Sage Journals: Discover world-class research

Abstract

Background

Cadonilimab (AK104) is a bispecific IgG-single-chain Fv fragment (ScFv) antibody that binds to PD-1 and CTLA-4. Cadonilimab has shown encouraging anti-tumour activity and a favourable safety profile in several tumour types. In second-line treatment, there is no defined standard of care for patients with extensive-stage small-cell lung cancer (ES-SCLC). Cadonilimab is expected to show substantial clinical efficacy.

Objective

To assess the antitumor activity and safety of cadonilimab monotherapy or combination with conventional therapy in ES-SCLC patients who failed first-line treatment.

Methods

In this multicenter, open-label, phase II study, ES-SCLC patients who had failed first-line treatment, also aged 18 years to 70 years with histologically or cytologically confirmed ES-SCLC, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–2 were eligible. Patients will receive cadonilimab 10 mg/kg every three weeks (Q3 W) among 24 months until progressive disease (PD) or adverse events (AE) discovery. The primary endpoint is progression-free survival (PFS).

Trial registration

NCT05901584.

Keywords

cadonilimab immunotherapy second-line treatment combination therapy small cell lung cancer

Background

In terms of morbidity and mortality, lung cancer is the most prevalent disease worldwide. Although Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. However, the 5-year overall survival only 6% due to highly aggressive.¹ Two-thirds of patients have distant metastatic disease at initial diagnosis.^2,3 In the rare patients who present with very early-stage disease at diagnosis, treatment can include surgery and adjuvant platinum-based chemotherapy although, more typically, patients with early-stage or locally advanced disease are treated with concurrent radiation and platinum-based chemotherapy.^4–6 Since 1980, etoposide combined with platinum with thoracic radiotherapy has been the primary first-line treatment in SCLC.^7–9 Available therapies are limited for the majority of SCLC patients who relapse. Topotecan, the most widely used second-line agent globally, has limited efficacy and an unfavorable safety profile.^10,11 Lurbinectedin, in 2020 became the first drug approval by the FDA in over 20 years to second-line treatment, was conditionally approved based on an objective response rate (ORR) of 35%; however, a randomized study failed to demonstrate OS benefit.¹² No agent is specifically for second-line treatment of relapsed SCLC. Further biomarker analyses in this context are warranted, including the exploration of emerging biomarkers such as SCLC molecular subtypes.¹³

Immune checkpoint inhibitors (ICIs) have emerged as a standard first-line treatment option for SCLC,^14–18 After many decades of minimal progress towards improving treatment outcomes in SCLC, recent clinical trials have shown longer overall survival for patients with ES-SCLC treated with ICI combined with chemotherapy, specifically the PD(L)-1 inhibitors atezolizumab and durvalumab, addebelimumab and serplulimab.^19,20 Another immune checkpoint protein that is being targeted in cancer treatment is CTLA-4, a co-inhibitory receptor that represses T-cell activity.CTLA-4 blockade prevents this downregulation of T cells, thereby releasing a brake on T-cell activation and enhancing immune function.²¹ The simultaneous blockade of both nonredundant immune checkpoint pathways by combining antibodies that target PD-1 or PD-L1 with anti-CTLA-4 might have additive or synergistic effects on antitumor T-cell responses,²² and has been shown to be an effective therapeutic approach in some tumor types, including NSCLC.^23,24 Combining chemotherapy with immunotherapy might further enhance tumor antigenicity. In the IMpower-133 study, to achieve a positive double endpoint of first-line treatment for ES-SCLC.²⁵ Showed a breakthrough in the median OS of 12 months for atezolizumab combination with chemotherapy instead of conventional first-line chemotherapy.²⁶ In the CASPIAN study, receiving of durvalumab in combination with chemotherapy importantly reduces OS in ES-SCLC patients compared to chemotherapy alone, the Food and Drug Administration (FDA) formally approved etoposide plus carboplatin and atezolizumab as first-line treatment of SCLC. However, patients who have failed first-line treatment still limited for second-line treatment options of current therapy. Subsequently, in the PASSION study, explored camrelizumab combined with apatinib in second-line treatments, patients can benefit from ICIs combination treatment strategies.²⁷ Given that the combination of PD-1 and CTLA-4 blockade significantly improves overall survival (OS) in several cancer types, this offers hope to patients who have failed first-line therapy.^{16,23,24,28,29} However, due to dose-dependent immune-related adverse events, therapeutic doses of anti-CTLA-4 monoclonal antibodies are low and when administered in combination, safety and tolerability issues may limit use.³⁰ Therefore, need for new approaches that can increase PD-1 combination with CTLA-4 blocking while improving safety.

