Sage Journals: Discover world-class research

Abstract

Immunotherapy now plays a key role in supplementing and even replacing conventional agents in tumor treatment. Immune checkpoint inhibitors (ICIs), represented by atezolizumab and durvalumab, have shown encouraging therapeutic effects in the combination chemotherapy for extensive-stage small cell lung cancer (SCLC) and have become preferred regimens. It has marked a seminal shift in the treatment landscape with achieving for the first time that overall survival exceed 1 year. However, the extent to which SCLC patients can benefit from ICIs is limited, and ICIs’ combination treatment strategies still need to be continuously explored. Beyond the ICIs in combination with radiotherapy, the anti-angiogenic target has been a combination option to improve effectiveness. And the novel formula of immune drugs, such as antibody–drug conjugates, bispecific T cell engager therapy, and chimeric antigen receptor T-cell immunotherapy, also promotes the potential option for SCLC patients. Based on the molecular development and biomarkers analysis of the sensitivity to immune checkpoint of the SCLC subtypes, the exploration of new targets and the development of drugs with novel mechanisms may provide fresh hope for immunotherapy in SCLC.

Keywords

antibody–drug conjugates combination ES-SCLC immunotherapy targeted therapy

Introduction

Small cell lung cancer (SCLC) is a type of lung cancer that is highly aggressive and accounts for approximately 15% of all lung cancer cases. In clinical practice, SCLC is categorized as either limited-stage SCLC (LS-SCLC) or extensive-stage SCLC (ES-SCLC), with 5-year survival rates of 10%–13% and 1%–2%, respectively.¹ SCLC is characterized by a rapid doubling time, high growth fraction, and early development of widespread metastases. Approximately two-thirds of all SCLCs are extensive stage, and most diagnoses are accompanied by distant metastases. In the past decade, immunotherapy has brought new light to first-line treatment for SCLC, increasing survival rates and improving patient outcomes.

The phase I/II CheckMate 032 trial started to identify the response to immune checkpoint inhibitors (ICIs) in SCLC. It failed to demonstrate improved survival between nivolumab alone and nivolumab plus ipilimumab, even though the objective response rate (ORR) was higher with nivolumab plus ipilimumab versus nivolumab (median overall survival (mOS): 28.4 vs 29.0 months, ORR: 21.9% vs 11.6%).² The KEYNOTE-604 study demonstrated that in the first-line treatment of patients with ES-SCLC, pembrolizumab plus etoposide and platinum improved progression-free survival (PFS) in patients compared to placebo plus etoposide and platinum, but OS only showed a trend toward benefit and did not reach the threshold of significance (median PFS (mPFS): 4.5 vs 4.3 months, mOS: 10.8 vs 9.7 months).³ The IMpower133 study first demonstrated that the addition of the anti-PD-L1 monoclonal antibody atezolizumab to carboplatin and etoposide improved PFS and OS in patients with ES-SCLC compared to chemotherapy alone (mPFS: 5.2 vs 4.3 months, mOS: 12.3 vs 10.3 months), while it merely resulted in a 2-month survival benefit.^4,5 Followed that the phase III CASPIAN study, first-line durvalumab in combination with etoposide plus either carboplatin (EC) or cisplatin (EP) significantly improved OS versus EC/EP alone in ES-SCLC (mPFS: 5.1 vs 5.4 months, mOS: 13.0 vs 10.3 months).⁶ While additional of tremelimumab to durvalumab plus EP did not improve either PFS or OS versus EP (mPFS: 4.9 vs 5.4 months, mOS: 10.4 vs 10.5 months).⁷ The ICIs produced a new landmark in the treatment of SCLC through US Food and Drug Administration (FDA) approval. Followed that, in China, several novel ICIs molecules also achieved promising results in SCLC (see Table 1). A randomized phase III study (CAPSTONE-1) evaluating adebrelimab or placebo plus chemotherapy in ES-SCLC met the primary mOS endpoint with 15.3 versus 12.8 months.⁸ Another international multicenter phase III trial (ASTRUM-005) of serplulimab combined with etoposide-carboplatin significantly improved the mPFS (5.7 vs 4.3 months) and mOS (15.4 vs 10.9 months) compared with the placebo.^9,10 Recently, tislelizumab plus chemotherapy as first-line treatment for ES-SCLC based on the phase III RATIONALE-312 study has exhibited a statistically significant OS benefit versus placebo plus chemotherapy with 15.5 versus 13.5 months. The mPFS was significantly improved with 4.7 versus 4.3 months.¹¹ Toripalimab plus chemotherapy as first-line treatment for ES-SCLC based on EXTENTORCH study showed a significant improvement in PFS for toripalimab over placebo of 5.8 versus 5.6 months. And mOS was also significantly improved in the toripalimab arm with 14.6 versus 13.3 months.¹² All of the above positive results granted the approval of the ICIs in combination with chemotherapy becoming the new standard frontline treatment in ES-SCLC. Updated clinical trial results indicate that the 3-year and 5-year OS of patients with ES-SCLC might be approaching 17.6% and 12% under immunotherapy, respectively.^13,14 The addition of ICIs to platinum-based chemotherapy confers only a modest prolongation of OS by approximately 2–4 months that seems to be more likely to respond to maintenance ICIs. Research is needed to identify biomarkers that may predict clinical benefit.

Table 1.

Efficacy of ICIs combined with chemotherapy in the first-line setting for ES-SCLC: phase III trials.

