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# FDA approves lurbinectedin in combination with atezolizumab for extensive-stage small cell lung cancer

Oliver Kepp, Guido Kroemer

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Oliver Kepp, Guido Kroemer. FDA approves lurbinectedin in combination with atezolizumab for extensive-stage small cell lung cancer. OncoImmunology, 2025, 14, 10.1080/2162402x.2025.2584898. [https://hal.science/hal-05384084](https://hal.science/hal-05384084)

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# FDA approves lurbinectedin in combination with atezolizumab for extensive-stage small cell lung cancer

Oliver Kepp & Guido Kroemer

**To cite this article:** Oliver Kepp & Guido Kroemer (2025) FDA approves lurbinectedin in combination with atezolizumab for extensive-stage small cell lung cancer, Oncolmmunology, 14:1, 2584898, DOI: 10.1080/2162402X.2025.2584898

**To link to this article:** https://doi.org/10.1080/2162402X.2025.2584898

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© 2025 The Author(s). Published with license by Taylor & Francis Group, LLC.

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Published online: 18 Nov 2025.

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# FDA approves lurbinectedin in combination with atezolizumab for extensive-stage small cell lung cancer

Oliver Kepp<sup>a,b</sup> and Guido Kroemer<sup>a,b,c</sup>

<sup>a</sup>Université Paris Cité, Sorbonne Université, Inserm, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Institut Universitaire de France, Paris, France; <sup>b</sup>Université Paris-Saclay, INSERM US23/CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France; <sup>c</sup>Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

## ABSTRACT

The recent FDA approval of lurbinectedin plus atezolizumab for advanced small cell lung cancer underscores the promise of combining immunogenic cell death (ICD) inducers with PD-1/PD-L1 blockade. This synergistic strategy induces durable responses in refractory tumors and may extend immunotherapy benefits across diverse malignancies through rational ICD-checkpoint inhibitor combinations.

## ARTICLE HISTORY

Received 14 October 2025
Revised 30 October 2025
Accepted 31 October 2025

## KEYWORDS

IMFORTE; eIF2α; STING

## Main text

The approval by the FDA of lurbinectedin in combination with atezolizumab for the treatment of advanced small cell lung cancer (SCLC) represents an important milestone in the clinical development of cancer immunotherapies. Here, a regimen designed to pair an immunogenic cell death (ICD) inducer with checkpoint inhibition (ICI) targeting the PD-1/PD-L1 axis gained regulatory endorsement. The combination of ICD with ICI holds substantial therapeutic promise, particularly for patients with immunologically “cold” malignancies that lack tumor-resident dendritic cells (DCs) and immune effectors. Moreover, it clinically validates the biological concept that ICD inducers able to prime T cell-mediated immunity can synergize with ICI to elicit durable anticancer responses.¹

ICD is a specific form of regulated cell death in which stressed and dying tumor cells emit danger-associated molecular patterns (DAMPs) including the exposure or release of calreticulin (CALR), ATP, annexin A1, high mobility group box 1 (HMGB1) and type I interferons that engage pattern recognition receptors (PRRs) expressed on antigen-presenting cells (APCs), such as LDL-related protein 1, formyl peptide receptor-1, purinergic receptors (P2Y2 and P2RX7), Toll-like receptor 4 and type 1 IFN receptors (IFNARs), respectively. If emitted in appropriate spatial and temporal patterns, DAMPs can serve as “find-me” and “eat-me” signals for dendritic cell (DC) infiltration and antigen uptake, promote DC maturation, and thereby stimulate antigen presentation to CD8+ cytotoxic T lymphocytes (CTLs).² Thus, ICD bridges innate and adaptive immunity, transforming cancer cell death into an *in situ* vaccine that elicits responses against tumor-associated antigens.

However, due to immunosuppressive mechanisms, including PD-1-PD-L1 signaling, in the tumor microenvironment, ICD on its own often has limited anticancer efficacy. Therefore, combining ICD inducers with T cell (re)-activating ICI provides a biologically coherent strategy to enhance antitumor immunity. Consistently, in preclinical models as well as in clinical trials, chemotherapeutic regimens based on well-established ICD inducers including anthracyclines and oxaliplatin synergize with antibodies blocking the PD-1-PD-L1 interaction to enhance T cell infiltration, delay cancer progression, and generate long-term immune memory against tumor-associated antigens.¹,³,⁴

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<figure><img src="image_15.png" /><figcaption>**Figure 1.** Integrated model of immunogenic cell death (ICD) and checkpoint inhibition synergy. (A) Lurbinectedin induces immunogenic cell death (ICD) in tumor cells. Mechanistically, lurbinectedin inhibits RNA polymerase II (Pol II), leading to activation of the integrated stress response (ISR) and the cGAS-STING signaling pathway. These stress responses promote the emission of danger-associated molecular patterns (DAMPs), including calreticulin (CALR), ATP, HMGB1, and type I interferons (IFNs). (B) Lurbinectedin-induced DAMPs engage pattern recognition receptors (PRRs) on dendritic cells (DCs), promoting their recruitment, tumor antigen uptake, and maturation. Cross-presentation of tumor antigens to CD8+ cytotoxic T lymphocytes (CTLs) primes adaptive anticancer immunity. Within the tumor microenvironment, PD-1/PD-L1 signaling suppresses CTL effector function; blockade of PD-L1 by the immune checkpoint inhibitor (ICI) atezolizumab restores T cell cytotoxicity and promotes durable antitumor responses. The combination of ICD induction and PD-1/PD-L1 inhibition reprograms an immunologically “cold” tumor into a “hot,” immune-responsive state, exemplified by the clinical success of lurbinectedin plus atezolizumab in small cell lung cancer (SCLC).</figcaption></figure>

