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.
Background
We present a comprehensive analysis of
KRAS
,
PIK3CA
,
MET,
and non-sensitizing
EGFR
mutations in advanced non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase ...inhibitors (TKIs), with the aim of clarifying the relative contribution of these molecular alterations to resistance.
Patients and methods
One hundred and sixty-six patients with advanced NSCLC treated with EGFR-TKIs with available archival tissue specimens were included.
EGFR
(exons 18–21),
KRAS
(exons 2, 3),
PIK3CA
(exons 9, 20), and
MET
(exons 14, 15) mutations were analyzed using PCR-based sequencing. Among all the mutations evaluated, only
KRAS
,
PIK3CA
,
MET,
and non-sensitizing
EGFR
mutations, defined as “TKI non-sensitizing mutations” were used for response, time to progression (TTP), and overall survival (OS) analysis.
Results
TKI non-sensitizing mutations were associated with disease progression (
p
= 0.001), shorter TTP (
p
< 0.0001), and worse OS (
p
= 0.03). Cox’s multivariate analysis including histology and performance status showed that TKI non-sensitizing mutations were independent factors for shorter TTP (
p
< 0.0001) and worse OS (
p
= 0.01).
Conclusions
When
KRAS
,
PIK3CA
,
MET,
and non-sensitizing
EGFR
mutations are concomitant, up to 96.0% of NSCLC patients unlikely to respond to TKIs can be identified, and they represented independent negative prognostic factors. Comprehensive molecular dissection of EGFR signaling pathways should be considered to select advanced NSCLC patients for TKIs therapies.
Background
In most cases, T790M
EGFR
-positive NSCLC patients receiving osimertinib developed “non-drugable” progression, as the patients with common
EGFR
-sensitizing mutations were treated with ...first-line osimertinib. In both settings, chemotherapy represents the standard treatment and local ablative treatments (LATs) are potential useful options in the case of oligo-progression.
Methods
We conducted a study on “post-progression” (pp) outcomes of T790M
EGFR
-positive NSCLC patients treated with osimertinib, according to the therapeutic strategy applied: osimertinib beyond progression (± LATs), “switched therapies” or best supportive care only (BSC).
Results
144 consecutive patients were evaluated: 53 (36.8%) did not received post-progression treatments (BSC), while 91 (63.2%) patients received at least 1 subsequent treatment; 50 patients (54.9%) received osimertinib beyond disease progression 19 (20.9%) of them with adjunctive LATs and 41 (45.1%) a switched therapy. Median ppPFS (progression-free survival) and median ppOS (overall survival) of patients who received osimertinib beyond progression vs. switched therapies were 6.4 months vs. 4.7 months, respectively HR 0.57 (95% CI 0.35–0.92),
p
= 0.0239 and 11.3 months vs 7.8 months, respectively HR 0.57 (95% CI 0.33–0.98),
p
= 0.0446. Among patients who received osimertinib beyond progression with and without LATs median ppPFS was 6.4 months and 5.7 months, respectively HR 0.90 (95% CI 0.68–1.18),
p
= 0.4560, while median ppOS was 20.2 months and 9.9 months, respectively HR 0.73 (95% CI 0.52–1.03),
p
= 0.0748. At the univariate analysis, the only factor significantly related to the ppPFS was the therapeutic strategy in favor of osimertinib beyond progression (± LATs). Moreover, the only variable which was significantly related to ppOS at the multivariate analysis was osimertinib beyond progression (± LATs).
Conclusion
Our study confirmed that in clinical practice, in case of “non-druggable” disease progression, maintaining osimertinib beyond progression (with adjunctive LATs) is an effective option.
Coronavirus disease 2019 (COVID-19) has rapidly spread to every country around the world taking on pandemic proportions. Since 8 March 2020, the Italian government ordered a nationwide lockdown with ...unavoidable social isolation. Healthcare professionals (HCPs) represent the most physically and emotionally involved category. The aim of this study is to assess the social distress among HCPs in Italy.
In this online, totally anonymous survey, 24 multiple choice questions were posed to medical staff employed in the Italian Healthcare System during the COVID-19 pandemic. Data collection was performed from 30 March to 24 April 2020.
A total of 600 HCPs completed the questionnaire. The majority of respondents expressed the fear of being at higher risk of contagion than the general population (83.3%) and the weighty concern of infecting their families (72.5%). An insufficient supply of personal protective equipment (PPE; P = 0.0003) and inadequate training about procedures to follow (P = 0.0092) were seen to significantly coincide with these worries. More than two-thirds declared a change in family organisation, which showed a significant correlation with the concern of infecting their relatives (P < 0.0001).
This is the first Italian survey on social distress among HCPs during the COVID-19 pandemic. The unavailability of PPE, screening procedures and adequate training strongly affected HCPs' emotional status. Although there was a predominance of oncologists (especially from the North of Italy), which impairs the generalisation of our findings, this survey underlined the social impact that this health emergency has had on HCPs.
•This is the first Italian survey on healthcare professionals’ (HCPs) social distress during the coronavirus disease 2019 (COVID-19) pandemic.•The majority expressed the fear of being at high risk of contagion and the weighty concern of infecting their families.•Insufficient supply of personal protective equipment and inadequate training about procedures correlate with these worries.•Reducing workers’ psychological distress will certainly yield significant positive benefits for HCPs and health system.
Purpose
KRAS
mutation has been associated with enhanced dependency on the folate metabolism in preclinical studies. However, whether
KRAS
mutation correlates to increased sensitivity to pemetrexed in ...patients with advanced NSCLC is unknown.
Methods
Patients with advanced non-squamous NSCLC who had a documented
EGFR
and
ALK
WT genotype with simultaneous
KRAS
mutation assessment were evaluated for clinical outcome to pemetrexed- and non-pemetrexed-based first-line platinum doublet according to
KRAS
mutation status.
Results
Of 356 patients identified, 138 harbored a
KRAS
mutation. Among
KRAS
-mutant NSCLCs, those treated with platinum/pemetrexed (81/138) had significantly lower ORR (30.9% versus 47.4%,
P
= 0.05), DCR (51.8% versus 71.9%,
P
= 0.02) and shorter median progression-free survival mPFS 4.1 versus 7.1 months, HR 1.48 (95% CI 1.03–2.12),
P
= 0.03 and median overall survival mOS 9.7 versus 26.9 months, HR 1.93 (95% CI 1.27–2.94),
P
= 0.002 compared to those who received a non-pemetrexed-based platinum doublet (57/138). No difference in ORR, DCR, mPFS and mOS was observed between
KRAS
WT patients who received a pemetrexed-based (124/218) versus non-pemetrexed base platinum doublets (94/218). After adjusting for performance status, age and the presence of brain metastasis at baseline, treatment with pemetrexed-based platinum doublet was associated with an increased risk of death HR 2.27 (95% CI 1.12–4.63),
P
= 0.02 among
KRAS
-mutant patients in multivariate analysis.
Conclusion
Patients with
KRAS
-mutant lung adenocarcinoma have a poorer outcome on pemetrexed-based first-line chemotherapy. Whether
KRAS
-mutant NSCLCs should be excluded from pemetrexed-containing regimens should be assessed prospectively.
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