Study/clinical trial number	Intervention	N	ORR (%)	mDOR, months	mPFS, months (HR; 95% CI)	mOS, months (HR; 95% CI)	1-Years OS (%)	2-Years OS (%)	Grade 3/4 TRAE
IMpower133/NCT02763579^4,5	Atezolizumab + EC → atezolizumab Placebo + EC → placebo	403	60.2% vs 64.4%	4.2 vs 3.9	5.2 vs 4.3 (0.77; 0.62, 0.96)	12.3 vs 10.3 (0.70; 0.54, 0.91)	51.9% vs 39.0%	/	56.6% vs 56.1%
CASPIAN/NCT03043872^6,7,13	Durvalumab + EC/EP → durvalumab Durvalumab + tremelimumab + EC/ EP → durvalumab + tremelimumab Placebo + EC/EP → placebo	805	68% vs 58% vs 58%	/	5.1 vs 5.4 (0.78; 0.65, 0.94) 4.9 vs 5.4	13.0 vs 10.3 (0.73; 0.59, 0.91) 10.4 vs 10.5 (0.81; 0.67, 0.97)	52.8% vs 43.5% vs 39.3%	22.9% vs 22.9% vs 13.9%	62% vs NR vs 62%
KEYNOTE-604/NCT03066778³	Pembrolizumab + EP/EC → pembrolizumab Placebo + EC/EP → placebo	453	70.6% vs 61.8%	4.2 vs 3.7	4.5 vs 4.3 (0.75; 0.61, 0.91)	10.8 vs 9.7 (0.80; 0.64, 0.98)	45.1% vs 39.6%	22.5% vs 11.2%	76.7% vs 74.9%
CAPSTONE-1/NCT03711305⁸	Adebrelimab + EC → adebrelimab Placebo + EC → placebo	462	70.4% vs 65.9%	90.0% vs 90.9%	5.8 vs 5.6 (0.67; 0.54, 0.83)	15.3 vs 12.8 (0.72; 0.58, 0.90)	62.9% vs 52.0%	31.3% vs 17.2%	85% vs 84%
ASTRUM-005/NCT04063163¹⁰	Serplulimab + EC → serplulimab Placebo + EC → placebo	585	76.9% vs 68.9%	4.4 vs 3.0	5.5 vs 4.3 (0.58; 0.48, 0.71)	15.4 vs 10.9 (0.63 0.49, 0.82)	60.7% vs 47.8%	43.1% vs 7.9%	33.2% vs 27.6%
RATIONALE-312/NCT04005716¹¹	Tislelizumab + EC/EP → tislelizumab Placebo + EC/EP → placebo	457	68% vs 62%	4.3 vs 3.7	4.7 vs 4.3 (0.64; 0.52, 0.78)	15.5 vs 13.5 (0.75; 0.61, 0.93)	63% vs 58%	33% vs 22%	85% vs 86%
EXTENTORCH/NCT04012606¹²	Toripalimab + EC/EP → toripalimab Placebo + EC/EP → placebo	442	/	/	5.8 vs 5.6 (0.667; 0.539–0.824)	14.6 vs 13.3 (0.798; 0.648–0.982)	63.1% vs 54.9%	/	⩾Grade 3 TEAE 89.6% vs 89.4%

CI, confidence interval; EC, etoposide-carboplatin; EP, etoposide-cisplatin; ES-SCLC, extensive-stage small cell lung cancer; HR, hazard ratio; ICI, immune checkpoint inhibitor; mDOR, median duration of response; mo, months; NR, not reported; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TEAE, treatment emergent adverse event; TRAE, treatment-related adverse event.

Furthermore, it is of vital importance to find out the promising combination treatment strategies to acquire better effects for ES-SCLC. In 2019, Rudin et al.¹⁵ proposed four subtypes of SCLC based on the elevated expression of transcription factors ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). In 2021, Gay et al. identified four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy.¹⁶ Most SCLCs with neuroendocrine (NE) tumor characteristics (~80%), including SCLC-A and SCLC-N, tended to have immune-cold properties. Other non-NE SCLCs (~20%) are more likely to have immune hot properties and increased immunogenicity, such as SCLC-P and SCLC-I.¹⁷ Thus, the subtype SCLC-I was proposed accompanied by high expression of inflammatory genes including numerous immune checkpoints and human leukocyte antigens. Recent studies have shown that SCLC exhibits strong intertumoral and intratumoral heterogeneity. It is reported that myelocytomatosis viral oncogene homology (MYC) amplification and alterations affecting the Notch signaling pathway have a major role in subtype switching, transforming from SCLC-A to SCLC-N and YAP1-driven subtypes.¹⁸ In addition, they show that the tumor heterogeneity is unstable, representing only a snapshot in the gradual evolution of a tumor, which exhibits significant plasticity.^19,20 And some reports highlight the critical role intratumoral heterogeneity may play in multiple aspects of SCLC development, progression, and prognosis such as metastasis, angiogenesis, and efficacy.²⁰

CASPIAN study analyzed the sensitivity to ICIs in the four subtypes. This study showed that SCLC-I has the greatest mOS benefit with durvalumab plus EP with or without tremelimumab at 24.0 months, compared to 12.1 and 11.5 months with SCLC-N and SCLC-A subtypes per Gay et al., respectively,²¹ and SCLC-P showed the poorest outcome with immunochemotherapy, consistent with previous findings (such as IMpower133). And the greatest mOS benefit from immunochemotherapy versus EP was also seen in the SCLC-Y subtypes at 15.0 months, compared to 8.1 and 12.4 months with SCLC-N and SCLC-A subtypes per Rudin et al. Given sample size limitations, the differential outcome between subtypes was not statistically significant. Some studies showed that SCLC-I was the most sensitive to immune checkpoint blockade, SCLC-A was the most sensitive to delta-like protein 3 (DLL3) and BCL2 inhibitors, while SCLC-N was the most sensitive to Aurora kinase inhibitors (more effective in those SCLC with increased MYC expression), and SCLC-P was the most sensitive to poly-ADP-ribose polymerase (PARP) inhibitors, thus suggesting different classes of drugs for different specific subtypes.²² The intratumoral heterogeneity of SCLCs, as well as its increase with chemotherapy, suggest that single-agent targeted therapies will have limited efficacy in SCLC, and that durable responses will be achieved only with combination therapies targeting simultaneously multiple SCLC subpopulations.

Prognosis for patients with SCLC remains a major clinical dilemma. It was not only a limited benefits and a minority of patients respond to ICIs treatment, but also current ICIs-response-associated biomarkers often failed to predict the ICIs treatment response. With the deeper unraveling of the molecular mechanisms underlying the carcinogenesis of SCLC of recent years, there is new hope that some molecular targeted drugs might achieve adequate clinical benefits by consequences for the tumor microenvironment. Thereby, combination immunotherapy and combination of immunotherapy with other therapy, such as chemotherapy, radiotherapy, and targeted therapy, represent a new modality for treating SCLC, which can achieve greater therapeutic effects through multiple synergistic mechanisms. This review reports the status of the SCLC treatment, as well as the challenges of novel therapies in SCLC, with particular emphasis on potential strategies for immune combination and antibody–drug conjugates (ADC) as well as enhancing the effects of immunotherapy (Figure 1). In this article, we review the current clinical trial treatment landscape based on immune-based combined therapies through company sponsored and investigator initiated studies. Furthermore, we outline early-stage trials of the emerging research and future strategies in ES-SCLC.

Figure 1.

A brief timeline of therapeutic advancements in ES-SCLC.

