Aim
A systematic literature review of immuno-oncology trials was conducted to assess the potential impact of open-label vs double-blind trial design on patient-reported outcome (PRO) data.
Methods
A ...systematic search of indexed literature published from January 2009 to May 2019 was conducted using PubMed/MEDLINE, Cochrane Library, and EMBASE database. All randomized clinical trials (RCTs) of immuno-oncology therapies on advanced cancer patients reporting PRO data were identified. Descriptive analyses were performed to quantify differences at baseline and over time, by the type of study, regarding questionnaire completion rate and PRO scores.
Results
In total, 23 studies were retained (15 open-label, 8 blinded). At baseline, no difference in completion rate was observed between arms irrespective of trial design (absolute mean difference of 2.8% and 2.2% for open label and blinded studies, respectively). No clinically significant difference in baseline PRO scores was observed between arms. Over time, impact on PRO scores could not be identified due to the limited number of studies, heterogeneity of questionnaires and tumor types.
Conclusions
Trial design had no impact on PRO completion rate or baseline scores. Future research should involve analyses by specific cancer types and ideally compare individual data from two similar RCTs (blinded vs. open-label).
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CEKLJ, DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Summary Background Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus ...Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC. Methods 148 patients with advanced (stage IIIB wet or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (108 plaque forming units) plus cisplatin (75 mg/m2 on day 1) and gemcitabine (1250 mg/m2 on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov , number NCT00415818. Findings 6-month PFS was 43·2% (32 of 74; 95% CI 33·4–53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9–45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3–4 adverse events were neutropenia (33 45·2% of patients in the TG4010 plus chemotherapy group vs 31 43·1% in the chemotherapy alone group) and fatigue (18 24·7% vs 13 18·1%); the only grade 3–4 events that differed significantly between groups were anorexia (three 4·1% vs 10 13·9%) and pleural effusion (none vs four 5·6%). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event. Interpretation This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B–3 trial has been initiated. Funding Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Non-small cell lung cancer is a very poor prognosis disease. Molecular analyses have highlighted several genetic alterations which may be targeted by specific therapies. In clinical practice, ...progression-free survival on EGFR TKI treatment is between 12 and 14 months. However, some patients progress rapidly in less than 6 months, while others remain free of progression for 16 months or even longer during EGFR TKI treatment.
We sequenced tumor exomes from 135 lung cancer patients (79 with EGFR-wildtype (WT), 56 with EGFR-mutant tumors) enrolled in the ALCAPONE trial (genomic analysis of lung cancers by next generation sequencing for personalized treatment).
Some germline polymorphisms were enriched in the EGFR-mutant subset compared to EGFR-WT tumors or to a reference population. However, the most interesting observation was the negative impact of some germline SNPs in immunity-related genes on survival on EGFR TKI treatment. Indeed, the presence of one of three particular SNPs in the HLA-DRB5 gene was associated with a decreased PFS on EGFR TKI. Moreover, some SNPs in the KIR3DL1 and KIR3DL2 genes were linked to a decrease in both progression-free and overall survival of patients with EGFR-mutant tumors.
Our data suggest that SNPs in genes expressed by immune cells may influence the response to targeted treatments, such as EGFR TKIs. This indicates that the impact of these cells may not be limited to modulating the response to immunotherapies. Further studies are needed to determine the exact mechanisms underlying this influence and to identify the associated predictive and prognostic markers that would allow to refine treatments and so improve lung cancer patient outcomes.
NCT02281214: NGS Genome Analysis in Personalization of Lung Cancer Treatment (ALCAPONE).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundThe IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC).MethodsIn a multicenter, single-arm, phase II ...trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable NSCLC received three doses of durvalumab (750 mg every 2 weeks) and underwent surgery between 2 and 14 days after the last infusion. The primary endpoint was the complete surgical resection rate. Secondary endpoints included tumor response rate, major histopathological response (MPR: ≤10% remaining viable tumor cells), disease-free survival (DFS), overall survival (OS), durvalumab-related safety, and 90-day postoperative mortality (NCT03030131).ResultsForty-six patients were eligible (median age 60.9 years); 67% were male, 98% were smokers, and 41% had squamous cell carcinoma. Regarding tumor response, 9% had a partial response, 78% had stable disease, and 13% had progressive disease. Among the operated patients (n=43), 41 achieved complete resection (89%, 95% CI 80.1% to 98.1%)), and eight achieved MPR (19%). The 12-month median OS and DFS rates were 89% (95% CI 75.8% to 95.3%) and 78% (95% CI 63.4% to 87.7%), respectively (n=46). The median follow-up was 28.4 months (12.8–41.1). All patients in whom MPR was achieved were disease-free at 12 months compared to only 11% of those with >10% residual tumor cells (p=0.04). No durvalumab-related serious or grade 3–5 events were reported. The unexpected 90-day postoperative mortality of four patients led to premature study termination. None of these four deaths was considered secondary to direct durvalumab-related toxicity.ConclusionsNeoadjuvant durvalumab given as monotherapy was associated with an 89% complete resection rate and an MPR of 19%. Despite an unexpectedly high rate of postoperative deaths, which prevented us from completing the trial, we were able to show a significant association between MPR and DFS.
