Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis.

The clinical benefits of immune checkpoint inhibitor (ICI)-based treatments in treating individuals with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who have progressed on EGFR tyrosine-kinase inhibitors (TKIs) remain controversial. We aimed to review the literature to comprehensively investigate the individual and comparative clinical outcomes of various ICI-based treatment strategies in this population. In this systematic review and meta-analysis, we used single-arm, pairwise, and network meta-analytical approaches. We searched PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and relevant international conference proceedings from database inception to Jan 31, 2024, without language restrictions, to identify eligible clinical trials that assessed ICI-based treatments for individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs. Studies considered eligible were published and unpublished phase 1, 2, or 3 clinical trials enrolling participants with histologically or cytologically confirmed advanced EGFR-mutated NSCLC who had progressed after at least one EGFR-TKI treatment, and that evaluated ICI-based treatment strategies on at least one of the clinical outcomes of interest. The primary outcome analysed was progression-free survival. The protocol is registered with PROSPERO, CRD42021292626. 17 single-arm trials and 15 randomised controlled trials, involving 2886 participants and seven ICI-based treatment strategies (ICI monotherapy, ICI plus chemotherapy [ICI-chemo], ICI plus antiangiogenesis [ICI-antiangio], ICI plus antiangiogenesis plus chemotherapy [ICI-antiangio-chemo], dual ICIs [ICI-ICI], dual ICIs plus chemotherapy [ICI-ICI-chemo], and ICI plus EGFR-TKI [ICI-TKI]), were included. Three of these strategies-ICI monotherapy, ICI-antiangio-chemo, and ICI-chemo-had sufficient data across the included studies to perform a pairwise meta-analysis. The pairwise meta-analysis showed that, compared with chemotherapy, ICI monotherapy led to shorter progression-free survival (hazard ratio [HR] 1·73 [95% CI 1·30-2·29], I2=0%), whereas ICI-antiangio-chemo (HR 0·54 [0·44-0·67], I2=0%) and ICI-chemo (HR 0·77 [0·67-0·88], I2=0%) prolonged progression-free survival. The network meta-analysis showed that ICI-antiangio-chemo yielded the best progression-free survival results, with substantial benefits over ICI-chemo (HR 0·71 [95% credible interval 0·59-0·85]), ICI monotherapy (HR 0·30 [0·22-0·41]), and non-ICI treatment strategies including antiangio-chemo (HR 0·76 [0·58-1·00]) and chemotherapy alone (HR 0·54 [0·45-0·64]). ICI-antiangio-chemo was associated with higher risks of both any-grade and grade 3 or worse adverse events over ICI-chemo and chemotherapy in the network meta-analysis. For individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs, ICI-antiangio-chemo was identified as the optimal treatment option. The toxicity of this treatment was acceptable but needs careful attention. ICI-chemo showed appreciably greater efficacy than the standard-of-care chemotherapy. These findings clarified the roles of ICI-based treatment strategies in this difficult-to-treat refractory population, potentially complementing recent guidelines. None.

Zhao Y ，He Y ，Wang W ，Cai Q ，Ge F ，Chen Z ，Zheng J ，Zhang Y ，Deng H ，Chen Y ，Lao S ，Liang H ，Liang W ，He J ... -  《-》

Systemic treatment options for non-small cell lung cancer after failure of previous immune checkpoint inhibitors: a bayesian network meta-analysis based on randomized controlled trials.

Although immune checkpoint inhibitors (ICIs) have brought survival benefits to non-small cell lung cancer (NSCLC), disease progression still occurs, and there is no consensus on the treatment options for these patients. We designed a network meta-analysis (NMA) to evaluate systemic treatment options for NSCLC after failure of ICIs. PubMed, Embase, Web of Science and Cochrane Library databases were searched, then literature screening was followed by NMA. We included all Phase II and III randomized controlled trials (RCTs). Progression-free survival (PFS) and overall survival (OS) used hazard ratio (HR) for evaluation. Objective response rate (ORR) and adverse events (AEs) used odds ratio (OR) and relative risk (RR) effect sizes, respectively. R software was applied to compare the Bayesian NMA results. We finally included 6 studies. 1322 patients received ICI plus Chemotherapy (ICI + Chemo), ICI plus Anti-angiogenic monoclonal antibody (ICI + Antiangio-Ab), ICI plus Tyrosine kinase inhibitor (ICI + TKI), Tyrosine kinase inhibitor plus Chemotherapy (TKI + Chemo), Standard of Care (SOC), Chemotherapy (Chemo). TKI + Chemo is associated with longer PFS, higher ORR (surface under cumulative ranking curve [SUCRA], 99.7%, 88.2%), ICI + TKI achieved the longest OS (SUCRA, 82.7%). ICI + Antiangio-Ab was granted the highest safety rating for adverse events (AEs) of any grade, AEs greater than or equal to grade 3 and AEs of any grade leading to discontinuation of treatment (SUCRA, 95%, 82%, 93%). For NSCLC after failure of ICIs, TKI + Chemo was associated with longer PFS and higher ORR, while ICI + TKI was associated with the longest OS. In terms of safety, ICI + Antiangio-Ab was the highest.

Wang K ，Fu Z ，Sun G ，Ran Y ，Lv N ，Wang E ，Ding H ... -  《BMC IMMUNOLOGY》

The efficacy and safety of immune checkpoint inhibitors for patients with EGFR-mutated non-small cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy: A systematic review and network meta-analysis.

Wang Z ，Zhou F ，Xu S ，Wang K ，Ding H ... -  《Cancer Medicine》

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.

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. 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. to maintain the currency of evidence using a living systematic review approach. 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. 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. 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 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 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.

Ferrara R ，Imbimbo M ，Malouf R ，Paget-Bailly S ，Calais F ，Marchal C ，Westeel V ... -  《Cochrane Database of Systematic Reviews》

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.

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. 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. 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. 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. 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 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 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.

Ferrara R ，Imbimbo M ，Malouf R ，Paget-Bailly S ，Calais F ，Marchal C ，Westeel V ... -  《Cochrane Database of Systematic Reviews》