Transcript Related Guidelines

Sequencing Therapeutic Options for ALK+ NSCLC: Standards of Care and Alternatives

Sandip P. Patel, MD · University of California at San Diego


December 16, 2020

Key Takeaways:

  • The next-generation tyrosine kinase inhibitor (TKI) drugs such as alectinib, brigatinib, and lorlatinib have a potential benefit over crizotinib in terms of maximizing survival for patients with ALK-rearranged non-small cell lung cancer (NSCLC)

  • With the advent of genomics, the sequencing of agents upon progression on a front-line ALK inhibitor is useful to treat ALK-rearranged NSCLC

  • Lorlatinib demonstrated promising results during clinical studies in patients who had progressed on prior ALK-TKI, including robust intracranial response

  • The targeted therapies are well-tolerated compared with chemotherapy in patients with NSCLC but they are associated with some side effects which require considering mitigation strategies to counter toxicities related to each of these agents 

This transcript has been edited for clarity.

One of the areas in the approach to targeted therapy that medical science and the ability for advanced genomics to elucidate has really come into the setting of an adaptive resistance to targeted therapy.[]

When we think about ALK-rearranged non-small cell lung cancer, the ability to treat initially with the next-generation inhibitor drugs like alectinib, brigatinib, lorlatinib—very soon we really see that the potential benefit over a drug that's very good, crizotinib, though in and of itself has an Achilles heel of lacking CNS penetration—we really see the potential benefit in terms of maximizing survival for our patients.[1,2] 

But another area in which it can really help our patients in the advent of genomics techniques, including liquid biopsy may be helpful, is in the sequencing of agents upon progression on your front-line ALK inhibitor. There are many options, and depending on your front-line treatment regimen, in the US, most commonly it currently remains alectinib or brigatinib in the front-line space, [the question] is: what to do next on progression?

And so one of the options here is lorlatinib which is another targeted TKI, another targeted therapy directed against ALK, which has demonstrated efficacy not only systemically but also with CNS penetration, including in patients who progressed on crizotinib, on alectinib, and potentially on chemotherapy.[1,2] 

And so in one of the key studies of lorlatinib in the refractory setting, we saw that there is a 47% response for patients who were on lorlatinib who had progressed on prior ALK-TKI and the median duration of response is approximately 7 months.[1] And this included robust intracranial responses for patients who, in fact, were on ALK-TKIs previously, including drugs like alectinib or crizotinib as well. And the immediate duration of those CNS responses was on the order of 14 months and greater. Over half these patients had a response.[1] 

Now we think about the targeted therapies. They have a much better side-effect profile than chemotherapy, but they do have unique aspects that must be considered—alectinib, in particular, with liver toxicity; brigatinib with the dosing considerations to mitigate risk of pulmonary toxicity, as well as some often asymptomatic elevations in lipase and muscle enzymes; and then with lorlatinib, some of the neurocognitive side effects and dyslipidemia that can occur with the utilization of this agent.[1] 

That said, compared to chemotherapy, all these agents are extraordinarily well-tolerated relatively. But given that patients go beyond these therapies for a prolonged period of time, it's important to recognize the toxicities related to each of these unique agents and the mitigation strategies around them to ensure that patients are able to unlock the maximum benefit they can from these very effective therapies.


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