, Genentech/Roche, Ventana, Helsinn, Loxo Oncology, Bayer, HTG Molecular Diagnostics, Biocept, and AbbVie; is on the speakers bureau for AstraZeneca and the University of Colorado; has received institution research funding from Genentech, Mersana Therapeutics, Amgen, Bayer, Merck, biodesix, HTG Molecular Diagnostics, Clovis, and Rain Therapeutics; and has an institution patent or intellectual property interest in EGFR IHC or FISH as predictive markers for EGFR therapy.


1. Solomon, BJ, Besse B, Bauer TM, et al: Lorlatinib in patients with ALK-positive non-small-cell lung cancer: Results from a global phase 2 study. Lancet Oncol 19:1654-1667, 2018.

2. Pacheco JM, Gao D, Smith D et al: Natural history and factors associated with overall survival in stage IV ALK rearranged non-small-cell lung cancer. J Thorac Oncol. December 29, 2018 (early release online).

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