Antibody-Based Therapeutics in Small Cell Lung Cancer: A Narrative Review

Introduction

Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer. It has an incidence of 1–5 cases per 100,000 people per year and accounts for 10–15% of all lung cancers.¹ The risk of developing SCLC is higher in older men (more than 65 years old) and in heavy smokers (more than 30 cigarettes per day).² Moreover, approximately 65–70% of patients are diagnosed with extensive-stage SCLC (ES-SCLC), which results in a poor prognosis.¹ Small-cell lung cancer is historically characterized by an initial high response to platinum-based chemotherapy, but also by the rapid development of resistance, with less than 10% of patients being alive after 5 years.³ Recently, the introduction of immune checkpoint inhibitors (ICIs) in combination with platinum-based chemotherapy in the first-line treatment of ES-SCLC has significantly increased survival rates.^4–8 Despite the benefits of immunotherapy, the majority of patients fail first-line treatment due to primary or acquired resistance to ICIs.⁹ Different ICIs combinations were evaluated to reinforce immune-checkpoint blockade with the addition of anti-CTLA4 or anti-TIGIT agents to first-line chemoimmunotherapy, however results were negative, and these combinations provided no additional benefit.^10,11 Currently, second-line treatment for ES-SCLC is based on chemotherapy. In particular, the choice of second-line treatment depends on the treatment-free interval (TFI) and the response to first-line. If the TFI is higher than 3 months (ie platinum-sensitive patients), rechallenging with platinum-based chemotherapy is recommended. For patients with a TFI lower than 3 months (ie platinum-refractory patients), survival rates are very poor, and the only therapeutic options are topotecan, lurbinectedin (currently only FDA-approved), or, if possible, participation in a clinical trial.¹² Another potential treatment option for this group of patients is represented by treatment beyond progression with second-line immunotherapy. Some studies have suggested that ICIs may continue to have an anti-tumor effect even after the failure of first-line chemoimmunotherapy. A recent retrospective analysis evaluated 150 patients with ES-SCLC who progressed after first-line chemoimmunotherapy and received immunotherapy beyond progression or second-line chemotherapy. Response and survival rates were higher in patients receiving immunotherapy, with a greater benefit in a subgroup of patients with baseline liver metastases, fewer than three metastatic sites, and those who were nonsmokers.¹³ However, the retrospective nature of these data and the limitation of the benefit only to certain subgroups do not allow immunotherapy beyond progression to be defined as a standard of care. Angiogenesis is involved in SCLC growth, spread, and development of resistance to chemotherapy, and overexpression of vascular endothelial growth factor (VEGF) is associated with a poor prognosis in historical data.^14,15 Different trials have investigated the efficacy of antiangiogenic agents combined with chemotherapy for the treatment of SCLC, with no clear benefit.^16–18 Novel pharmaceutical strategies are emerging in the treatment of solid tumors, including SCLC, a disease that still has limited therapeutic options and a poor prognosis. Antibody-based therapies have earned a prominent place in this setting, showing a significant efficacy in numerous tumor types.^19,20 After some negative trials conducted in the past years in SCLC,^21,22 new agents are showing promising results. In this review, we describe the role of novel antibody-based treatment in SCLC, gathering results from both completed and ongoing clinical trials from main medical research databases and international cancer meetings websites, and highlighting their potential impact on its treatment.

Results

T-Cell Engagers

T-cell engagers are antibody-based molecules binding, at the same time, a T-cell-specific target and a tumor-cell target, forcing them to interact and triggering the T-cell-mediated tumor cell death.²³ This strategy allows to bypass the antigen presentation pathway, needed for immunotherapy with ICIs to be effective, and intrinsically suppressed in SCLC.²⁴