Current therapeutic development

A better understanding of tumor immune microenvironment of SCLC will promote and evoke discovery of novel targets to overcoming the existing treatments. Several combination strategies and targeted agents are being tested for the treatment of SCLC (see Table 2, and more details in Supplemental Table 1). The mechanisms of action of these therapeutic agents are illustrated in the figure (original figure created by the authors; Figure 2).

Table 2.

Summary of ICIs combined therapies and novel targeted treatments in ES-SCLC.

Target	Agents	Intervention types	Clinical setting
PD-1/PD-L1	Atezolizumab Durvalumab Adebrelimab	PD-1/PD-L1 combined with radiotherapy	1st line
PD-1/PD-L1 Anti-angiogenic	Atezolizumab Durvalumab Benmelstobart	PD-1/PD-L1 combined with bevacizumab or anlotinib	1st line
DLL3 ADC	Rovalpituzumab tesirine (Rova-T) ZL-1310	Single agent	⩾2nd line
Trop-2 ADC	Sacituzumab govitecan	Single agent	⩾2nd line
B2-H3 ADC	Ifinatamab deruxtecan HS-20093	Single agent	⩾1st line
SEZ6 ADC	ABBV-011	Single agent	⩾2nd line
DLL3 Bispecific antibody ADC	PT217	Single agent	⩾2nd line
TIM-3/anti-PD-1 bispecific antibody	Lomvastomig (RO7121661)	Single agent	⩾1st line
DLL3 BiTE	Tarlatamab (AMG757) BI 764532 QLS31904	Tarlatamab combined with durvalumab single agent	1st line and maintenance ⩾2nd line
DLL3 TiTE	HPN328	Single agent	⩾2nd line
DLL3 CAR-T	AGM 119 LB2102	Single agent	⩾2nd line
DNA damage pathway PARP	Olaparib Fluzoparib Veliparib	PARP combined with PD-1/PD-L1 PARP combined with chemotherapy	1st line and maintenance
DNA damage pathway ATR	Ceralasertib (AZD6738)	Single agent	⩾1st line
TIGIT	Tiragolumab Vibostolimab	TIGIT combined with PD-1/PD-L1	1st line
LAG3	IBI110	LAG3 combined with PD-1	1st line
PP2A	LB-100	PP2A combined with PD-L1	1st line
MHC-I regulating direct EZH2	Tazemetostat	EZH2 combined with PD-1	2nd line
MHC-I regulating direct LSD1	Bomedemstat	PLK1 combined with PD-L1	1st line maintenance
MHC-I regulating direct PLK1	Onvansertib	Single agent	⩾2nd line

ADC, antibody–drug conjugates; ATR, ataxia telangiectasia and Rad3-related protein; BiTE, bispecific T-cell engagers; CAR-T, chimeric antigen receptor (CAR) T-cell; DLL3, Delta-like protein 3; ES-SCLC, extensive-stage small cell lung cancer; ICI, immune checkpoint inhibitors; PARP, poly-ADP-ribose polymerase; TiTE, trispecific T-cell engager; Trop-2, trophoblast cell surface antigen 2.

Figure 2.

Mechanisms of action of drugs in ES-SCLC.

Radiotherapy and ICIs combination therapies

In addition to systemic chemotherapy, radiotherapy also plays a pivotal role in the therapeutic management of patients with SCLC as part of either definitive or palliative therapy. Specifically, concurrent or sequential chemoradiotherapy is part of the standard of care for patients with limited stage disease (up to N3, M0), whereas radiotherapy in those with ES-SCLC mainly consists of consolidative thoracic radiation therapy (RT) or prophylactic cranial irradiation after first-line treatment. The Dutch CREST randomized trial of modest-dose thoracic RT (30 Gy in 10 fractions) with chemotherapy in patients with ES-SCLC demonstrated significantly improved 2-year OS rate (13% vs 3%, p = 0.004) and 6-month PFS rate (24% vs 7%, p = 0.001), although the protocol-defined primary endpoint of 1-year OS was not significantly improved (33% vs 28%, p = 0.066).²³ Based on two randomized trials, IMpower133 and CASPIAN, immunotherapy during and after chemotherapy is a first-line approach. Nevertheless, consolidative thoracic RT after chemoimmunotherapy can be considered for selected patients as above, during or before maintenance immunotherapy. Evidence suggests that current ICI treatments can synergize with radiotherapy to enhance antitumor efficacy. With the advancement of radiotherapy techniques, the focus has gradually shifted from cytotoxicity to immune modulation.²⁴ The MATCH study was a single-arm phase II trial That previously untreated ES-SCLC 56 patients received atezolizumab + Cisplatin/carboplatin + etoposide for four cycles, and concurrent low-dose radiotherapy (LDRT; 15 Gy/5 fr) were conducted from Day 1 to 5 in the first cycle. The confirmed ORR was 87.5% as all partial response. The mPFS and mOS were 6.9 m and not reached, respectively. The 12-month OS rate was 71.9%. Four patients experienced AEs leading to treatment discontinuation. Immune-related adverse events (irAEs) were reported in 21 (37.5%) patients, and the most common irAEs were hyperthyroidism (5.4%) and rash (5.4%). Radiation pneumonitis (grade 1) was observed in one patient. Adding LDRT to ICIs shows impressive antitumor activity including ORR, potential survival benefit, and well tolerability in first-line treatment of ES-SCLC.²⁵

Instead of therapeutic doses, LDRT may enhance the efficacy of ICI treatments with promising prolonged PFS with less toxicity. Meanwhile, LDRT with concurrent durvalumab and EP show less toxicity in first-line ES-SCLC patients. In LEAD study, patients received durvalumab plus EP every 3 weeks for 4 cycles, followed by durvalumab maintenance therapy. Concurrent LDRT were conducted in the first cycle. In 30 eligible patients as median follow up of 17.3 months, mPFS and mOS were 8.3 months not reached, respectively. Among patients with liver and brain metastases, ORR was 50% and 100%, respectively.²⁶ Grade 3 or higher (⩾grade 3) treatment emergent adverse event (TEAE) occurred in 80% patients, the most common ⩾grade 3 TEAEs were hematological toxicity. The ⩾grade 3 irAEs were reported in 13.3%. The incidence of radiation-related Serious Adverse Events (SAEs) was 16.7%. Interstitial lung disease occurred in one patient (grade 2). A total of 33.3% (10) patients were still on treatment at data cut-off.