Our study aimed to evaluate whether pathologic complete response (pCR) in early-stage non–small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy resulted in improved outcome, and to determine ...predictive factors for pCR.
Eligible patients with stage-IB or -II NSCLC were included in two consecutive Intergroupe Francophone de Cancérologie Thoracique phase-III trials evaluating platinum-based neoadjuvant chemotherapy, with pCR defined by the absence of viable cancer cells in the resected surgical specimen.
Among the 492 patients analyzed, 41 (8.3%) achieved pCR. In the pCR group, 5-year overall survival was 80.0% compared with 55.8% in the non-pCR group (p = 0.0007). In multivariate analyses, pCR was a favorable prognostic factor of overall survival (relative risk = 0.34; 95% confidence interval = 0.18–0.64) in addition to squamous-cell carcinoma, weight loss less than or equal to 5%, and stage-IB disease. Five-year disease-free survival was 80.1% in the pCR group compared to 44.8% in the non-pCR group (p < 0.0001). Two patients (4.9%) in the pCR group experienced disease recurrence compared to 193 patients (42.8%) in the non-pCR group. SCC subtype was the only independent predictor of pCR (odds ratio OR = 4.30; 95% confidence interval = 1.90–9.72).
Our results showed that pCR after preoperative chemotherapy was a favorable prognostic factor in stage-IB–II NSCLC. Our study is the largest published series evaluating pCRs after preoperative chemotherapy. The only factor predictive of pCR was squamous-cell carcinoma. Identifying molecular predictive markers for pCR may help in distinguishing patients likely to benefit from neoadjuvant chemotherapy and in choosing the most adequate preoperative chemotherapy regimen.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cardiopulmonary exercise testing (CPET) is an important clinical tool that provides a global assessment of the respiratory, circulatory and metabolic responses to exercise which are not adequately ...reflected through the measurement of individual organ system function at rest. In the context of critical COVID-19, CPET is an ideal approach for assessing long term sequelae.
In this prospective single-center study, we performed CPET 12 months after symptom onset in 60 patients that had required intensive care unit treatment for a severe COVID-19 infection. Lung function at rest and chest computed tomography (CT) scan were also performed.
Twelve months after severe COVID-19 pneumonia, dyspnea was the most frequently reported symptom although only a minority of patients had impaired respiratory function at rest. Mild ground-glass opacities, reticulations and bronchiectasis were the most common CT scan abnormalities. The majority of the patients (80%) had a peak O
uptake (V'O
) considered within normal limits (median peak predicted O
uptake (V'O
) of 98% 87.2-106.3). Length of ICU stay remained an independent predictor of V'O
. More than half of the patients with a normal peak predicted V'O
showed ventilatory inefficiency during exercise with an abnormal increase of physiological dead space ventilation (VD/Vt) (median VD/VT of 0.27 0.21-0.32 at anaerobic threshold (AT) and 0.29 0.25-0.34 at peak) and a widened median peak alveolar-arterial gradient for O
(35.2 mmHg 31.2-44.8. Peak PetCO
was significantly lower in subjects with an abnormal increase of VD/Vt (p = 0.001). Impairments were more pronounced in patients with dyspnea. Peak VD/Vt values were positively correlated with peak D-Dimer plasma concentrations from blood samples collected during ICU stay (r
= 0.12; p = 0.02) and to predicted diffusion capacity of the lung for carbon monoxide (D
) (r
= - 0.15; p = 0.01).
Twelve months after severe COVID-19 pneumonia, most of the patients had a peak V'O
considered within normal limits but showed ventilatory inefficiency during exercise with increased dead space ventilation that was more pronounced in patients with persistent dyspnea.
