Lorlatinib Addresses Resistance to ALK TKIs in NSCLC

Alexander M. Castellino, PhD

April 24, 2018

CHICAGO — Patients with non-small cell lung cancer (NSCLC) that harbors ALK rearrangement mutations, and who progress on treatment with existing ALK-targeted drugs, may soon have a new option: a third-generation ALK tyrosine kinase inhibitor (TKI), lorlatinib (under development by Pfizer).  

Analyses of tumor tissues and circulating-free DNA (cfDNA) from patients with NSCLC enrolled in a lorlatinib trial provided insights into how it may be used in clinical practice once it gains approval,  according to data reported here at the American Association for Cancer Research (AACR) 2018 Annual Meeting.

For presenter Alice T. Shaw, MD, PhD, from the Dana-Farber Cancer Institute, Boston, Massachusetts, the phase 2 study of lorlatinib provided a means of teasing out clinical efficacy based on prior use of one or more ALK TKIs.

The phase 2 study had several cohorts of patients treated with lorlatinib:

  • Patients who had progressed while receiving crizotinib, the first-generation ALK TKI, with or without chemotherapy;

  • Patients who had progressed while receiving second-generation ALK TKIs; and

  • Patients who had progressed while receiving two or more ALK TKIs.

"Secondary mutations in the ALK kinase domain can induce resistance to first- and second-generation ALK TKIs," Shaw said.

She explained that lorlatinib is a third-generation potent, selective, ALK/ROS1 TKI, which penetrates the central nervous system and has a broad-spectrum potency against most known ALK resistance mutations, including ALK G120R — the most common mutation.

"In patients relapsing on a second-generation ALK TKI, ALK mutations may serve as a biomarker to identify patients more likely to respond to lorlatinib," Shaw said.

"However, elucidating mechanisms of resistance to lorlatinib will be critical to developing the next generation of therapeutic strategies for ALK-positive NSCLC," she added.

Study Details

The study mandated that analyses be done on tumor tissue samples (de novo or archival). Next-generation sequencing assay (MolecularMD) was performed to detect ALK kinase domain mutations (exons 20 to 25).

cfDNA was analyzed in peripheral blood samples collected at screening, at the beginning of cycle 3 of treatment, and at the end of the study by using a next-generation sequence 73-gene panel (Guardian360).

Objective response rate (ORR) with lorlatinib was 69% for patients who had previously progressed while receiving crizotinib with or without chemotherapy, intracranial ORR was 68%, and median progression-free survival (PFS) was not reached.

ORR with lorlatinib in patients who had progressed while receiving a noncrizotinib TKI was 33%, intracranial ORR was 42%, and median PFS was 5.5 months. The results were similar for patients treated with two or more prior ALK TKIs.

Analyses of cfDNA and tumor tissue showed 24% and 21% of patients, respectively, had one or more ALK kinase domain mutations. Seventy-five ALK kinase domain mutations were seen in the cfDNA analysis and 58 in the tumor tissue analysis.

For patients who provided blood and tumor tissue samples, 59% of patients showed the same mutations in both samples and 41% showed different mutations in both samples.

Shaw next reported clinical responses based on mutational status and exposure to ALK TKIs. ORR was similar for patients receiving lorlatinib who had progressed during crizotinib treatment — 73% for those with ALK kinase domain mutation(s) and 72% for those without any such mutations.

For patients who had progressed while receiving one or more second-generation ALK TKI(s), ORR more than doubled when patients had ALK kinase domain mutation(s) as determined from cfDNA or tumor tissue analysis: 61% vs 26% for patients without any ALK kinase domain mutation.

"Patients resistant to a second-generation ALK TKI are less likely to respond to lorlatinib in the absence of a detectable ALK mutation," Shaw told Medscape Medical News.

"Molecular factors predict which patients may respond to lorlatinib," she added.

However, some mutation-negative patients do respond to lorlatinib, shepointed out, noting the 26% ORR seen in these patients.

"Longitudinal profiling of cfDNA and/or tumor tissue will help define the evolution and heterogeneity of lung cancers treated with lorlatinib," Shaw said.

ALK TKIs in Clinical Management

In her discussion, Christine Lovly, MD, PhD, from Vanderbilt University Medical Center, Nashville, Tennessee, provided a clinical context to the lorlatinib data.

Using the lorlatinib trial data as a framework, she discussed how ALK TKIs can be sequenced in the clinical management of patients with ALK-positive advanced NSCLC.

Crizotinib (Xalkori, Pfizer), alectinib (Alecensa, Genentech), and ceritinib (Zykadia, Novartis) have now all been approved for use in the first-line setting, she pointed out. Ceritinib and alectinib are favored for the first-line treatment of ALK-positive NSCLC, she commented.

After progressing during first-line therapy, patients may receive alectinib, ceritinib, or brigatinib (Alunbrig, Takeda Oncology).

While next-generation ALK inhibitors (ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, ensartinib) have documented efficacy in patients with acquired resistance to crizotinib, there are fewer data in the setting of treatment after progression during use of first-line ALK TKIs, she noted.

However, the currently preferred ALK TKIs — brigatinib, alectinib, and ceritinib — are all associated with the emergence of ALK kinase domain mutations, especially G120R.

The mutational analyses from the lorlatinib study suggest that it will emerge as the agent of choice in the second- and third-line setting of ALK-positive NSCLC, Lovly noted. Syncing with these data, lorlatinib has received breakthrough-therapy designation for patients who have received one or more ALK inhibitors.

However, acquired resistance to ALK TKIs is complicated by the fact that there are ALK-independent mechanisms of acquired resistance for which ALK inhibitors are not expected to work. "We need additional systematic evaluation of in vitro models and tumor biopsy samples to study the evolution of resistance," she noted. "These studies will inform better rational combination therapy trials," she added.

Shaw discloses relationships with Blueprint Medicines, KSQ Therapeutics, Pfizer, Roche/Genentech, Novartis, Ignyta, LOXO, Ariad/Takeda, and Natera. Lovly consults for Pfizer, Novartis, AstraZeneca, Genoptix, Sequenom, Ariad, Takeda, and Foundation Medicine. She is also on the advisory board for Cepheid Oncology.

American Association for Cancer Research (AACR) 2018 Annual Meeting. Abstract CT044. Presented April 15, 2018.

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