Current and emerging therapies targeting cell surface antigens and epigenetics in extensive stage small cell lung cancer: primer for clinicians

Abstract

Extensive stage small cell lung cancer (ES-SCLC) carries a very poor prognosis and has been the focus of intensive research. Targeting cell surface molecules is paying off. Moving beyond immune checkpoint inhibitors (ICI), targeting DLL3 with tarlatamab in previously treated ES-SCLC generated an unprecedented response. Use of a combination of vascular endothelial growth factor (VEGF)/PD-1/PD-L1 antibody and chemotherapy seemed more effective than ICI plus chemotherapy. Bispecific antibodies targeting PD-1/PD-L1/VEGF in combination with chemotherapy are being tested in the first-line setting. B7H3 and SEZ6 antibody-drug conjugates yielded encouraging results in the early phase. Modulation of epigenetic processes is being pursued for its potential to reprogram cancer cells to a disadvantage for growth and immune evasion. Due to tumor heterogeneity and plasticity, rational combinations pursuing broader cancer cell vulnerabilities are likely necessary in the future to prevent relapse. Better tools for response monitoring are urgently needed to gauge progress.

Plain language summary

Current and emerging targeted therapies for extensive stage small cell lung cancer

Metastatic/extensive stage small cell lung cancer (ES-SCLC) carries a very poor prognosis and has been the focus of intensive clinical research. Targeting cell surface molecules is paying off. Moving beyond immune checkpoint inhibitors (ICI) such as atezolizumab, targeting DLL3 with tarlatamab in previously treated ES-SCLC generated unprecedented response. Use of combination VEGF/PD-1/PD-L1 antibody and chemotherapy seems to be effective and is being compared to ICI plus chemotherapy in first line. B7H3 and SEZ6 antibody drug conjugates yielded very encouraging results in early phase. Modulation of epigenetic process is being pursued for its potential to reprogram cancer cells to a disadvantage for growth and immune evasion. Due to tumor heterogeneity and plasticity, rational combinations pursuing broader cancer cell vulnerabilities are likely necessary in the future to prevent relapse after initial treatment. Better tools for response monitoring are urgently needed to gauge progress and disease status.

Keywords

ADC BiTE CAR-T cells cell surface marker small cell lung cancer

Introduction

Small cell lung cancer (SCLC) is a high-grade neuroendocrine malignancy with a highly aggressive clinical course.^1–4 This cancer accounts for about 15% of all lung cancers⁵ and is predicted to kill up to 18,750 persons in the U.S. in 2026.⁶ Upon diagnosis, 70% of patients are at the extensive stage with no hope for a cure.⁷ While typically responding to first-line chemotherapy, recurrence is the rule rather than the exception for extensive stage cancer.^8,9 Front-line chemotherapy, frequently platinum doublets, discovered 4–5 decades ago, did not change until recently, when immune checkpoint inhibitors were found to improve overall survival when used concurrently with chemotherapy in the induction phase and maintained after induction.^10–14 Added to the maintenance phase following induction, lurbinectedin was recently approved by the US FDA¹⁵ with maintenance atezolizumab.¹⁶ However, similar to other types of chemotherapy, response is short-lived with progression-free survival (PFS) of only 3.38 months. In addition, side effects are significant during maintenance, highlighting the continued unmet need for a benign treatment with a durable response.¹⁷ Tarlatamab, a bispecific T-cell engager that performed well in the second-line setting, is among the latest FDA approvals, raising hope for continued success targeting cell surface markers since the earlier discovery and targeted efforts of DLL3.^18–21 Meanwhile, molecular targets that have a significant impact on cancer cell transcriptome shed a glimpse of light on targeted therapy in SCLC.

In this article, SCLC, cell surface marker, CAR-T cells, BiTE, and antibody-drug conjugates (ADC) were used as keywords to search PubMed database of NCBI. We review various SCLC cell surface antigens targeted in clinical trials so far using the different delivery approaches of bi/trispecific T-cell engagers (BiTE/TriTE), chimeric antigen receptor-T (CAR-T) cells, and ADC. We also touch on chromatin modulation with small molecule inhibitors that have the promise to alter the transcriptome to improve immune surveillance and alter tumor growth (Figure 1). We discuss progress made so far and issues encountered. We conclude by discussing future efforts that will be impactful in improving survival in this patient population.

Figure 1.

Therapies in development targeting cell surface antigens of small cell lung carcinoma.

Targeting cell surface markers

Immune checkpoint inhibitors

Immune checkpoints maintain a delicate balance between the destruction of targets and overstimulation of immune responses after stimulation of the T-cell receptor.^22,23 Recognition of antigenic peptides by T-cell receptors on the major histocompatibility complex molecules on the surface of antigen-presenting cells (APCs) triggers a specific T-cell response; however, activation by the costimulatory pathway or inhibition by immune checkpoints determines whether cytotoxic T cells will be activated to destroy tumor cells. Since the early success using CTLA-4 inhibitor ipilimumab to unleash the killing of melanoma by cytotoxic T cells,^24,25 many more such therapeutic agents have been tested in the treatment of SCLC,²⁶ including PD-1/PD-L1, TIGIT, and B7H3, among others.

