Clinical research progress of first-line immunotherapy for extensive-stage small cell lung cancer

Yong-Chao Yu, Hong-Xia Xie, Jin-Hui Zuo, Xiao-Jiang Li, Ying-Jie Jia, Fan-Ming Kong*

1Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China.

Abstract

Small cell lung cancer (SCLC) has a high degree of malignancy and rapid progression, and most of the patients are in the extensive stage when they are diagnosed.The traditional treatment of SCLC is mainly systematic chemotherapy combined with radiotherapy, but there has been no significant progress for many years.The emergence of immunotherapy represented by immune checkpoint inhibitors (ICIs) has changed the treatment pattern of SCLC.Some studies have confirmed the effect of ICIs monotherapy.However, the disadvantages of ICIs monotherapy such as low responsiveness, drug resistance, and adverse reactions limited the clinical application.The combined treatment of immune checkpoint inhibitors was newly developing treatment models.Clinical studies have found that ICIs combined with standard chemotherapy can significantly improve the survival of patients with extensive small cell lung cancer without increasing adverse reactions.Based on the synergistic effect of immunotherapy combined with chemotherapy, this paper reviews the current progress, deficiency and future exploration direction of first-line immunotherapy for extensive small cell lung cancer.

Keywords: small cell lung cancer; extensive-stage; immunotherapy; PD-1/PD-L1

Background

Although the incidence of female breast cancer exceeds of lung cancer,lung cancer remains the leading cause of cancer death, in which SCLC accounts for 10% to 15% of the total lung cancer, and 70% of SCLC patients are in the extensive stage (ES) when the disease is diagnosed[1-3].SCLC is a special neuroendocrine malignant tumor, which has the characteristics of a high degree of malignancy, rapid progression,high invasiveness, short doubling time of tumor cells, easy to occur early metastasis (high incidence of brain metastasis) and so on.Its treatment and prognosis are poor.Although SCLC is sensitive to chemotherapy and radiotherapy, and the initial chemotherapy is effective.It is easy to relapse and metastasis, and the second chemotherapy after recurrence is mostly ineffective [4].The median overall survival time of patients with the extensive stage is only 8 months to 11 months, and the 5-year survival rate is less than 2% [5].And patients are often complicated with chronic obstructive pulmonary disease (COPD), ischemic heart disease and hypertension,which make it more difficult to treat.Different from non-small cell lung cancer, due to the lack of clear driving genes, the progress of targeted therapy in SCLC is slow [6].With the advent of immunotherapy, we have seen hope in the way we manage and treat cancer.The advantages of immunotherapy are exemplified not only by adult malignancies, but equally in the pediatric space [7].Meanwhile,ICIs combined with chemotherapy rewrote the guidelines of the National Comprehensive Cancer Network (NCCN) in SCLC for the first time.ICIs combined chemotherapy has become a hot field of clinical research in SCLC.

The mechanism of immunotherapy

Based on the theory that the body's immune system can recognize and clear tumor cells, treating tumors is intervening in the relationship between the immune system and tumor cells in the body [8].To break the hold between the body and tumor cells and win the anti-tumor war, there are 2 strategies: either weakening the enemy or strengthening itself.Modalities such as chemotherapy and targeted therapy are to "weak the enemies" in nature, while immunotherapy approaches "strengthen oneself ".The novel immunotherapy of tumor takes the body's own immune system as the target, which is different from the previous treatment strategies [9].This enhancement strategy usually falls into two categories: the first is by artificially engineering immune cells, enforcing the functionality of the cells before reinfusion into the patient.This is called "passive" immunotherapy [10],including antibody targeted therapies and their derivatives (eg,antibody drug conjugates), adoptive immune cell therapies, the latest genetically engineered T cells (eg, chimeric antigen receptor (CAR-T),T cell receptor (TCR-T), etc [11-14].The second is to enhance and amplify the immune system by restoring immune function to patients,which is also referred to as "active" immunotherapies such as cancer vaccines, ICIs, oncolytic viruses, etc [10-17].

Referring to immune checkpoint inhibitors, a question-what are immune checkpoints ? -inevitably involved.Our immune system is the body's defense system, responsible for clearing foreign pathogens,clearing senescent cells in the body, and also for monitoring cells that have undergone xenomutation in the body [18].The anti-tumor immune response is mainly mediated by cellular immunity, which is mainly affected by T cells, natural killer cells and macrophages.Among them, the immune response mediated by T cell is the most important, which is mainly divided into three stages: T cell specific recognition of tumor antigen, T cell activation, proliferation and differentiation, and effector T cell clearance of tumor cells [19-22].But the immune system, composed of dozens to hundreds of millions of immune cells, does not never err and in some cases attacks our normal body cells, which is also responsible for some autoimmune diseases [23].Our body therefore designs a brake system that will be naturally activated when immune cells activate to a certain state,avoiding the possibility of over activated immune responses, acting to maintain a state of immune balance in the human body.However, this set of system is utilized by tumor cells in some cases, which inhibits the killing and clearance of tumor cells, thus forming immune escape and promoting the continuous growth of tumors [21-24].Based on this, the ICIs can specifically bind to the corresponding ligands, block the immunosuppressive pathway, and then relieve the immune tolerance state of the body, restore the activity of T cells, and achieve endogenous anti-tumor ability [25].

