Oncol Ther (2022) 10:167–184 https://doi.org/10.1007/s40487-021-00182-0 ORIGINAL RESEARCH Addition of Immune Checkpoint Inhibitors to Chemotherapy vs Chemotherapy Alone as First- Line Treatment in Extensive-Stage Small-Cell Lung Carcinoma: A Systematic Review and Meta-Analysis Edurne Arriola . Marı́a González-Cao . Manuel Domine . Javier De Castro . Manuel Cobo . Reyes Bernabé . Alejandro Navarro . Ivana Sullivan . José Manuel Trigo . Joaquı́n Mosquera . Leonardo Crama . Dolores Isla Received: November 23, 2021 / Accepted: December 23, 2021 / Published online: January 15, 2022 Ó The Author(s) 2022 ABSTRACT lung cancer (ES-SCLC). The aim of this meta- analysis was to determine the relative efficacy of Introduction: The addition of immune check- first-line ICIs compared with CT in patients point inhibitors (ICIs) to conventional with ES-SCLC. chemotherapy (CT) as first-line treatment Methods: Two independent reviewers extracted improves survival in extensive-stage small-cell relevant data according to PRISMA guidelines and assessed the risk of bias using the Cochrane Collaboration’s risk-of-bias tool. Meta-analysis Supplementary Information The online version was conducted using random-effects models to contains supplementary material available at https:// doi.org/10.1007/s40487-021-00182-0. calculate an average effect size for overall R. Bernabé E. Arriola (&) Medical Oncology Department, Hospital Virgen del Medical Oncology Department, Hospital Rocı́o, Sevilla, Spain Universitari del Mar-CIBERONC, Passeig Marı́tim e-mail: mariar.bernabe.sspa@juntadeandalucia.es 25-29, 08003 Barcelona, Spain e-mail: earriola@parcdesalutmar.cat A. Navarro Medical Oncology Department, Vall d’Hebron M. González-Cao University Hospital & Vall d’Hebron Institute of Medical Oncology Department (IOR), Hospital Oncology (VHIO), Barcelona, Spain Dexeus, Barcelona, Spain e-mail: anavarro@vhio.net e-mail: mgonzalezcao@oncorosell.com I. Sullivan M. Domine Medical Oncology Department, Hospital de la Santa Medical Oncology Department, Fundación Jiménez Creu i Sant Pau, Barcelona, Spain Dı́az, Madrid, Spain e-mail: ISullivan@santpau.cat e-mail: mdomine@fjd.es J. M. Trigo J. De Castro Medical Oncology Department, Hospital Virgen de Medical Oncology Department, Hospital la Victoria, Málaga, Spain Universitario La Paz, Madrid, Spain e-mail: jmtrigo@seom.org e-mail: javier.decastro@salud.madrid.org J. Mosquera M. Cobo Medical Oncology Department, Hospital Inter-Center Medical Oncology Clinical Universitario A Coruña, A Coruña, Spain Management Unit, Regional and Virgen de la e-mail: Joaquin.mosquera.martinez@sergas.es Victoria University Hospitals, IBIMA, Málaga, Spain e-mail: manuelcobodols@yahoo.es 168 Oncol Ther (2022) 10:167–184 survival (OS), progression-free survival (PFS), age (\ 65 years/C 65 years), sex (men/women), and safety outcomes in the overall populations and ECOG performance status (0/1). Analysis by and clinically relevant subgroups. specific ICI revealed significant improvements Results: A literature search of PubMed and in OS only for atezolizumab ? CT (HR 1.36; Embase was performed. Six randomized con- 95% CI 1.09–1.69) and durvalumab ? CT (HR trolled clinical trials (IMpower133, CHECK- 1.35; 95% CI 1.12–1.62) compared with CT MATE-451, CASPIAN, KEYNOTE-604, and phase alone. II and III ipilimumab plus CT trials) with a total Conclusion: Combining anti-programmed cell of 3757 patients were included. Compared with death ligand 1 antibodies with platinum/eto- CT alone, ICIs plus CT showed a favourable poside is a superior therapeutic approach com- effect on OS (hazard ratio [HR] 0.85; 95% con- pared to CT alone for the first-line treatment of fidence intervals [CI] 0.79–0.96) and PFS (HR patients with ES-SCLC. 0.78; 95% CI 0.72–0.83) but a non-significant Graphic abstract: increase in the risk of experiencing any adverse Keywords: Anti-PD-1/PD-L1 antibodies; event (relative risk, 1.05; 95% CI 0.99–1.11). Chemotherapy; Immunotherapy; Meta- The estimated HR for OS favoured ICI combi- analysis; Small cell lung carcinoma nations in all planned subgroups according to L. Crama Medical Department Roche, Madrid, Spain e-mail: leonardo.crama@roche.com D. Isla Medical Oncology Department, Hospital Universitario Lozano Blesa, Zaragoza, Spain e-mail: disla@salud.aragon.es Oncol Ther (2022) 10:167–184 169 INTRODUCTION Key Summary Points Lung cancer is one of the most common cancers Why carry out this study? globally, with 2.2 million new cases diagnosed in 2020 [1]. Small-cell lung cancer (SCLC) Small-cell lung cancer is a very aggressive accounts for 10–15% of all newly diagnosed neoplasm with a dismal prognosis that lung cancers, with more than 275,000 new cases accounts for 10–15% of all newly diagnosed worldwide every year [2]. SCLC is a diagnosed lung cancers. very aggressive neoplasm with few treatment With the standard of care (combination of options and a dismal prognosis [3]. Several fac- platinum agents with etoposide), most tors can explain this poor outcome; the rapid patients progress soon after initial growth rate and the early development of treatment, with a median overall survival metastases mean that more than two thirds of of 10 months. patients present at diagnosis with extensive- stage (ES) disease [4]. In recent years, several studies have shown Until recently, there had been no significant good results with the