CTLA-4

CTLA-4 is expressed on the surface of cytotoxic T cells or T regulatory cells, competing with CD28 for B7.1/B7.2 binding with much higher affinity.²⁷ Two antibodies, ipilimumab and tremelimumab, were approved for cancer immunotherapy in various solid tumors, including melanoma, renal cell carcinoma, colorectal cancer, hepatocellular cancer, and non-small cell lung cancer (NSCLC). Despite success in NSCLC^28–32 and suggestions that phased ipilimumab may improve survival in front-line treatment of SCLC with chemotherapy in a randomized phase II study with carboplatin, paclitaxel, and ipilimumab,³³ ipilimumab following induction chemotherapy with carboplatin and etoposide failed to add benefit in a phase III trial enrolling 1132 patients.³⁴ It also failed in the maintenance setting after chemoradiation therapy in Checkmate 451.³⁵ The latest evidence from the CASPIAN trial showed that tremelimumab added to carboplatin, etoposide, and durvalumab was not superior to carboplatin, etoposide, and durvalumab alone.¹² It is thought that upregulated EZH2 expression in human T cells as a tumor adaptation to CTLA-4 inhibition could be responsible for the resistance.³⁶

PD-1/PD-L1

The PD-1 (CD279)/PD-L1 (B7H1, CD274) pathway is a T-cell coinhibitory pathway, and chronic exposure to increased levels of antigens and inflammatory cytokines in cancer can result in increased expression of PD-1 and PD-L1. The latter is a characteristic feature of T-cell exhaustion and dysfunction, characterized by poor proliferative capacity and decreased cytotoxicity.³⁷ Engagement of PD-1 by PD-L1 inhibits T-cell proliferation, survival, and blockade of this pathway and enhances antitumor immunity.³⁸

Nivolumab was tested in recurrent and refractory SCLC in the third-line setting in Checkmate 032 alone³⁹ or in combination with ipilimumab,⁴⁰ and pembrolizumab was tested in Keynote 028 in PD-L1 positive cancer after two or more lines of treatment.^41,42 The results suggested promising activity, and both agents received accelerated FDA approval. However, the activity was not confirmed in the subsequent phase III trial in Checkmate 331,⁴³ in which patients were treated with nivolumab or chemotherapy at second line. Furthermore, nivolumab and ipilimumab maintenance therapy after induction chemotherapy did not provide any benefit in Checkmate 451,³⁵ leading to FDA withdrawal of nivolumab approval in SCLC in December 2020. Similarly, approval was revoked after pembrolizumab failed to meet the objectives in the first-line setting in the Keynote 604 study⁴⁴ in March 2021. The NCCN guideline panel considers these two drugs as effective as other chemotherapy options after the first line if patients have not received prior ICI (version 2, 2026 https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462).

The current standard of care for treatment naïve ES-SCLC with no contraindication to ICI is carboplatin/etoposide with atezolizumab or carboplatin/cisplatin with etoposide and durvalumab for 4–6 cycles followed by atezolizumab or durvalumab (both are PD-L1 inhibitors) for 1 year. In the IMpower 133 trial, adding atezolizumab improved overall survival (OS); the median OS was 12.3 months in the atezolizumab arm compared to 10.3 months in the placebo (hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.54–0.91, p = 0.007).^10,11 In the CASPIAN trial, adding durvalumab to chemotherapy decreased the risk of death by 29% compared with chemotherapy alone (HR 0.71, 95% CI 0.6–0.86, p = 0.0003). The median OS was 12.9 months compared with 10.5 months with chemotherapy alone. The addition of tremelimumab to durvalumab with chemotherapy did not improve survival compared to durvalumab alone with chemotherapy.^13,45

In the Keynote 604 study, adding anti-PD-1 (pembrolizumab) to chemotherapy in ES-SCLC did not meet the primary objectives.⁴⁴ On the other hand, the anti-PD-1 serplulimab improved OS of ES-SCLC in combination with carboplatin and etoposide based on the ASTRUM-005 study and has gained approval in China and the European Union.^46,47 In this study, 585 patients were randomized in a 2:1 ratio to receive carboplatin, etoposide with either serplulimab (4.5 mg/kg) or placebo every 3 weeks for four cycles before maintenance. The median OS in the final analysis was 15.8 months in the serplulimab arm and 11.1 months in the chemotherapy arm (HR 0.62, 95% CI 0.50–0.76, p < 0.001). Although we cannot compare across trials, the HR is numerically lower than the hazard ratios in the IMpower 133 and the CASPIAN trial. PD-1 inhibitors are considered more powerful than PD-L1 inhibitors since PD-L1 is one of the PD-1 ligands.³⁷ A meta-analysis of patients who have received neoadjuvant therapy from 31 trials totaling 14,974 patients supports this view. Compared to PD-L1 inhibitors, PD-1 inhibitor use had a disease-free survival HR of 0.82, response rate of HR 1.63, and mean platelet volume-to-platelet count ratio of HR 1.43.⁴⁸ The tradeoff is more Grade 3–5 adverse events (AEs). Serplulimab is not approved in the U.S. but has received FDA orphan drug designation status.

T-cell immunoreceptor IG ITIM domain

TIGIT (T-cell immunoreceptor IG ITIM domain) is a coinhibitory receptor that critically limits antitumor and CD8(+) T-cell–dependent immune responses. TIGIT is highly expressed on human tumor-infiltrating T cells and in models of cancer.⁴⁹ The anti-TIGIT antibody works by blocking TIGIT and promoting interaction between CD112/CD155 (PVR) and the activating receptor CD226 on T cells, activating the immune system to attack cancer cells. Antibody co-blockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8(+) T-cell effector function, resulting in significant tumor clearance.⁴⁹

TIGIT expression correlates significantly with PD-1 expression in tumor samples from lung cancer patients, and the combination of anti-TIGIT and anti-PD-1 antibodies showed synergistic effects in mouse tumor models, suggesting that targeting TIGIT and PD-1 could be advantageous in lung cancer.³⁷ Expression of PD-L1, CD155, or both correlated with shorter survival in SCLC.⁵⁰ Combination therapy with ICI is considered to be a rational combination in SCLC.⁵¹ Among the anti-TIGIT antibodies are tiragolumab and ociperlimab.