The common negative regulators involved in the regulation of immune checkpoints are programmed cell death 1 (PD-1),programmed cell death ligand 1 (PD-L1), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), CD80, CD86, Tim-3,Galectin-9 and so on.At present, the two most popular immune checkpoints are PD-1/PD-L1 and CTLA-4.CTLA-4 was the first negative regulator expressed on T cells with a better affinity than the T-cell co-stimulatory molecule CD28 to inhibit T-cell function by competitively binding to its ligands CD80 (B7.1) and CD86 (B7.2)[26].PD-1 is predominantly expressed on the surface of activated T cells.The main ligands that binding to PD-1, PD-L1 (CD274) and PD-L2 (CD273), are widely expressed on the surface of non-lymphocytes such as tumor cells and DCs [27].When engaged by PD-L1 or PD-L2, PD-1 transduces negative costimulatory signals that suppress local T cell responses [28].

Current status of ES-SCLC immunotherapy

In the past 30 years, the first-line treatment of ES-SCLC was mainly etoposide combined with carboplatin, cisplatin and other platinum drugs [29].The effect of initial chemotherapy is obvious, but the drug resistance and recurrence rate are high, which cannot bring obvious survival benefits [30].In recent years, with the in-depth study of SCLC, the characteristics of its high mutation load and high immunogenicity were become more and more clear, which makes SCLC benefit from immunotherapy [31].On the other hand, more and more studies showed that the low proportion of tumor lymphocyte infiltrated in patients with SCLC [32] and the risk of superior vena cava syndrome required hormone therapy, which limited the efficacy of ICIs monotherapy to some extent [31-33].

It has been found that ICIs combined with chemotherapy can produce a synergistic effect, which is the basis of ES-SCLC immunotherapy combined with chemotherapy.On the one hand, ICIs can maintain the activated state of specific anti-tumor immune cells stimulated by high-frequency and low-dose chemotherapy, and enhance the anti-tumor immune response [34].On the other hand,chemotherapeutic drugs can enhance immunotherapy by inhibiting regulatory T cell (Treg) and myeloid-derived suppressor cells(MDSCs), thus weakening their immunosuppressive function [35, 36].The above effect cannot be achieved by any kind of treatment alone.

Clinical research progress of ES-SCLC first-line immunotherapy

Ipilimumab

Ipilimumab is the first CTLA-4 inhibitor to be tested in combination with chemotherapy in SCLC.An early phase II study reported a randomized, double-blind, multicenter study of paclitaxel/carboplatin with or without ipilimumab in extensive stage SCLC [37].The administration methods of the study were ipilimumab administered synchronously at the early stage of chemotherapy-induced tumor antigen release (concurrent group), ipilimumab administered after chemotherapy-induced tumor antigen release (phased group), and paclitaxel/carboplatin chemotherapy alone (control group).Median immune related progression free survival (IrPFS) times in the three arms were 5.7, 6.4, 5.3 months, median progression free survival(PFS) times were 3.9, 5.2, 5.2 months, and median overall survival(OS) times were 9.1, 12.9, 9.9 months.IrPFS was significantly higher in the staged group compared with the control group, and ipilimumab did not increase the rate of adverse events.However, there was no significant improvement in mPFS and mOS among the three groups.This indicated that ipilimumab combined with chemotherapy had better clinical efficacy without obvious safety risks.But in the subsequent phase III clinical trial, ipilimumab combined with platinum-etoposide did not lead to a significant improvement in overall survival (11vs.10.9 months, HR = 0.94; 95% CI: 0.81 - 1.09;P= 0.377,5) [38].The progression-free survival time (PFS) of the two groups was 4.6 months and 4.4 months (HR = 0.85,P= 0.0161),respectively.The objective response rate (ORR) of both groups were 62%, and the 1-year OS rate was 40%.In the combined Ipilimumab group, no subgroup patients benefited from treatment were found in each preset subgroup analysis.Another one-arm trial to evaluate the efficacy of Ipilimumab combined with EP in the first-line treatment of ES-SCLC was also terminated due to excessive toxicity, and the 1-year progression-free survival rate was only 15.8% [39].Although the results of the study on Ipilimumab are not satisfactory, it does prove the feasibility of chemotherapy combined with immunotherapy in SCLC.

