Defining molecular risk in ALK+ NSCLC

Abstract

Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancers (NSCLC) have the best prognosis among metastatic pulmonary malignancies, with a median patient survival currently exceeding 5 years. While this is definitely a major therapeutic success for thoracic oncology, it may not be entirely attributable to rapid drug development and the strenuous clinical efforts. At the genetic level, ALK + disease is also unique, distinguished by the lowest tumor mutational burden (mean below 3 mutations/Mbp), the lowest frequency of TP53 mutations (20–25%) and very few other co-mutations compared to other NSCLC. The relative simplicity and stability of the genetic landscape not only contribute to the relatively favourable clinical course, but also make study of the effects from individual molecular features easier. EML4-ALK fusion variant 3 (E6;A20) and TP53 mutations were recently identified as main molecular determinants of adverse outcome: they occur in about 30–40% and 20–25% of newly-diagnosed cases, respectively, have possibly synergistic effects and are independently associated with more aggressive disease, shorter progression-free survival under treatment with ALK inhibitors and worse overall survival. Secondary detection of TP53 mutations at disease progression in previously negative patients defines another subset (about 20%) with similarly poor outcome, while detection of ALK resistance mutations guides next-line therapy. As our biological understanding deepens, additional molecular risk factors will be identified and refine our concepts further. The translation of clinical risk at the molecular level and the ability to predict early events are of key importance for individualized patient management and preclinical modeling in order to advance therapeutic options.

Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors

“…This is in line with the result of a smaller series including 81 immunotherapy-treated patients that detected a rate of 11% (9/81) for OPD using slightly different criteria [14]. The lower rate of OPD in IO-treated NSCLC could be related to its presumably higher genetic instability, as inferred by the higher tumor mutational burden (TMB) [15,16], and to the lower efficacy of current immunotherapies compared to molecularly targeted drugs [17][18][19][20]. Interestingly, our results suggest similar OPD rates for first-line IO monotherapy compared to first-line chemoimmunotherapy ( Figure 4A), which parallels the roughly similar efficacy of these treatments in terms of response rates and overall survival in the respective clinical studies, especially for patients with a higher PD-L1 expression, who are also more likely to develop OPD [19,20].…”

Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA

“…Moreover, t-MAD scores correlate with established molecular features of higher risk, i.e. with the presence of TP53 mutations and the EML4-ALK variant 3, which themselves portend worse survival, both in carefully controlled retrospective [ 5 , [54] , [55] , [56] ] and prospective trials [57] . While the EML4-ALK variant does not change during the disease, TP53 mutations do emerge under treatment, and their appearance is a marker of increased risk [6] .…”

“…3b). In addition, significantly higher t-MAD scores were found in cfDNA of patients with known molecular risk factors [5]. Specifically, EML4 (Echinoderm Microtubule-Associated Protein-Like 4)-ALK variant E6:A20 (V3)-positive samples showed higher t-MAD scores compared to variants E13:A20/E20:A20 (V1/V2; median 0.0076 vs. 0.0083, Mann-Whitney U test p < 0.05, Fig.…”

“…4 data available for 59/73 cases; two cases with E18A20, one with E9A20, one with E17A20, one with K9A20 (KLC1), one with K24A20 (KIF5B), and one with HIP1-ALK. 5 data available for 61 cases by NGS of tissue biopsies at diagnosis of stage IV disease.…”

“…However, clinical courses vary widely, since acquired resistance mutations in the ALK kinase domain, ALK amplifications, or activation of bypass signaling pathways emerge in a poorly predictable manner [2] , [3] , [4] . Recent studies suggest that the risk is affected by specific molecular factors, including the ALK fusion variant and the presence of TP53 ( Tumour Protein p53 ) co-mutations [5] , [6] , [7] , [8] , [9] , [10] . Importantly, for patients failing TKI treatment, a second and even a third disease remission is possible by applying different compounds [1] , the efficacy of which depends on individual resistance mechanisms [2] .…”