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Lorlatinib exhibits antitumor activity in ALK-positive non-small cell lung cancer
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CHICAGO — Lorlatinib demonstrated antitumor activity among patients with non-small cell lung cancer and ALK kinase domain mutations, according to study results presented at American Association for Cancer Research Annual Meeting.
Lorlatinib (PF-06363922, Pfizer) — a third-generation, central nervous system-penetrant ALK/ROS1 tyrosine kinase inhibitor — induced responses in patients who received crizotinib (Xalkori, Pfizer) as their only prior ALK TKI. Response rates were comparable between those who had ALK mutations detected and those who did not (73.3% vs. 72.1%).
Lorlatinib also induced responses in patients previously treated with one or more second-generation ALK TKIs. However, in this group, the response rate with lorlatinib was considerably higher among patients with at least one ALK mutation detected (61%.2 vs. 26.4%).
“In patients relapsing on a second-generation ALK inhibitor, ALK mutations may serve as a biomarker to identify patients more likely to respond to lorlatinib,” Alice T. Shaw, MD, PhD, professor of medicine at Harvard Medical School and attending physician in the thoracic cancer program at Massachusetts General Hospital, said during her presentation. “Patients resistant to a second-generation ALK inhibitor are less likely to respond to lorlatinib in the absence of a detectable ALK mutation; however, some mutation-negative patients do respond.”
Lorlatinib has demonstrated preclinical activity against most known resistance mutations.
In a phase 1/phase 2 study, the agent exhibited robust clinical activity among patients with ALK-positive advanced NSCLC. Most patients in that study had received prior treatment and had central nervous system metastases.
Shaw and colleagues performed molecular profiling of circulating free DNA and tumor tissue in an effort to identify molecular correlates of response among patients who previously received ALK TKI therapy and received the recommended phase 2 dose of lorlatinib (100 mg daily).
Overall and intracranial tumor activity measured as confirmed overall and intracranial response by independent central review served as the primary objective. Other objectives included secondary measures of clinical efficacy, safety and tolerability, patient-reported outcomes and selected molecular profiling.
Researchers analyzed samples from patients enrolled in one of four expansion cohorts of patients with previously treated ALK-positive disease included in the ongoing phase 2 study:
- Participants in expansion cohort 2 received prior crizotinib (Xalkori, Pfizer) only;
- Participants in expansion cohort 3 received prior crizotinib plus chemotherapy, or any one other ALK TKI with or without chemotherapy;
- Participants in expansion cohort 4 received two prior ALK TKI with or without chemotherapy; and
- Participants in expansion cohort 5 received three prior ALK TKI with or without chemotherapy.
Researchers collected baseline plasma from 190 patients, and they collected tumor tissue — either from archival or de novo biopsy — from 188 patients.
Investigators performed digital sequencing with Guardant360 (Guardant Health) to analyze plasma DNA for ALK mutations, and they used ALK-mutation-focused next-generation sequencing panel (Molecular MD) to analyze tumor tissue DNA.
Sixty-nine patients had available data from plasma analysis and de novo tumor tissue biopsy. These methods identified the same mutations in blood and tumor samples from 41 (59.4%) patients, whereas different mutations were identified in blood and tumor samples in 28 cases (40.6%).
The majority (73%; n = 139) of plasma samples did not harbor detectable ALK kinase domain mutations. This group included 38 samples with no detectable circulating free DNA.
Forty-five samples (24%) plasma samples harbored detectable ALK kinase domain mutations, with as many as eight mutations detected in a single sample.
Six samples (3%) were not analyzable.
The analysis revealed 75 ALK mutations overall, 27 of them unique.
The most frequent ALK mutations included G1202R (25%), F1174 (15%), L1196M (15%), G1269A (11%) and I1171 (8%).
Researchers reported a higher response rate among patients whose samples harbored at least one ALK mutation (29 of 45; 64%) than among those whose circulating free DNA had no detectable ALK mutation (58 of 139; 42%).
Investigators did not detect ALK G1202R mutations — which are particularly hard to treat — in any samples from patients who received prior crizotinib only. However, the mutation appeared common among patients who received two prior ALK TKI (nine of 17 patients with at least one ALK mutation detected in circulating free DNA) and those who received three prior ALK TKI (eight of 14 patients with at least one ALK mutation detected in circulating free DNA).
Shaw and colleagues detected ALK G1202R mutations in plasma samples from 19 patients; of these, 11 (58%) achieved response to lorlatinib. At the time of analysis, researchers reported ongoing responses ranging from 1.4 months to 14.5 months.
Further investigation into tissue vs. plasma genotyping are continuing, Shaw said.
“Longitudinal profiling of circulating free DNA and/or tumor tissue will help define the evolution and heterogeneity of lung cancers treated with lorlatinib,” Shaw said. “Elucidating mechanisms of resistance to lorlatinib will be critical to developing the next generation of therapeutic strategies for ALK-positive NSCLC.” – by Mark Leiser
Reference:
Shaw AT, et al. Abstract CT044. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
Disclosure: Shaw reports financial relationships with Ariad/Takeda, Blueprint Medicines, Ignyta, KSQ Therapeutics, Loxo Oncology, Pfizer, Genentech/Roche, Natera and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Hossein Borghaei, DO, MS
Lorlatinib is highly active, especially for patients who have received multiple other ALK inhibitors. In this study, the researchers used plasma and tissue to look at the mutational changes as a result of treatment with different TKIs. The concept is, if you know what the mutation is, you might be able to select a drug to specifically hit that mutation. If a patient progresses on one TKI, you can perform a biopsy, identify the mutation and then administer a drug that is going to work against that particular mutation to hopefully rescue the progression. That is a really cool thing to be able to do. The questions are, how fast can we do it and how many patients will have adequate tissue to do that? That is where plasma comes in. If we can truly do this from plasma, it would be revolutionary for this patient population. Given the activity observed with lorlatinib, we are probably going to see studies conducted in the frontline setting, if they aren’t already underway. If I have a patient with an ALK translocation, I definitely would look for a study that allows lorlatinib and see if my patient could get on it.
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