Atezolizumab

Atezolizumab is a humanized monoclonal IgG1 antibody against PD-L1.IMPower 133 is a phase III, multicenter, double-blind,randomized placebo-controlled study to evaluate the efficacy and safety of Atezolizumab combined with etoposide and carboplatin (EC)in patients with ES-SCLC [40].A total of 403 untreated ES-SCLC patients with a performance status (PS) of 0-1 was enrolled and randomly divided into two groups at 1: 1.One group received Atezolizumab maintenance therapy after 21 days/cycle × 4 treatment with Atezolizumab combined with EC, and the other group received placebo combined with EC followed by sequential placebo maintenance therapy until progression disease (PD) or no clinical benefit.The main endpoints of the study were the progression-free survival period (PFS) and the overall survival (OS) of the patients, and the secondary endpoints are objective response rate (ORR), duration of remission (DOR) and safety.At the same time, the experiment also explored the biomarkers.Compared with the EC regimen alone, the combination of Atezolizumab significantly improved OS and PFS.The Median follow-up was 13.9 months, the median PFS (5.2 months vs.4.3 months, HR = 0.77, 95% CI: 0.62 - 0.96,P= 0.017); The median follow-up was 22.9 months, the median OS (12.3 months vs.10.3 months, HR = 0.76, 95% CI: 0.60 - 0.95,P= 0.0154).OS rate increased by 13% in 12 months and 18 months (51.9% vs.39.0% and 34.0% vs.21.0%).Further analysis showed that there was no significant correlation between PD-L1/bTMB and the efficacy of immunotherapy.This study was the first phase III trial to gain OS benefit in the first-line systematic treatment of ES-SCLC in the past 30 years, and it was also the only first-line ES-SCLC immunochemotherapy regimen that meets the dual-end-point benefits in PFS and OS.The benefits of OS and PFS were also consistent in all predefined subgroups selected according to clinical, pathological and molecular characteristics (such as sex, age, blood tumor mutation load, Eastern Cooperative Oncology Group (ECOG) score, brain metastasis, liver metastasis, etc).This study showed that regardless of patients and disease characteristics, ES-SCLC patients can benefit from Atezolizumab combined with EC treatment.

Durvalumab

Duravelumab is another humanized monoclonal IgG1 antibody against PD-L1.The CASPIAN study is another randomized, open-label,multicenter phase III clinical trial to compare the efficacy of durvalumab, with or without tremelimumab (CTLA-4 inhibitor), in combination with EP (Etoposide + Platinum, carboplatin or cisplatin)versus standard first-line EP regimens [41].This study is the first to try the four-drug treatment model of CTLA-4 inhibitor and PD-L1 inhibitor combined with chemotherapy, with OS as the main endpoint, PFS, ORR, safety, tolerance, QoL (quality of life) (PRO,Patient-reported outcomes) as the secondary endpoint and PD-L1 biomarker as the exploratory endpoint.In the interim analysis,compared with the EP arm, the OS of the durvalumab + EP arm was longer (13.0 months vs.10.3 months, HR = 0.73, 95% CI: 0.5918-0.909,P= 0.0047), and the OS rate of 12-month and 18-month respectively from 39.8% to 53.7% and from 24.7% to 33.9%, and the confirmed ORR was higher: 68% versus 58% (odds ratio 1.56, 1.10-2.22), which is different from IMpower133.With the median follow up of more than 2 years, in the comparison between durvalumab +EP arm and EP arm, the benefit of OS is still significant (12.9 vs.10.5 months, HR = 0.75, 95% CI: 0.62-0.91,P= 0.0032).However, both OS and PFS did not meet the expectations in tremelimumab +durvalumab + EP arm, but accompanied by an increase in the rates of grade 3-4 adverse reactions (AEs) and AEs leading to treatment discontinuation.The relationship between tumor mutation load (TMB)and efficacy in the ITT population showed that tTMB could not predict the efficacy.Although there is something unsatisfactory, this study provides strong data support for Durvalumab combined with EP regimen to become a new standard treatment for first-line treatment of ES-SCLC.