addition of improvement in the effectiveness of treatments checkpoint inhibitors as first-line available for SCLC in the past few decades. The treatment; however, more research is standard of care for ES-SCLC has been the needed to deepen the knowledge combination of platinum agents (cisplatin or regarding efficacy and safety, and carboplatin) with etoposide as the first-line subgroup analysis. treatment [5]. Even though the objective What was learned from the study? response rate with this combination is 60–80% [6], most patients with SCLC experience disease The addition of immune checkpoint progression soon after initial treatment, with a inhibitors to chemotherapy as first-line median overall survival of 10 months [7]. Sev- treatment improves the survival of eral therapeutic approaches have been proposed patients with extensive-stage small-cell in an attempt to improve the survival outcomes lung cancer, specifically in terms of overall for SCLC patients. Among these, adding survival and progression-free survival. immunotherapy to conventional chemother- Among the analysed checkpoint apy has recently been explored as a first-line inhibitors, atezolizumab and durvalumab strategy in ES-SCLC patients. Previous observa- combinations showed the best results. tions suggested a possible role of immunother- apy in SCLC and provided the rationale for the use of immune checkpoint inhibitors (ICIs). However, there were also reasons why immunotherapy may not be a good option for the treatment of SCLC. First, SCLC tumours DIGITAL FEATURES have a high mutation burden due to the effect of tobacco exposure in its pathogenesis [8]. This article is published with digital features, Second, immune-mediated paraneoplastic dis- including a graphical abstract, to facilitate orders are more common in SCLC than in other understanding of the article. To view digital tumours [9]. Some paraneoplastic syndromes features for this article, go to https://doi.org/10. are associated with the production of presumed 6084/m9.figshare.17429642. tumour neoantigen-directed humoral antibod- ies that cross-react with somatic antigens in other organs, such as neurological paraneo- plastic syndromes. Finally, the last reason is the existence of exceptional long-term survivors 170 Oncol Ther (2022) 10:167–184 after chemotherapy, accounting for fewer than with human participants or animals performed 5% of cases from historical series [10]. Recent by any of the authors. advances in immunotherapy include the development of therapeutic antibodies blocking Identifying Relevant Studies the inhibitory checkpoint molecules pro- grammed cell death protein-1 (PD-1)/pro- We performed a comprehensive literature grammed cell death ligand-1 (PD-L1) and search, and specific search strategies were cytotoxic T-lymphocyte-associated antigen 4 designed for major citation databases, including (CTLA-4) antibody that blocks the binding of MEDLINE and Embase databases, up to 17 July CTLA-4 to the ligands CD80 and CD86. How- 2020. Free and controlled terminology (Medical ever, determining which SCLC patients derive Subject Headings [MeSH] and EMTREE, respec- benefit from PD-1/PD-L1-directed tively) were used and combined by Boolean immunotherapy remains a key question. operators to develop the search strategies. Unfortunately, the use of PD-L1 immunohisto- Details of the search strategies are presented in chemistry as a predictive biomarker may be Tables S1 and S2 in the online supplementary confounded by multiple unresolved issues, such materials. The search was restricted to human as variable detection antibodies, differing cut- studies, with no restrictions on the language of offs, or tissue preparation. Indeed, preliminary publication. Moreover, we checked the refer- data suggest that in SCLC patients, PD-L1 ence lists of all eligible primary studies and expression is low and does not appear to be a reviewed articles for additional potentially eli- predictive biomarker of response to gible studies. immunotherapy combined with chemotherapy [11, 12]. Study Selection Although the addition of anti-PD-L1 to first- line chemotherapy with anti-PD-L1 mainte- nance is emerging as a promising therapeutic Following the removal of duplicates, the titles option, currently, the studies analysing longer- and abstracts of retrieved articles were screened term follow-up are not available. Data on the according to the following inclusion criteria: (1) benefits and risks of ICIs in combination with randomized controlled trials (RCTs) published conventional chemotherapy as a first-line ther- in any format (full paper, conference abstracts) apeutic strategy in patients with ES-SCLC are with sufficient data available to estimate out- heterogeneous because different immunother- comes; (2) enrolled patients who were newly apy strategies have been tried in different trials diagnosed with ES-SCLC (e.g., tumour beyond of various designs. The aim of the present sys- ipsilateral hemithorax and regional nodes tematic review and meta-analysis is to analyse including distant metastases, malignant peri- the efficacy and safety of adding ICIs to con- cardial or pleural effusions, and contralateral ventional chemotherapy compared with con- supraclavicular and contralateral hilar involve- ventional chemotherapy alone or associated ment) and previously untreated; (3) compared with placebo as first-line