An ever-stronger case for circulating tumor DNA monitoring in ALK⁺ lung cancer

Anaplastic lymphoma kinase positive (ALK⁺) metastatic non-small cell lung cancer (NSCLC) has seen the greatest therapeutic progress and is distinguished by the longest survival in thoracic oncology, currently (1). Most patients started on second- or third-generation (2/3G) tyrosine kinase inhibitors (TKI), like alectinib, brigatinib, and lorlatinib will stay under these drugs for longer than 2.5 years and surpass the 5-year overall survival mark (2-4). However, the disease remains incurable and will eventually develop resistance, while some cases suffer particularly aggressive courses with accelerated metastatic disemination and early therapy failure (5). This prognostic heterogeneity poses two major challenges for ALK⁺ NSCLC today: (I) the need for improved prognostic stratification and prediction of long-term outcome already at baseline; and (II) the need for improved disease monitoring with earlier detection of subclinical disease progression, tumor evolution and acquired resistance.

The recently published work “Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC” by Soo et al. showed how circulating tumor DNA (ctDNA) assays can be applied to serve both needs (6). Using the high-quality dataset of the randomized phase 3 CROWN trial, the authors showed that patients with non-detectable ctDNA at baseline had lower tumor burden and very favourable outcomes with a progression-free survival (PFS) rate >80% at 3 years. Furthermore, a reduction in the variant allele frequency (VAF) of somatic tumor variants already after 4 weeks of treatment was associated with a longer PFS in the lorlatinib, but not in the crizotinib arm. Of note, this application of liquid biopsies reported in their work is quite different from the previously published use of ctDNA assays in order to detect the ALK fusion at initial diagnosis, e.g., in the BFAST trial, or characterize mechanisms of acquired resistance (7,8).

Yet, both the baseline molecular risk stratification and ctDNA monitoring are not entirely new concepts for the ALK⁺ NSCLC, either. Besides initial ctDNA levels, several other molecular tumor properties have long been known to correlate with the subsequent clinical course (Table 1) (3,6,9-12). In particular, presence of the shorter EML4-ALK variant 3 and TP53 co-mutations are independently associated with shorter PFS under TKI and shorter overall survival in several retrospective analyses as well as the prospective phase 3 ALTA-1L trial (3,11,13). Biochemically, the adverse impact of V3 is explained by the higher stability and stronger signaling of the respective oncoprotein (14), which facilitates the development of both ALK-dependent and off-target resistance (10). On the other hand, TP53 co-mutations cause genetic destabilization of the tumor cells, which favors the complex, off-target resistance mechanisms, particularly on the background of higher cell fitness due to the stronger V3 oncoprotein (15). More metastatic sites as well as more co-mutations, higher VAF and higher ctDNA tumor fractions (TF) are established features of V3-positive and/or TP53-mutated ALK⁺ tumors (9,15), therefore if would be very interesting to analyze the relationship between higher ctDNA levels, as detected by Soo et al. in worse-prognosis patients of the CROWN study (6), and other molecular tumor properties. Unfortunately, the Guardant360 method used for ctDNA analysis in CROWN study is not very sensitive (16), and therefore the results regarding ALK fusion variants have limited utility, as discussed previously (1).

The higher abundance of ctDNA abnormalities in high-risk ALK⁺ NSCLC (Table 1) is actually a favorable coincidence, because they can be leveraged for non-invasive disease monitoring, which is more imperative in thes worse-prognosis patients. The type of ALK fusion variant does not change during the disease course of individual patients (8), but longitudinal assays of other molecular features can provide useful information. One early effort was to monitor the TP53 mutation status, whose conversion from wild-type at initial diagnosis to mutated at the time of TKI failure was associated with poor prognosis similar to that of tumors with TP53 mutations present already at baseline (12). Finer granularity can be achieved by quantification of the VAF for single-nucleotide variants (SNV) of TP53 and other mutated genes, whose longitudinal levels in serial assays proved to be a faithful indicator of tumor remission status in individual patients (9). It should be noted here that ALK⁺ NSCLC is a disease with a very low tumor mutational burden (TMB), uniquely below 3 mut/MB in median (5), and approximately 30–50% of these patients may not have detectable SNV in the ctDNA, as also noted by Soo et al. in their recent work (6). For patients with unremarkable targeted ctDNA NGS, quantification of copy number variations (CNV) using shallow whole genome sequencing (sWGS) and the trimmed mean absolute deviation from copy number neutrality (tMAD) score can provide an alternative and more universally applicable marker of disease activity (9). Interestingly, both the SNV VAF and the tMAD can facilitate earlier detection of disease progression than imaging studies with a median lead time of approximately 3 months in about 50% of patients (17). Other emerging parameters for the molecular monitoring of ALK⁺ NSCLC are epigenetic ctDNA changes as well as serum cytokines (18,19). A polyparametric approach combining several biomarkers parameters in a tailored manner can increase accuracy, and has shown promise in pilot studies for the improved monitoring of individual patients (20,21).

How important is this progress for our patients actually? The potential clinical utility of a closer surveillance for metastatic NSCLC is underlined by the fact that approximately 25% of ALK⁺ patients will forego available next-line targeted therapies due to rapid clinical deterioration (22). In the final analyses of the ALEX and ALTA-1L phase 3 trials, the percentage of deceased patients that did not receive any further therapy after 2G TKI in the experimental arms was even higher at 40% (2,3), while a comparable 35% attrition between therapy lines has also be reported for EGFR⁺ NSCLC (23). Another compelling reason to push radiation-free, non-invasive disease monitoring methods forward for metastatic disease is the very long duration of therapy with modern TKI for oncogene-driven NSCLC. On the other hand, for early-stage NSCLC after resection, serial monitoring of minimal-residual disease in the blood offers the prospect to assess individual patient risk more accurately and detect relapses earlier compared to imaging studies (24). Longitudinal ctDNA assays could fill these gaps, but remain underutilized due to the lack of reimbursement in Europe and most other countries. High-quality prospective data, like the evidence provided by Soo et al (6) and currently generated by the ongoing ABP and other studies for 2G ALK inhibitors (25), will be instrumental in order to convince regulatory bodies and improve the situation. With concerted efforts from several investigators, ALK⁺ NSCLC is increasingly becoming a model disease not only for the development of potent targeted drugs, but also for the successful clinical application of novel molecular tools.

Acknowledgments

Funding: This work was funded by the German Center for Lung Research (DZL).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-4/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-4/coif). This work was funded by the German Center for Lung Research (DZL). The author declares research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. The author has no other conflicts of interest to declare.

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