Another exploratory trial of adebrelimab with EC then combined with concurrent RT is under recruitment. Patients will receive adebrelimab plus EC induction therapy, then concurrent chemoradiotherapy, and consolidation with adebrelimab plus EC for one to two cycles, finally maintenance with adebrelimab monotherapy.²⁷ The radical intensity-modulated RT will be performed for the primary tumor in the chest and lymph node region, and stereotactic radiotherapy will be given to metastatic lesions. This trial is estimated to have a primary result in the mid-2026. These results highlighted the importance of combination of radiotherapy and immunotherapy in ES-SCLC. Consolidation immunotherapy following concurrent chemoradiotherapy has demonstrated survival benefits.

Anti-angiogenic agents and ICIs combination therapies

Anti-angiogenic therapy targets the formation of new blood vessels needed for the tumors to grow and spread, while ICIs reinvigorate the immune systemic ability to attack cancer cells. Both anti-angiogenic drugs and immuno-checkpoint inhibitors eventually result in a lower immune-suppressive tumor microenvironment by inhibiting tumor growth and metastasis; anti-angiogenic drugs reprogram the tumor milieu to an immune permissive microenvironment. This combination may win by improving the infiltration of immune cells and the delivery of ICIs to the tumor bed, potentially improving their effectiveness.²⁸ Combination with these two strategies was performed in many clinical trials with results of improvement antitumor efficacy and prolonged survival following the addition of anti-angiogenic agents to ICIs. The vascular endothelial growth factor inhibitor bevacizumab (bev) approved for the treatment of many tumor types and having synergistic effects when combined with ICIs, as demonstrated by the phase III IMpower150 study in non-SCLC. The BEAT-SC trial (jRCT2080224946) is evaluating the efficacy and safety of bev combined with atezolizumab and platinum-based chemotherapy (ACE) in patients with ES-SCLC from Japan and China. As the median follow-up of 10.2 months for total 333 patients, mPFS of investigator assessed was 5.7 months for bev plus ACE versus 4.4 months for ACE. The mOS was 13.0 months for bev plus ACE versus 16.6 months for ACE.²⁹ Previous opinion has suggested that SCLC, as a central type of lung cancer, may increase the risk of bleeding when treated with anti-angiogenic drugs such as bevacizumab. However, data from the BEAT-SC study showed that the safety of anti-angiogenic therapy in SCLC patients is controllable, which contrasts sharply with the contraindications of bevacizumab use in Non-Small Cell Lung Cancer (NSCLC).

The phase III ETER701 trial shows four-drug regimen improves survival outcomes in ES-SCLC. Patients randomly received benmelstobart (PD-L1) and anlotinib plus EC (benmelstobart and anlotinib arm), placebo, and anlotinib plus EC (anlotinib arm) or double placebo plus EC (EC arm), followed by matching maintenance therapy. The PFS in benmelstobart and anlotinib arm was significantly longer than in EC arm with 6.9 versus 4.2 months (p < 0.0001). And the similar mPFS was prolonged in the anlotinib arm than EC arm with 5.6 versus 4.2 months (p < 0.0001). Compared with EC alone, mOS was prolonged with benmelstobart and anlotinib arm (19.3 vs 11.9 months, p = 0.0002), while improvement of OS was not statistically significant with anlotinib arm (13.3 vs 11.9 months, p = 0.1723). The incidence of ⩾grade 3 treatment-related adverse events (TRAEs) were 93.1%, 94.3%, and 87.0%, respectively.³⁰

DURABLE study is to investigate the safety and efficacy of durvalumab combined with anlotinib as maintenance treatment in ES-SCLC patients. Approximately 66 patients who complete the 4 cycles of durvalumab plus EP treatment will be randomized in a 1:1 ratio to receive maintenance treatment durvalumab plus anlotinib (Arm 1) or durvalumab (Arm 2) until confirmed progressive disease.³¹ At data cutoff, durvalumab plus anlotinib significantly improved PFS compared with durvalumab alone (mPFS (from first dose of treatment): 9.0 vs 5.6 months, hazard ratio = 0.66). The mOS from first dose of treatment in two arms were 20.4 versus 15.4 months. During the same period an investigator-initiated trial reported that 22 patients with ES-SCLC were enrolled to receive durvalumab plus anlotinib plus EP/EC, followed by durvalumab plus anlotinib maintenance. The ORR was 100%, with 27.3% complete response rate. The mPFS of all patients was 8.51 months, and the mPFS of patients with liver metastasis and brain metastasis were 9.43 and 8.51 months, respectively.³² Results of PD-L1 combined with anti-angiogenic agent regime show promising efficacy and manageable safety profile.

Targeting therapies and potential combination therapies with ICIs

Targeting ADC agents and combination with ICIs

ADCs have emerged as novel therapeutic options for patients with cancer as they have the potential to deliver a therapeutic payload with reduced off-target toxicity. The linker allows for intratumoral release of therapeutic concentrations of cytotoxic agents, as well as release extracellularly within the surrounding tumor microenvironment, providing a bystander effect. ADCs have broad application prospects in the treatment of SCLC. Current clinical studies focus on DLL3, Trophoblast cell surface antigen 2 (Trop-2), B7-H3, SEZ6, and CD47. Although toxicities exceeding expectations have been observed with Rovalpituzumab tesirine (Rova-T), drugs targeting TROP-2 (Sacituzumab govitecan, SG), B7-H3 (DS-7300), and SEZ6 (ABBV-011) have shown exciting clinical benefits.

DLL3 targeting ADC

DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1. Its relevance is underscored by its high distribution of expression, reaching up to 85%, across various SCLC disease stages and treatment statuses. SCLC-A has high expression of DLL3.¹⁶ Presently, strategies to target DLL3 are diverse, encompassing approaches such as ADCs, bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell (CAR-T) therapies.