Delta-Like Ligand 3

Delta-like ligand 3 (DLL3) is an inhibitory Notch signaling ligand promoting neuroendocrine tumor cells proliferation, migration, and invasion,²⁵ aberrantly expressed in up to 85% of SCLC patients, and minimally expressed in normal cells.^26,27 Tarlatamab is a bi-specific T-cell engager (BiTE) targeting both DLL3 on tumor cells and CD3 on T-cells, triggering T-cells activation and tumor cells lysis (Figure 1). It was the first DLL3-targeting BiTE advancing to clinical evaluation in SCLC, after showing antitumor activity in preclinical models.^28,29 Its efficacy and safety were evaluated in the phase 2 DeLLphi-301 trial (Table 1),³⁰ including SCLC patients previously treated with a single line of platinum-based chemotherapy (73% received chemoimmunotherapy), ECOG PS 0–1, and with treated, asymptomatic, and stable brain metastases. In the first part of the trial, two dose regimens were evaluated, 10 mg and 100 mg, both administered intravenously every 2 weeks. The 10 mg regimen was selected by an independent committee as target dose and enrollment only continued in this group. The efficacy, evaluated in 188 patients (100 in the 10 mg group, 88 in the 100 mg group), exceeded the historical control benchmark, with an objective response rate (ORR) of 40% in the 10 mg group. Responses were durable, with 59% of them still ongoing after 6 months. Positivity for DLL3 expression was not required for enrollment. Of the 157 patients evaluable for DLL3 expression, 151 resulted positive (defined as DLL3 expression on more than 0% of tumor cells). Responses were recorded in patients both positive, negative, and without evaluable tissue sample. Regarding safety, the 10 mg regimen was better tolerated, with a lower percentage of dose interruption and reduction than the 100 mg regimen. Due to the mechanism of action of tarlatamab, its adverse events (AEs) profile included the cytokine-release syndrome (CRS) and the immune effector cell–associated neurotoxicity syndrome (ICANS). Most CRS cases were of grade 1–2, did not require dose adjustments of tarlatamab, and were managed with supportive care with steroids, paracetamol, and hydration, seldom requiring more specific interventions (eg tocilizumab). More severe cases were more common in the 100 mg group. ICANS was significantly less frequent and less severe in the 10 mg group: grade 3 or higher cases were reported only in the 100 mg group, and it led to dose interruption or reduction more frequently in the higher dose group. Most cases have arisen after the first 2 cycles of treatment both for CRS and ICANS. The main limitations of the study are the lack of a control group, and the exclusion of ECOG PS 2 patients. The randomized, phase 3 DeLLphi-304 trial is currently ongoing to compare tarlatamab to standard of care chemotherapy as a second line treatment of ES-SCLC with OS as primary endpoint.³¹ Furthermore, the safety and efficacy of tarlatamab combined to ICIs as first-line maintenance has been evaluated in the phase 1b DeLLphi-303 trial, showing a clinically significant activity and a manageable safety profile of the combination without new safety signals,³² and in the ongoing phase 3 DeLLphi-305 trial (Table 1).³³

Table 1 Clinical Trials on Novel Antibody-Based Therapeutics in ES-SCLC

Figure 1 The main antibody-based agents used for the treatment of SCLC and their mechanisms of action are shown in Figure 1. Tarlatamab is a bi-specific T-cell engager (BiTE) targeting both DLL3 on tumor cells and CD3 on T-cells, leading to T-cell activation and tumor cell lysis. The other three drugs described in the figure are ADCs: Sacituzumab govitecan (SG), which consists of a humanized anti-Trop-2 antibody linked through a hydrolyzable linker to SN-38, an irinotecan metabolite with TOP1 inhibition effects. Ifinatamab-deruxtecan (I-DXd) is a B7-H3-directed ADC consisting of an anti-B7-H3 antibody, a cleavable tetra-peptide linker, and the payload deruxtecan, a DNA topoisomerase I inhibitor. Finally, ABBV-011 is a SEZ6-directed ADC consisting of an anti-SEZ6 monoclonal antibody, SC17, conjugated through a non-cleavable linker to the payload LD19.10, a DNA-damaging calicheamicin linker drug. Created in BioRender. Ciappina, G. (2025) https://BioRender.com/ v97z557. Abbreviations: B7-H3, B7 homolog 3; DLL3, Delta-like ligand 3; SCLC, small cell lung cancer; SEZ6, Seizure-related homolog 6; TOP1, topoisomerase 1; TROP-2, Trophoblast cell surface antigen 2.