Tiragolumab was added to chemotherapy with carboplatin, etoposide, and atezolizumab or placebo in extensive stage, treatment-naïve SCLC in the SKYSCARPER-02 study.⁵² A total of 490 patients were enrolled onto the atezolizumab (1200 mg, every 3 weeks) and tiragolumab (600 mg every 3 weeks) with chemotherapy (N = 243) and the atezolizumab/placebo with chemotherapy arm (N = 247) and treated for four cycles before maintenance after dropping chemotherapy. There was no improvement in PFS, with 5.4 months in the tiragolumab arm and 5.6 months in the placebo arm (HR 1.11, p = 0.3504). No benefit was observed by adding tiragolumab. There was no new safety signal detected. AEs leading to study withdrawal were 8.4% and 9.3%, respectively.

B7 Homolog 3

B7H3 (B7 Homolog 3 or CD276), is a member of the B7 family that plays a dual role in the immune system during T-cell activation, acting as a T-cell costimulatory/coinhibitory immunoregulatory protein, and promoting tumor growth, immune evasion, and immune therapy resistance.^53–55 Overexpressed in tumor tissues while showing only limited expression in normal tissues, B7H3 has become an attractive target for cancer immunotherapy for SCLC.⁵³ A recent analysis of protein expression in 1721 SCLC specimens from the Caris database showed B7H3 was expressed consistently at a high level across 1483 molecular subtypes in evaluable cases, compared to DLL3 and SEZ6 expression, which varied significantly.⁵⁶ A recent study of 146 SCLC patients treated with chemotherapy and PD-L1 inhibitor revealed that high expression of B7H3 was associated with poor survival compared with low expression. The PFS for B7H3 high and low were 4.3 and 5.4 months, respectively (HR 2.11, 95% CI 1.08–4.10, p = 0.03). Gene expression profile analysis showed high expressors had more CD8 T-cell dysfunction, suggesting that high B7H3 expression confers resistance to ICI.⁵⁷

B7H3 ADC ifinatamab with a topoisomerase payload deruxtecan (I-Dxd) was tested in a phase II study (IDeate-Lung 01) in a pretreated SCLC population.⁵⁸ A total of 183 patients were treated in two stages—dose optimization and dose extension. Of the 137 patients who received 12 mg/kb of study drug, the objective response rate (ORR) was 48.2% (38.6–56.9) with a median duration of response of 5.3 months, a time in therapeutic range (TTR) of 1.4 months, and a median PFS of 4.9 months. The 9-month survival was 59.1%. AE of any grade appeared in 89.8% of patients, with 36.5% being Grade 3 or higher. Pneumonitis was 12.4% overall, and Grade 3 or above occurred in 4.4%. A phase III, global, open-label trial was launched and is ongoing (NCT06203210).⁵⁹ Approximately 540 patients will be randomized to receive 12 mg/kg of I-Dxd or the physician’s choice of topotecan, amrubicin, or lurbinectedin in a 1:1 ratio. The dual primary objectives are OS and ORR, and the secondary objectives are disease-free survival and duration of response.

Angiogenesis VEGF/VEGF(R)

Cancers, especially fast-growing ones such as SCLC, need to ensure a robust blood supply to the mass, hence abundant neo-angiogenesis takes place under the influence of growth factors signaling through their receptors. Among these factors are vascular endothelial growth factors (VEGF) and fibroblast growth factors (FGFs), as well as their receptors, VEGFRs and FGFRs, which play important roles in cancer growth and progression. Although targeting angiogenesis did not make a difference in SCLC management with thalidomide traditionally,^60,61 recent use of multi-targeted kinase inhibitors in combination with ICI and chemotherapy or chemotherapy with bispecific PD-1 and VEGF seemed to be a promising strategy in the treatment of SCLC.

Apatinib, a VEGFR2 inhibitor, was used in a phase II study in 40 patients with ES-SCLC after two or three lines of therapy.⁶² A PFS of 3 months and OS of 5.8 months were reported. Objective response was seen in 7 of the 40 intention-to-treat population. In the third- and fourth-line study, apatinib with oral etoposide capsule was given to 53 patients with a median follow-up of 9.8 months; the median PFS was 3.0 months (95% CI 2.1–3.9), and the median OS was 5.0 months (95% CI 3.6–6.4). The ORR was 20.8% (11 of 53 patients). Eleven patients (21%) showed a best response of partial response, and 37 (70%) achieved stable disease. The disease control rate was 90.6% (48 of 53 patients). The 6-month OS rate was 40.1% (95% CI 26.2–54), and the 12-month OS rate was 18.4% (95% CI 4.7–32.1).⁶³ In the phase II PASSION study in second-line treatment of ES-SCLC, apatinib 375 mg once daily was given to 47 of 59 patients enrolled with camrelizumab (PD-1 antibody) 200 mg IV once every 2 weeks until disease progression.⁶⁴ ORR was 34% with a median PFS of 3.6 months and a median OS of 8.4 months. Platinum sensitive relapse (>90 days since last chemo) and resistant patients (<90 days) had similar response (37.5% vs 32.3%), and Grade 3 or high AE occurred in 72.9% (43 of 59 patients) of all.