Rova-T represents the first-in-class DLL3-targeted ADC only produced modest antitumor activity in the phase II TRINITY study for the treatment of ES-SCLC.³³ However, the subsequent phase III TAHOE trial was halted because of Rova-T exhibited inferior OS and higher rates of toxicities compared with the current standard second-line chemotherapy.³⁴ At the same time, a phase I/II study evaluated the safety and efficacy of Rova-T plus nivolumab with or without ipilimumab in previously treated ES-SCLC. In this combination therapy, mPFS and mOS showed encouraging antitumor activity with 4.8 and 7.4 months in Rova-T plus nivolumab, while 4.1 and 11.0 months in additional ipilimumab. The safety result was similar to previous trials that it was not well tolerated at the dose levels and administration schedules evaluated.³⁵ ZL-1310, another novel ADCs targeting DLL3, showed promising primary result from a phase I study (NCT06179069). Data reported from part 1a monotherapy dose-escalation portion of the study; the ORR in evaluable of 19 patients was 74%. Responses were seen in patients with DLL3 H-scores from 5 (range: 5–260). No response was observed in a patient whose tumor did not express DLL3. Grade ⩾3 TRAEs occurred in 5 of the 25 patients (20%).³⁶

Trop-2 targeting ADC

SG is a novel, Trop-2-directed antibody–drug. In the phase I/II IMMU-132-01 basket trial, a total of 62 patients with refractory SCLC were treated with SG, reported an ORR of 17.7% and mOS of 7.1 months.³⁷ In the phase II TROPiCS-03 trial, the ORR was 41.9% in 43 patients that progressed after no more than 1 prior line of platinum-based chemo and anti-PD-(L)1 therapy. The mPFS was 4.40 months, and mOS was 13.60 months.³⁸ Investigators just tried to learn more about adding SG to pembrolizumab in NSCLC, such as NCT06055465, NCT05609968, and NCT05186974 (EVOKE-02). It might be also a chance for SCLC patients.

B7-H3 targeting ADC

The B7-H3 ADCs also show promising efficacy with higher dose of the drug almost doubling the response rate over a lower dose in early study of ES-SCLC. Ifinatamab deruxtecan (I-Dxd, DS-7300) is a B7-H3 directed ADC with a topoisomerase I inhibitor payload (DXd). A phase I/II clinical trial (NCT04145622) in patients with advanced solid tumors treated with DS-7300 showed an ORR of 52.4%, mPFS of 5.6 months, and mOS of 12.2 months in a total of 21 participants.³⁹ A phase II IDeate-Lung01 study of patients with second- or third-line ES-SCLC currently presented the efficacy of two dosage cohorts. There showed a confirmed ORR of 26.1% versus 54.8%, mPFS of 4.2 versus 5.5 months, and mOS of 9.4 versus 11.8 months in a total of 187 participants, respectively.⁴⁰ A phase I/II IDeate-Lung03 study (NCT06362252) is designed to evaluate the safety and efficacy of DS-7300 combination with atezolizumab ± carboplatin in ES-SCLC in first line setting and is on recruiting.⁴¹ While another B7-H3 ADC HS-20093 recently updated the result of ARTEMIS-001 study that were 56 patients in 8 and 10 mg/kg cohorts achieved ORR of 61.3% versus 50.0%. The mPFS was 5.9 and 7.3 months, respectively.⁴² The phase III ARTEMIS-008 study is estimated to start at the end of 2024.

SEZ6 targeting ADC

Approximately two-thirds of primary SCLC are classified as ASCL1-driven (SCLC-A) SEZ6, which is identified as a downstream target of ASCL1. ABBV-011, designed to specifically target SEZ6 and utilizes calicheamicin for the treatment of SCLC. ABBV-011 has shown promising efficacy phase I trials (NCT03639194). The ORR was 19% for the total cohort of 99 SCLC participants (including extensive stage and limited stage and missing staging) and 25% of 40 patients among for the 1 mg/kg dose-expansion cohort. The clinical benefit rate was 69% and 65% for the total and 1 mg/kg dose-expansion cohorts, respectively. The median duration of response (mDOR) was 4.2 months for the 1 mg/kg dose-expansion cohort, and the median treatment duration was 12 weeks.⁴³ The mPFS was 3.5 months in total patients.

Other potential targeting ADC

And other ADCs reported the early-stage clinical trial design recently, such as PT217 (anti-DLL3/anti-CD47) SKYBRIDGE phase I/II study in patients with neuroendocrine carcinomas expressing DLL3.

DLL3 targeting BiTEs agents and combination therapies

Even though Rova-T produced a survival benefit neither in the phase II TRINITY trial nor in the phase III TAHOE trial, DLL3 remains an intriguing target for multiple alternative therapeutic strategies. DLL3-targeted BiTEs, a novel technology, are engineered to link DLL3-positive cancer cells with CD3-positive T-cells, leading to MHC-I-independent T-cell activation and triggering the release of granzyme and perforin, resulting in the lysis of tumor cells.⁴⁴ Tarlatamab (AMG757) represents the first-in-class DLL3-targeted BiTEs and the DeLLphi-series trials of tarlatamab combination with ICIs are ongoing. In the phase I DeLLphi-300 study involving pretreated patients with ES-SCLC, of whom 50% were refractory to ICIs, tarlatamab exhibited promising clinical activities. The ORR was 23.4%, with mPFS of 3.7 months and mOS of 13.2 months.⁴⁵ The phase II DeLLphi-301 study conducted a comparative analysis of the treatment efficacy of tarlatamab at 2 dosage levels, 10 versus 100 mg. The study demonstrated that tarlatamab, administered at 10 mg, yielded comparable ORR (40% vs 32%), mPFS (4.9 vs 3.9 months), and mOS (15.2 vs 15.1 months) to those observed at 100 mg.^46,47 These data suggested that tarlatamab might represent a breakthrough in treating patients with SCLC who had disease progression over previous chemotherapy and immunotherapy options. Due to a robust ORR of 40% and mDOR of 9.7 months, FDA has approved tarlatamab-dll3 for the disease progression on or after platinum-based chemotherapy of adult ES-SCLC patients. The mOS was 14.3 months, with final and complete survival data yet to mature.⁴⁸ In 2024 WCLC, the phase Ib DeLLphi-303 study that evaluated tarlatamab plus PD-L1 inhibitor as first-line maintenance (1LM) therapy following chemo-immunotherapy reported the safety and efficacy. The median time from initiation of first-line chemo-immunotherapy to start of 1LM was 3.6 months. Beginning from 1LM, mPFS was 5.6 months, and the incidence of ⩾grade 3 TEAEs was 53.4% in total patients.⁴⁹ The ongoing phase III DeLLphi-304 study will further compare second-line tarlatamab with a regimen of 10 mg to the standard of care in chemotherapy-pretreated ES-SCLC patients.⁵⁰ In the first-line treatment setting, the DeLLphi-305 study will compare tarlatamab and durvalumab versus durvalumab alone in ES-SCLC following platinum, etoposide, and durvalumab.⁵¹ Additionally, several studies are investigating the synergistic potential of combining tarlatamab with ICIs. There are other DLL3-targeting BiTEs under clinical investigation including BI 764532 and QLS31904, as well as the trispecific T-cell engager HPN328 are in the early stage of study.^52,53