NCT04519320 (19/08/2020).
The French healthcare system is a universal healthcare system with no financial barrier to access to health services and cancer drugs. The objective of the study is to investigate associations ...between, on the one hand, incidence and survival of patients diagnosed with lung cancer in France and, on the other, the socioeconomic deprivation and population density of their municipality of residence. A national, longitudinal analysis using data from the French National Hospital database crossed with the population density of the municipality and a social deprivation index based on census data aggregated at the municipality level. For lung cancer diagnosed at the metastatic stage, one-year and two-year survival was not associated with the population density of the municipality of residence. In contrast, mortality was higher for people living in very deprived, deprived and privileged areas compared to very privileged areas (hazard ratios at two years: 1.19 1.13-1.25, 1.14 1.08-1.20 and 1.10 1.04-1.16 respectively). Similar associations are also observed in patients diagnosed with non-metastatic disease (hazard ratios at two years: 1.21 1.13-1.30, 1.15 1.08-1.23 and 1.10 1.03-1.18 for people living in very deprived, deprived and privileged areas compared to very privileged areas). Despite a universal healthcare coverage, survival inequalities in patients with lung cancer can be observed in France with respect to certain socioeconomic indicators.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are approved for second-line treatment of
wild-type (
-wt) nonsmall cell lung cancer (NSCLC). However, results from randomised ...trials performed to compare EGFR-TKIs with chemotherapy in this population did not show any survival benefit. In the era of immunotherapy, many drugs are approved for second-line treatment of
wt NSCLC and there is a need to reassess the role of EGFR-TKIs in this setting.The Biomarkers France study is a large nationwide cohort of NSCLC patients tested for
mutations. We used this database to collect clinical, biological, treatment and outcome data on
wt patients who received second-line treatment with either EGFR-TKIs or chemotherapy.Among 1278 patients, 868 received chemotherapy and 410 received an EGFR-TKI. Median overall survival and progression-free survival were longer with chemotherapy than with an EGFR-TKI. Overall survival was 8.38
4.99 months, respectively (hazard ratio 0.70, 95% CI 0.59-0.83; p<0.0001) and progression-free survival was 4.30
2.83 months, respectively (hazard ratio 0.66, 95% CI 0.57-0.77; p<0.0001).This study is helpful to guide a multiline treatment strategy for
wt NSCLC patients. Immunotherapy is approved for second-line treatment. For third-line treatment, chemotherapy results in longer overall survival and progression-free survival, and should be preferred to EGFR-TKIs.
This randomized, double-blind, placebo-controlled phase III study aimed to determine whether thalidomide prolongs survival of patients with extensive-disease small-cell lung cancer (SCLC).
One ...hundred nineteen patients received two courses of etoposide, cisplatin, cyclophosphamide, and 4'-epidoxorubicin (PCDE). Responder patients who had recovered from chemotherapy toxicity were randomly assigned to receive four additional PCDE cycles plus thalidomide (400 mg daily) or placebo.
After the first two PCDE cycles, objective response rate was 81.5%, and 92 patients were randomly assigned to placebo (n = 43) or thalidomide (n = 49). Median exposure duration to placebo was 4.5 months, and median exposure to thalidomide was 4.9 months. Patients treated with thalidomide had a longer survival compared with patients who received placebo, although the difference was not statistically significant (minimal follow-up, 3 years; median survival time, 11.7 v 8.7 months, respectively; log-rank test: hazard ratio HR = 0.74; 95% CI, 0.49 to 1.12; P = .16). Patients with a performance status (PS) of 1 or 2 who received thalidomide had a significantly longer survival (HR = 0.59; 95% CI, 0.37 to 0.92; P = .02). The disease also progressed slower in patients with PS of 1 or 2 receiving thalidomide (HR = 0.54; 95% CI, 0.36 to 0.87; P = .02), whereas the difference did not reach statistical significance for the whole population (HR = 0.74; 95% CI, 0.49 to 1.12; P = .15). Neuropathy occurred more frequently in the thalidomide group compared with the placebo group (33% v 12%, respectively).
Treatment with thalidomide was not associated with a significant improvement in survival of SCLC patients. There was pronounced heterogeneity in survival outcomes between groups of patients. Some benefit was observed among patients with a PS of 1 or 2 (exploratory analyses), deserving further studies targeting angiogenesis in this disease.
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