Anlotinib is a multi-targeted kinase inhibitor of VEGFR1, VEGFR2/KDR, VEGFR3, c-Kit, PDGFR-α, and the fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3).⁶⁵ A meta-analysis of 13 studies included 779 pretreated SCLC patients showed that anlotinib, as a single agent, had an ORR of 21%; disease control rate 76%; PFS of 3.46 months (2.68–4.24) and OS of 6.86 months (5.79–7.93), suggesting that it is an active agent. Grade 3 or higher toxicities included hypertension in 9%, hand and foot syndrome in 6%, and fatigue in 4%.⁶⁶ Importantly, in subsequent studies in ES-SCLC, anlotinib and benmelstobart, a PD-L1 inhibitor, significantly prolonged the PFS and the OS of ES-SCLC in combination with four cycles of frontline platinum-etoposide chemotherapy.^67–69 ETER701 was a phase III randomized, placebo-controlled, double-blinded multicentre study in China, enrolling treatment naïve ES-SCLC patients into the chemotherapy arm plus double placebo (carboplatin and etoposide for four cycles) (247 patients), chemotherapy plus anlotinib plus placebo (245 patients), and chemotherapy plus anlotinib plus benmelstobart arms (246 patients). The study met its primary objective, which was OS. The OS for the three groups was 11.9 months, 13.3 months, and 19.3 months, respectively. Compared with chemotherapy and double placebo, the HR for anlotinib and benmelstobart was 0.61, p = 0.0002; whereas the HR was 0.86, p = 0.1723 when anlotinib and chemotherapy were compared with chemotherapy alone, registering a significant prolonged OS benefit when PD-L1 inhibitor and antiangiogenesis inhibitor are used with chemotherapy.

Bevacizumab, a VEGF-A inhibitor, was compared with placebo in the BEAT-SC trial in the front line in combination with cisplatin/carboplatin, etoposide, and atezolizumab. The phase III trial enrolled 166 in the bevacizumab arm and 164 in the placebo arm with PFS as the primary objective. After a median follow-up of 10.2 months, the PFS was 5.7 months and 4.4 months in the treatment and placebo arm, respectively (HR 0.70, 95% CI 0.54–0.90, p = 0.0060). It should be noted, however, that the OS was not different between the two groups or possibly worse outcome in the treatment group (HR 1.22, 95% CI 0.89–1.67, p = 0.2212).⁷⁰

In the latest, bispecific antibodies of PD-1/PD-L1 and VEGF were developed. A phase Ib study⁷¹ showed ivonescimab, a humanized IgG1 bispecific anti-PD-1/VEGF antibody, is safe and has promising activity in combination with four cycles of carboplatin and etoposide in 35 patients with treatment naïve ES-SCLC. With a median follow-up of 13.3 (range: 0.3–28.5) months, the confirmed ORR and disease control rate were 80% and 91.4%, respectively. The ORR was 66.7%, 90.9%, and 76.2% at the doses of 3 mg/kg, 10 mg/kg, and 20 mg/kg, respectively. Grade 3 or higher treatment-related AEs occurred in 66.7%, 54.5%, and 61.9% of patients in the 3, 10, and 20 mg/kg groups, respectively. Treatment-related AEs leading to death were reported in two patients (5.7%). Immune-related AEs, most of them grade 1 or 2, occurred in 40.0%. It should be noted that these are initial results from early phase trial, one region with a small sample size. Caution is advised when interpreting these data.

Other cell surface markers

SSTR2

Somatostatin receptors (SSTRs) are G-protein-coupled receptors (SSTR1–5) found on cell surfaces that regulate hormone release and cell proliferation. SSTR2 was found to be expressed at high levels in the SCLC cell line.⁷² In a preclinical model, 177Lu DOTA octreotide that targets SSTR2 seemed to synergize with chemotherapy carboplatin and etoposide in killing cancer in a xenograft model.⁷³ However, SSTR2 expression detected by 68Ga-DOTATATE or histology was not a predictor of PFS or OS in advanced SCLC.⁷⁴ PEN221 is a peptide drug conjugate linking SSTR2 binding peptide to cytotoxic microtubule targeting payload mertansine (DM1). PEN221 was tested in a phase I clinical trial in SCLC. Peptide receptor radioligand therapy (PRRT) targeting of SSTR2+ SCLC in ES-SCLC with 177Lu DOTATATE or 225Actinium DOTATATE in combination with carboplatin, etoposide, and atezolizumab has just completed phase I clinical trial.^75,76

