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First-line immune-checkpoint inhibitor treatment in extensive-disease small-cell lung cancer: A classical and network meta-analysis


1 Department of Oncology, Istinye University School of Medicine, Istanbul, Turkey
2 Department of Oncology, Lara Medicalpark Hospital, Antalya, Turkey
3 Department of Oncology, Necmettin Erbakan University, Meram School of Medicine, Konya, Turkey
4 Department of Thoracic Surgery, Lara Medicalpark Hospital, Antalya, Turkey

Date of Submission01-May-2021
Date of Acceptance19-Jun-2021
Date of Web Publication28-Jan-2022

Correspondence Address:
Hasan Mutlu,
Department of Oncology, Istinye University School of Medicine, Maltepe, Çırpıcı Yolu B Çk. No. 9, 34010 Zeytinburnu, İstanbul
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_721_21

 > Abstract 


Background: Small-cell lung cancer (SCLC) has a poor prognosis. For the last 30 years, first-line systemic treatment has remained unaltered. After the integration of ımmunotherapy, a new first-line gold standard, atezolizumab in combination with carboplatin plus etoposide, was approved in extensive-disease SCLC (ED-SCLC) in 2019.
Materials and Methods: First-line randomized controlled studies that investigated anti-programmed cell death protein 1 (PD-1)/PD-1 ligand-1 (PD-L1) and anti-T-lymphocyte-associated protein 4 (CTLA-4) agents in combination with platinum plus etoposide (EP) were scoured. A total of six studies (two – anti-CTLA-4 and four – anti-PD1/PD-L1) were included and classic and network meta-analyses (NMAs) were performed.
Results: Fixed model for overall survival (OAS) in the PD-1- or PD-L1-treated subgroup yielded a hazard ratio (HR) of 0.746 with a 95% confidence interval (CI) =0.662–0.840 and in the CTLA-4-treated subgroup a HR of 0.941 with a 95% CI = 0.816–1.084 for the immune therapy + chemotherapy versus chemotherapy comparison (CTLA-4-based versus PD-1- or PD-L1-based groups' comparison of OAS effect Q = 6.05, df = 1, P = 0.014). NMA showed that all chemotherapy + immunotherapy combinations were equally potent and more efficient than PE in terms of OAS and progression-free survival (PFS). Rank probability plots demonstrated nivolumab + EP as the most probable effective treatment modality in terms of OAS and PFS.
Conclusion: The usage of anti-PD1/PD-L1 immunotherapy agents results in significant OAS advantage, and anti-PD1/PD-L1 agents are superior to anti-CTLA-4 approach in combination with platinum plus etoposide regimen in ED-SCLC.

Keywords: Anti-CTLA-4, anti-death protein 1/death protein-ligand 1, extensive-disease small-cell lung cancer, first-line immunotherapy, network meta-analysis



How to cite this URL:
Mutlu H, Bozcuk H, Artaç M, Eser &. First-line immune-checkpoint inhibitor treatment in extensive-disease small-cell lung cancer: A classical and network meta-analysis. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 8]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=336701




 > Introduction Top


Lung cancer is the third most common cancer in both sexes and in all ages and is the most leading cause of cancer-related mortality in the world.[1] Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancer.[2] In patients with SCLC, despite the prognosis being very poor, the first-line systemic treatment regimen has not changed for the last 30 years. Agents such as bevacizumab, roniciclib, or vandetanib were tried to be incorporated into the first-line treatment, but the studies that included these agents had not revealed any significant overall survival (OAS) benefit.[3],[4],[5]

In the era of immunotherapy, CTLA-4 and anti-programmed cell death protein 1 (PD-1)/PD1 ligand-1 (PD-L1) agents achieved significant success in many cancer types. The relationship between tumor mutation burden (TMB) and PD-L1 expression and tumor response was presented earlier.[6] SCLC has high TMB and sometimes significant PD-L1 expression; in addition, it is one of the cancer types in which a variety of paraneoplastic syndromes are encountered.[7] The platinum plus etoposide regimen has been the standard first-line regimen in extensive-disease SCLC (ED-SCLC) until 2019; however, after the studies that included immunotherapeutic agents, the addition of atezolizumab against PD-L1 to first-line platinum plus etoposide has shown promising results and represents a valuable first-line option in appropriate patients with ED-SCLC.[8]

In the present analysis, we aim to evaluate the effectiveness of anti-CTLA-4 and anti-PD1/PD-L1 agents in combination with chemotherapy and to define the most effective treatment combination in patients with ED-SCLC.