Trispecific T-cells activating constructs (TriTACs) are T-cell engager molecules binding to a tumor-specific antigen, human serum albumin, and CD3 on the T-cell surface. Similarly to BiTEs, they can bypass the antigen presentation pathway, directly activating T-cells against tumor cells.³⁴ HPN328 (or MK-6070) is a TriTAC targeting DLL3, able to recruit T-cells in tumor microenvironment and with anti-tumor activity.³⁵ Its efficacy and safety in patients with high-grade neuroendocrine tumors, comprising SCLC, is currently being evaluated in the phase 1/2 MK-6070-001/HPN328-4001 trial (NCT04471727) (Table 1). Included patients had a neuroendocrine malignancy associated with DLL3 expression, brain metastases were allowed if treated, stable, and asymptomatic. The ongoing trial is currently evaluating HPN328/MK-6070 administered alone or in combination with atezolizumab or with the antibody-drug conjugate (ADC) ifinatamab-deruxtecan. Results relative to HPN328/MK-6070 monotherapy efficacy and safety in pretreated ES-SCLC according to the presence of brain metastases were recently reported.³⁶ All included patients had ECOG PS 0–1, received platinum-based chemotherapy, 96% received immunotherapy, 57% had history of brain metastases. Forty-nine patients were treated with the minimum effective dose of the study drug, ie at least 1.215 mg. In patients with brain metastases and without brain metastases, ORR was 37% and 19%, extra-cranial ORR 52% and 19%, disease control rate (DCR) 78% and 48%, respectively. Nine CNS progression events were reported in patients with brain metastases at baseline, none in patients without them. Treatment-related AEs included CRS (64% of patients with brain metastases, 57% in patients without brain metastases) and ICANS, occurring only in patients with brain metastases (14%, all grade 1–2). Despite the benefits of T-cell engagers like tarlatamab, acquired drug resistance seems inevitable, and there is currently insufficient data available on the molecular pathogenesis of resistance mechanisms. It has been speculated that an alteration of the NOTCH signaling pathway, previously implicated in SCLC development and DLL3 regulation in cancer and other biological processes, could be responsible for resistance to these drugs.³⁷ In a recent study by Lee et al, an nCounter assay was conducted to evaluate transcriptional changes after tarlatamab treatment, in the absence of notable genomic alterations and following an unsuccessful attempt at RNA sequencing, in patients who progressed on tarlatamab. Using cell lines derived from pre- and post-tarlatamab tumors, upregulation of NOTCH family genes and downregulation of Delta-like family genes were observed. This finding aligns with the previously proposed hypothesis regarding the alteration of NOTCH signaling, which may deviate DLL3 expression during the development of tarlatamab resistance.^38,39

Antibody-Drug Conjugates

Antibody-drug conjugates are molecules consisting of a tumor-directed monoclonal antibody (mAb) conjugated, through a linker with variable chemical properties, to a cytotoxic payload, able to selectively target tumor cells.⁴⁰ Antibody-drug conjugates can kill tumor cells through the cytotoxic activity of the payload, both released into cells after the ADC internalization and spread to neighboring cells (bystander effect) and inducing antibody-dependent cell-mediated cytotoxicity, antibody dependent phagocytosis, and complement dependent cytotoxicity⁴¹ (Figure 1).

B7 homolog 3

B7 homolog 3 (B7-H3, also known as CD276 and encoded by the CD276 gene) is a transmembrane protein with an immunomodulatory effect. In normal tissue, it suppresses T-cell activation and proliferation; in malignant tissues, it inhibits tumor-directed immune response. Furthermore, it exerts a protumorigenic effect promoting migration and invasion of tumor cells, chemoresistance, endothelial-to-mesenchymal transition, and angiogenesis, and is associated with disease progression and lower survival. It is heterogeneously expressed in normal tissue, while highly expressed in tumors, comprising SCLC.^42,43