Delta-like ligand 3

Delta-like ligand 3 (DLL3) is an inhibitory NOTCH receptor ligand differentially expressed in SCLC and in normal tissue.⁷⁷ While DLL3 is expressed in low levels in the cytoplasm in normal cells,⁷⁸ it is homogenous on the cell surface of SCLC at high levels, making it a desirable target.⁷⁹ DLL3 was first targeted with an ADC, rovalpituzumab tesirine (Rova-T), in a phase I study of recurrent SCLC.²¹ Of 84 patients enrolled, 74 had SCLC, and 8 had large-cell neuroendocrine carcinomas. Eleven of the 60 evaluable patients responded to treatment, but not all responders had high expression. Of the responders, 38% were DLL3 high expressers (DLL3 >50%). Dose-limiting toxicities included Grade 4 thrombocytopenia and Grade 4 liver function test. The side effects profile included thrombocytopenia (11%), pleural effusion (8%), and increased lipase (7%). Serious treatment-related AE occurred in 38% of the 74 treated patients. In the subsequent phase II study enrolling SCLC failing two or more treatment regimens, one or more dose at 0.3 mg/kg of Rova-T (MTD 0.4 mg/kg) were given once every 6 weeks to 339 patients.⁸⁰ ORR was 12.4%, 14.3%, and 13.2%, respectively, in patients whose tumor had DLL3 high (⩾75%), positive (⩾25%), or negative/unknown, respectively. Median OS was 5.6 months for DLL3-positive tumors and 5.7 months for DLL3-high patients. The most common AEs included fatigue, pleural effusion, and photosensitivity. High-grade (Grade 3 or above) AEs were seen in 63% of treated patients. Two phase III trials were conducted—one in the maintenance setting after first-line chemotherapy compared with placebo (MERU).⁸¹ However, the OS of the Rova-T was inferior to that of the placebo. Another phase III was in the second line compared with topotecan (TAHOE).⁸² Again, Rova-T was inferior to topotecan in efficacy. The Rova-T arm had a high incidence of serosal effusion, photosensitivity, and peripheral edema, all of which were attributed to the study drug. This lack of efficacy and high incidence of AEs is thought to be caused by an unstable linker in the ADC, causing leakage of payload to the blood.

Success in the use of bispecific T-cell engager tarlatamab has changed the landscape for the treatment of SCLC after failing first-line immunochemotherapy.^19,83 Following accelerated approval, a phase III trial was reported in DeLLphi-304 comparing tarlatamab with chemotherapy with either topotecan, lurbinectedin or amrubicin in the second-line setting.¹⁸ The OS of the 254 patients in the tarlatamab arm was significantly longer (13.6 months, 95% CI 11.1–NR, HR 0.60, range 0.47–0.77, p < 0.001) than the 255 patients in the chemotherapy group (OS 8.3 months, 95% CI 7.0–10.2 months). Grade 3 or higher AEs were lower (54% vs 80%) in the tarlatamab arm, and discontinuation of treatment rate was lower compared to chemotherapy (5% vs 12%). Importantly, tarlatamab was well tolerated, with the majority of patients reporting generally only mild to moderate severity occurring rarely or occasionally on trial.⁸⁴ Tarlatamab used as maintenance with atezolizumab or durvalumab following initial induction chemoimmunotherapy with either atezolizumab or durvalumab was well tolerated and supported a phase III trial.⁸⁵ With a median of 35 weeks of exposure to tarlatamab, the most common Grade 3/4 AE was hyponatremia. Owing to its manageable safety profile in combination with ICI atezolizumab or durvalumab, a phase II trial with maintenance tarlatamab and durvalumab in combination in comparison with durvalumab alone has been launched (NCT06211036).⁸⁶

Tarlatamab has activity in the brain. In the phase I DeLLphi-300 and phase II DeLLphi-301 trials, previously treated SCLC patients, including those with treated and stable brain metastases treated with tarlatamab, central nervous system (CNS) tumor shrinkage of 30% or more was documented in 62.5% of patients using modified RANO criteria for brain metastases. Some lesions shrank long after radiotherapy.⁸⁷ In a case series of 10 patients with untreated brain metastasis, including one with suspected leptomeningeal metastasis, tarlatamab treatment resulted in a rapid and dramatic clinical response reaching stability in 90% of patients.⁸⁸

Although the targets are the same, analysis of tarlatamab (AMG757), obrixtamig (BI764532), and gocatamig (HPN328, MK 6070) indicates that structural features are intimately associated with efficacy and safety.⁸⁹ It will be interesting to see how their efficacy and side effect profiles differ in clinical trials. The trispecific T-cell activators are being tested in several clinical trials.

EGFR mutation-driven adenocarcinomas can transform into SCLC under TKI selection pressure. These cancers are considered to have a different biology than cancer induced by smoking. Efficacy with tarlatamab was moderate.⁹⁰ In this case series of 14 efficacy evaluable patients, 1/14 had a partial response (PR), 3 had mixed response, 1 had stable disease (SD), while most (9/14) had progressive disease (PD) in a median follow-up of 1.45 months (0.2–8 months). Median OS was 2.7 months, and the time of treatment was 2.5 months.

DLL3-targeted CAR-T cells emerged in the treatment of relapsed SCLC. Although still in the early stage, the CAR-T cells potentially offer durable benefits with a single infusion as an alternative to tarlatamab. AMG119 was a third-generation CAR-T that targets DLL3 in relapsed/refractory SCLC after one or more lines of treatment. The CAR-T has both CD28 and 4-1BB as a costimulatory domain intracellularly. In a phase I study, three patients were treated with a 3.3 × 10⁵/kg dose and two were treated with 1 × 10⁶/kg. CAR-T cells persisted for 86 days. Of the four patients evaluable for efficacy, one patient had PR, another had PD, and two others had SD. Median PFS was 3.7 months, and median OS was 7.4 months (range 4.6–18.9 months). CAR-T-cell expansion resulted in rapid clearance of circulating SCLC cells (NCT03392064).⁹¹