Targeting DNA damage pathway agents and combination therapies

In the past decade, researchers have focused on identifying the molecular and therapeutic landscape of SCLC. The high incidence of genomic aberrations observed in SCLC leads to aggregation of DNA damage and genomic instability mechanisms. First of all, the tumor mutational burden is a robust predictive biomarker for checkpoint immunotherapy in metastatic SCLC.¹⁸ DNA damage and repair mechanisms are to enhance sensitivity and/or overcome resistance to conventional DNA damaging treatments. Several molecules have been identified as drug targets, including PARP, checkpoint kinase 1 (CHK1), ataxia telangiectasia and Rad3-related protein (ATR), and WEE1.⁵⁴ PARP inhibitors subject to clinical trials in SCLC include Olaparib,^55,56 fluzoparib and veliparib,⁵⁷ and the combination therapy. The targeting DNA damage pathway therapy combination with ICIs also showed primary efficacy in early clinical trials by activating the antigen presentation pathway and tumor immunogenicity in SCLC. Phase II trial of MEDIOLA is a signal-seeking study assessing the safety, tolerability, and antitumor activity of durvalumab in combination with olaparib in patients with metastatic or recurrent solid tumors. Of 40 ES-SCLC patients previously treated, ORR was 10.5%. The mPFS and mOS were 2.4 and 7.6 months, respectively.⁵⁵ TRIDENT is a single arm phase II study of durvalumab plus olaparib as maintenance therapy in ES-SCLC. The median cycle of durvalumab was 7, and durvalumab plus olaparib as maintenance therapy was 3.5. The ORR was 75% (45/60), and the mDOR was 5.0 months. The mPFS was 5.8 months as calculated from the first cycle of treatment. The mOS was not reached.⁵⁶ AZD1775, the WEE1 inhibitor, has demonstrated clinical utility in a cohort of SCLC patients that the combination of olaparib and AZD1775 is helpful in reversing disease relapse.⁵⁸ However, the efficacy of these drugs has been detected in a fraction of SCLC patients and the further study is suspending. ATR and CHK1 inhibitors have been developed and their combined treatments with either radiotherapy or chemotherapies in preclinical or early stage clinical studies.^59–62

Other potential target agents and combination therapies

TIGIT is transmembrane protein expressed by a variety of immune cells that, when activated, induces a tolerogenic microenvironment. In-phase III SKYSCRAPER-02 trial 490 untreated ES-SCLC patients have been enrolled and randomized to receive atezolizumab plus EC either with or without tiragolumab. In the interim analysis, this study reported no improvement in the dual endpoints of mPFS (5.4 vs 5.6 months) and mOS (13.1 vs 13.1 months).⁶³ In general, the negative result of tiragolumab has reduced research interest in other TIGIT inhibitors for SCLC. Vibostolimab, another anti-TIGIT antibody, is starting a phase III study, KeyVibe-008 (NCT05224141) currently. It is comparing the efficacy and safety of first-line treatment with vibostolimab plus pembrolizumab, in combination with EP versus atezolizumab plus EP in patients with ES-SCLC.⁶⁴ However, this study is halted for futility, and it is another setback for TIGIT blockade. To overcome the ICI resistance, other immune checkpoint targets beyond TIGIT, such as TIM3 and LAG3, remain under investigation (NCT03708328 and NCT05026593; see Table 2).

Based on the outcomes of genome-wide association studies of cancer, the landscape of SCLC is from “genomics,” “transcriptomics,” to “epigenomics” that have defined the relevance of different epigenetic marks that regulate the biology of SCLC and have provided a roadmap for designing therapeutic modalities targeting epigenetic vulnerabilities. The studies in the last decade prove the importance of epigenetic modifications in various aspects of SCLC, including NE differentiation, lineage specificity, drug resistance, and metastasis. Research on the potential role of these epigenetic drugs is at a very early stage.

Some novel potential targets are on early stage clinical trial, such as PP2A inhibition LB-100 plus carboplatin, etoposide, and atezolizumab in phase I study (NCT04560972), regulating MHC-I direct EZH2 inhibition tazemetostat plus topotecan and pembrolizumab (NCT05353439),⁶⁵ LSD1 inhibition bomedemstat with atezolizumab (NCT05191797), and PLK1 inhibitor onvansertib (NCT05450965).⁶⁶

CAR-T targeting DLL3 therapies

CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies with six U.S. approved products. However, there are no approved CAR-T cell therapies for solid tumors. AMG 119, the first CAR-T cell therapy targeting DLL3, reported the phase I study preliminary results of five patients (NCT03392064). Among evaluable four patients, one patient had confirmed Partial Response (PR), two patients had Stable Disease (SD), and one had Progressive Disease (PD). The mPFS was 3.7 months and mOS was 7.4 months. It was associated with a manageable safety profile and promising antitumor activity. It has been suspended since 2022.⁶⁷ LB2102 is another designed to selectively target DLL-3, a ligand that is highly restricted to various malignancies, including SCLC, large cell neuroendocrine carcinoma, certain other neuroendocrine tumors, and some prostate cancers. A first-in-human study of LB2102 in subjects with ES-SCLC is ongoing (NCT05680922).⁶⁸

Conclusion and future perspectives

Chemoimmunotherapy is currently the preferred first-line treatment option for patients with ES-SCLC. Immune-based combination therapies synergistically convert cold tumors into hot tumors and achieve better antitumor effects than monotherapy. Conventional therapies, such as chemotherapy, radiotherapy, targeted therapy, and anti-angiogenic therapy, all participate in the regulation of the cancer-immunity cycle and synergistically promote antitumor responses when combined with immunotherapy. Meanwhile, CAR-T cells and novel targeted therapies have also opened new avenues for immunotherapy in lung cancer.

The envisioned paradigm of transcriptional subtype-based precision oncology in SCLC is challenged by several issues, including lack of clear prognostic significance, unclear subtype-specific target expression, and intratumoral heterogeneity. Other ways to personalize therapies should be investigated and perhaps prioritized in the future. More effective immune-based combination therapies require further research, such as MHC-I regulating direct target agents and ICIs combination therapies. Further studies and better data are expected to bring more survival benefits to patients with SCLC in the future.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251359057 – Supplemental material for Advances in immuno-based and targeted therapies in extensive-stage small cell lung cancer

Supplemental material, sj-docx-1-tam-10.1177_17588359251359057 for Advances in immuno-based and targeted therapies in extensive-stage small cell lung cancer by Xiao-Tong Zou, Jie Huang, Hao Sun, Li-Na Chen, Xiu-Hao Zhang and Jin-Ji Yang in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Xiao-Tong Zou

Supplemental material

Supplemental material for this article is available online.

