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.
Purpose
Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome ...benefit, the most effective sequential strategy is still unknown. We describe outcomes of real-life patients according to the treatment strategy received.
Patients
We retrospectively collected 290 ALK rearranged advanced NSCLC diagnosed between 2011 and 2017 in 23 Italian institutions.
Results
After a median follow-up of 26 months, PFS for crizotinib and a new generation ALKis were 9.4 CI 95% 7.9–11.2 and 11.1 months CI 95% 9.2–13.8, respectively, while TTF were 10.2 CI 95% 8.5–12.6 and 11.9 months CI 95% 9.7–17.4, respectively, being consistent across the different settings. The composed outcomes (the sum of PFS or TTF) in patients treated with crizotinib followed by a new generation ALKis were 27.8 months CI 95% 24.3–33.7 in PFS and 30.4 months CI 95% 24.7–34.9 in TTF. The median OS from the diagnosis of advanced disease was 39 months CI 95% 31.8–54.5. Patients receiving crizotinib followed by a new generation ALKis showed a higher median OS 57 months (CI 95% 42.0–73.8) compared to those that did not receive crizotinib 38 months (CI 95% 18.6–NR) and those who performed only crizotinib as target agent 15 months (CI 95% 11.3–34.0) (
P
< 0.0001).
Conclusion
The sequential administration of crizotinib and a new generation ALKis provided a remarkable clinical benefit in this real-life population, being an interesting option to consider in selected patients.
The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical ...trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects.
61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology.
A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005).
Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.
Background and ImportancePembrolizumab (P) is a monoclonal antibody used in immunotherapy, indicated for NSCLC.Aim and ObjectivesEvaluate the effectiveness of P in terms of progression free survival ...(PFS) in patients affected by NSCLC in an Italian Hospital (IH), and comparing it with the PS. The Italian regulatory agency (AIFA) authorised P at 2 mg per kg dose, subsequently at a flat dose of 200 mg. 1 Therefore, a secondary aim is to verify whether there was a difference in terms of PFS between flat dose and per kg dose.Material and MethodsThe death and progression data were taken from the AIFA monitoring registers (RA) and compared with the company management system. PFS is the time from the first prescription to the date of end of treatment due to death or progression. The period considered is 2017–2023. The PS is Keynote0242. Patients were divided into two homogeneous groups: the first at <3mg/kg(group1) and the second ≥ 3mg/kg(group2). We calculated OS and PFS for each group.ResultsPatients evaluated were 165, 71.6% male, median age 71 years. All administrations were recorded in the RAs. Median PFS IH 218 days (0.95CI 114;230) vs PS 288 (0.95CI 187.6;nr). At 182 days, 57% of patients progressed (IH) vs 62.1% (PS). 52% of patients took a dose < 3 mg/kg, 48% ≥ 3 mg/kg. Median PFS is 258 days for the group1 (0.95CI 186;456) and 218 for the group2 (0.95CI 158;393). At 182 days: 30 patients had an event (group1) vs 29 patients (group2).Conclusion and RelevancePFS data resembles PS data. There is no significant difference in using a dose > 3 mg/kg compared to a lower one, this means that a dose per kg would lead to a reduction in drug consumption and in costs. The future goal is to reach significant numbers and to investigate adverse reactions from immunotherapy, related to different doses.References and/or Acknowledgements1. Gazzetta Ufficiale Repubblica Italiana, n° 328, 2019.2. ClinicalTrials.gov ID NCT02142738: Study of Pembrolizumab (MK-3475) Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non-Small Cell Lung Cancer (MK-3475–024/KEYNOTE-024).Conflict of InterestNo conflict of interest.
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