Ifinatamab-deruxtecan (I-DXd) is a B7-H3 directed ADC consisting of an anti-B7-H3 antibody, a cleavable tetra-peptide linker, and the payload deruxtecan, a DNA topoisomerase I inhibitor, designed for target-dependent internalization and intracellular release of the payload.^44,45 Results from the interim analysis of the phase 2 trial IDeate-Lung01 (Table 1), evaluating I-DXd in ES-SCLC, were recently reported.⁴⁶ Included patients were pretreated, and asymptomatic brain metastases, treated or untreated, were permitted. In the dose optimization phase, 2 dose regimens were evaluated: 8 mg/kg and 12 mg/kg, both administered intravenously every 3 weeks. Both cohorts have proven to be effective treatments for pretreated ES-SCLC, with an ORR in the 12 mg/kg cohort of 55%. Treatment was well tolerated at both doses, however AEs were more common in the 12 mg/kg cohort, in particular grade 3 or higher ones. Most were gastrointestinal and hematologic, the incidence of interstitial lung disease was similar between the cohorts (7–8%), all infusion-related reactions recorded in the 12 mg/kg cohort (14.3% of patients) were grade 1–2. Based on these results, I-DXd at the selected dose of 12 mg/kg has a meaningful anti-tumor activity in pretreated ES-SCLC patients with an acceptable safety profile. The main limitations of the trial are the lack of a control arm due to the study design and the exclusion of patients with ECOG PS 2. A phase 3 trial, IDeate-Lung02 (Table 1), is currently ongoing to compare I-DXd to the standard of care in relapsed SCLC including, among secondary objectives, the relationship between B7-H3 expression and clinical outcome.⁴⁷

The study ARTEMIS-001 (Table 1) is an open-label, phase 1 trial evaluating the safety and efficacy of HS-20093 (also known as GSK’227) in advanced solid tumors, comprising SCLC.^48,49 HS-20093/GSK’227 is an anti-B7-H3 ADC consisting of a fully humanized antibody linked to a topoisomerase inhibitor payload. Included patients were pretreated with standard platinum-based chemotherapy, 73% also received immunotherapy. During the dose-escalation and dose-expansion phases, 56 patients received either 8 mg/kg (31) or 10 mg/kg (25) of the study drug. Objective response rate was 61% and 50% in the 8 mg/kg and 10 mg/kg groups, respectively, DCR was 81% and 96%, and mPFS was 5.9 months and 7.3 months, respectively. Responses were observed regardless of B7-H3 expression. The most common treatment related AEs (TRAEs) were hematologic. The limitations of this study are mainly due to the early phase of the ongoing clinical development and to the poor representativeness of the study population. However, a phase 3 study is currently ongoing in China to compare HS-20093 to standard chemotherapy in relapsed SCLC, and a global phase 1 trial began in August 2024.⁵⁰

Trophoblast Cell Surface Antigen 2

Trophoblast cell surface antigen 2 (Trop-2) is a cell surface glycoprotein and calcium signaling transducer encoded by the TACSTD2 gene. In normal conditions, it has a role in the development of embryonic organs.⁵¹ It is overexpressed in cancer cells, with a low or absent expression in normal cells, and it promotes tumor growth and invasiveness.^52,53

Sacituzumab govitecan (SG) is an ADC consisting of a humanized anti-Trop-2 antibody coupled through an hydrolyzable linker to SN-38, an irinotecan metabolite.⁵³ It has already been evaluated in the treatment of other histologies and is currently approved for the treatment of breast cancer.^54,55 The TROPiCS-03 (Table 1) trial is a multi-cohort, phase 2, basket trial evaluating SG in solid tumors, comprising SCLC.⁵⁶ Included patients received only one line of previous systemic anti-tumor therapy (both platinum-sensitive and resistant were included) and had an ECOG PS 0 or 1, brain metastases were allowed only if treated and stable. Sacituzumab govitecan showed significant activity, both in platinum-sensitive and resistant patients, with an ORR of 42% and a DCR of 84%. The safety profile was consistent with other clinical trials in other histologies: all patients had AEs of any grade, 74.4% reported AEs of grade 3 or higher (most common: neutropenia and diarrhea). Treatment related AEs were reported in 61% of patients, serious AEs in 51%, 3 deaths were reported, 1 considered related to treatment (neutropenic sepsis). No patient discontinued the treatment due to AEs. The main limitations of the trial are the lack of control group, the small sample size, and the exclusion of patients with ECOG PS 2.

