This study aimed at generating a new simplified prognostic score (SPS) using common clinical and biological variables to discriminate a limited number of subgroups of patients with SCLC differing by ...their overall survival (OS).
The SPS was developed exploring the Montpellier University Hospital retrospective database of 401 patients over a 16-year period. All patients had received etoposide - platinum-based chemotherapy as first-line treatment. The SPS development took into account significant determinants of OS in the Cox model, weighted by their regression β coefficients. Validation of the consequent SPS has been done separately in a combined population of 213 patients accrued from two different published trials (NCT03059667 and NCT00930891).
The significant independent determinants of OS included the following: (1) American Joint Committee on Cancer TNM stage IV (hazard ratio HR: 2.52; 95% confidence interval CI: 1.91-3.33); (2) Eastern Cooperative Oncology Group performance status greater than 1 (HR: 2.27; 95% CI: 1.79-2.87); (3) the presence of liver metastases (HR: 1.66; 95% CI: 1.29-2.15); and (4) neutrophil-to-lymphocyte ratio greater than 4 (HR: 1.39; 95% CI: 1.11-1.92). The SPS generated with these four variables, segregated three groups (good, intermediate, and poor prognosis) with respective median OS of 26.9 months (95% CI: 20.1-38.9), 11.5 months (95% CI: 9.8-13.0), and 6.8 months (95% CI: 5.8-8.3; log-rank
< 10
). Harrell's C statistic estimate was 0.68 ± 0.012, suggesting goodness of calibration. In the validation cohort, the SPS segregated the aforementioned three subgroups in a nearly similar manner, with respective median OS: 27.2, 12.3, and 8.6 months (log-rank
< 10
; Harrell's C statistic: 0.58 ± 0.02).
The SPS is easy to calculate in real-life practice and efficiently discriminates three populations with different prognoses. This study deserves further validation of this score in patients with SCLC receiving immunochemotherapy.
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In the NELSON study, nodule management that was based on growth-rate assessment for intermediate nodules was shown to increase the sensitivity of lung cancer detection.2 Such pulmonary nodule ...management was implemented in France during the course of our trial.3 Compared with the NELSON screening programme, chest CT scans in the IFCT-0302 trial were standard dosed, and done more frequently, which might have counterbalanced the potential loss in sensitivity for the detection of small pulmonary nodules. ...as emphasised by Goto, in our study, CT-based follow-up enabled the detection of more cases of early recurrence and second primary lung cancer than the minimal follow-up group, and they were more frequently treated with curative intent. Whether a trial implementing a personalised follow-up strategy and using a more up-to-date nodule management could translate into survival benefit remains unknown.
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In The Lancet Oncology, Rina Hui and colleagues report the patient-reported outcomes (PROs) data of the PACIFIC study.1 The PACIFIC study2,3 set a new standard of care in patients with stage III ...non-small-cell lung cancer, finding a significant benefit in survival with adjuvant durvalumab after chemoradiotherapy compared with placebo. ...the toxicity profile of immunotherapy is different to that of non-immunotherapy interventions, and new approaches might be necessary to capture specific immunotherapy-related changes in HRQOL. ...since the development and validation of new questionnaires is a lengthy process, addition of items from the EORTC Item Library to validated questionnaires (such as regarding experience of muscle weakness) could improve evaluation of HRQOL in patients being treated with immune checkpoint inhibitors.9 Beyond the choice of the questionnaire, the requirements of HRQOL assessment in immunotherapy might differ from that of chemotherapy. Since immune-related adverse events affect few patients and severe adverse events remain infrequent, it is not surprising that, overall, quality of life was unaffected.
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Background
Immune checkpoint inhibitors (ICIs) targeting the PD‐1/PD‐L1 axis have changed the first‐line treatment of people with advanced non‐small cell lung cancer (NSCLC). Single‐agent ...pembrolizumab (a PD‐1 inhibitor) is currently the standard of care as monotherapy in patients with PD‐L1 expression ≥ 50%, either alone or in combination with chemotherapy when PD‐L1 expression is less than 50%. Atezolizumab (PD‐L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti‐angiogenic antibody) in first‐line NSCLC regardless of PD‐L1 expression. The combination of first‐line PD‐1/PD‐L1 inhibitors with anti‐CTLA‐4 antibodies has also been shown to improve survival compared to platinum‐based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD‐1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD‐L1 expression ≥1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best‐treatment strategy, the role of different biomarkers for treatment selection and the effectiveness of immunotherapy according to specific clinical characteristics.
Objectives
Primary objective: to determine the effectiveness and safety of first‐line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum‐based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD‐L1 expression. Secondary objective: to maintain the currency of evidence using a living systematic review approach.
Search methods
We performed an electronic search of the main databases (Cochrane Lung Cancer Group Trial Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 21 October 2020 and conferences meetings from 2015 onwards.
Selection criteria
We included randomised controlled trials (RCTs) reporting on the efficacy or safety of first‐line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single‐ or double‐ICI treatment to standard first‐line therapy (platinum‐based chemotherapy +/‐ bevacizumab). All data come from ‘international multicentre studies involving adults, age 18 or over, with histologically‐confirmed stage IV NSCLC who had not received any previous systemic anti‐cancer treatment for advanced disease.