Pembrolizumab

Pembrolizumab is a humanized monoclonal IgG4 antibody against PD-L1.The KEYNOTE-604 study is a phase III clinical trial designed to evaluate the efficacy and safety of Pembrolizumab plus EP(carboplatin or cisplatin) versus placebo plus EP in the first-line treatment of ES-SCLC [42].However, it released a negative result.The study eventually included 453 patients with newly diagnosed ES-SCLC who had not received central nervous system (CNS) metastasis treatment.These patients were randomly (1:1) assigned to the Pembrolizumab + EP group and the placebo + EP group and received up to 35 cycles of Pembrolizumab (200 mg Q3W) /placebo + 4 cycles of EP.After 4 cycles of treatment, patients with complete remission(CR) or partial remission (PR) can receive prophylactic craniocerebral irradiation (PCI) according to the judgment of the researchers.The main endpoints of the study were OS and PFS in the ITT population,and the secondary endpoints are ORR, DOR, and security.The study presupposes the second interim analysis (IA2) and the final analysis(FA).The results showed that PFS and OS were prolonged by Pembrolizumab+EP, compared with EP alone, and no new safety events were found.At a median follow-up of 13.5 months (IA2), the median PFS of the two groups was 4.5 months vs.4.3 months (HR =0.75, 95% CI: 0.61-0.91,P= 0.0023), and the 12-and 18-month PFS rates were 15.9% versus 5.0% and 10.8% versus 2.1% for pembrolizumab + EP and EP, respectively.However, the final analysis showed that although Pembrolizumab + EP prolonged OS in ITT population (10.8 months vs.9.7 months, HR = 0.80, 95% CI:0.64-0.98,P= 0.0164), there was no significant difference.The ORR of the two groups was 70.6% vs.61.8%, and the median DOR was 4.2 months vs.3.7 months.At a median follow-up of 21.6 months, 9% and 1% of patients in the Pembrolizumab group and placebo group were still in the study, and 12% and 14% of the patients received PCI respectively.The observed adverse events are in line with expectations.In the two groups, the incidence of treatment-related grade 3-4 adverse events accounted for 77% and 75% respectively.Grade 5 adverse events were 6% and 5% respectively, while 15% and 6% led to drug withdrawal.

Nivolumab

Nivolumab is a humanized monoclonal IgG4 antibody against PD-L1.The ECOG-ACRIN EA5161 study is a phase II clinical study for first-line treatment of ES-SCLC to compare the efficacy and safety of EP (carboplatin or cisplatin) alone or in combination with Nivolumab[43].The study included 160 ES-SCLC patients with assessable lesions(RECIST v1.1), an ECOG score of 0 or 1 and those who had not previously received systematic treatment.All patients were randomly(1:1) divided into Nivolumab + EP arm or EP arm.The primary endpoint was PFS, Secondary endpoints included OS, ORR and safety.The study showed that the Nivolumab + EP regimen significantly improved the PFS of ES-SCLC patients compared with the EP regimen alone.The median PFS of the two groups was 5.5 months and 4.7 months respectively (HR = 0.68, 95% CI: 0.48-1.00,P= 0.047).Moreover, compared with the EP group, the Nivolumab + EP regimen can also prolong the OS of patients.The median OS was 11.3 months and 8.5 months respectively (HR = 0.67, 95% CI: 0.48-0.98,P=0.038).The ORR of the two groups was 52.29% and 47.71%.The median duration of remission was 5.6 months and 3.3 months.The incidence of treatment-related grade 3-4 adverse events was 77% and 62% respectively, and the incidence of adverse events leading to drug withdrawal was 6.21% and 2.07%.Ten patients continued to receive nivolumab maintenance therapy.The results of this study show that for the first-line treatment of ES-SCLC patients, the addition of Nivolumab to the EP regimen can significantly improve the PFS and OS of the patients and have good safety.

Summary and prospect

ICIs combined with chemotherapy can significantly improve the survival of SCLC patients, and quickly become the new standard treatment for these patients, finally breaking the situation that there has been no progress in this field for decades.SCLC has the characteristic of high mutation load, which should be more beneficial to its benefit in immunotherapy, but it does not achieve the desired effect.Due to the unique mechanism of ICIs, and the lack of basic research explanation of the synergistic mechanism of combined therapy, ICIs combined therapy has some complexity and uncertainty.From the above studies, we can see that the advantage of PD-L1 monoclonal antibody seems to be greater than that of PD-1 monoclonal antibody in SCLC.And recent studies have extended the scope of immunotherapeutics by unveiling DNA damage-induced innate immunity as a novel target for cancer treatment [44].It shows that the benefit population of SCLC immunotherapy is not clear, and its efficacy may be affected by other mechanisms.Therefore, screening highly sensitive and specific biomarkers (that is, dominant population) that can predict efficacy, exploring the best mode of combination therapy (including the combination regimen and the type, dose, treatment sequence, timing of administration, etc), and timely detection and reasonable disposal of immune-related adverse events (IrAEs) become the direction of exploration in the future.At present, there are still many related experiments that are worth expecting.It is believed that shortly, the immunotherapy of SCLC will be more and more promising.