 > Materials And Methods Top


Trial search strategy and criteria for selection

This is both a network and a classical meta-analysis making the use of published summary data. Three reviewers employed various search algorithms to guarantee accurate selection of clinical trials for the purpose of classical and network analyses. All papers in the English language were evaluated starting from database inception to June 7, 2020, in PubMed, Science of Web, and “Clinicaltrials.Gov.” In addition to this, we also searched congress-proceedings books as well as online presentations of the American Society of Clinical Oncology and European Society for Medical Oncology congresses. To start with, all randomized clinical trials (RCTs) that evaluated the utilization of any monoclonal antibody in the treatment of SCLC were taken into account. Out of these, trials with first-line immunotherapy used concomitantly with chemotherapy, and recruiting patients with extensive-stage SCLC, were selected. Trials of pure maintenance nature, which do not make the use of concomitant chemotherapy and immunotherapy, were excluded from this meta-analysis. Studies meeting the selection criteria explained above were considered only if they reported OAS and/or progression-free survival (PFS) results. Potential conflicts over inclusion of trials were resolved by discussion among the authors of this study. We followed the PRISMA NMA guidelines throughout the article.[9]

Analysis of data

We used the GeMTC software that is freely available on “https://gemtc.drugis.” This software is an online tool for Bayesian network meta-analysis.[10] We performed consistency models for PFS and OAS analyses only in the first-line usage of checkpoint inhibitors (CPIs). OAS was the main and PFS the secondary end point in this analysis. The principal summary measure we used in this study was hazard ratio (HR). The logarithmic transformation and the corresponding standard errors were calculated and loaded on the database. Standard errors were calculated using previously published methods or comprehensive meta-analysis tool.[11]

Funnel plots were used to check for heterogeneity, and rank probability plots were evaluated in order to rank CPIs and their combinations.

For the classical meta-analysis part, we compared the efficacy of chemotherapy (platinum and etoposide) with that of chemotherapy plus immune therapy, making the use of comprehensive meta-analysis software.[11]


 > Results Top


General findings

We selected six clinical trials recruiting a total of 2490 patients.[8],[12],[13],[14],[15],[16] [Figure 1] demonstrates the PRISMA flowchart for inclusion of the studies. The phased ipilimumab arm of Reck 2012 trial was excluded from the analysis, and only the concurrent ipilimumab chemotherapy and chemotherapy-alone arms were included in the analysis, as our analysis focused solely on concomitant immune therapy and chemotherapy trials.
Figure 1: Flowchart of references included in network meta-analysis

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Five different CPIs (nivolumab, pembrolizumab, ipilimumab, atezolizumab, and durvalumab) in conjunction with etoposide and platinum, and paclitaxel and carboplatin doublets, had been utilized in these trials. [Table 1] shows the details of these clinical trials.
Table 1: Characteristics of trials

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Efficacy

For the conduction of classical meta-analysis, Q tests and funnel plots showed a homogeneous structure of clinical trials, and thus, fixed model was chosen to combine and compare trials for the OAS and PFS end points. Fixed model for OAS in the PD-1- or PD-L1-treated subgroup yielded a HR of 0.746 with a 95% confidence interval [CI] =0.662, 0.840 and in the CTLA-4-treated subgroup a HR of 0.941 with a 95% CI = 0.816, 1.084 for the immune therapy + chemotherapy versus chemotherapy comparison. Of note, comparison of the OAS effect yielded by these two subgroups gave statistically significant difference (Q = 6.05, df = 1, P = 0.014). Similarly, fixed model for PFS demonstrated statistically significant effects in the two immune therapy subgroups (CTLA-4 versus PD-1 or PD-L1 treated), when compared to chemotherapy alone. These two subgroups did not demonstrate a difference in terms of efficacy (Q = 2.01, df = 1, P = 0.156). [Figure 2] and [Figure 3] show the forest plots of OAS and PFS achieved by immunotherapy + chemotherapy, and chemotherapy alone.
Figure 2: Concomitant immune therapy with chemotherapy alone in extensive-disease small-cell lung cancer; Overall survival (anti-CTLA-4-based versus anti-death protein 1/death protein 1 ligand 1-based groups' comparison (Q = 6.05, df = 1, P = 0.014)