SHR-A1921 is a Trop2-directed ADC with a topoisomerase inhibitor payload linked to an anti-Trop2 mAb via a cleavable tetrapeptide linker. Its efficacy and safety in pretreated ES-SCLC is being evaluated in a phase 1 trial (NCT05154604) (Table 1), whose results have been recently reported.⁵⁷ Included patients had an ECOG PS 0–1, brain metastases were allowed only if treated and stable. Seventeen patients were enrolled, 53% had received at least 2 previous lines of therapy, 65% had been treated with immunotherapy. All 16 evaluable patients had a low level Trop2 expression. The study drug showed clinical activity, with an ORR of 33%, a DCR of 67%, a median duration of response (mDOR) of 4.4 months, and a mPFS of 3.8 months. The safety profile was manageable: all included patients had a TRAEs of any grade, 6 patients (35%) reported a TRAEs of grade 3 or higher, with stomatitis being the most common (12%), no TRAEs caused discontinuation of study treatment or death.

Seizure-Related Homolog 6

Seizure-related homolog 6 (SEZ6) is a transmembrane protein involved in neurons development and function.^58,59 It has an elevated expression on SCLC cells membrane, while being minimally expressed in normal tissues.⁶⁰ ABBV-011 is a SEZ6-directed ADC consisting of an anti-SEZ6 mAb, SC17, conjugated through a non-cleavable linker to the payload LD19.10, a DNA-damaging calicheamicin linker drug.⁶⁰ Its safety and efficacy alone and in combination with budigalimab, an anti-PD-1 mAb, in SCLC is being evaluated in a phase 1 trial (NCT03639194) (Table 1), whose initial outcomes on ABBV-011 monotherapy were recently reported.⁶¹ Included patients were pretreated, received at least 1 line of platinum-based chemotherapy, had ECOG PS 0–1, brain metastases were allowed if treated and stable. They were not selected based on SEZ6 expression for the dose escalation phase, while for the dose expansion phase only patients with SEZ6-positive tumors were included (defined, based on preclinical data on efficacy of ABBV-011, as at least 25% of tumor cells with at least 1+ of staining intensity by immunohistochemistry). Ninety-nine patients were enrolled and received at least 1 dose of ABBV-011, of whom 77% received immunotherapy with an anti-PD-L1/PD-1 agent. In the dose escalation phase, the 2 mg/kg dose was initially selected for the expansion phase. However, the onset of delayed hepatotoxicity, a class effect of calicheamicin-based ADCs, led to its reduction to 1 mg/kg. In the safety population, defined as patients receiving at least 1 dose of the study drug, TRAEs of any grade occurred in 77% of patients, grade 3 or higher in 34% of patients, and no on-target ocular or neurological toxicities were reported. Grade 5 treatment-emergent AEs (TEAEs) occurred in 19% of the safety population, none of them was considered related to the study drug. Most common TEAEs of grade 3 or higher were hepatotoxicity (12%), fatigue (9%), thrombocytopenia (9%), anemia (6%), and hypokalemia (6%). In the dose-expansion cohort, the ORR was 25%, the clinical benefit rate (CBR), defined as the rate of patients with an objective response and stable disease, 65%, and the CBR lasting for at least 12 weeks 43%. The mDOR was 4.2 months, the mPFS 3.5 months. The study drug showed antitumor activity both in platinum-sensitive and in platinum-resistant patients. The main limitations of the study, mostly related to the early stage of clinical development of the drug, are the small sample size, the lack of a control arm, the optimal dosing not yet defined, and the exclusion of ECOG PS 2 patients.

Antibody-Drug Conjugates Resistance

Few data are currently available on the mechanisms of resistance to ADCs in SCLC. In vivo evaluation would require multiple tissue biopsies making it impractical in the clinical routine.

