exon 20 insertions (ex20ins) are an uncommon genotype in non-small cell lung cancer (NSCLC) for which targeted therapies are under development. We sought to describe treatment outcomes and genomic ...and immunophenotypic characteristics of these tumors.
We identified sequential patients with NSCLC with
ex20ins and compared their clinical outcomes and pathologic features with other patients with NSCLC.
Among 6,290 patients with NSCLC, 106 (2%) had
ex20ins. Patients with
ex20ins were more likely to be Black (14% vs. 6%;
< 0.001) or Asian (22% vs. 10%;
< 0.001) compared with all other patients with NSCLC. Median tumor mutational burden (TMB; 3.5 vs. 5.9;
< 0.001) and proportion of tumors with PD-L1 expression ≥1% (22% vs. 60%;
< 0.001) were lower in
ex20ins compared with other NSCLCs (TMB,
= 5,851 and PD-L1 expression,
= 282) and
del 19/L858R (median TMB, 3.5;
= 0.001 and 39% PD-L1 ≥ 1%;
= 0.02). Compared with a 2:1 cohort of patients with metastatic NSCLC without targetable alterations (
= 192),
ex20ins patients had longer overall survival (median 20 vs. 12 months; HR, 0.56;
= 0.007) and longer time to treatment discontinuation (TTD) for platinum chemotherapy (median, 7 vs. 4 months; HR, 0.6;
= 0.02) and no improvement in TTD for immune checkpoint inhibitors (ICI; HR, 1.75;
= 0.05).
With better outcomes on platinum chemotherapy, patients with
ex20ins NSCLC have improved prognosis, lower PD-L1 expression and TMB, and derive less benefit from ICIs compared with patients with NSCLC without targetable oncogenes. Improving molecularly targeted therapies could provide greater benefit for patients with
ex20ins.
Central nervous system (CNS) metastases develop in nearly half of patients with RET fusion-positive NSCLCs and cause morbidity and mortality. The selective RET inhibitor selpercatinib treats existing ...intracranial disease, but no studies have investigated whether early initiation of selpercatinib is associated with decreased development of CNS metastases.
A total of 61 patients with RET fusion-positive advanced NSCLC with and without CNS metastases treated with selpercatinib on the LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 expanded access program (NCT03906331) were identified. Cumulative incidence rates (CIRs) for CNS metastases were assessed as an event of interest; systemic progression of disease and death were considered competing risks.
The median age was 65 years, and the most common 5′ fusion partners were KIF5B (67%) and CCDC6 (18%). There were 24 patients (39%) who received prior platinum chemotherapy and 20 patients (33%) who received prior multikinase inhibition. The median time on selpercatinib was 21.8 months. Furthermore, 30 patients (49%) had CNS disease at baseline and 31 patients (51%) had no baseline CNS disease. CIRs of CNS progression among patients with baseline CNS disease were 3% (95% confidence interval CI: 0%–10%), 10% (95% CI: 0%–22%), 17% (3%–30%), 17% (3%–30%), and 20% (5%–35%) at 6, 12, 18, 24, and 36 months, respectively. CIR for CNS progression among patients without baseline CNS disease was 0% at 6, 12, 18, 24, and 36 months (95% CI: 0%–0%).
CNS progression was not observed with selpercatinib therapy in patients without baseline CNS disease. CNS progression on selpercatinib was rare in patients with baseline CNS disease. Early initiation of selpercatinib is associated with decreased rates of CNS metastasis formation and progression and may play a preventive role.
The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find ...that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression.
Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent
mutations or specific gene fusions, most commonly involving
. Comprehensive ...analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically.
A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT;
= 136) or hotspot 8-oncogene genotyping (
= 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS).
Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including
mutations (76%),
fusions (7%),
alterations (6%), and other less common events. In addition, WTS identified a novel
fusion (
-
). Overall, targetable gene fusions were identified in 51% of
wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with
-mutant IMAs,
-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (
< 0.0001).
This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of
-rearranged IMAs,
as the third most common alteration, and a novel
fusion in these tumors. Comprehensive molecular testing of
wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.
Clinical relevance thresholds and laboratory methods are poorly defined for MET amplification, a targetable biomarker across malignancies.
The utility of next-generation sequencing (NGS) in assessing ...MET copy number alterations was determined in >50,000 solid tumors. Using fluorescence in situ hybridization as reference, we validated and optimized NGS analysis.
Incorporating read-depth and focality analyses achieved 91% concordance, 97% sensitivity, and 89% specificity. Tumor heterogeneity, neoplastic cell proportions, and genomic focality affected MET amplification assessment. NGS methodology showed superiority in capturing overall amplification status in heterogeneous tumors and defining amplification focality among other genomic alterations. MET copy gains and amplifications were found in 408 samples across 23 malignancies. Total MET copy number inversely correlated with amplified segment size. High-level/focal amplification was enriched in certain genomic subgroups and associated with targeted therapy response.
Leveraging our integrated bioinformatic approach, targeted therapy benefit was observed across diverse MET amplification contexts.
Preferred first-line treatment for patients with metastatic EGFR-mutant lung cancer is osimertinib, yet it is not known whether patient outcomes may be improved by identifying and intervening on ...molecular markers associated with therapeutic resistance.
All patients with metastatic EGFR-mutant lung cancer treated with first-line osimertinib at the Memorial Sloan Kettering Cancer Center (n = 327) were identified. Available pretreatment and postprogression tumor samples underwent targeted gene panel sequencing and mutational signature analysis using SigMA algorithm. Progression-free survival (PFS) and overall survival were estimated using the Kaplan-Meier method.