References

Lally

Urbanic

Blackstock

, et al. Small cell lung cancer: have we made any progress over the last 25 years? Oncologist 2007; 12(9): 1096–1104.

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.

Rudin

Awad

Navarro

, et al. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol 2020; 38(21): 2369–2379.

Horn

Mansfield

Szczȩsna

, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 2018; 379(23): 2220–2229.

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.

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.

Goldman

Dvorkin

Chen

, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2021; 22(1): 51–65.

Wang

Zhou

Yao

, et al. Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2022; 23(6): 739–747.

Cheng

Han

, et al. Serplulimab, a novel anti-PD-1 antibody, plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small-cell lung cancer: an international randomized phase 3 study. J Clin Oncol 2022; 40(16_Suppl): 8505–8505.

10.

Cheng

Han

, et al. Effect of first-line serplulimab vs placebo added to chemotherapy on survival in patients with extensive-stage small cell lung cancer: the ASTRUM-005 randomized clinical trial. JAMA 2022; 328(12): 1223–1232.

11.

Cheng

Fan

Zhao

, et al. Tislelizumab plus platinum and etoposide versus placebo plus platinum and etoposide as first-line treatment for extensive-stage SCLC (RATIONALE-312): a multicenter, double-blind, placebo-controlled, randomized, phase 3 clinical trial. J Thorac Oncol 2024; 19(7): 1073–1085.

12.

Cheng

Liu

Zhang

, et al. LBA93 EXTENTORCH: a randomized, phase III trial of toripalimab versus placebo, in combination with chemotherapy as a first-line therapy for patients with extensive stage small cell lung cancer (ES-SCLC). Ann Oncol 2023; 34: S1334.

13.

Paz-Ares

Chen

Reinmuth

, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open 2022; 7(2): 100408.

14.

Liu

Dziadziuszko

Sugawara

, et al. OA01.04 Five-year survival in patients with ES-SCLC treated with atezolizumab in IMpower133: Imbrella a extension study results. J Thorac Oncol 2023; 18(11): S44–S45.

15.

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.

16.

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): 346–360.e7.

17.

Tian

Yang

, et al. Single-cell transcriptomic profiling reveals the tumor heterogeneity of small-cell lung cancer. Signal Transduct Target Ther 2022; 7(1): 346.

18.

Sen

Takahashi

Chakraborty

, et al. Emerging advances in defining the molecular and therapeutic landscape of small-cell lung cancer. Nat Rev Clin Oncol 2024; 21(8): 610–627.

19.

Ikematsu

Tanaka

Toyokawa

, et al. NEUROD1 is highly expressed in extensive-disease small cell lung cancer and promotes tumor cell migration. Lung Cancer 2020; 146: 97–104.

20.

Ireland

Micinski

Kastner

, et al. MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate. Cancer Cell 2020; 38(1): 60–78.e12.

21.

Xie

Vuko

Rodriguez-Canales

, et al. Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study. Mol Cancer 2024; 23(1): 115.

22.

Belluomini

Calvetti

Inno

, et al. SCLC treatment in the immuno-oncology era: current evidence and unmet needs. Front Oncol 2022; 12: 840783.

23.

Slotman

van Tinteren

Praag

, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015; 385(9962): 36–42.

24.

Kang

Yao

, et al. Tackling the current dilemma of immunotherapy in extensive-stage small cell lung cancer: a promising strategy of combining with radiotherapy. Cancer Lett 2023; 565: 216239.

25.

Zhou

Sun

Xie

, et al. Abstract CT219: efficacy and safety of low dose radiotherapy (LDRT) concurrent atezolizumab (Atezo) plus chemotherapy as first line (1L) therapy for ES-SCLC: primary analysis of phase II MATCH study. Cancer Res 2023; 83(8_Suppl): CT219.

26.

Zhang

Xie

Gong

, et al. 194MO Phase II study of low-dose radiation (LDRT) plus durvalumab (D) and etoposide/platinum (EP) as first-line treatment in ES-SCLC (LEAD): efficacy and safety results. ESMO Open 2024; 9: S3.

27.

Dong

Wei

Ruan

, et al. A phase II exploratory trial of adebrelimab in combination with chemotherapy and concurrent radiotherapy as a first-line treatment for oligo-metastatic extensive-stage small-cell lung cancer. J Clin Oncol 2024; 42(16_Suppl): TPS8131.

28.

Brest

Mograbi

Pagès

, et al. Checkpoint inhibitors and anti-angiogenic agents: a winning combination. Br J Cancer 2023; 129(9): 1367–1372.

29.

Ohe

Han

Nishio

, et al. BEAT-SC: a randomized phase III study of bevacizumab or placebo in combination with atezolizumab and platinum-based chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). J Clin Oncol 2024; 42(16_Suppl): 8001.

30.

Cheng

Chen

Zhang

, et al. Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial. Nat Med 2024; 30(10): 2967–2976.

31.

Han

Zhang

Zhong

, et al.MA17.07 Durvalumab plus anlotinib versus durvalumab as maintenance treatment in ES-SCLC (DURABLE): a randomized, phase 2 trial. J Thorac Oncol 2024; 9(10): S125–S126.

32.

Chen

Zhao

Phase II study of anlotinib plus durvalumab and chemotherapy as first-line treatment in extensive-stage small cell lung cancer (ES-SCLC): efficacy and safety analysis. J Clin Oncol 2024; 42(16_Suppl): e20131.

33.

Morgensztern

Besse

Greillier

, et al. Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: results from the phase II TRINITY study. Clin Cancer Res 2019; 25(23): 6958–6966.

34.

Blackhall

Jao

Greillier

, et al. Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high SCLC: results from the phase 3 TAHOE study. J Thorac Oncol 2021; 16(9): 1547–1558.

35.

Malhotra

Nikolinakos

Leal

, et al. A phase 1–2 study of rovalpituzumab tesirine in combination with nivolumab plus or minus ipilimumab in patients with previously treated extensive-stage SCLC. J Thorac Oncol 2021; 16(9): 1559–1569.

36.

Spira

Dowlati

Zhao

, et al. Preliminary results from a phase Ia/Ib, open-label, multicenter study of ZL-1310, a DLL3-targeted ADC, to evaluate the safety, tolerability, and pharmacokinetics in subjects with small cell lung cancer—NCT06179069. 36th EORTC-NCI-AACR symposium. Eur J Cancer 2024; 211: S1–S5.

