Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase (
) positive (
) non-small cell lung cancer (NSCLC) in a French temporary authorisation ...for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced
or ROS proto-oncogene 1 positive (
) tumours. Patients received oral ceritinib (750 mg·day
as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had
NSCLC and 13 had
NSCLC. The median age of
patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and 50.0% had brain metastases. Of the 149 efficacy evaluable
NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0%
42.4%) and those receiving prior crizotinib for >5 months (51.6%
36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day
) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with
NSCLC.
TPS9144
Background: Second generation ALK tyrosine kinase inhibitors (ALK-TKI), including brigatinib, provide substantial therapeutic benefit in first-line treatment of ALK-positive NSCLC patients ...(pts) but relapse eventually occurs in all pts due to development of drug resistance, possibly caused by emergence of drug-tolerant cells (DTC). Combining chemotherapy to TKI may prevent DTC emergence in preclinical studies, and results in prolonged progression-free survival (PFS) and overall survival in EGFR-mutant NSCLC. We hypothesize that combination of second generation ALK-TKI with chemotherapy will improve clinical outcomes in advanced ALK-positive NSCLC patients. The IFCT-2101 MASTERPROTOCOL ALK trial will evaluate the efficacy and safety of brigatinib and carboplatin-pemetrexed combination in treatment-naïve metastatic ALK-positive NSCLC. Methods: The IFCT-2101 MASTERPROTOCOL ALK randomized, open-label phase II trial will enrol 110 pts in 30 French centers over 24 months. Eligible pts will have metastatic NSCLC with ALK-fusion according to local testing, be untreated for advanced disease, and have an ECOG Performance Status (PS) of 0-1 and at least one measurable lesion per RECIST 1.1. Pts with asymptomatic and stable brain metastases (BM) will be eligible. Exclusion criteria include leptomeningeal metastases. Patients will be randomized 1:1 to receive brigatinib monotherapy (Arm A) or combination brigatinib and carboplatin-pemetrexed therapy (Arm B), with PS (0 vs 1) and BM (presence vs absence) as stratification factors. Brigatinib will be administered at a dose of 90 mg QD for a 7-day lead-in period followed by 180 mg QD continuously, in 28-day cycles. In Arm B, 4 cycles of carboplatin (AUC 5) and pemetrexed (500 mg/m
2
) therapy every 3 weeks will be added at Day 8 of brigatinib treatment. Treatment will continue until progression, intolerable toxicity or discontinuation. The first 26 pts enrolled in Arm B will represent the population of a safety phase, during which adverse events (AE) will be closely monitored by an independent data monitoring committee. The primary endpoint is investigator-assessed 12-month PFS rate. Secondary endpoints include independently-reviewed 12-month PFS rate, overall response rate (ORR), 12-month intracranial PFS and ORR, incidence, nature and severity of AEs, and impact of ALK-fusion detection, co-mutations and clearance of circulating tumor (ct) DNA (Guardant360) on outcome. Exploratory objectives include the evaluation of early blood ctDNA decrease on patient outcome. The study is enrolling and primary completion date is March 2025. Clinical trial information: NCT05200481.
Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) ...inhibitors. The rate and outcome of HPD in advanced non-small cell lung cancer (NSCLC) are unknown.
To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD.
In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required.
The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%.
The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy.
Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% 35 of 56 vs 42.6% 149 of 350; P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months 95% CI, 2.8-7.5 months vs 6.2 months 95% CI, 5.3-7.9 months; hazard ratio, 2.18 95% CI, 1.29-3.69; P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD.
Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.
Summary Background The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the ...feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov , number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years range 18–98, 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% 95% CI 34·7–38·2 for presence of a genetic alteration vs 33% 29·5–35·6 for absence of a genetic alteration; p=0·03) and in second-line treatment (17% 15·0–18·8 vs 9% 6·7–11·9; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months 95% CI 9·2–10·7 vs 7·1 months 6·1–7·9; p<0·0001) and overall survival (16·5 months 15·0–18·3 vs 11·8 months 10·1–13·5; p<0·0001) compared with absence of a genetic alteration. Interpretation Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit. Funding French National Cancer Institute (INCa).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Combination chemotherapy has been the mainstay of treatment for extensive stage small celI lung cancer (SCLC) over the last 30 years, even though it only gives a short prolongation in ...median survival time. The main goal for these patients should be palliation with the aim of improving their quality of life.
