We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
ALK-rearranged stage IIIB/IV NSCLC patients were analyzed ...with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients PFS 3.9months (95% CI: 2.4–5.6) versus 10.3months (95% CI: 8.6–12.0), P<0.001; OS 15.0months (95% CI: 5.0–24.9) versus 50.0months (95% CI: 22.9–77.1), P=0.002. This difference was confirmed in all treatment-related subgroups including chemotherapy only PFS first-line chemotherapy 2.6months (95% CI: 1.3–4.1) versus 6.2months (95% CI: 1.8–10.5), P=0.021; OS 2.0months (95% CI: 0.0–4.6) versus 9.0months (95% CI: 6.1–11.9), P=0.035, crizotinib plus chemotherapy PFS crizotinib 5.0months (95% CI: 2.9–7.2) versus 14.0months (95% CI: 8.0–20.1), P<0.001; OS 17.0months (95% CI: 6.7–27.3) versus not reached, P=0.049 and crizotinib followed by next-generation ALK-inhibitor PFS next-generation inhibitor 5.4months (95% CI: 0.1–10.7) versus 9.9months (95% CI: 6.4–13.5), P=0.039; OS 7.0months versus 50.0months (95% CI: not reached), P=0.001).
In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical and atypical carcinoids TCs and ACs). SPINET (EudraCT: ...2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) versus placebo plus BSC, with an optional open label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n=51 TCs, n=29; ACs, n=22; placebo, n=26 TCs, n=16; ACs, n=10). Median (95% confidence interval CI) PFS during double-blind and OL phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable NC) months in TCs and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN versus 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients’ quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR positive TCs and ACs and suggests clinical benefit in TCs.
Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we ...aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor.
Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator’s choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS).
Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T.
In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.
•Adjuvant platinum-based chemotherapy is accepted as standard of care in stage II and III (NSCLC) patients.•Several studies addressed the question of whether molecular tumor markers may serve as predictive biomarkers.•ITACA was planned to evaluate the predictive utility of ERCC1 and TS mRNA expression levels in completely resected NSCLC.•ITACA results indicate that adjuvant chemotherapy customization based on ERCC1 and TS mRNA levels did not improve efficacy.•In terms of safety, the pharmacogenomic-driven arm was associated with better efficacy/toxicity ratio.
There is a paucity of data about the at home monitoring and the outpatient setting and care of patients with non-invasive ventilation. We here show, in a prospective study, that both standardized ...outpatient care visits as well as quality of life monitoring at home are safe and feasible. Monitoring and managing the quality of care at home did not lead to an increase of non-elective hospitalisations or deterioration of respiratory disease burden.
Rates of disease recurrence and death following surgery remain high in early-stage non-small-cell lung cancer (NSCLC), despite adjuvant treatment and curative intent. Recently, osimertinib showed ...overwhelming evidence for disease-free survival (DFS), as demonstrated by an overall reduction in the risk of disease recurrence or death in the adjuvant setting of 80% versus control in the ADAURA study (stage IB-IIIA; hazard ratio 0.20; 99.12% confidence interval 0.14-0.30; P < 0.001). However, due to the early unblinding of ADAURA and lack of mature overall survival data, there is a need to qualitatively confirm consensus on the clinical and patient relevance of DFS.
We conducted a modified Delphi panel study consisting of two rounds of surveys, followed by a consensus meeting. An international panel of experts in the field of NSCLC and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (n = 13) was asked to rate agreement and comment on a list of pre-defined statements covering key consensus gaps. Statements were eliminated or updated between surveys, depending on the level of agreement. A final list of agreed-upon statements was drafted in the consensus meeting.
Consensus was reached on 32 qualitative statements, with topics including unmet needs in early-stage NSCLC, the value of DFS, and the value of osimertinib. Crucially, DFS was agreed to be a clinically and patient-relevant endpoint in adjuvant NSCLC. The relevance of DFS was found to relate to the ability of an adjuvant therapy, such as osimertinib, to keep patients in the clinically valuable curative intent setting, while preventing the burden associated with distant and locoregional recurrence, and progressive disease.
Addressing the need for measures that reflect clinical benefit is essential to continue improving outcomes for NSCLC patients. To that end, this work provides a qualitative framework for clinicians to consider the clinical and patient relevance of DFS in adjuvant NSCLC and the benefit demonstrated in ADAURA thus far.
•There is a need for qualitative consensus assessment of the clinical and patient relevance of DFS in the adjuvant setting.•An international panel of experts viewed DFS as a clinically and patient-relevant endpoint in adjuvant NSCLC.•DFS relevance in adjuvant therapy, e.g. osimertinib, relates to keeping early-stage patients in a curative intent setting.•Curative intent prevents or significantly delays locoregional and distant (CNS) recurrence burden and progressive disease.
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