LB2102, a DLL3-targeted CAR-T with a 4-1BB costimulatory domain and a dnTGFBR2 armor to reduce exhaustion, is being studied in relapsed/refractory SCLC and large-cell neuroendocrine tumors (NCT05680922). A total of 20 subjects with 17 SCLC and 3 LCNET were enrolled. Dose escalation up to 16 million/kg was well tolerated with no dose-limiting toxicities. Of the 17 efficacy evaluable subjects, ORR was 18%, and DCR was 76%. Cytokine release syndrome was Grade 1–2, and only one Grade 3 immune effector cell-associated neurotoxicity syndrome was observed and recovered promptly. Median duration of response was 208 days. CAR-T cells expanded well.⁹²

CD56

CD56 (also known as NCAM or neuronal cell adhesion molecule) is known to be preferentially expressed in SCLC and cells of neuroectoderm origin, dendritic cells, and natural killer (NK) cells.⁹³ Targeting CD56 on the SCLC surface was performed with a monoclonal antibody against CD56 linked to “blocked” ricin (N901bR) initially to prevent non-specific binding of ricin to other tissues in a phase I study.⁹⁴ Liver enzyme elevation and capillary leak syndrome were noted among the side effects. After 20 years, another phase I study of IMGN901 (lorvotuzumab mertansine, a CD56-targeted ADC linked with maytansinoid DM1) was conducted in solid tumors, including SCLC, for safety, tolerability, pharmacokinetics, and efficacy when given intravenously once every 3 weeks. There were only subtle signs of efficacy.⁹⁵ In the phase I/II study, 141 chemotherapy naïve SCLC patients were randomized in a 2:1 ratio to receive carboplatin (AUC5) and etoposide (100 mg/m² on days 1–3) plus lorvotuzumab mertansine (arm 1) or alone (arm 2) after a lead-in in 33 patients. Lorvotuzumab mertansine did not improve survival. The median PFS in arm 1 and arm 2 was 6.2 and 6.7 months, respectively. Peripheral neuropathy (29%) was the most common AE leading to discontinuation. A total of 18 patients died in arm 1 compared to 3 in arm 2. Ten other individuals had pneumonia or sepsis related to the study drug. CD56 expression in glia and NK, gamma/delta cells makes it a poor target.⁹⁶

Trophoblast cell protein 2

TROP2 (trophoblast cell protein 2) is a cell surface antigen (transmembrane calcium signal transducer) overexpressed in many epithelial cell carcinomas, including SCLC.^97,98 Overexpression is necessary and sufficient to drive cancer growth. TROP2 targeting has the potential to become a histological-agnostic approach.⁹⁹ The antibody-drug conjugate sacituzumab govitecan (SG) has shown success so far in the treatment of advanced triple-negative breast cancer.^100,101 The latest accelerated FDA approval included EGFR-mutated lung adenocarcinoma after failing EGFR TKI and platinum-based chemotherapy, based on a pooled analysis of a phase II (TROPION-Lung05) and a phase III (TROPION-Lung01) study.¹⁰² SG was first tested in a trial of SCLC in 50 patients who had received a median of 2 (range 1–7) lines of treatment. Given at 8–10 mg/kg at day 1 and 8 every 3 weeks, ORR was 14% and 17% for those who received 10 mg/kg. Grade 3 or higher AE included neutropenia (34%), diarrhea (9%), fatigue (13%) and anemia (6%). Median PFS was 3.7 months and median OS was 7.5 months.¹⁰³ Overall safety analysis from a basket trial of 495 patients showed that 41 cases discontinued the drug due to side effects (8.3%). Grade 3 or above AEs included neutropenia 42.4% and febrile neutropenia in 4.0% and diarrhea 2.8%.¹⁰⁴ A phase II trial (TROPiCS-03) was recently reported in 43 patients in the second-line setting. Patients who received front-line treatment with disease progression were given SG on day 1 and day 8 every 21 days with ICI. After a 12.3-month median follow-up, the PFS was 4.4 months and OS was 13.6 months. ORR occurred in 41.9%. Grade 3 treatment-emergent AEs occurred in 74.4% patients, with one dying from neutropenic sepsis.¹⁰⁵ A phase II trial enrolling 21 patients using pembrolizumab and SG during maintenance on days 1 and 8 of every 21-day schedule for 31 cycles after induction treatment with carboplatin, etoposide, and pembrolizumab is underway.¹⁰⁶ SG was found to be safe in combination with berzosertib, an ATR inhibitor, in three dose levels. No dose-limiting toxicity was found. Three patients responded, including two small cell carcinomas from the prostate, and one transformed to small cell carcinoma from lung adenocarcinoma in a solid tumor population who had received one or more lines of treatment.¹⁰⁷