treatment in patients the combination of chemotherapy plus an ICI with ES-SCLC. (including atezolizumab, durvalumab, pem- brolizumab, nivolumab, and/or ipilimumab) with chemotherapy alone, with or without METHODS placebo, as the first-line treatment (chemotherapy could include cisplatin, We conducted the current systematic review cyclophosphamide, doxorubicin, vincristine, and meta-analysis in accordance with the Pre- epirubicin, carboplatin, etoposide, irinotecan, ferred Reporting Items for Systematic Reviews or topotecan, in any combination); and (4) the and Meta-Analyses (PRISMA) statement [13]. primary outcome was survival, expressed as This article is based on previously conducted overall survival (OS), progression-free survival studies and does not contain any new studies (PFS) and/or survival rates at 12 months, and/or Oncol Ther (2022) 10:167–184 171 adverse events. The exclusion criteria were as participants and staff (performance bias); (4) follows: (1) trials enrolling participants with blinding of outcome assessment (detection non-small cell lung cancer or mixed popula- bias); (5) incomplete outcome data (attrition tions; (2) studies analysing ICI monotherapy or bias); (6) selective reporting of results (reporting using any ICI or chemotherapy not listed above; bias); and (7) other biases. Each study was and (3) trials with a single arm or any other assessed for these potential sources of bias; the design (narrative reviews, editorial comments, risk was categorized as low, high, or unclear, and letters). Full-text versions of all those arti- and the corresponding justification recorded. cles deemed potentially relevant and those We used GRADEpro GDT software to assess the whose inclusion was doubtful were obtained to quality of the evidence and to create the ’sum- verify that they explicitly met the inclusion/ mary of findings’ tables (GRADEpro GDT) based exclusion criteria. on the five GRADE considerations (study limi- tations, consistency of effect, imprecision, Data Extraction and Risk-of-Bias indirectness, and publication bias). All decisions Assessment to downgrade the certainty of the evidence were identified and explained as needed. Relevant data from each included study were extracted according to predefined criteria and Data Synthesis and Statistical Analysis recorded using a specific extraction form. The data included publication details (e.g., the For time-to-event outcomes, the HR and corre- name of the first author, country, and publica- sponding 95% confidence interval (CI) were tion year), characteristics of enrolled patients estimated. For OS and PFS outcomes, we calcu- (e.g., age, number, sex, functional status), lated the median value of the durations repor- intervention details (e.g. drugs, dose, route of ted by different studies to represent the assumed administration, duration of treatment), infor- risk. For dichotomous variables, the risk ratio mation about the study design (e.g., the type of (RR) and 95% CIs were calculated for each blinding, type of control, methods used for study. A meta-analysis was performed for each randomization and allocation), survival out- outcome with a random-effects model to comes (expressed as hazard ratio [HR] for OS account for heterogeneity, using Review Man- and PFS and number of patients alive at ager (version 5.4) software. Statistical hetero- 12 months and the end of follow-up), adverse geneity between trials in each meta-analysis was events (any grade or severe [grades 3–5]) and assessed using the I2 statistic, and values of 25%, any other relevant information such as study 50%, and 75% were considered to indicate low, funding or any notable conflict of interest moderate, and high heterogeneity, respectively according to the authors’ judgement). When [15]. Where heterogeneity I2 was C 20%, possi- multiple reports from the same study were ble sources of heterogeneity were explored by identified, the information was collated so that subgroup analysis. A p value of \ 0.05 was each study (rather than each report) was the regarded as statistically significant for all statis- unit of interest in the review. For each trial, the tical analyses, and all tests were two-sided. combination of ICIs with chemotherapy was Publication bias was evaluated by examining considered the experimental arm, and the use of the asymmetry of the funnel plot when C 10 chemotherapy alone or associated with placebo studies were pooled. Predefined subgroup anal- as the control arm. yses were performed to investigate the sources The potential risk of bias of each included of heterogeneity for primary outcomes RCT was assessed using the criteria summarized (I2 C 20%), according to the following charac- in the Cochrane Handbook for Systematic Reviews teristics: (a) different ICIs, and (b) different of Interventions [14]: (1) random sequence gen- chemotherapy regimens. In addition, to answer eration (selection bias); (2) allocation conceal- specific questions about subsets of patients, ment (selection bias); (3) blinding of subgroup analyses were performed based on the 172 Oncol Ther (2022) 10:167–184 following variables: age, sex, presence of serum parallel-group RCTs; five were phase III studies, biomarkers (lactate dehydrogenase [LDH] and one was a phase II study. These studies levels), presence of brain or liver metastases, included 3757 patients with ES-SCLC (1628 functional status according to Eastern Cooper- received chemotherapy plus ICI, 1582 were ative Oncology Group (ECOG)/World Health treated with chemotherapy alone, and 547 were Organization (WHO) criteria, and type of ICI in treated with other combinations). The mean long-term survivors ([ 12 months). Sensitivity age of subjects was 62.4 years (range 24–- analyses were also conducted by (1) restricting 90 years), 58.6% were male patients, 56.0% were the initial analysis to phase III trials, (2) current smokers, and 26.4% were ex-smokers. removing from the initial analysis studies with a The mean duration of follow-up was high risk of bias in at least one critical domain, 13.4 months (range 9.0–21.6). None of the and (3) using both fixed-effects and random- included studies provided data about the pres- effects models for the analysis. ence of oncogenic driver mutations in analysed populations. Patients received various ICI Public and Patient Involvement agents in combination with chemotherapy, including ipilimumab [33, 34], nivolumab [27], There was no public or patient involvement in pembrolizumab [35], atezolizumab [18, 22], and the conduct of this study. durvalumab [31] as induction therapy. Only one study [27] investigated maintenance ther- apy with ICI plus chemotherapy in ES-SCLC Ethics Statement patients; the ICI in this study was nivolumab. Except for the CASPIAN study, in which the This project was based on secondary analysis of comparator was chemotherapy alone [31], all existing data; therefore, ethics approval was not trials included placebo associated with the required. chemotherapy comparator arm. The character- istics of the studies included in the meta-anal- ysis are summarized in Table 1. RESULTS Eligible Studies Risk of Bias of the Included Studies Our search retrieved 708 references. A single Overall, the studies were considered adequate reviewer reviewed and selected the final chosen for performing random sequence generation as studies from the references obtained. After well as having a low risk of detection and excluding duplicates and screening titles of the reporting bias. Five of the trials required the studies, 47 publications were selected based on masking of participants and personnel, but one relevance to the study topic. After abstract and study [29] was open-label, and therefore the risk full article review, 20 publications [16–35] cor- of selection bias for this study was considered responding to six studies met the inclusion high. Four trials [27, 31, 34, 35] reported com- criteria and were included for analysis in the plete outcome data, but in two studies [18, 34] present review. The PRISMA flowchart of this there was an imbalance between the trial arms process is provided in Figure S1 in the online in the withdrawal rate. This is likely to have supplementary material. affected the comparability between the treat- ment arms, and the risk of attrition bias was considered high. Characteristics of Included Studies In four studies [18, 31, 34, 35], a significant imbalance between study groups in the number All six studies included in this meta-analysis of patients undergoing prophylactic cranial (IMPOWER-133 [16–24], CHECKMATE-451 irradiation may also represent a potential source [27], CASPIAN [25, 28–31], KEYNOTE-604 [35], of bias. Detailed information on the risk of bias and two studies by Reck et al. [32, 34]) were Table 1 Characteristics of the trials included in the meta-analysis Author, year Study acronym Study Total Group No. Treatment arms (drug and dose) phase no. Reck et al. 2013 – II 130 1 43 Concurrent regimen (4 doses of ipilimumab/paclitaxel/carboplatin followed by 2 doses of [33] placebo/paclitaxel/carboplatin) 2 42 Phased regimen (2 doses of placebo/paclitaxel/carboplatin followed by 4 doses of ipilimumab/paclitaxel/carboplatin) Oncol Ther (2022) 10:167–184 3 45 Control regimen (up to 6 doses of placebo/paclitaxel/carboplatin) (control group) Reck et al. 2016 – III 1132 1 566 Etoposide 100 mg/m2 IV and cisplatin 75 mg/m2 IV or carboplatin area under the [34] concentration–time curve 5 IV (cycles 1–4 of induction) plus ipilimumab 10 mg/kg (cycles 3–4 of induction) ? ipilimumab alone (cycles 5 to 6) 2 566 Etoposide 100 mg/m2 IV and cisplatin 75 mg/m2 IV or carboplatin area under the concentration–time curve 5 IV (cycles 1–4 of induction) plus placebo (cycles 3–4 of induction) ? placebo alone (cycles 5–6) (control group) Rudin et al. KEYNOTE-604 III 453 1 228 Etoposide 100 mg/m2 ? carboplatin/cisplatin 75 mg/m2 ? pembrolizumab 200 mg (first 2020 [35] 4 cycles) 2 225 Etoposide 100 mg/m2 ? carboplatin/cisplatin 75 mg/m2 ? placebo (first 4 cycles) (control group) Paz-Ares et al. CASPIAN III 805 1 268 Etoposide 80–100 mg/m2 ? carboplatin/cisplatin 75–80 mg/m2 ? 1500 mg durvalumab 2019 [31] (4 cycles) 2 268 Etoposide 80–100 mg/m2 ? carboplatin/cisplatin 75–80 mg/m2 ? 