Cadonilimab binds to PD-1 and CTLA-4 and blocks PD-1/PD-L1, PD-1/PD-L2, CTLA-4/B7.1, and CTLA-4/B7.2 interactions,³¹ effective in tumors including liver cancer, lung cancer, gastric cancer, oesophageal squamous cell cancer and nasopharyngeal carcinoma.³² It has a higher affinity for tumor infiltrating lymphocytes in the tumor microenvironment than other cells in surrounding tissue.³² Cadonilimab was approved by the New Drug Application (NDA) on June 29, 2022 for patients with recurrent or metastatic cervical cancer who had failed previous platinum-containing chemotherapy. Cadonilimab combined with platinum-containing chemotherapy, has emerged as an effective first-line treatment for patients with unresectable advanced gastric cancer/GEJ.³² This combination therapy yielded median DoR of 6.93 months, while the median PFS and OS were 7.10 months and 17.41 months, respectively. Meanwhile, comparative studies highlight the effectiveness of other treatments. However, cadonilimab has emerged antitumor activity in patients with metastatic nasopharyngeal carcinoma. Additionally, in the cadonilimab study conducted in Australia has shed light on the drug's promising antitumor activity and a favorable safety profile across various tumor types.³³ The safety and efficacy of cadonilimab are likely attributable to its high binding avidity with PD-1 and CTLA-4, enhancing its tumoricidal action. Moreover, its FC-NULL design and lack of fragment crystallizable (Fc) receptor binding may also be related to its low toxicity.³⁴

In the study, we prospectively evaluated the antitumor activity and safety of cadonilimab 10 mg/kg intravenously once every 3 weeks (conventional therapy with or without combination) in patients with ES-SCLC, patients had failed first-line treatment. Primary endpoint analyses, treatment recipient efficacy and IRAE-related biomarkers analyses. The study will explore that the synergistic effect may lead to improved antitumor activity and a favorable safety profile with ES-SCLC.

Study Design

This was a multicentre, open-label, phase II trial of cadonilimab (Chemotherapy with or without combination) in previously first-treatment failed patients with advanced SCLC, and was conducted across seven centers in China. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. The study protocol was reviewed and approved by relevant institutional review boards or ethics committees at each hospital. All patients provided written informed consent (Figure 1).

Figure 1.

Trial profile: inclusion of patients and interventions. ES-SCLC, extensive-stage small cell lung cancer; ECOG, eastern cooperative oncology group. AK104, cadonilimab.

Inclusion Criteria

All patients provided written informed consent for participation. Pathologically supported diagnosis of small cell lung cancer, extensive stage and large lesions are confirmed on imaging. The study design has been previously reported. Briefly, eligible patients were aged 18 years to 75 years with first -treatment failed. Histologically or cytologically documented ES-SCLC that was American Joint Committee on Cancer (seventh edition) stage IV (any T-stage, any N-stage, M-stage M1 a or M1b), or T-stage T3–4. ECOG physical performance score of 0–2 at the time of enrollment. A life expectancy of ≥3 months, Laboratory tests required to assess eligibility included a hematology test, blood chemistry, cardiac function, urinalysis, coagulation, and thyroid function. Patients with or without radiotherapy (Supplemental Material). Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The criteria for left ventricular ejection fraction (LVEF) must be greater than or equal to the lower limit of normal (50%). Pre-menopausal women had to have a negative pregnancy test.

Exclusion Criteria

Exclusion criteria included cadonilimab used prior to study participation. Non-small cell lung cancer and lung cancers including mixed small cell and non-small cell cancers. patients with a history of another malignancy within the past 5 years or who currently have another malignancy are excluded, with the exception of those who have been cured of cervical carcinoma in situ, non-melanoma skin cancer, and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invades the lamina propria)]. patients should not have received systemic antitumor treatments, including cytotoxic therapy, signal transduction inhibitors, or immunotherapy, within 4 weeks prior to enrollment in this study, or plan to receive any such treatments during the study period. This includes the use of Mitomycin C within 6 weeks before receiving the study drug. Patients have undergone extended-field radiation therapy (EF-RT) within 4 weeks prior to grouping or site-specific radiation therapy for the tumor to be evaluated within 2 weeks prior to grouping are also excluded. Additional exclusion criteria included significant irregularities in laboratory testing or unregulated active comorbidities (refer to the Supplemental Material for further information).