The combination of lurbinectedin and atezolizumab (anti-PD-L1 antibody) constitutes a prime example illustrating this strategy at the clinical level. Lurbinectedin was developed as a cytotoxic agent, which selectively inhibits transcription by covalently binding to guanine-rich promoter regions of actively transcribed genes, thereby stalling RNA polymerase II and inducing transcriptional stress.⁵ Preclinical work showed that inhibition of DNA-to-RNA transcription can generate features consistent with ICD, including the activation of the integrated stress response culminating in the phosphorylation of eukaryotic translation initiation factor 2 subunit 1 (eIF2α), which is a pathognomonic feature of ICD, the release of DAMPs and robust activation of the STING pathway leading to type I interferon secretion⁶,⁷) (Figure 1A). In the IMFORTE phase III trial enrolling patients with advanced SCLC whose disease had not progressed after induction therapy, maintenance therapy with lurbinectedin plus atezolizumab (anti-PD-L1 antibody) significantly prolonged progression-free survival compared with atezolizumab alone.⁸ Notably, SCLC has historically been characterized by resistance to immunotherapy, largely due to deficient antigen presentation and an intrinsically immunosuppressive tumor microenvironment.⁹ However, preclinical observations suggest that ICD-inducing therapies can overcome these hurdles and reprogram immune cold malignances into “hot” tumors heavily infiltrated by T lymphocytes, thereby rendering these cancers susceptible to subsequent ICI (10) (Figure 1B). Altogether, these proof-of-concepts advocate for broader integration of ICD inducers into immunotherapy frameworks.

In clinical practice, significant challenges remain. Many cytotoxic anticancer agents lack the ability to induce bona fide ICD. The capability of a drug to induce ICD depends on the induction of a specific array of premortem stress responses, the availability of a series of DAMPs, and the integrity of downstream immune sensing pathways in the host. Excessive cytotoxicity may deplete immune effector cells or damage lymphoid niches, thus compromising immune responses. Thus, it is crucial to balance immunogenic and cytotoxic effects on cancer cells while minimizing immunosuppressive side effects. Additionally, combining chemotherapeutics with immunotherapies may increase the risk of overlapping toxicities. Preclinical studies indicate that sequential strategies, i.e. administering ICD inducers before ICIs, can mitigate adverse events and improve efficacy.¹⁰ Integrating ICD biomarkers such as circulating DAMP levels and interferon-related gene signatures following cytotoxic therapy could further refine patient selection for
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ICI therapy and aid in further personalizing the treatment. Moreover, adaptive trial designs coupled with longitudinal immune monitoring will be essential to capture the complex dynamics and inform oncolo-gists on optimal treatment options.

In sum, the approval of lurbinectin plus atezolizumab represents a regulatory milestone that embodies a new therapeutic paradigm - one that seeks to eliminate malignant cells in an immunogenic manner, thereby generating an immune response amplified by ICI. Rather than viewing cytotoxic therapy and immunotherapy as opposing paradigms, this approach recognizes them as synergistic components of the same immunobiological continuum. Consistently employing this logic will help moving oncology closer to making tumor immune control a routine clinical reality rather than an exceptional outcome. Elucidating the full therapeutic scope of ICD induction will ultimately determine how widely this strategy can be deployed to transform the landscape of cancer immunotherapy.

Acknowledgments

Images have been generated with BioRender.

Author contributions statement

Conceptualization; Writing — original draft: OK has conceptualized the work and has written the original draft. Writing — review & editing; Visualization: OK, GK have reviewed and edited the manuscript and have prepared the figures. Supervision GK and OK have jointly supervised the work. All authors have read and approve the final version of the manuscript.

Disclosure statement

OK and GK are inventors of a patent application describing the utility of combining lurbinectin with ICIs. OK is a scientific co-founder of Samsara Therapeutics. LG is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, AbbVie, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Biopharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is in the scientific advisory boards of Centenara Labs (formerly Rejuveron Life Sciences), Hevolution, and Institut Servier. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK'wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix Biopharma, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. GK's brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results.