Using multivariate analysis, baseline atypical EGFR (median PFS = 5.8 mo, p < 0.001) and concurrent TP53/RB1 alterations (median PFS = 10.5 mo, p = 0.015) were associated with shorter PFS on first-line osimertinib. Of 95 patients with postprogression biopsies, acquired resistance mechanisms were identified in 52% (off-target, n = 24; histologic transformation, n = 14; on-target, n = 12), with MET amplification (n = 9), small cell lung transformation (n = 7), and acquired EGFR amplification (n = 7), the most frequently identified mechanisms. Although there was no difference in postprogression survival on the basis of identified resistance (p = 0.07), patients with subsequent second-line therapy tailored to postprogression biopsy results had improved postprogression survival (hazard ratio = 0.09, p = 0.006). The paired postprogression tumors had higher tumor mutational burden (p = 0.008) and further dominant APOBEC mutational signatures (p = 0.07) compared with the pretreatment samples.
Patients with EGFR-mutant lung cancer treated with first-line osimertinib have improved survival with treatment adaptation on the basis of identified mechanisms of resistance at time of progression using tissue-based genomic analysis. Further survival gains may be achieved using risk-based treatment adaptation of pretreatment genomic alterations.
Spontaneous chylous effusions are rare; however, they have been observed by independent investigators in patients treated with RET tyrosine kinase inhibitors (TKIs).
This multicenter, retrospective ...study evaluated the frequency of chylous effusions in patients treated with RET TKIs. Clinicopathologic features and management of patients with chylous effusions were evaluated.
A pan-cancer cohort of 7517 patients treated with one or more multikinase inhibitor or selective RET TKI and a selective TKI cohort of 96 patients treated with selpercatinib or pralsetinib were analyzed. Chylous effusions were most common with selpercatinib (7%), followed by agerafenib (4%), cabozantinib (0.3%), and lenvatinib (0.02%); none were observed with pralsetinib. Overall, 12 patients had chylothorax, five had chylous ascites, and five had both. Time from TKI initiation to diagnosis ranged from 0.5 to 50 months. Median fluid triglyceride level was lower in chylothoraces than in chylous ascites (397 mg/dL interquartile range: 304–4000 versus 3786 mg/dL interquartile range: 842–6596, p = 0.035). Malignant cells were present in 13% (3 of 22) of effusions. Chyle leak was not identified by lymphangiography. After initial drainage, 76% of patients with chylothorax and 80% with chylous ascites required additional interventions. Selpercatinib dose reduction and discontinuation rates in those with chylous effusions were 47% and 0%, respectively. Median time from diagnosis to disease progression was not reached (95% confidence interval: 14.5–undefined); median time from diagnosis to TKI discontinuation was 11.4 months (95% confidence interval: 8.2–14.9).
Chylous effusions can emerge during treatment with selected RET TKIs. Recognition of this side effect is key to prevent potential misattribution of worsening effusions to progressive malignancy.
MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in
exon 14-altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly ...characterized and comprehensive proteomic analyses have not previously been performed.
We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of
exon 14-altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated.
Seventy-five of 168
exon 14-altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS (
> 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS (
= 15) or immunochemistry (
= 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87;
= 0.02).
In
exon 14-altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials.
Residual cancer cells that survive drug treatments with targeted therapies act as a reservoir from which eventual resistant disease emerges. Although there is great interest in therapeutically ...targeting residual cells, efforts are hampered by our limited knowledge of the vulnerabilities existing in this cell state. Here, we report that diverse oncogene-targeted therapies, including inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and BRAF, induce DNA double-strand breaks and, consequently, ataxia-telangiectasia mutated (ATM)-dependent DNA repair in oncogene-matched residual tumor cells. This DNA damage response, observed in cell lines, mouse xenograft models, and human patients, is driven by a pathway involving the activation of caspases 3 and 7 and the downstream caspase-activated deoxyribonuclease (CAD). CAD is, in turn, activated through caspase-mediated degradation of its endogenous inhibitor, ICAD. In models of
mutant non-small cell lung cancer (NSCLC), tumor cells that survive treatment with small-molecule EGFR-targeted therapies are thus synthetically dependent on ATM, and combined treatment with an ATM kinase inhibitor eradicates these cells in vivo. This led to more penetrant and durable responses in
mutant NSCLC mouse xenograft models, including those derived from both established cell lines and patient tumors. Last, we found that rare patients with
mutant NSCLC harboring co-occurring, loss-of-function mutations in
exhibit extended progression-free survival on first generation EGFR inhibitor therapy relative to patients with
mutant NSCLC lacking deleterious
mutations. Together, these findings establish a rationale for the mechanism-based integration of ATM inhibitors alongside existing targeted therapies.
Experience Sampling Response Modes French, Kimberly A.; Falcon, Christina N.; Allen, Tammy D.
Journal of business and psychology,
10/2019, Letnik:
34, Številka:
5
Journal Article
Recenzirano
When conducting experience sampling studies, one important decision that researchers must make is the method by which surveys are administered. Dozens of reviews and recommendations cover types of ...response modes, including paper and pencil, online survey, and interactive voice response. However, few studies have empirically tested differences across response methods, and no studies have compared online surveys to interactive voice response surveys. Using a time-based experience sampling design, the present study investigates differences in compliance, data quality, and participant burden when using interactive voice response and online surveys. Results indicate no differences in terms of compliance rates and number of responses between the two methods. Interactive voice response produced lengthier qualitative responses, although there were no differences in the clarity of qualitative responses. Finally, online surveys may alleviate time burden, particularly as the number of items increases.
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