Study Treatment Overview

Medication: Cadonilimab injection (Kaitanib), produced by Kangfang Pharmaceutical Co.

Dosage and Administration: 10 mg/kg, given intravenously every three weeks (Q3 W) on the first day of each 3-week cycle.

Storage and Handling: Stored at room temperature, protected from light, sealed, with a shelf life of 24 months.

Duration and Monitoring: Treatment continues up to 24 months or until the investigator determines no additional clinical benefits, based on a total of eight cycles. Hospitals manage drug storage and distribution, maintaining strict records. Post-trial, unused drugs are returned to the sponsor.

Method of Treatment Assignment

Participants: Patients with ES-SCLC who have failed first-line treatment (platinum-based chemotherapy, with or without atezolizumab and divalirizumab).

Treatment Regimen: Cadonilimab alone or combined with chemotherapy, administered as per the dosing cycle. Treatment continues until toxicity becomes intolerable, there's no further clinical benefit (judged by the investigator), completion of 24 months, or other protocol defined termination criteria.

Consent and Guidelines: Participants must sign informed consent forms, approved by the institutional review board and adhering to institutional guidelines.

Safety and Tolerability Assessment

Tests and Examinations: Patients undergo vital signs check, physical exams, laboratory tests, and physical status scoring, within 72 h before each dose.

Dosing Cycle: A 3-week cycle with a ± 3-day window.

Termination Criteria: Treatment ceases if the investigator deems the patient unfit for further dosing or if progressive disease (PD) is confirmed based on RECIST, version 1.1.

Cadonilimab Dose Modification

The AK104 treatment regimen is designed with a fixed dosage and should not be altered during the course of treatment. However, provisions are made for delayed administration, permitting a postponement of up to 12 weeks following the last dose. In circumstances where glucocorticoids are administered to manage immune-related adverse events (irAEs), AK104 treatment can be temporarily suspended for an extended period exceeding 12 weeks, particularly during the phase of glucocorticoid tapering. Similarly, in cases where an adverse event (AE), whether related to AK104 or not, necessitates a treatment pause of more than 12 weeks, the investigator retains discretion to assess and decide if the patient would still derive therapeutic benefit from the continuation of treatment. In such scenarios, resumption of dosing is advised to be undertaken in consultation with the medical ombudsman from the sponsoring company. For chemotherapy agents, dosage modifications are permitted, along with a maximum dosing delay of 6 weeks. In the event of chemotherapy intolerance, two dose reductions should be attempted prior to considering treatment discontinuation.

Criteria for Discontinuation of Study Medications

The criteria for discontinuing participation in the study are as outlined below:

Identification of disease progression (PD), as determined through clinical assessment and based on established efficacy evaluation criteria.

Recommendation by the attending study physician to cease treatment, considering it to be in the patient's best interest.

Occurrence of a serious adverse reaction or event, as confirmed by the investigating team.

Non-compliance with the prescribed medication regimen, specifically if the patient administers doses outside the acceptable range of 80% to 120% of the prescribed amount, potentially leading to suboptimal treatment outcomes.

Voluntary withdrawal of informed consent by the patient.

Initiation of treatment with other antineoplastic agents (such as chemotherapy, targeted therapy, or biological therapy) that could potentially confound the assessment of treatment efficacy.

Occurrence of an unintended pregnancy during the study period.

Death of the participant.

Efficacy Analyses

This study concentrates on patients with ES-SCLC who have not responded to first-line treatment, treatment involves 3-week dosing cycles where patients will receive cadonilimab, either as a monotherapy or in combination with chemotherapy. Treatment discontinuation will occur if toxicity reaches an intolerable level or if there is no further clinical benefit, as determined by the participating investigators. This determination will be based on imaging assessments and clinical conditions in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Patients will be monitored for a duration of 24 months or until other specified termination criteria outlined in the study protocol are met.

Endpoint

Primary efficacy endpoint:

The primary endpoints was progression-free survival (PFS), as assessed by investigators per RECIST, version 1.1.

Secondary efficacy endpoints:

The study obtained objective efficacy indicators for overall survival (OS), objective response rate (ORR) including complete response (CR) and partial response (PR), and disease control rate (DCR) including CR, PR, and stable disease (SD). These indicators were evaluated using solid tumor efficacy evaluation criteria, specifically RECIST, version 1.1.

Disease control rate (DCR): the proportion of patients who achieved a complete response, partial response, or stable disease as the best overall response.

Overall survival (OS): the time from the first dose of study medication to death due to any cause.