Data collection and analysis
Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression‐free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment‐related adverse events (AEs) (CTCAE v 5.0) and health‐related quality of life (HRQoL). We performed meta‐analyses where appropriate using the random‐effects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the I² statistic to investigate heterogeneity.
Main results
Main results
We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first‐line single‐ (six trials) or double‐ (two trials) agent ICI with platinum‐based chemotherapy, one trial comparing both first‐line single‐ and double‐agent ICsI with platinum‐based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate‐to‐low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD‐L1 expressions, with PD‐L1 ≥ 50 being considered the most clinically useful cut‐off level for decision makers. Also, iIn order to avoid overlaps between various PDL‐1 expressions we prioritised the review outcomes according to PD‐L1 ≥ 50.
Single‐agent ICI In the PD‐L1 expression ≥ 50% group single‐agent ICI probably improved OS compared to platinum‐based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate‐certainty evidence). In this group, single‐agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low‐certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low‐certainty evidence). HRQoL data were available for only one study including only people with PD‐L1 expression ≥ 50%, which suggested that single‐agent ICI may improve HRQoL at 15 weeks compared to platinum‐based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low‐certainty evidence). In the included studies, treatment‐related AEs were not reported according to PD‐L1 expression levels. Grade 3‐4 AEs may be less frequent with single‐agent ICI compared to platinum‐based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50, I² = 62%, 5 RCTs, 3346 participants, low‐certainty evidence).
More information about efficacy of single‐agent ICI compared to platinum‐based chemotherapy according to the level of PD‐L1 expression and to TMB status or specific clinical characteristics is available in the full text.
Double‐agent ICI Double‐ICI treatment probably prolonged OS compared to platinum‐based chemotherapy in people with PD‐L1 expression ≥50% (HR: 0.72, 95% CI 0.59 to 0.89 2 RCTs, 612 participants, moderate‐certainty evidence). Trials did not report data on HRQoL, PFS and ORR according to PD‐L1 groups. Treatment related AEs were not reported according to PD‐L1 expression levels. The frequency of grade 3‐4 AEs may not differ between double‐ICI treatment and platinum‐based chemotherapy (RR: 0.78, 95% CI 0.55 to 1.09, I² = 81%, 2 RCTs, 1869 participants, low‐certainty evidence).
More information about efficacy of double‐agent ICI according to the level of PD‐L1 expression and to TMB status is available in the full text.
Authors' conclusions
Authors' conclusions
The evidence in this review suggests that single‐agent ICI in people with NSCLC and PD‐L1 ≥50% probably leads to a higher overall survival rate and may lead to a higher progression‐free survival and overall response rate when compared to platinum‐based chemotherapy and may also lead to a lower rate of adverse events and higher HRQoL. Combined ICI in people with NSCLC and PD‐L1 ≥50% also probably leads to a higher overall survival rate when compared to platinum‐based chemotherapy, but its effect on progression‐free survival, overall response rate and HRQoL is unknown due to a lack of data. The rate of adverse events may not differ between groups.
Background. Although a minimal follow-up with periodic clinic visits and chest radiographs is usually recommended after complete operation for non–small cell lung cancer, the ideal follow-up has not ...been defined yet. Objectives of this prospective study were to determine the feasibility of an intensive surveillance program and to analyze its influence on patient survival.
Methods. Follow-up consisted of physical examination and chest roentgenogram every 3 months and fiberoptic bronchoscopy and thoracic computed tomographic scan with sections of the liver and adrenal glands every 6 months. Influence of patient and recurrence characteristics on survival from recurrence was successively analyzed using the log-rank test and a Cox model adjusted for treatment.
Results. Among the 192 eligible patients, recurrence developed in 136 patients (71%) and was asymptomatic in 36 patients (26%). In 35 patients, recurrence was asymptomatic and detected by a scheduled procedure: thoracic computed tomographic scan in 10 (28%) patients and fiberoptic bronchoscopy in 10. Fifteen patients (43%) had a thoracic recurrence treated with curative intent. From the date of recurrence, 3-year survival was 13% in all patients and 31% in asymptomatic patients whose recurrence was detected by a scheduled procedure. Asymptomatic recurrences (
p < 0.001), female sex (
p < 0.001), performance status 2 or less (
p = 0.01), and age 61 years or younger (
p = 0.01) were shown to be significantly favorable prognostic factors.
Conclusions. This intensive follow-up is feasible and may improve survival by detecting recurrences after surgery for non–small cell lung cancer at an asymptomatic stage.