Seizure-related homolog protein 6

SEZ6 (seizure-related homolog protein 6) is a cell surface protein that is involved in neuronal development. In adult tissue, SEZ6 is limited to the CNS and is found overexpressed in cancer with neuroendocrine differentiation, such as SCLC and LCNET.¹⁰⁸ ABBV-011 was engineered for the treatment of SCLC by linking an antibody against SEZ6 to calicheamicin with an acid-stable linker.¹⁰⁹ ABBV-011 was tested in a phase I trial enrolling 99 patients (39 in dose escalation and 60 in expansion) with approximately one-third of each receiving 1, 2 or 3 lines of treatment. Patients whose tumors expressed 1+ immunohistochemistry marker or 25% of tumor cells were included. Patients received 0.3–2.0 mg/kg every 3 weeks with no dose-limiting toxicity detected. Dose expansion was conducted in 60 patients, and ORR was 25% in the 1 mg/kg portion. Median PFS was 3.5 months. Fatigue was noted in 50% of patients, nausea in 42%, and decreased platelet counts in 41%. Serious AEs included increased liver function tests (22%), increased bilirubin (17%), and venous occlusive disease (2%).¹¹⁰ An improved version of ADC known as ABBV-706 linking a SEZ6 antibody to govitecan via a stable linker was tested with encouraging results (drug to antibody ratio 1:6). In a phase I study of 65 patients with SCLC and neuroendocrine carcinoma, ABBV-706 monotherapy had a PFS of 7.62 months (95% CI 5.52–8.31).^111,112 In the latest report on 80 heavily treated patients (30 with ⩾2 lines and 50 with ⩾3 lines), the confirmed ORR reached 58% across all groups, including platinum-resistant brain metastasis. SEZ6 expression level was not associated with response.¹¹³

Targeting epigenetic modulators

Cancer cells have a distinct transcriptome to maintain their hallmark and meet their need for continued growth, unaffected by immune surveillance.¹¹⁴ The altered epigenetic machineries are the enablers. One important mechanism involved is the modification of the histone methylation status, resulting in transcriptional silencing of some tumor suppressor genes and genes involved in immune surveillance.^115,116 Targeting epigenetic modulators to “reprogram the tumor and its microenvironment” has the potential to boost immunotherapy by decreasing resistance.

Enhancer of zeste homolog 2

In SCLC, characteristic methylation patterns were identified.^117,118 These changes affect the expression of polycomb-target genes, including enhancer of zeste homolog 2 (EZH2). EZH2 encodes the catalytic subunit of histone methyltransferase of the polycomb repressive complex 2 (PRC2). It catalyzes methylation reactions at lysine 27 of histone H3 (H3K27), resulting in the trimethylated H3K27 (H3K27me3), which serves as a repressive mark effectively silencing gene transcription.¹¹⁹ EZH2 also cooperates with other epigenetic silencing enzymes, including DNA methyltransferases and histone deacetylases, to control gene expression.¹²⁰ EZH2 inhibitors are shown to derepress genes such as SLFN11 and MHC II that might be involved in chemotherapy and immunotherapy resistance, making it a promising agent to use in combination with chemotherapy and/or immunotherapy.^121–123 A clinical trial boosting the efficacy of PD-1 inhibitor and topoisomerase inhibitor in relapsed/refractory SCLC by tazemetostat has been concluded (NCT05353439).

Lysine-specific histone demethylase I

Lysine-specific histone demethylase I (LSD1 or KDM1A) is another epigenetic modulator of interest that has shown promise in SCLC therapeutics.¹²⁴ This enzyme regulates gene expression by removing mono- and di-methyl groups from the histone H3K4 or H3K9, resulting in transcriptional activation/repression essential in embryonic development and stem cell maintenance.¹²⁵

LSD1 inhibitors activate the NOTCH pathway in SCLC, resulting in suppression of ASCL1 expression.¹²⁶ SCLC has marked low expression of MHCII antigen.¹²⁷ LSD1 inhibition can upregulate MHCII expression and address the resistance to ICI in SCLC.^128,129 Sustained inhibition of LSD1 can rescue the exhausted CD8-positive T cells and boost ICI efficacy.^130,131 Maintenance immunotherapy in SCLC provides a perfect scenario during which LSD1 inhibitors can be added to address ICI resistance caused by low or absent expression of MHC II antigen. In a phase II clinical trial treating patients with SCLC in the second-line setting with carboplatin and etoposide, 4 of 10 patients responded.¹³² An ETCTN (10629) trial is underway in SCLC post-induction chemotherapy and immunotherapy (NCT 06287775) to further test this hypothesis at the early stage.

Prospectives and trials to watch

DLL3 targeted BiTE therapy drastically changed the prognosis of patients with relapsed and refractory disease, resulting in often durable response with minimal side effects since its approval in ES-SCLC. Efficacy in the CNS is especially promising. However, > 60% patients in this setting do not respond to tarlatamab, and most patients experience recurrence on treatment. Tarlatamab treatment starts with a step dose and is given once every 2 weeks subsequently. There is no trial to inform how long the patients will need treatment, considering the time and financial toxicity to patients. The molecular mechanism of primary and acquired resistance is poorly understood. Unlike NSCLC, there are no markers, such as PD-L1 or (tumor mutation burden) TMB, that can be used to predict response before treatment initiation, and response monitoring remains imaging-based at this point.

SCLC is known to express low levels of MHC II antigen, leading to immune escape and resistance to ICI. Restoration of MHCII expression using EZH2 or LSD1 inhibitors may sensitize cancer cells to ICI inhibition and chemotherapy by reprogramming the tumor and its microenvironment and by improving immune memory, decreasing immune exhaustion, and boosting the killing of cancer cells by CD8+ T cells. DLL3 targeting with a higher affinity molecule, such as alveltamig (ZG006), might improve engagement of T cells with cancer cells that are weak expressors of DLL3. Loss of DLL3 under selective pressure for tumors might be responsible for acquired resistance, since intratumor heterogeneity or plasticity is well known. Molecular type shift is a mechanism of escape in acquired resistance.¹³³ Rational combinations that lead to synergy are necessary to benefit the vast majority of patients, given the heterogeneity of SCLC. SSTR2 targeting in combination with chemotherapy and ICI can be viable when SSTR2 represents a chemotherapy-resistant population and does not induce overlapping bone marrow toxicity with chemotherapy. A better understanding of the biology of these cancers is vital. Repeat biopsy on recurrence or residual disease before maintenance is feasible, and may inform the tumor vulnerability.¹³⁴ For example, repeat biopsy revealed three classes of cancer that respond to one type of treatment or neither.¹³⁵ Given the high frequency of circulating tumor cells (CTC), repeat biopsy does not necessarily need to be a tissue biopsy, and response monitoring can be CTC-based or liquid biopsy-based.^136–138 Early use of BiTE is desirable due to the efficacy of BiTE in the CNS and unacceptable CNS toxicity, including cognitive decline, often associated with whole brain radiation. Development of DLL3-targeted CAR-T cells as an effective treatment offers hope for a durable response after only one-time infusion. This is especially welcoming when it can be positioned at the end of the induction chemoimmunotherapy. Trials to watch are summarized in Table 1.

