Single or combined immune checkpoint inhibitors compared to first‐line platinum‐based chemotherapy with or without bevacizumab for people with advanced non‐small cell lung cancer

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.</p

Single or combined immune checkpoint inhibitors compared to first‐line platinum‐based chemotherapy with or without bevacizumab for people with advanced non‐small cell lung cancer

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.</p

Occupational exposure to petroleum-based and oxygenated solvents and hypopharyngeal and laryngeal cancer in France the ICARE study

International audienceBACKGROUND:To examine associations between occupational exposure to petroleum-based and oxygenated solvents and the risk of hypopharyngeal and laryngeal cancer.METHODS:ICARE is a large, frequency-matched population-based case-control study conducted in France. Lifetime occupational history, tobacco smoking and alcohol consumption were collected. Analyses were restricted to men and included 383 cases of hypopharyngeal cancer, 454 cases of laryngeal cancer, and 2780 controls. Job-exposure matrices were used to assess exposure to five petroleum-based solvents (benzene; gasoline; white spirits; diesel, fuels and kerosene; special petroleum products) and to five oxygenated solvents (alcohols; ketones and esters; ethylene glycol; diethyl ether; tetrahydrofuran). Odds ratios (ORs) adjusted for smoking, alcohol drinking and other potential confounders and 95% confidence intervals (CI) were estimated with unconditional logistic models.RESULTS:No significant association was found between hypopharyngeal or laryngeal cancer risk and exposure to the solvents under study. Non-significantly elevated risks of hypopharyngeal cancer were found in men exposed to high cumulative levels of white spirits (OR = 1.46; 95% CI: 0.88-2.43) and tetrahydrofuran (OR = 2.63; 95CI%: 0.55-12.65), with some indication of a dose-response relationship (p for trend: 0.09 and 0.07 respectively).CONCLUSION:This study provides weak evidence for an association between hypopharyngeal cancer and exposure to white spirits and tetrahydrofuran, and overall does not suggest a substantial role of exposure to petroleum-based or oxygenated solvents in hypopharyngeal or laryngeal cancer risk

Prognostic nomogram and score to predict overall survival in locally advanced untreated pancreatic cancer (PROLAP)

Background: The management of locally advanced pancreatic cancer (LAPC) patients remains controversial. Better discrimination for overall survival (OS) at diagnosis is needed. We address this issue by developing and validating a prognostic nomogram and a score for OS in LAPC (PROLAP). Methods: Analyses were derived from 442 LAPC patients enrolled in the LAP07 trial. The prognostic ability of 30 baseline parameters was evaluated using univariate and multivariate Cox regression analyses. Performance assessment and internal validation of the final model were done with Harrell's C-index, calibration plot and bootstrap sample procedures. On the basis of the final model, a prognostic nomogram and a score were developed, and externally validated in 106 consecutive LAPC patients treated in Besançon Hospital, France. Results: Age, pain, tumour size, albumin and CA 19-9 were independent prognostic factors for OS. The final model had good calibration, acceptable discrimination (C-index=0.60) and robust internal validity. The PROLAP score has the potential to delineate three different prognosis groups with median OS of 15.4, 11.7 and 8.5 months (log-rank P<0.0001). The score ability to discriminate OS was externally confirmed in 63 (59%) patients with complete clinical data derived from a data set of 106 consecutive LAPC patients; median OS of 18.3, 14.1 and 7.6 months for the three groups (log-rank P<0.0001). Conclusions: The PROLAP nomogram and score can accurately predict OS before initiation of induction chemotherapy in LAPC-untreated patients. They may help to optimise clinical trials design and might offer the opportunity to define risk-Adapted strategies for LAPC management in the future