1500 mg durvalumab (4 cycles) ? tremelimumab 75 mg 3 269 Etoposide 80–100 mg/m2 ? carboplatin/cisplatin 75–80 mg/m2 (control group) Horn et al. IMPOWER-133 I/III 403 1 201 Etoposide 100 mg/m2 ? carboplatin ? atezolizumab 1200 mg (4 cycles) 2018 [18] 2 202 Etoposide 100 mg/m2 ? carboplatin ? placebo (4 cycles) 173 174 Oncol Ther (2022) 10:167–184 of included RCTs is shown in Figure S2 in the 279 Platinum-based chemotherapy (4 cycles) ? nivolumab 1 mg/kg ? ipilimumab 3 mg/kg online supplementary material. Efficacy Meta-Analysis Overall Survival The median OS with chemotherapy plus ICIs 275 Platinum-based chemotherapy (4 cycles) ? placebo (control group) was 10.90 months (range from 9.10 months [33] 280 Platinum-based chemotherapy (4 cycles) ? nivolumab 240 mg to 13.00 months [31]), while the median OS in the control group receiving chemotherapy alone or combined with placebo was 10.30 months (range 9.60 months [27] to 10.90 months [34]). The HR for OS in the indi- vidual studies ranged from 0.70 (95% CI 0.54–0.91) [18] to 0.95 (95% CI 0.59–1.54) [33]. The lowest and statistically significant HR val- ues (0.70 and 0.73) were reported in studies Group No. Treatment arms (drug and dose) with anti-PD-L1 agents (atezolizumab and dur- valumab) in combination with chemotherapy. Across all the studies, the estimated HR for OS was 0.85 (95% CI 0.78–0.93; p = 0.0002), indi- cating a significant improvement in median OS for the combinations of chemotherapy plus ICIs (max 4 doses) versus chemotherapy alone or in combination with placebo (Fig. 1). Statistical heterogeneity among trials was low (p = 0.24, I2 = 23%), and the quality of the evidence was rated as high. Progression-Free Survival The median PFS in patients treated with chemotherapy plus ICIs was 4.55 months (range 1.70 months [27] to 5.20 months [33]), while 1 2 3 the median PFS in those treated with Total chemotherapy alone or in combination with 834 no. placebo was 4.35 months (range 1.40 months [27] to 5.40 months [31]). In individual studies, Study phase the HR of PFS ranged from 0.64 (95% CI CHECKMATE- III 0.40–1.02) [33] to 0.85 (95% CI 0.75–0.97) [34]. In the meta-analysis, the estimated HR was 0.78 Study acronym (95% CI 0.72–0.83; p \ 0.00001) (Fig. 2), indi- cating an improvement in median PFS for the combination of ICIs and chemotherapy versus 451 chemotherapy alone or in combination with Table 1 continued placebo. There was no statistical heterogeneity between the studies (I2 = 0%; p = 0.47). The IV intravenously Author, year quality of the evidence was rated as moderate, et al. 2019 Owonikoko mainly due to the inclusion of trials with a high or unclear risk of bias. [27] Oncol Ther (2022) 10:167–184 175 Fig. 1 Forest plot of comparison of overall survival in with placebo. CI confidence interval, IV inverse variance, patients receiving chemotherapy plus immune checkpoint SE standard error inhibitors (ICIs) versus chemotherapy alone or combined One-Year Survival Rate chemotherapy (Fig. 3). Moderate statistical In all studies, one-year survival rates with heterogeneity was detected in this analysis chemotherapy plus ICIs were slightly better (I2 = 50%; p = 0.07). The quality of the evidence than those with chemotherapy alone or com- was rated as low, mainly due to the inconsis- bined with placebo. The estimated RR was 1.14 tency between the included studies and the (95% CI 1.02–1.28; p = 0.02), showing a statis- inclusion of trials with a high or unclear risk of tically significant reduction in the risk of death bias. in favour of the combination of ICIs and Fig. 2 Forest plot of comparison of progression-free combined with placebo. CI confidence interval, IV inverse survival in patients receiving chemotherapy plus immune variance, SE standard error checkpoint inhibitors (ICIs) versus chemotherapy alone or 176 Oncol Ther (2022) 10:167–184 Fig. 3 Forest plot of comparison of 12-month survival combined with placebo. CI confidence interval, MH rate in patients receiving chemotherapy plus immune Mantel–Haenszel checkpoint inhibitors (ICIs) versus chemotherapy alone or Safety significantly higher incidence of rash, dizziness, fatigue, loss of appetite, elevated transaminase Adverse Events levels, abdominal pain, colitis, thyroid function The analysis showed that the addition of ICIs to disorders, hypothermia, and pneumonitis chemotherapy alone or with placebo did not among patients treated with ICIs and increase the risk of experiencing adverse events chemotherapy versus those treated with among ES-SCLC patients (RR 1.05; 95% CI chemotherapy alone or combined with placebo. 0.99–1.11; p = 0.09; Fig. 4). Statistical hetero- geneity was high for this analysis (I2 = 77%; Severe Adverse Events p \ 0.0002). Independent meta-analysis Adverse events of grades 3–5, according to the according to the type of adverse event showed a National Cancer Institute Common Fig. 4 Forest plot of comparison of adverse event rate in with placebo. CI confidence interval, MH patients receiving chemotherapy plus immune checkpoint Mantel–Haenszel inhibitors (ICIs) versus chemotherapy alone or combined Oncol Ther (2022) 10:167–184 177 Terminology Criteria for Adverse Events (NCI- combined with placebo (Figure S9 in the sup- CTCAE), were reported in all included studies plementary material). [18, 22, 27, 31, 33–35]. Immune-related adverse The results of the sensitivity analyses were events were reported when ICIs were added to consistent with the main analysis for primary chemotherapy. However, the estimated RR outcomes after limiting the analysis to phase III showed that patients receiving ICIs in combi- trials or removing studies with a high risk of nation with chemotherapy did not have a sig- bias, or using different statistical models for the nificantly higher risk of serious adverse events analysis. than controls (RR 1.15, 95% CI 0.95–1.39). Subgroup and Sensitivity