Alternating Lorlatinib & Crizotinib in ALK+ NSCLC With ALK-Inhibitor Resistance

Despite significant gains in treating ALK-rearranged nonsmall cell lung cancer(NSCLC) with ALKIs, resistance emerges via ALK-dependent or ALK-independent mechanisms, particularly MET-dysregulation or compound ALK mutations in later-line therapy. With its dual activity against ALK and MET, Crizotinib might offer advantages in this setting.

Researchers aimed to investigate whether alternating lorlatinib and crizotinib therapy affect clonal selection and resistance development in ALK+ NSCLC, using ctDNA as a surrogate marker for early detection.

The study conducted a proof-of-concept by alternating lorlatinib with crizotinib on a fixed schedule for patients who had experienced progression on second-generation ALK inhibitors (ALKi). They utilized Resolution Bioscience’s ctDxTM to analyze plasma ctDNA samples, LabCorp for drug PK concentrations, and in-house validated LC-MS/MS methods for plasma proteomics. Survival and time-to-event analyses were performed using Kaplan-Meier methodology, and ctDNA variant allelic frequency (VAF) plots and a swimmer plot were generated and presented using R version 4.1.3. 

Of 15 patients enrolled, 12 proceeded to alternating therapy after achieving disease control with lorlatinib induction (“alternaters”). The median time from diagnosis to enrollment was 27 months, and the median follow-up duration was 29 months. The median age was 68, with 77% males, 73% whites, 60% ECOG 0, and 47% never-smokers. The median prior lines of therapy were 1 (range: 1-4), and 33% had CNS metastases.

The result showed a median time to treatment failure (TTTF) of 13 months. Progression-free survival (PFS1) for all patients was 6.1 months, while alternaters had a PFS1 of 10.1 months. PFS2 with continuous lorlatinib cross-over was 6.8 months. The overall response rate (ORR) was 60%. Median overall survival (OS) was 23 months, with alternaters having a median OS of 29 months. 

In those with cleared/reduced ctDNA at 6 months after one cycle of alternating therapy, PFS was 8.9 months, compared to 5.8 months in ‘non-clearers’ and 5.4 months in baseline ALK-dominant resistance, versus 11.0 months in mixed/ALK-independent. The most frequent toxicities included hypercholesterolemia (lorlatinib), diarrhea, nausea (crizotinib), and fatigue, all low-grade. 

At baseline, 83% had detectable ctDNA, increasing to 100% at progression. ALK variants included 5-V1, 4-V3, 1-V2, 1-V5, and 1-KIF5B. Across patient plasma samples, 56 different genomic variants were identified (range: 0-10/patient/per sample). Half of those progressing on alternating therapy harbored compound ALK mutations (range: 2-5), while the other half had a single ALK mutation. 

Co-occurring bypass variants included EGFR and MYC amplification, BRAF, ERBB2, TP53, and ROS1 point mutations, and an STRN-NTRK2 fusion. No patients progressed with MET-alterations. Cholesterol pathway proteins were significantly elevated at progression in ‘good’ responders, and acute-phase reactant proteins were elevated in baseline samples of those with ‘good’ survival.

The study showed that the alternating lorlatinib and crizotinib are safe, preserve quality of life(QoL), and show similar survival rates to historical data, supporting further exploration of this novel treatment approach.

Source: https://cattendee.abstractsonline.com/meeting/10925/presentation/2352 

Clinical Trial: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377668&isReview=true 

Itchins M, Liang S, Brown C, Barnes T, Marx G, Chin V, Kao S, Yip PY, Mersiades AJ, Nagrial A, Bray V, Peters G, Parakh S, John T, Li M, Li BT, McKay M, Molloy M, O’Byrne K, Lee C, Gill A, Solomon BJ, Pavlakis N. ALKTERNATE: A Pilot Study Alternating Lorlatinib with Crizotinib in Patients with ALK+ NSCLC and ALK-inhibitor Resistance. Journal of Thoracic Oncology.