Lorlatinib active in ALK-positive NSCLC, regardless of EML4-ALK variants
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Lorlatinib appeared to be an effective treatment for non-small cell lung cancer with ALK resistance mutations, regardless of EML4-ALK variants, according to results of a study presented at the virtual American Association for Cancer Research Annual Meeting.
Researchers found the presence of an ALK resistance mutation may enrich for certain EML4-ALK variants among previously treated patients with ALK-positive NSCLC.
Lorlatinib (Lorbrena, Pfizer), a third-generation ALK/ROS1 tyrosine kinase inhibitor, showed preclinical activity against most known ALK resistance mutations. It also has shown clinical activity among patients with ALK-positive advanced NSCLC with disease progression following second-generation ALK TKIs.
Tumor genotyping for ALK mutations may identify patients more likely to respond to lorlatinib, according to the researchers.
“Secondary mutations in ALK kinase domain can induce resistance to first- and second-generation ALK TKIs,” Todd M. Bauer, MD, associate director of drug development and principal investigator at Sarah Cannon Research Institute, said during a presentation. “This is why patients ultimately stop responding to other drugs. Lorlatinib does have broad spectrum potency against most known ALK resistance mutations.”
Bauer and colleagues sought to further determine molecular correlates of response in an exploratory subgroup analysis of 156 patients with ALK-positive NSCLC who were previously treated with at least one second-generation ALK TKI and enrolled in an ongoing registrational phase 2 study of lorlatinib.
Study participants received 100 mg lorlatinib daily, the recommended phase 2 dose.
Researchers collected baseline plasma samples and analyzed cell-free DNA using the Guardant360 (Guardant Health) assay to determine EML4-ALK variant and ALK kinase domain mutations. They evaluated objective response rate and duration of response according to EML4-ALK variant type and ALK resistance mutation status.
Results showed detectable ALK fusions in 64 patient plasma samples. EML4-ALK variant 1 was detected at a frequency of 17.3%, variant 2 was detected at a frequency of 2.6% and variant 3 was detected at 15.4%.
Researchers detected other EML4-ALK variants — including types 4, 5, 7 and 8 — in 3.2% of patients, as well as KIF5B and other less common mutations in 2.6% of patients.
Among 40 patients with ALK resistance mutations based on cell-free DNA, six harbored EML4-ALK variant 1, one had variant 2 and 18 had variant 3.
Twenty-three patients had G1202R deletion mutations. Of those, 15 also had EML4-ALK variant 3.
Results showed an ORR of 33.3% (95% CI, 16.5-54) for variant 1, 75% (95% CI, 19.4-99.4) for variant 2 and 45.8% (95% CI, 25.6-67.2) for variant 3.
Median duration of response was 6.9 months for patients with variant 1 or variant 3 and not reached for those with variant 2.
Researchers observed no responses in the patients with other ALK rearrangement types.
Ninety-two patients had no detectable ALK fusions in cell-free DNA, including 12 patients who had detectable ALK mutations. ORR among these 92 patients was 39.1% (95% CI 29.1-49.9), with a median duration of response of 7.1 months (95% CI, 5.5 to not reached).
“With respect to the primary endpoint of ORR, lorlatinib exhibited antitumor activity irrespective of EML4-ALK variant and across a variety of ALK resistance mutations,” Bauer said. “Confirmation of these results in the tumor tissue is ongoing.” – by John DeRosier
Reference:
Bauer TM, et al. Abstract CT025. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Disclosures: Pfizer funded this study. Bauer reports consultant/advisory roles with and research funding from Pfizer and several other companies, as well as speakers bureau roles with Bayer and travel expenses from Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, EMD Serono, Eli Lilly, Genentech, Merck, Novartis, Pharmacyclics and Pfizer. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Nicholas Rohs, MD
It’s always good to see more data highlighting the importance of tumor genotyping to help us best select targeted therapies for our patients. This is something I have been doing in clinic for a while now, including my patients with ALK fusions. Not only does this allow us to help choose therapy, but also to prognosticate and better inform our patients. The more we are studying these potent, selective TKIs in lung cancer, the more we are appreciating the diverse mutational landscape they can harbor, particularly with regard to resistance mechanisms upon progression. Hopefully these data will encourage practitioners to consider using circulating tumor DNA (ctDNA) analysis as a less invasive option for genotyping in place of, or in combination with, tissue biopsy. We should continue to include evaluation of ctDNA in future studies to continue to build this data set.
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Bauer TM, et al. Abstract CT025. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
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