Analyses DISCUSSION This meta-analysis included six phase-II/III In terms of OS, subgroups according to age RCTs in a total of 3757 patients, evaluating the (\ 65/C 65 years), sex (men/women), and base- benefits and risks of adding ICIs to conven- line functional status (0/1) showed an estimated tional chemotherapy compared with conven- HR in favour of ICIs combined with tional chemotherapy alone or associated with chemotherapy versus chemotherapy alone or placebo as first-line treatment for patients with combined with placebo (Figures S3, S4 and S5, ES-SCLC. High, moderate, and low quality of respectively, in the supplementary material). In evidence, respectively, showed that the OS and the subgroup analysis, according to the pres- PFS were longer and 12-month survival rates ence of elevated levels of serum LDH higher in patients receiving chemotherapy plus (LDH B upper limit of normal (ULN)/LDH [ ICIs than in those receiving chemotherapy ULN), there was no significant difference in OS alone or combined with placebo, without a between ICI and chemotherapy combined statistically significant increase in the risk of treatment and chemotherapy without ICIs in experiencing adverse events of any severity. The either subgroup (Figure S6 in the supplementary addition of an ICI agent to chemotherapy material). The estimated HR for OS was in reduced the risk of death by 15% (HR 0.85, 95% favour of combined therapy in the subgroup of CI 0.78–0.93) and improved the relative 1-year patients without brain metastases at diagnosis, survival rate by 14% (RR 1.14, 95% CI but there were few patients in the subgroup 1.02–1.28), with absolute improvement in with brain metastases, so CIs were wide, and no 1-year survival of 5%. The subgroup analyses for conclusions could be drawn (Figure S7 in the OS showed that the benefit from the addition of supplementary material). In the subgroup ICIs did not differ significantly across subgroups analysis by liver metastases, the estimated HR defined by age, sex, or baseline functional sta- for OS favoured combined treatment (Figure S8 tus. However, in the subgroup analysis by in the supplementary material). Subgroup individual ICI agent, the combination of analysis by specific ICI agent revealed a signifi- chemotherapy with either atezolizumab or cantly higher rate of 12-month survivors in durvalumab (PD-L1 inhibitors) significantly those receiving atezolizumab (HR 1.36, 95% CI increased the proportion of 12-month survivors 1.09–1.69) or durvalumab (HR 1.35, 95% CI compared with chemotherapy only, whereas 1.12–1.62) in combination with chemotherapy the combinations with ipilimumab (CTLA-4 versus chemotherapy alone. For the other ICIs, inhibitor), pembrolizumab, or nivolumab (PD- the HR did not reach statistical significance L1 inhibitors) did not significantly increase the (pembrolizumab HR 1.14 [95% CI 0.92–1.42], proportion of 12-month survivors compared ipilimumab HR 1.00 [95% CI 0.87–1.15], and with chemotherapy alone ± placebo. Although nivolumab HR 1.06 [95% CI 0.92–1.22]), indi- all studies included in the present meta-analysis cating that in these subgroups, the proportion were RCTs, some factors such as study limita- of 12-month survivors showed little or no dif- tions or inconsistency of results downgraded ference versus chemotherapy alone or the quality of evidence for some outcomes. 178 Oncol Ther (2022) 10:167–184 Our findings suggest several implications for and its potential benefit in combination with clinical practice. Notably, the debate regarding immunotherapy have been poorly explored, the superiority of ICI as induction or mainte- and efficacy and safety data regarding the nance therapy in combination with combination of cranial radiation plus ICIs chemotherapy persists. In our meta-analysis, remain sparse. In our meta-analysis, only two only one study [27] investigated nivolumab trials [19, 33] reported the number of partici- plus chemotherapy as maintenance therapy in pants who underwent PCI, and neither study ES-SCLC patients. The results demonstrated included more than 12% of PCI patients in any that maintenance therapy with nivolumab did treatment arm, whereas up to 23% of patients not prolong OS vs placebo for ES-SCLC patients. with ES-SCLC undergo PCI in clinical practice Indeed, our subgroup analysis looking at the [36]. Data from an exploratory analysis of the relative efficacy for each type of ICI showed that IMpower133 study showed a delay in intra-cra- only atezolizumab and durvalumab combined nial progression with atezolizumab combined with chemotherapy exhibited improved OS with chemotherapy vs placebo combined with compared with chemotherapy alone ± placebo, chemotherapy [35], suggesting potential CNS but no difference in the proportion of efficacy in a disease in which brain metastases 12-month survivors was seen with nivolumab are common. However, to date, studies assess- maintenance therapy compared with ing the role of ICIs in patients with brain chemotherapy ± placebo. In addition, in the metastases are limited, and the generalizability nivolumab study, the analysis of PFS took into of ICI data to this group is still challenging. account data starting from the randomization Biomarkers may play a key role in the treat- phase; this may explain why the PFS results ment of ES-SCLC, which is characterized by with nivolumab are clearly different from