Objectives
To determine the effectiveness of first‐line chemotherapy versus placebo or best supportive care (BSC) in prolonging survival in patients with extensive SCLC at diagnosis and the effectiveness of second‐line chemotherapy at relapse or progression after first‐line chemotherapy compared with BSC or placebo in prolonging survival in patients with extensive SCLC; as well as to evaluate the adverse events of treatment and the quality of life of patients.
Search methods
This is the second update of the review. MEDLINE (1966 to October 2013), EMBASE (1974 to October 2013), and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 3) were searched. Experts in the field were contacted.
Selection criteria
Phase III randomised controlled trials in which any chemotherapy treatment was compared with placebo or BSC in patients with extensive SCLC, as first‐line or second‐line therapy at relapse.
Data collection and analysis
Two authors independently extracted data and assessed study quality. We resolved disagreements by discussion. Additional information was obtained from one study author.
Main results
Two studies of unclear risk of bias were included for first‐line chemotherapy. A total of 88 men under 70 years with good performance status were randomised to receive either supportive care, placebo infusion or ifosfamide. Ifosfamide gave an extra mean survival of 78.5 days compared with supportive care or placebo infusion. Partial tumour response was greater with the active treatment. Toxicity was only seen in the chemotherapy group and quality of life was only assessed at the beginning of treatment. The quality of the evidence for overall survival and adverse effects was very low.
Three studies of moderate risk of bias were included for second‐line chemotherapy at relapse (one identified in the last search). A total of 932 men and women under 75 years and any performance status were randomised to receive either methotrexate‐doxorubicin, topotecan, or picoplatin versus symptomatic treatment or BSC. The methotrexate‐doxorubicin treatment gave a median survival of 63 days longer than in the symptomatic‐treatment group for patients allocated to receive four cycles of first‐line chemotherapy, and 21 days longer for patients allocated to receive eight cycles of first‐line chemotherapy.
Treatment with topotecan gave a median survival of 84 days longer than in the BSC group (log‐rank P = 0.01). The adjusted hazard ratio (HR) for overall survival was 0.61 (95% CI 0.43 to 0.87). Treatment with picoplatin gave a median survival time of six days longer than BSC (HR 0.817, 95% CI 0.65 to 1.03, P = 0.0895). A meta‐analysis of topotecan and picoplatin gave a HR of 0.73 (95% CI 0.55 to 0.96, P = 0.03; low‐quality evidence).
Partial or complete response in the methotrexate‐doxorubicin group was 22.3%. Five patients (7%, 95% CI 2.33 to 15.67) showed a partial response with topotecan. No data were provided about tumour response in the picoplatin study. Toxicity was worst in the chemotherapy group (moderate‐quality evidence). Quality of life was better in the topotecan group and was not measured in the methotrexate‐doxorubicin and picoplatin studies (low‐quality evidence).
Authors' conclusions
Two small RCTs from the 1970s suggest that first‐line chemotherapeutic treatment (based on ifosfamide) may provide a small survival benefit (less than three months) in comparison with supportive care or placebo infusion in patients with advanced SCLC. However platinum‐based combination chemotherapy regimens have been shown to increase complete response rates when compared to non‐platinum chemotherapy regimens with no significant difference in survival, and so these are currently the standard first‐line treatment for patients with SCLC.
Second‐line chemotherapy at relapse or progression may prolong survival for some weeks in relation to BSC. Nevertheless, the impact of first‐line chemotherapy on quality of life, older patients, women and patients with poor prognosis is unknown and the benefits of second‐line chemotherapy are also unclear for older people. Globally, the evidence on which these conclusions are based is very scarce and of uncertain or low quality, which calls for well‐designed, controlled trials to further evaluate the trade‐offs between benefits and risks of different chemotherapeutic schedules in patients with advanced SCLC.
exon 20 insertions and point mutations are oncogenic drivers found in 1%-2% of patients with non-small-cell lung cancer (NSCLC). No targeted therapy is approved for this subset of patients. We ...prospectively evaluated the effectiveness of the combination of two antibodies against human epidermal growth factor 2 (HER2 HER2 trastuzumab and pertuzumab with docetaxel; trastuzumab and pertuzumab) and docetaxel.