Theoretically, the mechanisms of acquired resistance to ADCs are based on three main mechanisms: 1) downregulation or increased degradation of the target antigen after chronic exposure to a target-directed ADC, 2) decreased endosomal/lysosomal acidification and proteolytic activity, leading to altered intracellular trafficking of the mAb-payload complex, and 3) impairment of payload activity by direct alteration of the payload target (eg, microtubules or DNA repair mechanisms) or upregulation of drug efflux pumps.⁶² A mechanism of resistance to SG was described in a patient with triple-negative breast cancer (TNBC) in whom genetic alterations comprising mutations, copy number variations, and structural variations drove the resistance. They affected both the target antigen (Trop2) and the payload (SN-38), resulting in reduced Trop-2 expression and increased drug efflux, with reduced drug exposure and development of resistance to SG.⁶³ Potential strategies to overcome ADCs resistance could be represented by targeting multiple antigens, as in bispecific antibodies, improving payload design, combining different therapies, such as ICIs, and targeting efflux pumps.⁶²

Antiangiogenics

In recent years, the combined use of bispecific antibodies targeting both VEGF and PD-(L)1 has renewed interest in this research line. Ivonescimab is a bispecific antibody targeting PD-1 and VEGF⁶⁴ approved in China for the treatment of epidermal growth factor receptor (EGFR)-mutant advanced non-squamous non-small cell lung cancer (NSCLC)⁶⁵ and in clinical development in other countries.⁶⁶ Its use in the first-line treatment of ES-SCLC is being evaluated in a phase 1b trial whose preliminary results were recently reported⁶⁷ (Table 1). Included patients were untreated, had ECOG PS 0–1, could not have active brain metastases. Thirty-five patients were treated with ivonescimab in combination with first-line chemotherapy with carboplatin and etoposide, followed by ivonescimab as maintenance. In the dose-escalation phase, patients received the study treatment at three dose levels: 3, 10, and 20 mg/kg every 3 weeks. Antitumor activity was evaluated in all 35 patients: the ORR was 80% (66.7%, 90.9%, and 76.2% at 3, 10, and 20 mg/kg dose levels, respectively), with a mDOR of 5.6 months. The mPFS was 6.9 months, the PFS rate after 1 year was 23.5%. The mOS was 14.5 months, the OS rate after 1 year was 72.0%. All included patients had at least 1 AE, 91.4% of them had a TRAE. Grade 3 or higher TRAEs occurred in 60% of patients (66.7%, 54.5%, and 61.9% in 3, 10, and 20 mg/kg dose levels, respectively), the most common being decreased neutrophil count (22.9%). Grade 5 TRAEs occurred in 2 patients: one was attributed to disease progression and the other to cardiac arrest. Immune-related AEs (irAEs) of grade 3 or higher were reported in 11.4% of patients (enteritis and colitis).

PM8002 is a bispecific antibody targeting PD-L1 and VEGF-A, currently in clinical development in China for the treatment of different solid tumors, comprising SCLC.^68,69 Results from a phase 2 clinical trial evaluating its use in combination with paclitaxel as a second-line treatment for SCLC have been published by Cheng et al⁶⁹ (Table 1). Included patients were pretreated with a platinum-based chemotherapy, previous treatment with ICIs were not mandatory, brain metastases were allowed only if treated and asymptomatic. Efficacy was reported for patients who did not received ICIs (26/27) and were evaluable (22/26): ORR was 72.7%, DCR was 81.8%, mPFS was 5.5 months. Safety was reported for ICI-naïve patients (26/27): TEAEs occurred in 96.2% of subjects, 73.1% had grade 3 or higher TEAEs. Most common TRAEs of grade 3 or higher were neutropenia (53.8%) and leukopenia (34.6%). Immune-related AEs occurred in 30.8% of patients, 4.0% of grade 3 or higher (one grade 3 proteinuria).

Apart from novel antibody-based therapeutics, different clinical trials are evaluating the role of the anti-VEGF mAb bevacizumab combined with the standard first-line chemo-immunotherapy. Results from the second interim analysis of the phase 3 BEAT-SC clinical trial conducted in Japan and China were recently presented:⁷⁰ the addition of bevacizumab was associated with an improvement in PFS (mPFS 5.7 vs 4.4 months, HR 0.73) with no effect on OS (HR 1.13). In the phase 2 CeLEBrATE trial⁷¹ the combination of standard chemo-immunotherapy plus bevacizumab was active in the first-line treatment of SCLC (mOS: 12.7 months, mPFS: 6.2 months, ORR: 67.9%) with a tolerable safety profile.