Table 1.

Targeted therapy in small cell lung cancer: clinical trials to watch.

Drug name	Target	Molecule	Phase	Title	NCT #
Pumitamig	VEGF/PD-L1	Bi-sp Ab	III	Safety and Efficacy of BNT327, an Investigational Therapy in Combination With Chemotherapy for Patients With Untreated Small-cell Lung Cancer	06712355
Ivonescimab	VEGF/PD-1	Bi-sp Ab	2	Phase II Study of Platinum/Etoposide Plus Ivonescimab for Extensive Stage Small Cell Lung Cancer (PrE0510)	07057791
Tarlatamab + durvalumab	DLL3+PD-L1	Ab + Ab	III	Study Comparing Tarlatamab and Durvalumab Versus Durvalumab Alone in First-Line Extensive Stage Small-Cell Lung Cancer (ES-SCLC) Following Platinum, Etoposide and Durvalumab (DeLLphi-305)	06211036
Ifinatamab + deruxtecan (I-DXD)	B7H3	ADC, Dxd	III	A Study of Ifinatamab Deruxtecan Versus Treatment of Physician’s Choice in Subjects With Relapsed Small Cell Lung Cancer (IDeate-Lung02)	06203210
177Lu-DOTATATE	SSTR2	177LuDota	II	A Study of [177Lu]Lu-DOTA-TATE in Newly Diagnosed ES-SCLC Patients in Combination With Carboplatin, Etoposide and Atezolizumab	05142696
RYZ101-DOTATATE	SSTR2	225AcDota	II	Study of RYZ101 in Combination With SoC in Subjects With SSTR+ ES-SCLC	05595460
Obrixtamig	DLL3	BiTE	II	DAREON™-5: A Study to Test Whether Different Doses of BI 764532 Help People With Small Cell Lung Cancer or Other Neuroendocrine Cancers	05882058
Gocatamig	DLL3	BiTE	I/II	A Clinical Study of Gocatamig (MK-6070) and Infinatamab Deruxtecan (MK-2400) in People With Small Cell Lung Cancer (MK-6070-003)	07227597
Alveltamig	DLL3	Tri TE	I/II	A Phase 1 Dose Escalation Study of ZG006 in Patients With Small Cell Lung Cancer	06592638
LB2102	DLL3	CAR	I	DLL3-Directed Chimeric Antigen Receptor-T cells in Subjects With Extensive Stage Small Cell Lung Cancer	05680922
DJI136	DLL3	CAR	I/II	A phase ½ open-label study of DJI136, a DLL3 targeted CAR-T-cell therapy in adult patients with ES-SCLC	523276-23 European*
ABBV-706	SEZ6	ADC	I	A Study to Evaluate the Optimal Dose, Adverse Events and Change in Disease Activity of Intravenous ABBV-706 in Combination With Atezolizumab Versus Standard of Care as First-Line Treatment in Adult Participants With Previously Untreated Extensive Stage Small Cell Lung Cancer (SEZanne)	05599984
Sacituzumab govitecan	TROP2	ADC	III	Study of Sacituzumab Govitecan Versus Standard of Care in Participants With Previously Treated Extensive Stage Small Cell Lung Cancer (EVOKE-SCLC-04)	06801834
Tazemetostat	EZH2	Small mol	I	Testing of Tazemetostat in Combination With Topotecan and Pembrolizumab in Patients With Recurrent Small Cell Lung Cancer	05353439
Iadademstat	LSD1	Small mol	I/II	Testing the Combination of an Anti-cancer Drug, Iadademstat, With Other Anti-cancer Drugs (Atezolizumab or Durvalumab) at Improving Outcomes for Small Cell Lung Cancer	06287775
Ifinatamab deruxtecan (I-DXd) + MK-6070	B7H3, DLL3	ADC+BiTE	I/II	A Clinical Study of Gocatamig (MK-6070) and Infinatamab Deruxtecan (MK-2400) in People With Small Cell Lung Cancer (MK-6070-003)	07227597

Dana Farber Protocol #26-110.

Ab, antibody; ADC, antibody-drug conjugate; Bi-sp, bi-specific; BiTE, bispecific T-cell engager; CAR, chimeric antigen receptor; Dxd, deruxtecan; ES-SCLC, extensive stage small cell lung cancer; mol, molecule; SOC, standard of care; TriTE, tri-specific T-cell engager.

Footnotes

Acknowledgements

Markey Cancer Center’s Research Communications Office assisted with manuscript preparation and graphics.

Declarations

ORCID iD

Zhonglin Hao

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