The IFCT 1703-R2D2 trial is a multicenter, nonrandomized phase II study. Patients with
-mutated, advanced NSCLC who progressed after ≥ 1 platinum-based treatment were enrolled. Patients received pertuzumab at a loading dose of 840 mg and 420 mg thereafter; trastuzumab at an 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at a dose of 75 mg/m
every 3 weeks. The primary outcome was the objective response rate (ORR). Other end points included the duration of response, progression-free survival, and safety (NCT03845270).
Forty-five patients were enrolled and treated. The median age was 64.5 years (range, 31-84 years), 35% were smokers, 72% were females, 15% had an Eastern Cooperative Oncology Group performance status of 2, and 30% had brain metastases. The objective response rate was 29% (n = 13), and 58% had stable disease (n = 26). The median progression-free survival was 6.8 months (95% CI, 4.0 to 8.5). The median duration of response in patients with a confirmed response (n = 13) was 11 months (95% CI, 2.9 to 14.9). Grade 3/4 treatment-related adverse events were observed in 64% of the patients. No patient discontinued treatment because of toxicity. The most frequent grade ≥ 3 treatment-related adverse events were neutropenia (33%), diarrhea (13%), and anemia (9%).
Triple therapy with trastuzumab, pertuzumab, and docetaxel is feasible and effective for
-mutated pretreated advanced NSCLC. These results highlight the effectiveness of the HER2 antibody-based strategy, which should be considered for these patients.
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary
To determine the efficacy and safety of first‐line immune checkpoint inhibitors, or immuno‐oncology ...therapy (IO), as monotherapy or in combination for patients with advanced non‐small cell lung cancer (NSCLC).
Secondary
To maintain the currency of evidence by taking a living systematic review approach.
Health-related quality of life (HRQoL) is recognized as a component endpoint for cancer therapy approvals. The aim of this review was to evaluate the methodology of HRQoL analysis and reporting in ...phase III clinical trials of first-line chemotherapy in advanced non-small cell lung cancers (NSCLC).
A search in MEDLINE databases identified phase III clinical trials in first-line chemotherapy for advanced NSCLC, published between January 2008 to December 2014. Two authors independently extracted information using predefined data abstraction forms.
A total of 55 phase III advanced NSCLC trials were identified. HRQoL was declared as an endpoint in 27 studies (49%). Among these 27 studies, The EORTC questionnaire Quality of Life Questionnaire C30 was used in 13 (48%) of the studies and The Functional Assessment of Cancer Therapy-General was used in 12 (44%) trials. The targeted dimensions of HRQoL, the minimal clinically important difference and the statistical approaches for dealing with missing data were clearly specified in 13 (48.1%), 9 (33.3%) and 5 (18.5%) studies, respectively. The most frequent statistical methods for HRQoL analysis were: the mean change from baseline (33.3%), the linear mixed model for repeated measures (22.2%) and time to HRQoL score deterioration (18.5%). For each targeted dimension, the results for each group, the estimated effect size and its precision were clearly reported in 4 studies (14.8%), not clearly reported in 11 studies (40.7%) and not reported at all in 12 studies (44.4%).
This review demonstrated the weakness and the heterogeneity of the measurement, analysis, and reporting of HRQoL in phase III advanced NSCLC trials. Precise and uniform recommendations are needed to compare HRQoL results across publications and to provide understandable messages for patients and clinicians.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction: Intermediate endpoints are often used as primary endpoints instead of overall survival (OS) in lung cancer trials but they are not systematically validated as surrogate endpoints for ...OS.
Areas covered: The aim of the study was to review the studies which assessed potential surrogate endpoints for OS in lung cancer trials.
Expert commentary: Twenty studies were identified. In operable non-small cell lung cancer (NSCLC) (adjuvant trials) and locally advanced NSCLC (radiotherapy trials), one individual-patient data meta-analysis found a high correlation of disease-free survival (DFS) and progression-free survival (PFS) with OS at patient and trial level. In trials of adjuvant chemotherapy, correlation between disease-free survival DFS and OS were 0.83 at the individual level (95% CI 0.83-0.83) and 0.92 at trial level (95% CI 0.88-0.95). In locally advanced disease, correlation between PFS and OS was 0.77 to 0.85 at the individual level, and 0.89 to 0.97 at trial level. This study provides a 'proof' of the surrogacy of PFS and DFS on OS according to the IQWiG framework and the surrogacy of PFS and DFS on OS was classified level 2 according to Fleming hierarchy. In all the other setting, no endpoint was judged to be valid surrogate for OS.
To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on ...Lung Cancer was held on 11–12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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