It is essential to meticulously record any tumor assessment results obtained during follow-up in medical records, particularly for patients who withdraw from the study before experiencing disease progression. All administered antitumor therapies should be comprehensively documented. For patients who are alive at the time of data analysis, their survival duration should be recorded up to their most recent known survival date. Additionally, patients who have withdrawn from the study will be subject to ongoing follow-up. This will include periodic monitoring (including telephonic check-ins) every 4 weeks to gather information regarding their ongoing anti-tumor treatments and current survival status (Figure 2).

Figure 2.

Study period description. etc, etcetera; t0, registration time point; A, cadonilimab monotherapy; B, cadonilimab with chemotherapy.

Reporting of Safety Events

The recording of symptoms and severity of adverse reactions both during and post-treatment is mandatory, alongside the documentation of corresponding treatment measures and their outcomes. Resident staff members are obligated to diligently complete case reporting forms and promptly report these findings to the Principal Investigator and the Good Clinical Practice (GCP) Officer. Additionally, data from abnormal laboratory tests must be systematically re-evaluated and recorded at least on a weekly basis until the patient's recovery or the conclusion of the study.

Follow-Up Assessments

Follow-up sessions will commence following the administration of the final dose of the study drug to patients. This process of treatment and subsequent follow-up will persist until the patient's condition improves to a Grade 1 severity as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, or until full recovery from any adverse events is achieved. These follow-up sessions, conducted every 4 weeks (including telephone consultations), are designed to collect information regarding any additional antitumor treatments received prior to each session. In cases where other treatments have been administered, it is crucial to meticulously document the specific treatment regimen, the number of treatment cycles, and the outcomes observed. This follow-up process will be maintained up to the event of the patient's death. For the purpose of evaluating overall survival (OS), both the cause and the timing of death will be thoroughly recorded.

Statistical Consideration and Analysis Plan

Statistical Analysis

For the purposes of safety evaluation, all subjects who received at least one dose of the investigational drug are included in the safety analysis set. The efficacy analysis is conducted on the Full Analysis Set (FAS), which encompasses subjects presenting with measurable lesions at baseline and who have received a minimum of one dose of the investigational drug.

Primary Efficacy Analysis

In this study, the Objective Response Rate (ORR) and Disease Control Rate (DCR) are calculated based on the RECIST, version 1.1, utilizing data from the Full Analysis Set (FAS). Precise 80% and 95% confidence intervals are estimated bilaterally employing the Clopper-Pearson method. The Kaplan-Meier approach is utilized to assess Duration of Response (DoR), Time to Response (TTR), Progression-Free Survival (PFS), and Overall Survival (OS), with the generation of Kaplan-Meier plots for visual representation. Graphical analyses including spider and waterfall plots are implemented. The safety analysis set is employed for the analysis of PFS and OS data.

Safety Analyses

Safety analyses will be performed on all participants who have received at least one dose of the study drug. This safety analysis set encompasses the evaluation of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) that resulted in discontinuation of the drug. Adverse events are graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 and classified using the Medical Dictionary for Regulatory Activities (MedDRA). Summary statistics for these events will be provided. Abnormal laboratory results and toxicity levels will be summarized using NCI-CTCAE version 5.0. Additionally, a cross-tabulation of clinical laboratory tests will be presented to further elucidate the safety profile.

Biomarker, and Other Biological Samples

This study sought to investigate the link between PD-L1 expression (combined positive score) and efficacy or irAE. Exploratory endpoints included pharmacodynamic biomarkers, the correlation between PD-L1 expression and antitumor response, and antitumor activity assessed with immune-related RECIST (irRECIST), blood-based tumor mutational burden (bTMB). Available tumor specimens retrieved using any method (eg, fine needle aspirations, tissue biopsies, bronchoscopy, or cytological samples) were collected. Exploratory biomarker analyses according to PD-L1 expression levels on both tumor cells (TCs) and tumor-infiltrating immune cells (ICs) were conducted in the biomarker evaluable population (BEP).

Trial Status

The recruitment process is ongoing.