Funding statement

OK receives funding from Institut National du Cancer (INCa), Association pour la recherche sur le cancer (ARC), the European Innovation Council (EIC) and the Fondation Gustave Roussy. GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR-22-CE14-0066 VIVORUSH, ANR-23-CE44-0030 COPPERMAC, ANR-23-R4HC-0006 Ener-LIGHT); ARC; Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); European Research Council Advanced Investigator Award (ERC-2021-ADG, Grant No. 101052444; project acronym: ICD-Cancer, project title: Immunogenic cell death (ICD) in the cancer-immune dialog); The ERA4 Health Cardinoff Grant Ener-LIGHT; European Union Horizon 2020 research and innovation programs Oncobiome (grant agreement number: 825410, Project Acronym: ONCOBIOME, Project title: Gut OncoMicrobiome Signatures [GOMS] associated with cancer incidence, prognosis and prediction of treatment response, Prevalung (grant agreement number 101095604, Project Acronym: PREVALUNG EU, project title: Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception), Neutrocure (grant agreement number 861878: Project Acronym: Neutrocure; project title: Development of “smart” amplifiers of reactive oxygen species specific to aberrant polymorphonuclear neutrophils for treatment of
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inflammatory and autoimmune diseases, cancer and myeloablation); National support managed by the Agence Nationale de la Recherche under the France 2030 program (reference number 21-ESRE-0028, ESR/ Equipex + Onco-Pheno-Screen); Hevolution Network on Senescence in Aging (reference HF-E Einstein Network); INCa; Institut Universitaire de France; PAIR-Obésité INCa_1873, the RHUs Immunolife and LUCA-pi (ANR-21-RHUS-0017 and ANR-23-RHUS-0010, both dedicated to France Relance 2030); Seerave Foundation; SIRIC Cancer Research and Personalized Medicine (CARPEM, SIRIC CARPEM INCa-DGOS-Inserm-ITMO Cancer_18006 supported by Institut National du Cancer, Ministère des Solidarités et de la Santé and INSERM). This study contributes to the IdEx Université de Paris Cité ANR-18-IDEX-0001.

ORCID

Oliver Kepp ID 0000-0002-6081-9558

Guido Kroemer ID 0000-0002-9334-4405

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

References

1. Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, Yamazaki T, Poirier-Colame V, Newton A, Redouane Y, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44(2):343-354. doi: 10.1016/j.immuni.2015.11.024.

2. Kroemer G, Galassi C, Zitvogel L, Galluzzi L. Immunogenic cell stress and death. Nat Immunol. 2022;23(4):487-500. doi: 10.1038/s41590-022-01132-2.

3. Xu J, Xu N, Bai Y, Liu R, Mao C, Sui H, Wang X, Jiang Q, Dou Y. Anti-PD-1 antibody HX008 combined with oxaliplatin plus capecitabine for advanced gastric or esophagogastric junction cancer: a multicenter, single-arm, open-label, phase Ib trial. Oncoimmunology. 2020;10(1):1864908. doi: 10.1080/2162402X.2020.1864908.

4. Faivre-Finn C, Vicente D, Kurata T, Planchard D, Paz-Ares L, Vansteenkiste JF, Spigel DR, Garassino MC, Reck M, Senan S, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the pacific trial. J Thorac Oncol. 2021;16(5):860-867. doi: 10.1016/j.jtho.2020.12.015.

5. Vidal A, Munoz C, Guillen MJ, Moreto J, Puertas S, Martinez-Iniesta M, Muñoz C, Guillén M, Moretó J, Martínez-Iniesta M, et al. Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of cisplatin-resistant epithelial ovarian cancer. Clin Cancer Res. 2012;18(19):5399-5411. doi: 10.1158/1078-0432.CCR-12-1513.

6. Cerrato G, Liu P, Zhao L, Petrazzuolo A, Humeau J, Schmid ST, Abdellatif M, Sauvat A, Kroemer G. AI-based classification of anticancer drugs reveals nucleolar condensation as a predictor of immunogenicity. Mol Cancer. 2024;23(1):275. doi: 10.1186/s12943-024-02189-3.

7. Chakraborty S, Sen U, Ventura K, Jethalia V, Coleman C, Sridhar S, Banerjee A, Ozakinci H, Mahendravarman Y, Snioch K, et al. Lurbinectedin sensitizes PD-L1 blockade therapy by activating STING-IFN signaling in small-cell lung cancer. Cell Rep Med. 2024;5(12):101852. doi: 10.1016/j.xcrm.2024.101852.

8. Paz-Ares L, Borghaei H, Liu SV, Peters S, Herbst RS, Stencel K, Majem M, Şendur MAN, Czyżewicz G, Caro RB, et al. Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2025;405(10495):2129-2143. doi: 10.1016/S0140-6736(25)01011-6.

9. Reck M, Dziadziuszko R, Sugawara S, Kao S, Hochmair M, Huemer F, de Castro G, Havel L, Bernabé Caro R, Losonczy G, et al. Five-year survival in patients with extensive-stage small cell lung cancer treated with atezolizumab in the Phase III IMpower133 study and the phase III IMbrella a extension study. Lung Cancer. 2024;196:107924. doi: 10.1016/j.lungcan.2024.107924.

10. Kroemer G, Kepp O. Small cell lung cancer responds to immunogenic chemotherapy followed by PD-1 blockade. Oncoimmunology. 2021;10(1):1996686. doi: 10.1080/2162402X.2021.1996686.