those multiple genetic defects and cellular hetero- with the other ICIs. Therefore, ICI as mainte- geneity. In our subgroup analysis, there was nance therapy in combination with a little or no difference in the effect of ICI plus chemotherapy regimen deserves further explo- chemotherapy on OS between subgroups with ration, including the study of the mechanisms elevated or low levels of serum LDH. The two involved. trials included in this analysis were consistent SCLC often causes brain or liver metastases, in showing that LDH level is not a biomarker for which are historically associated with a poor lack of benefit [34, 35]. These results demon- prognosis and for which no specific treatment is strate that there is still a lack of biomarkers to available. However, few data are available about select treatment for SCLC patients and high- the efficacy of immunotherapy in SCLC light the need to identify biomarkers that are patients with brain or liver metastases, since able to distinguish between patients likely or most RCTs assessing immunotherapy in first- unlikely to benefit from ICI plus chemotherapy line settings excluded patients with active or combined therapy. untreated metastases. In our subgroup analysis, Our meta-analysis suggests that combination an OS benefit of the combination of ICI with treatment with ICI plus chemotherapy is an chemotherapy was observed only in the sub- effective and tolerable option for first-line group without brain metastases at diagnosis. treatment for previously untreated ES-SCLC However, the ICI and chemotherapy combina- patients. Our results are consistent with those of tion did confer a benefit irrespective of the previous meta-analyses that have also evaluated presence of liver metastases, despite these the efficacy and safety of ICIs in combination patients having a worse prognosis. It should be with chemotherapy [37–42] and reported sur- remembered, however, that these observations vival results in favour of the combination of are based on subgroup analyses from larger trials immunotherapy with chemotherapy. The HR that did not assess the specific characteristics of for survival varied slightly between these meta- the central nervous system (CNS) disease or the analyses, from 0.76 [39] to 0.84 [40] for OS and role of prophylactic cranial irradiation (PCI). In from 0.75 [39] to 0.82 [37] for PFS. Moreover, as this sense, the role of PCI in ES-SCLC patients in our analysis, two of the previous meta- Oncol Ther (2022) 10:167–184 179 analyses reported responses at 12 months that not taken into account by researchers and also favoured combined therapy [38, 39]. The which are important when evaluating the earlier meta-analyses were based on four or five results of immunotherapy. trials (in some cases including only completed However, the present meta-analysis has cer- phase II–III RCTs [42]), whereas our analysis tain limitations. First, we explored a limited included all these studies in addition to one number of databases and therefore may have new trial [27], as well as data from longer-term missed studies published in journals not cov- follow-up (at 18 and 24 months) in two of the ered by those databases. Second, arguments included studies [20, 31]. Previous meta-analy- have been made that the single screening of the ses also included populations with limited-stage titles and abstracts of studies retrieved in bibli- SCLC (not only ES-SCLC) [41] or other thera- ographic searches is not equivalent to screening peutic strategies in addition to immunotherapy- by two reviewers, as substantially more studies based combination (e.g., standard-of-care or ICI may be missed. However, in our work, the study monotherapy) [40, 41]. In contrast, we excluded selection was conducted by an experienced all trials enrolling patients with limited-stage reviewer and the results were validated inde- SCLC or exploring ICI monotherapy or other pendently by another investigator, minimizing immunotherapeutic agents, in order to main- the likelihood of errors and reducing the possi- tain uniformity across the two arms in our bility that the selection process was influenced meta-analysis. These differences may explain by a single reviewer’s interpretation and the the slight discrepancies between our results and missing studies. Third, few studies were inclu- those of the previous meta-analyses. ded in our review, and most of them had small Unlike other previous studies comparing OS sample sizes, although we did not detect pub- and PFS across different therapeutic regimens lication bias in the main analyses. Fourth, the plus chemotherapy, our work provides unique trials analysed in our review did not take into and valuable information regarding specific account gene mutation status or potential pre- subgroup analysis (including levels of serum dictive factors of benefit to ICI (e.g., tumour LDH or presence of metastases, for example) mutational burden and PD-L1 expression) in and longer-term safety analysis for previously deciding the initial approach in ES-SCLC untreated ES-SCLC, all supported by robust patients. Lastly, although our meta-analysis was methods. Subgroup analyses are often per- undertaken using frequentist methods, in gen- formed as part of the analysis of intervention eral terms, a Bayesian approach is increasingly studies to assess whether treatment effects vary used to assess