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Figure 3: Concomitant immune therapy with chemotherapy alone in extensive-disease small-cell lung cancer; Overall survival (anti-CTLA-4-based versus anti-death protein 1/death protein-ligand 1-based groups' comparison (Q = 2.01, df = 1, P = 0.156)

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As a difference in efficacy in terms of OAS was demonstrated in CTLA-4 versus PD-1- or PD-L1-treated subgroups, two ipilimumab-containing trials were excluded from the network analysis. Thus, network analysis focused on trials where PD-1 or PD-L1 inhibitors were used (n = 4). In terms of OAS and PFS, network meta-analysis showed that all chemotherapy + immunotherapy combinations were equally potent and more efficient than etoposide–platinum chemotherapy. Rank probability plots demonstrated nivolumab + EP as the most probable effective treatment modality in terms of OAS and PFS. [Table 2] and [Figure 4] show the details of OAS associated with the effect of different CPIs combined with PE chemotherapy. Likewise, [Table 3] and [Figure 5] show the details of PFS associated with various treatment approaches.
Table 2: Network meta-analysis and comparison of overall survival benefit by first-line immunotherapy agents in small-cell lung cancer

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Figure 4: Probability plot for overall survival

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Table 3: Network meta-analysis and comparison of progression-free survival benefit by first-line immunotherapy agents in small-cell lung cancer

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Figure 5: Probability plot for progression-free survival

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 > Discussion Top


In this paper, we demonstrate that anti-PD1/PD-L1 immunotherapy agents result in a significant OAS gain when used in combination with standard platinum plus etoposide regimen in ED-SCLC, and in this regard, anti-PD-1/PD-L1 agents are superior to anti-CTLA-4 agents.

In parallel to our findings, the major breakthrough in the treatment of SCLC happened when, based on the results of IMpower133, atezolizumab was approved in 2019 by the Food and Drug Administration as the first immunotherapeutic agent to be used front line in the treatment of ED-SCLC. Except for the studies presented by Reck et al., in the other studies (IMpower133, CASPIAN, KEYNOTE-604, and ECOG-ACRIN EA5161), the anti-PD1/PD-L1 agents atezolizumab, durvalumab, nivolumab, or pembrolizumab in combination with the PE chemotherapy have revealed an OAS advantage compared to PE-alone arm as a first-line treatment. Among anti-PD1/PD-L1 agents, nivolumab in combination with PE was the most probable effective treatment modality in terms of OAS and PFS prolongation in ED-SCLC, as demonstrated by NMA.

The mechanism of PD-1 is dependent on blocking of PD-1 receptor or PD-L1 function and then maintenance of T lymphocyte function on tumor cells. In patients who had higher PD-L1 levels with different cancer types, anti-PD1/PD-L1 agents can reveal significant response rate or survival advantage.[17],[18],[19] The prevalence of PD-L1 expression was found to be 15%–72% in patients with SCLC, and it is significantly more expressed in limited disease than in patients with ED-SCLC.[18],[19],[20] The correlation between PD-L1 levels and survival is controversial in patients with SCLC.[18],[19],[20] Yu et al. have found a favorable trend for OAS in patients with PD-L1 tumor proportion score ≥1%.[18] Ishii et al. have shown that the patients with positive PD-L1 expression had a significantly longer OAS than that of others while Xu showed that the higher PD-L1 level was an independent negative prognostic factor for OAS in patients with SCLC.[19],[20] Of the studies included in this analysis, only KEYNOTE-604 has reported that PD-L1 combined positive score status (PD-L1 CPS <1 or ≥1) was not effective on OAS. Similarly, the tumor response was provided irrespective of PD-L1 levels in CheckMate-032.[21]