Discussion

Small cell lung cancer (SCLC) comprises approximately 15% of all lung cancer cases. It is characterized by its high malignancy, poorly differentiated cell structure, and rapid proliferation. The therapeutic landscape for SCLC presents significant challenges, particularly in the treatment of the extensive stage (ES), which is diagnosed in about 65% of SCLC patients. This stage is associated with notably poor treatment outcomes and prognosis. Since 1985, platinum-etoposide chemotherapy has been the cornerstone of first-line therapy for SCLC.³⁵ However, disease progression during or after this platinum-based therapy limits subsequent treatment options. Immunotherapy has emerged as a promising approach in SCLC treatment. Combining immune checkpoint inhibitors with chemotherapy has demonstrated synergistic effects, potentially enhancing antitumor efficacy. 2019 produced a new landmark in the treatment of SCLC through US FDA approval of the PD-L1 inhibitor atezolizumab in combination with first-line platinum doublet chemotherapy for patients with extensive-stage disease.³⁶ Topotecan, the standard second-line therapy for years, shows limited effectiveness, with a response rate of 25% in patients responsive to platinum therapy and less than 10% in those who are platinum-insensitive.^37–39

Immunotherapy has shown effectiveness in first-line treatment, yet the options for effective second-line therapy remain insufficient. In the PASSION study, camrelizumab with apatinib as a second-line treatment exhibited a median progression-free survival (PFS) of 3.6 months and overall survival (OS) of 8.4 months. This study highlighted that dual antibody combinations significantly boost the function of tumor-infiltrating T cells, compared to the use of anti-CTLA-4 or PD-L1 antibodies alone. The complementary roles of PD-1 and CTLA-4 in immune response regulation (via preventing T cell depletion and promoting T cell activation, respectively) suggest that dual immunotherapy additional activity or synergistic,²² and combination therapy is more effective than monotherapy. Cadonilimab received its first approval on 29 June 2022 in China.³² Is the first dual immune checkpoint inhibitor bi-specific anti-body treatment to be approved. In view of cadonilimab promising application in several studies, we will investigate its benefits in survival of patients with SCLC, explore new markers in post-treatment patient specimens and search for new molecular typing possibilities.

Immunotherapies that enhance the activity of T cells against cancer cells, such as blockade of CTLA4, PD1 or PDL1, have some beneficial effects in patients with SCLC.^40,41 However, the response to T cell checkpoint blockade is limited to ∼15% of patients with SCLC.^1,40 However, advancements in immunotherapy for SCLC critically depend on identifying predictive biomarkers and devising novel therapeutic strategies. Currently, emerging research has illuminated the interactions between macrophages and SCLC tumor cells, as well as the role of natural killer cells in modulating the SCLC microenvironment. The ganglioside GM2 has been identified as a promising target for NK cell-based therapies.^42,43 However, the genetic and non-genetic heterogeneity of SCLC, further complicated by recent advances in sequencing techniques, poses a challenge to the application of precision oncology in this domain. To address this, ongoing research is focused on exploring SCLC's therapeutic vulnerabilities through advanced molecular profiling technologies, which hold promise for both the development of targeted therapies and the utilization of predictive biomarkers in patients treatment. Molecular subtyping has significantly enhanced our understanding of SCLC, revealing several subtypes, including ASCL1, NEUROD1, YAP1, and POU2F3, along with a newly identified inflammatory subtype, SCLC-I, characterized by high immune cell infiltration and upregulated CD47 expression, which aids SCLC cells in evading immune response. In addition, SCLC with high neuroendocrine(NE) expressing ASCL1 is considered an immune desert tumor, while SCLC with low NE, especially SCLC-I, shows higher concentrations of cytotoxic T cells, NK cells, and macrophages.^36,40,41,44However, some study showed that SCLC-I may not be a predictive biomarker.⁴⁵Therefore, further research is needed to confirm reliable SCLC biomarkers and their relevance in treatment outcomes, which is critical to improving the efficacy of SCLC treatment.^46–48

The present study aims to assess the therapeutic impact and safety of dual targeted therapy with cadonilimab, combined with or without chemotherapy, in patients with ES-SCLC. This study will also explore potential efficacy predictors to identify the SCLC population most likely to benefit from ICI therapy.

Supplemental Material

sj-docx-1-tct-10.1177_15330338241249690 - Supplemental material for A Single-Arm Multi-Center Phase II Clinical Trial of Cadonilimab (anti-PD-1/CTLA-4) in Combination with or without Conventional Second-Line Treatment for Patients with Extensive Stage Small Cell Lung Cancer

Supplemental material, sj-docx-1-tct-10.1177_15330338241249690 for A Single-Arm Multi-Center Phase II Clinical Trial of Cadonilimab (anti-PD-1/CTLA-4) in Combination with or without Conventional Second-Line Treatment for Patients with Extensive Stage Small Cell Lung Cancer by Can Chen, Minjun Chen, Yuju Bai, Yajun Li, Jie Peng, Biao Yao, Jiangping Feng, Jian-Guo Zhou and Hu Ma in Technology in Cancer Research & Treatment

Footnotes

Abbreviations

Accessibility Materials and Data

In line with the criteria, the research datasets used in the study were supplied by the participating authors.