the variation between studies in a across subpopulations. Such analyses can pro- random-effects analysis. This Bayesian approach vide valuable information for hypothesis gen- is particularly advantageous when the number eration, but they are only conducted in an of studies in the meta-analysis is small (fewer exploratory manner. Consequently, the results than 5 or 10). In our review, Tau2 (a measure of identified through these analyses require fur- the between-study variability in treatment ther studies correctly designed and powered as effect) is mostly zero, likely not because there is the primary objective for drawing firm conclu- no variability in the treatment effect but sions. Furthermore, other strengths of our study because there are too few studies to estimate it. include the application of a strict set of eligi- These limitations may have affected our final bility criteria, especially regarding population results analysis, although it is difficult to and intervention characteristics and specific quantify their impact. Therefore, more ran- analysis of the effects of the combination of ICI domized, multicentre, and large-scale studies with chemotherapy in several different subsets are needed to further explore these unaddressed of patients. Another strength is the use of the questions and novel combinations of ICI and random-effects model to minimize the influ- chemotherapy as the first-line treatment in ence of heterogeneity and performing subgroup untreated ES-SCLC patients. analyses to explore the detected heterogeneity and identify possible modifiers, which are often 180 Oncol Ther (2022) 10:167–184 CONCLUSION AstraZeneca, Lilly, Pfizer, Boehringer, Takeda; advisory/consultancy fees from Roche, Merck, The addition of ICIs to chemotherapy as first- BMS, AstraZeneca, Lilly, Pfizer, Boehringer, line treatment improves the survival of patients Takeda; speaker fees from Roche, Merck, BMS, with ES-SCLC compared with chemotherapy AstraZeneca, Lilly, Pfizer, Boehringer and alone. Benefits were observed in terms of OS Takeda; research grant/funding (institution) and PFS, while there was no significant increase from Roche, BMS, Pfizer, Boehringer; travel/ac- in the rate of adverse events. Atezolizumab and commodation/expenses from Roche, Merck, durvalumab combinations showed the best BMS, AstraZeneca, Lilly, Pfizer and Boehringer. results. These data confirm that adding Dr Domine has received advisory/consultancy immunotherapy, specifically anti-PD-L1 agents, fees from Roche, Merck, BMS, AstraZeneca, Pfi- to platinum-etoposide chemotherapy from the zer, Abbvie, Boehringer; speaker fees from induction phase is currently a superior thera- Roche, Merck, BMS, AstraZeneca, Pfizer; travel/ peutic approach for patients with ES-SCLC. accommodation/expenses from Roche, BMS, AstraZeneca, Lilly, Pfizer and Boehringer. Dr Castro has received advisory/consultancy fees from Roche, Merck, BMS, AstraZeneca, Pfizer, ACKNOWLEDGEMENTS PharmaMar, Boehringer, Takeda, Tesauro; speaker fees from Roche, Merck, AstraZeneca, Boehringer, Takeda; travel/accommodation/ex- Funding. This work was supported by penses from Roche, Merck, BMS and AstraZe- Roche, including the Journal’s Rapid Service neca. Dr Cobo has received Fee. advisory/consultancy fees from Roche, BMS, Medical writing/Editorial assistance. The AstraZeneca, Pfizer, Boehringer; travel/accom- authors thank Esther Martin, who wrote this modation/expenses from Roche, BMS, AstraZe- manuscript on behalf of Springer Healthcare neca. Dr Navarro has received Communications, and to Catherine Rees from advisory/consultancy from Roche, Pfizer, Boeh- Springer Healthcare Communications, who ringer; speaker fees from Roche and BMS; travel/ edited the English language. This medical writ- accommodation/expenses from Pfizer and ing assistance was funded by Roche. Boehringer; and has had a leadership role (medical monitor) for Oryzon Genomics. Dr Authorship. All named authors meet the Sullivan has participated in advisory boards for International Committee of Medical Journal Roche, Novartis and Boehringer Ingelheim; Editors (ICMJE) criteria for authorship for this- acted as a speaker for Roche, Merck Sharp & article, take responsibility for the integrity of Dohme, Pfizer, Bristol-Myers Squibb, AstraZe- the work as a whole, and have given their neca; received travel grants from Roche, approval for this version to bepublished. Novartis, Bristol-Myers Squibb, Pfizer, Boehrin- ger Ingelheim. Dr Trigo has received advi- Author contributions. Conceptualization: sory/consultancy fees from Merck, BMS, GSK, all authors; methodology: EA, MGC, DI, LC; Boehringer, Takeda; speaker fees from Roche, formal analysis: all authors; data curation: EA, Merck, BMS, AstraZeneca, Bayer, Boehringer; MGC, DI, LC; writing (original draft prepara- travel/accommodation/expenses from Roche, tion): MGC, EA, LC; writing (reviewing and Merck, BMS and AstraZeneca. Dr Mosquera has editing): all authors; supervision: LC, MGC, EA. acted as a speaker for Roche, BMS, AstraZeneca All authors have read, approved and agreed to and received travel/accommodation/expenses submit this version of the manuscript for from Roche, Merck and Lilly. Dr Isla has publication. received advisory/consultancy fees from Roche, BMS, AstraZeneca, Lilly, Pfizer, Bayer, Abbvie, Disclosures. 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