When evaluating TMB in SCLC, a study has shown that the patients with higher TMB, who received nivolumab monotherapy or in combination with ipilimumab, had a higher response and survival rates in ED-SCLC.[22] However, Impower133 has reported no relationship between TMB status and survival.[8]

Except for ECOG-ACRIN EA5161, the three studies including anti-PD1/PD-L1 agents have reported that there was no significant OAS gain in patients who had cranial metastasis at the time of diagnosis of SCLC. In four studies included in our analysis, the ratios of patients with cranial metastasis were similar among studies and between arms. As an explanation of the lack of benefit with CPIs in subgroups with cranial metastasis, it was speculated that CPIs may be ineffective in patients with untreated symptomatic brain metastasis due to the presence of excessive vasogenic edema and inflammatory response.[23]

The prevalence of CTLA-4 expression in SCLC was found to be 89.5%, and there was not any correlation between the CTLA-4 expression and OAS of the patients with SCLC.[24] In the first study (Phase II) presented by Reck et al. in SCLC, ipilimumab in combination with carboplatin plus paclitaxel did not reveal any significant OAS advantage compared to carboplatin plus paclitaxel like the Phase III study mentioned in our meta-analysis.[15] In addition, when compared to carboplatin + paclitaxel, phased ipilimumab (after two doses of carboplatin + paclitaxel, concurrent ipilimumab had been given) has been shown to be more effective, compared to the concurrent regimen. The reason for this may be due to the rise of tumor antigen levels in circulation in relation to the front-line chemotherapy. In the other study evaluating the safety and efficacy of first-line ipilimumab in combination with carboplatin plus etoposide, the primary end point of the study was not met.[25] However, in a subgroup analysis, in patients who had any positive autoantibodies at baseline, immune-related PFS was significantly longer than others who had no positive autoantibodies. In the Phase III study, Reck et al. found that ipilimumab arm had a significantly worse OAS compared to placebo arm in patients who had cranial metastasis. However, the best overall response rates were similar in each arm (62%).

All of the three studies with ipilimumab did not result in a significant OAS advantage.[15],[25] Perhaps, the decision of treatment with anti-CTLA-4 agents in SCLC may be done according to cranial metastasis status and autoantibody analysis, and the regimen including anti-CTLA-4 agents may be evaluated in a sequential schedule.

In addition to classic anti-PD-L1 and CTLA-4 agents, the addition of the new-generation immune-checkpoint agents targeting LAG-3 (lymphocyte-activation gene-3), 4-1BB, OXO-40 (CD134), or IDO (indoleamine 2,3-dioxygenase) may increase hope to improve treatment outcomes in SCLC.[26]

In this present analysis, rank probability plots imply that nivolumab + PE is the most probable effective treatment modality in terms of OAS and PFS prolongation in ED-SCLC. Recently, the indications of nivolumab and pembrolizumab have been withdrawn in patients with metastatic SCLC after at least one prior line of therapy by its manufacturers in conjunction with FDA. Despite this decision of withdrawal of these anti-PD-L1 agents in second- or later-line setting, their effectiveness in metastatic SCLC may occur in first-line setting in combination with chemotherapy. As a matter of fact, we show that the usage of anti-PD1/PD-L1 immunotherapy agents results in a significant OAS advantage and anti-PD1/PD-L1 agents are superior to anti-CTLA-4 approach in combination with standard platinum plus etoposide regimen in ED-SCLC.


 > Conclusion Top


The usage of anti PD1/PD L1 immunotherapy agents results in significant OAS advantage, and nivolumab + PE is the most probable effective treatment modality in ED SCLC. Anti PD1/PD L1 agents are superior to anti CTLA 4 approach in combination with platinum plus etoposide regimen in ED SCLC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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