This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: We aim to compare overall survival in people with recurrence and second primary lung cancer (SPLC) after lung ...cancer surgery. If survival differs between those people categorised as having index lung cancer recurrence and those categorised as having SPLC, it might be possible to identify the definition that has the best discriminatory capacity from the various published definitions of these conditions, so that it can be used in future.OBJECTIVESThis is a protocol for a Cochrane Review (prognosis). The objectives are as follows: We aim to compare overall survival in people with recurrence and second primary lung cancer (SPLC) after lung cancer surgery. If survival differs between those people categorised as having index lung cancer recurrence and those categorised as having SPLC, it might be possible to identify the definition that has the best discriminatory capacity from the various published definitions of these conditions, so that it can be used in future.
Background
Immune checkpoint inhibitors (ICIs) targeting the PD‐1/PD‐L1 axis have changed the first‐line treatment of people with advanced non‐small cell lung cancer (NSCLC). Single‐agent ...pembrolizumab (a PD‐1 inhibitor) is currently the standard of care as monotherapy in patients with PD‐L1 expression ≥ 50%, either alone or in combination with chemotherapy when PD‐L1 expression is less than 50%. Atezolizumab (PD‐L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti‐angiogenic antibody) in first‐line NSCLC regardless of PD‐L1 expression. The combination of first‐line PD‐1/PD‐L1 inhibitors with anti‐CTLA‐4 antibodies has also been shown to improve survival compared to platinum‐based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD‐1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD‐L1 expression ≥1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best‐treatment strategy, the role of different biomarkers for treatment selection and the effectiveness of immunotherapy according to specific clinical characteristics.
Objectives
To determine the effectiveness and safety of first‐line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum‐based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD‐L1 expression.
Search methods
We performed an electronic search of the main databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 31 December 2020 and conferences meetings from 2015 onwards.
Selection criteria
We included randomised controlled trials (RCTs) reporting on the efficacy or safety of first‐line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single‐ or double‐ICI treatment to standard first‐line therapy (platinum‐based chemotherapy +/‐ bevacizumab). All data come from ‘international multicentre studies involving adults, age 18 or over, with histologically‐confirmed stage IV NSCLC.
Data collection and analysis
Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression‐free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment‐related adverse events (AEs) (CTCAE v 5.0) and health‐related quality of life (HRQoL). We performed meta‐analyses where appropriate using the random‐effects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the I² statistic to investigate heterogeneity.
Main results
Main results
We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first‐line single‐ (six trials) or double‐ (two trials) agent ICI with platinum‐based chemotherapy, one trial comparing both first‐line single‐ and double‐agent ICsI with platinum‐based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate‐to‐low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD‐L1 expressions, with PD‐L1 ≥ 50 being considered the most clinically useful cut‐off level for decision makers. Also, iIn order to avoid overlaps between various PDL‐1 expressions we prioritised the review outcomes according to PD‐L1 ≥ 50.
Single‐agent ICI In the PD‐L1 expression ≥ 50% group single‐agent ICI probably improved OS compared to platinum‐based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate‐certainty evidence). In this group, single‐agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low‐certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low‐certainty evidence). HRQoL data were available for only one study including only people with PD‐L1 expression ≥ 50%, which suggested that single‐agent ICI may improve HRQoL at 15 weeks compared to platinum‐based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low‐certainty evidence). In the included studies, treatment‐related AEs were not reported according to PD‐L1 expression levels. Grade 3‐4 AEs may be less frequent with single‐agent ICI compared to platinum‐based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50, I² = 62%, 5 RCTs, 3346 participants, low‐certainty evidence).
More information about efficacy of single‐agent ICI compared to platinum‐based chemotherapy according to the level of PD‐L1 expression and to TMB status or specific clinical characteristics is available in the full text.
Double‐agent ICI Double‐ICI treatment probably prolonged OS compared to platinum‐based chemotherapy in people with PD‐L1 expression ≥50% (HR: 0.72, 95% CI 0.59 to 0.89 2 RCTs, 612 participants, moderate‐certainty evidence). Trials did not report data on HRQoL, PFS and ORR according to PD‐L1 groups. Treatment related AEs were not reported according to PD‐L1 expression levels. The frequency of grade 3‐4 AEs may not differ between double‐ICI treatment and platinum‐based chemotherapy (RR: 0.78, 95% CI 0.55 to 1.09, I² = 81%, 2 RCTs, 1869 participants, low‐certainty evidence).
More information about efficacy of double‐agent ICI according to the level of PD‐L1 expression and to TMB status is available in the full text.
Authors' conclusions
Authors' conclusions
The evidence in this review suggests that single‐agent ICI in people with NSCLC and PD‐L1 ≥50% probably leads to a higher overall survival rate and may lead to a higher progression‐free survival and overall response rate when compared to platinum‐based chemotherapy and may also lead to a lower rate of adverse events and higher HRQoL. Combined ICI in people with NSCLC and PD‐L1 ≥50% also probably leads to a higher overall survival rate when compared to platinum‐based chemotherapy, but its effect on progression‐free survival, overall response rate and HRQoL is unknown due to a lack of data. The rate of adverse events may not differ between groups.
This review used to be a living review. It is transitioned out of living mode because current research is exploring ICI in association with chemotherapy or other immunotherapeutic drugs versus ICI as single agent rather than platinum based chemotherapy.
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 of treatment 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 locally advanced disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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