Authors’ Donations

Jian-Guo Zhou and Hu Ma led the overall conceptual and methodological design of the study conducted statistical analyses, critically revised the manuscript, agreed on the final published version, and took responsibility for all aspects of the research. Can Chen and Minjun Chen participated in the conception and design of the study, drafted the manuscript, made important revisions to the manuscript, approved the final version for publication, and agreed to be responsible for all aspects of the work. Yajun Li, Jie Peng, Yuju Bai, Jiangping Feng and Biao Yao were responsible for patient recruitment and randomization, obtaining informed consent, administering protocol treatments, assigning participants to interventions, providing medical care, and follow-up. Jian-Guo Zhou and Hu Ma participated in the conception and design, made critical revisions to the manuscript, approved the final published version, and agreed to be responsible for all aspects of the work.

Approval by the Institutional Review Board or Ethics Committee

This study was approved by the Medical Ethics Review Committee of the Second Affiliated Hospital of Zunyi Medical University (No. KYLL-2023-010). Written informed consent will be given to patients prior to enrolment, while the trial is monitored and managed by an ethics committee. It will be conducted in strict accordance with the Declaration of Helsinki.

Consent for Publication

The outcome will be propagated by various means. including reviewed journals, presentations and policy forum. Results will detail the results of a single-arm, multicenter phase II clinical trial evaluating the efficacy of cadonilimab as a second-line treatment for ES-SCLC with or without conventional therapy.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (Grant No. 82060475), Guizhou Anti-Cancer Association Fund (Grant No. KXKJ002(2023)), Chunhui program of the Chinese Ministry of Education (Grant No. HZKY20220231), the Natural Science Foundation of Guizhou Province (Grant No. ZK2022-YB632), Youth Talent Project of Guizhou Provincial Department of Education (Grant No. QJJ2022-224), China Lung Cancer Immunotherapy Research Project, Excellent Young Talent Cultivation Project of Zunyi City (Zunshi Kehe HZ (2023) 142), Future Science and Technology Elite Talent Cultivation Project of Zunyi Medical University (ZYSE-2023-02) and Collaborative Innovation Center of Chinese Ministry of Education (Grant No. 2020-39).

ORCID iD

Jian-Guo Zhou

Supplemental Material

Supplemental material for this article is available online.

References

Rudin

Brambilla

Faivre-Finn

, et al. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7(1):3. doi: https://doi.org/10.1038/s41572-020-00235-0 [published Online First: 2021/01/16].

Pesch

Kendzia

Gustavsson

, et al. Cigarette smoking and lung cancer–relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer. 2012;131(5):1210-1219. doi: https://doi.org/10.1002/ijc.27339 [published Online First: 2011/11/05].

Varghese

Zakowski

, et al. Small-cell lung cancers in patients who never smoked cigarettes. J Thorac Oncol. 2014;9(6):892-896. doi: https://doi.org/10.1097/jto.0000000000000142 [published Online First: 2014/05/16].

Takada

Fukuoka

Kawahara

, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: Results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002;20(14):3054-3060. doi: https://doi.org/10.1200/jco.2002.12.071 [published Online First: 2002/07/16].

Sundstrøm

Bremnes

Kaasa

, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: Results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol. 2002;20(24):4665-4672. doi: https://doi.org/10.1200/jco.2002.12.111 [published Online First: 2002/12/19].

Rossi

Di Maio

Chiodini

, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: The COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30(14):1692-1698. doi: https://doi.org/10.1200/jco.2011.40.4905 [published Online First: 2012/04/05].

Turrisi

3rd Kim

Blum

, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340(4):265-271. doi: https://doi.org/10.1056/nejm199901283400403 [published Online First: 1999/01/28].

Schild

Bonner

Shanahan

, et al. Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;59(4):943-951. doi: https://doi.org/10.1016/j.ijrobp.2004.01.055 [published Online First: 2004/07/06].

Spigel

Townley

Waterhouse

, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: Results from the SALUTE trial. J Clin Oncol. 2011;29(16):2215-2222. doi: https://doi.org/10.1200/jco.2010.29.3423 [published Online First: 2011/04/20].

10.