Discussion

Despite the advancements in solid tumors treatment in recent years, patients with ES-SCLC still have a poor prognosis and only few therapeutic options, despite the initial high sensitivity to platinum-based chemotherapy and the introduction of ICIs. Primary or acquired resistance to ICIs is common, and reinforcing the immune-checkpoint blockade did not bring significant survival benefit.^9–11 Second-line treatment options, consisting of platinum-based chemotherapy rechallenge or other chemotherapeutic agents such as topotecan and lurbinectedin, are not satisfying and the 5-year OS is still lower than 10%.³ Antibody-based therapies, such as T-cell engagers, ADCs, and bispecific anti-VEGF and anti-PD-(L)1 antibodies are gaining a prominent place in the treatment of various solid tumors, including SCLC. The DLL3-directed BiTE tarlatamab showed a promising and lasting antitumor activity in the phase 2 DeLLphi-301 trial, with a favorable safety profile for the 10 mg dose regimen, also with regards to CRS and ICANS.³⁰ In the phase 2 TROPiCS-03 trial, the anti-Trop2 ADC SG also showed a clinically significant antitumor activity and a favorable safety profile, coherent with already known data from its use in other histologies.⁵⁶ In the phase 2 IDeate-Lung01 trial, the anti-B7-H3 ADC I-DXd, at the selected dose of 12 mg/kg, had a considerable antitumor activity maintaining an acceptable safety profile.⁴⁶ The phase 2 trial evaluating PM8002, bispecific antibody targeting VEGF-A and PD-L1, reported a significant clinical activity in pretreated SCLC patients with manageable safety profile.⁶⁹ Other antibody-based agents are currently in an earlier phase of clinical development, all showing promising results: HPN328/MK-6070,³⁵ HS-20093/GSK’227,⁴⁸ SHR-A1921,⁵⁷ ABBV-011,⁶¹ and ivonescimab.⁶⁷ These novel therapeutic strategies have characteristic AEs, in particular CRS and ICANS for T-cell engagers and gastrointestinal and hematologic toxicity for ADCs, requiring caution and further optimization also due to the early phase of clinical development of the drugs. Based on available data, the safety profiles of the agents reported here is manageable. However, further data are needed to better characterize their safety profile and to define the optimal management of AEs. The above mentioned trials share some limitations: except the trials evaluating ivonescimab and bevacizumab, they all included pretreated patients but only the TROPiCS-03 required the administration of chemoimmunotherapy, current first-line standard of care treatment of ES-SCLC; patients with ECOG PS 2 and with untreated brain metastases were excluded from the trials, even though they represent a significant proportion of patients with ES-SCLC in the second-line setting; all studies, being them phase 1 and 2 trials, lack the comparator arm; the correlation between the antibody target expression and the antitumor activity of the study drug is not clear and, apart from ABBV-011 and SEZ-6, it is not possible to determine if there is an expression threshold predicting response. Furthermore, expression of the tumor antigens can be influenced by different factors, both clinical and molecular: Ajay et al⁷² reported lower expression of SEZ6 in female, of TACSTD2 in samples obtained from lymph nodes and from pretreated patients, of DLL3, TACSTD2, and SEZ6 in samples from brain metastases. Furthermore, SCLC is increasingly recognized as a heterogeneous disease with different transcriptional subtypes,⁷³ associated with different levels of expression of target antigens. Available data suggest a higher expression of SEZ6 in SCLC-A and SCLC-N subtypes and of DLL3 in SCLC-A subtype;^72,74 data on CD276 expression are less consistent.^74,75 Although no treatment has yet demonstrated superiority over the current standard of care, the results reported here are promising and pave the way for the use of novel pharmacological strategies in a disease with significant unmet clinical needs. Regarding antiangiogenics, data from the phase 3 trial evaluating bevacizumab in the first-line setting did not show any benefit in OS. However, data on bispecific antibodies, both in untreated and treated patients, remain promising. International, randomized, phase 3 trials are currently ongoing to compare tarlatamab and I-DXd to standard of care in first-line maintenance and second-line settings.^31,33,47