Petrelli

Ghidini

Luciani

. Topotecan or other agents as second-line therapy for relapsed small-cell lung cancer: A meta-analysis of randomized studies. Mol Clin Oncol. 2021;15(4):218. doi: https://doi.org/10.3892/mco.2021.2383 [published Online First: 2021/09/04].

11.

von Pawel

Schiller

Shepherd

, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658-667. doi: https://doi.org/10.1200/jco.1999.17.2.658 [published Online First: 1999/03/18].

12.

Paz-Ares

Champiat

Lai

, et al. Tarlatamab, a first-in-class DLL3-targeted bispecific T-cell engager, in recurrent small-cell lung cancer: An open-label, phase I study. J Clin Oncol. 2023;41(16):2893-2903. doi: https://doi.org/10.1200/jco.22.02823 [published Online First: 2023/01/24].

13.

Rudin

Poirier

Byers

, et al. Molecular subtypes of small cell lung cancer: A synthesis of human and mouse model data. Nat Rev Cancer. 2019;19(5):289-297. doi: https://doi.org/10.1038/s41568-019-0133-9 [published Online First: 2019/03/31].

14.

Robert

Long

Brady

, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330. doi: https://doi.org/10.1056/NEJMoa1412082. published Online First: 2014/11/18.

15.

Robert

Schachter

Long

, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-2532. doi: https://doi.org/10.1056/NEJMoa1503093. [published Online First: 2015/04/22].

16.

Larkin

Chiarion-Sileni

Gonzalez

, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34. doi: https://doi.org/10.1056/NEJMoa1504030. [published Online First: 2015/06/02].

17.

Reck

Rodrأ╦guez-Abreu

Robinson

, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi: https://doi.org/10.1056/NEJMoa1606774. [published Online First: 2016/10/11].

18.

Mok

TSK

Kudaba

, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi: https://doi.org/10.1016/s0140-6736(18)32409-7. published Online First: 2019/04/09.

19.

Paz-Ares

Dvorkin

Chen

, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi: https://doi.org/10.1016/s0140-6736(19)32222-6. published Online First: 2019/10/09.

20.

Horn

Mansfield

Szczؤ└sna

, et al. First-Line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi: https://doi.org/10.1056/NEJMoa1809064. [published Online First: 2018/10/04].

21.

Tarhini

. Tremelimumab: A review of development to date in solid tumors. Immunotherapy. 2013;5(3):215-229. doi: https://doi.org/10.2217/imt.13.9. [published Online First: 2013/03/01].

22.

Pardoll

. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. doi: https://doi.org/10.1038/nrc3239. [published Online First: 2012/03/23].

23.

Motzer

Tannir

McDermott

, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi: https://doi.org/10.1056/NEJMoa1712126. [published Online First: 2018/03/22].

24.

Hellmann

Paz-Ares

Bernabe Caro

, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi: https://doi.org/10.1056/NEJMoa1910231. [published Online First: 2019/09/29].

25.

Horn

Mansfield

Szczęsna

26.

Reddy

Qin

Kalemkerian

. Emerging drugs for small cell lung cancer: A focused review on immune checkpoint inhibitors. Expert Opin Emerg Drugs. 2020;25(3):353-366. doi: https://doi.org/10.1080/14728214.2020.1798929. published Online First: 2020/07/21.

27.

Fan

Zhao

Wang

, et al. Camrelizumab plus apatinib in extensive-stage SCLC (PASSION): A multicenter, two-stage, phase 2 trial. J Thorac Oncol. 2021;16(2):299-309. doi: https://doi.org/10.1016/j.jtho.2020.10.002. published Online First: 2020/11/10.

28.

Larkin

Chiarion-Sileni

Gonzalez

, et al. Five-Year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546. doi: https://doi.org/10.1056/NEJMoa1910836. [published Online First: 2019/09/29].

29.

Gao

, et al. Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): A multicentre, open-label, phase 1b/2 trial. Lancet Oncol. 2023;24(10):1134-1146. doi: https://doi.org/10.1016/s1470-2045(23)00411-4. published Online First: 2023/10/06.

30.

Dovedi

Elder

Yang

, et al. Design and efficacy of a monovalent bispecific PD-1/CTLA4 antibody that enhances CTLA4 blockade on PD-1(+) activated T cells. Cancer Discov. 2021;11(5):1100-1117. doi: https://doi.org/10.1158/2159-8290.Cd-20-1445. published Online First: 2021/01/10.

31.

Chen

Yao

, et al. 2023 A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer. Br J Cancer 2024;130:450-456. doi: 10.1038/s41416-023-02519-0.

32.

Keam

. Cadonilimab: First approval. Drugs. 2022;82(12):1333-1339. doi: https://doi.org/10.1007/s40265-022-01761-9. published Online First: 2022/08/21.

33.

Zhao

Fan

, et al. A multicenter, open-label phase Ib/II study of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) monotherapy in previously treated advanced non-small-cell lung cancer (AK104-202 study). Lung Cancer. 2023;184:107355. doi: https://doi.org/10.1016/j.lungcan.2023.107355. published Online First: 2023/09/08.

34.

Qiao

Han

, et al. The efficacy and safety of cadonilimab combined with lenvatinib for first-line treatment of advanced hepatocellular carcinoma (COMPASSION-08): A phase ib/II single-arm clinical trial. Front Immunol. 2023;14:1238667. doi: https://doi.org/10.3389/fimmu.2023.1238667. published Online First: 2023/11/09.

35.

Evans

Shepherd

Feld

, et al. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985;3(11):1471-1477. doi: https://doi.org/10.1200/jco.1985.3.11.1471. published Online First: 1985/11/01.

36.

Megyesfalvi

Gay

Popper

, et al. Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions. CA Cancer J Clin. 2023;73(6):620-652. doi: https://doi.org/10.3322/caac.21785. [published Online First: 2023/06/17].

37.

Dingemans

Früh

Ardizzoni

, et al. Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up(⋆). Ann Oncol. 2021;32(7):839-853. doi: https://doi.org/10.1016/j.annonc.2021.03.207. published Online First: 2021/04/18.

38.

Cheng

Evans

Stys-Norman

, et al. Chemotherapy for relapsed small cell lung cancer: A systematic review and practice guideline. J Thorac Oncol. 2007;2(4):348-354. doi: https://doi.org/10.1097/01.Jto.0000263720.15062.51. [published Online First: 2007/04/06].

39.

Zugazagoitia

Paz-Ares

. Extensive-Stage small-cell lung cancer: First-line and second-line treatment options. J Clin Oncol. 2022;40(6):671-680. doi: https://doi.org/10.1200/jco.21.01881. [published Online First: 2022/01/06].

40.

Ready

Ott

Hellmann

, et al. Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: Results from the CheckMate 032 randomized cohort. J Thorac Oncol. 2020;15(3):426-435. doi: https://doi.org/10.1016/j.jtho.2019.10.004. [published Online First: 2019/10/21].

41.

Antonia

Lأ╠pez-Martin

Bendell

, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): A multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883-895. doi: https://doi.org/10.1016/s1470-2045(16)30098-5. published Online First: 2016/06/09.

42.

Best

Hess

Souza-Fonseca-Guimaraes

, et al. Harnessing natural killer immunity in metastatic SCLC. J Thorac Oncol. 2020;15(9):1507-1521. doi: https://doi.org/10.1016/j.jtho.2020.05.008. published Online First: 2020/05/30.

43.

Ando

Hoon

Suzuki

, et al. Ganglioside GM2 on the K562 cell line is recognized as a target structure by human natural killer cells. Int J Cancer. 1987;40(1):12-17. doi: https://doi.org/10.1002/ijc.2910400104. [published Online First: 1987/07/15].

44.

Fridman

Giaccone

Kanemoto

, et al. Reconstituted basement membrane (matrigel) and laminin can enhance the tumorigenicity and the drug resistance of small cell lung cancer cell lines. Proc Natl Acad Sci U S A. 1990;87(17):6698-6702. doi: https://doi.org/10.1073/pnas.87.17.6698. [published Online First: 1990/09/01].

45.

Gay

Stewart

Park

, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39(3):346-60.e7. doi: https://doi.org/10.1016/j.ccell.2020.12.014. published Online First: 2021/01/23.

46.

Liu

Reck

Mansfield

, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi: https://doi.org/10.1200/jco.20.01055. [published Online First: 2021/01/14].

47.

Gadgeel

Pennell

Fidler

, et al. Phase II study of maintenance pembrolizumab in patients with extensive-stage Small Cell Lung Cancer (SCLC). J Thorac Oncol. 2018;13(9):1393-1399. doi: https://doi.org/10.1016/j.jtho.2018.05.002. [published Online First: 2018/05/19].

48.

Hellmann

Callahan

Awad

, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell. 2018;33(5):853-61.e4. doi: https://doi.org/10.1016/j.ccell.2018.04.001. published Online First: 2018/05/08.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.02 MB