37.

Bardia

Messersmith

Kio

, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol 2021; 32(6): 746–756.

38.

Dowlati

Chiang

Cervantes

, et al.OA04.04 Sacituzumab govitecan as second-line treatment in patients with extensive stage small cell lung cancer. J Thorac Oncol 2024; 19(10): Supplement S16.

39.

Johnson

Awad

Koyama

, et al.OA05.05 Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with refractory SCLC: a subgroup analysis of a phase 1/2 study. J Thorac Oncol 2023; 18(11): S54–S55.

40.

Rudin

Ahn

M-J

Johnson

, et al.OA04.03 Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer (ES-SCLC): interim analysis of IDeate-lung01. J Thorac Oncol 2024; 19(10): S15–S16.

41.

Rudin

Salkeni

Gutierrez

, et al. 1812TiP IDeate-Lung03: a phase Ib/II study of ifinatamab deruxtecan (I-DXd) plus atezolizumab (atezo) with or without carboplatin (carbo) as first-line (1L) induction or maintenance in patients (pts) with extensive stage (ES) small cell lung cancer (SCLC). Ann Oncol 2024; 35(Suppl. 2): S1074.

42.

Wang

Duan

, et al.OA04.06 Efficacy and safety of HS-20093 in extensive stage small cell lung cancer in a multicenter, phase 1 study (ARTEMIS-001). J Thorac Oncol 2024; 19(10): S17.

43.

Morgensztern

Ready

Johnson

, et al. First-in-human study of ABBV-011, a seizure-related homolog protein 6 (SEZ6)-targeting antibody-drug conjugate, in patients with small cell lung. J Clin Oncol 2023; 41(16_Suppl): 3002.

44.

Rudin

Reck

Johnson

, et al. Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer. J Hematol Oncol 2023; 16(1): 66.

45.

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.

46.

Ahn

Cho

Felip

, et al. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med 2023; 389(22): 2063–2075.

47.

Sands

Cho

Ahn

, et al.OA10.03 Tarlatamab sustained clinical benefit and safety in previously treated SCLC: DeLLphi-301 phase 2 extended follow-up. J Thorac Oncol 2024; 19(10_Suppl): S30–S31.

48.

Avanza

FDA approves Imdelltra™(Tarlatamab-Dlle), the first and only T-cell engager therapy for the treatment of extensive-stage small cell lung cancer, (2024, accessed 16 May 2024).

49.

Lau

Ahn

Moskovitz

, et al.OA10.04 Tarlatamab with a PD-L1 inhibitor as first-line maintenance after chemo-immunotherapy for ES-SCLC: DeLLphi-303 phase 1b study. J Thorac Oncol 2024; 19(10_Suppl): S30–S31.

50.

Paz-Ares

Felip

Ahn

, et al. Randomized phase-3 study: tarlatamab, a DLL3-targeting bispecific T-cell engager (BiTE), compared to standard-of-care in relapsed small cell lung cancer (DeLLphi-304). J Clin Oncol 2023; 41(16_Suppl): TPS8611.

51.

Perol

Ahn

Cheng

, et al.P1.13A.02 Tarlatamab plus durvalumab as first-line maintenance in extensive-stage small cell lung cancer: DeLLphi-305 phase 3 trial. J Thorac Oncol 2024; 19(10_Suppl): S206–S207.

52.

Wermke

Felip

Kuboki

, et al. First-in-human dose-escalation trial of BI 764532, a delta-like ligand 3 (DLL3)/CD3 IgG like T-cell engager in patients (pts) with DLL3-positive (DLL3+) small-cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC). J Clin Oncol 2023; 41(16_Suppl); 8502.

53.

Beltran

Johnson

Jain

, et al. Updated results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager in patients (pts) with small cell lung cancer (SCLC) and other neuroendocrine cancers (NEC). J Clin Oncol 2024; 42(16_Suppl): 8090.

54.

Zhang

Wang

, et al. Orchestrating smart therapeutics to achieve optimal treatment in small cell lung cancer: recent progress and future directions. J Transl Med 2023; 21(1): 468.

55.

Krebs

Delord

Jeffry Evans

, et al. Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): an open-label, multicenter, phase 1/2, basket study. Lung Cancer 2023; 180: 107216.

56.

Huang

Jia

Wang

, et al. Phase II study of durvalumab plus olaparib as maintenance therapy in extensive-stage small-cell lung cancer (TRIDENT): preliminary efficacy and safety results. J Clin Oncol 2023; 41(16_Suppl): 8518.

57.

Owonikoko

Dahlberg

Sica

, et al. Randomized phase II trial of cisplatin and etoposide in combination with veliparib or placebo for extensive-stage small-cell lung cancer: ECOG-ACRIN 2511 study. J Clin Oncol 2019; 37(3): 222–229.

58.

Lallo

Frese

Morrow

, et al. The combination of the PARP inhibitor olaparib and the WEE1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer. Clin Cancer Res 2018; 24(20): 5153–5164.

59.

Doerr

George

Schmitt

, et al. Targeting a non-oncogene addiction to the ATR/CHK1 axis for the treatment of small cell lung cancer. Sci Rep 2017; 7(1): 15511.

60.

Park

Mortimer

Simon

, et al. The clinical efficacy of olaparib monotherapy and combination with ceralasertib (AZD6738) in relapsed small cell lung cancer. J Clin Oncol 2021; 39(15_Suppl): 8562.

61.

Lee

Kim

Park

, et al. A phase II, open-label, combination therapy of durvalumab and ceralasertib in relapsed and refractory small cell lung cancer (SUKSES-N4). J Clin Oncol 2024; 42(16_Suppl): 8104.

62.

Zhao

Kim

Kallakury

, et al. Acquired small cell lung cancer resistance to Chk1 inhibitors involves Wee1 up-regulation. Mol Oncol 2021; 15(4): 1130–1145.

63.

Rudin

Liu

Soo

, et al. SKYSCRAPER-02: tiragolumab in combination with atezolizumab plus chemotherapy in untreated extensive-stage small-cell lung cancer. J Clin Oncol 2024; 42(3): 324–335.

64.

Sands

Reck

Navarro

, et al. KeyVibe-008: randomized, phase 3 study of first-line vibostolimab plus pembrolizumab plus etoposide/platinum versus atezolizumab plus EP in extensive stage small cell lung cancer. J Clin Oncol 2022; 40(16_Suppl): TPS8606.

65.

Desai

Takahashi

Lissa

, et al. Tazemetostat in combination with topotecan and pembrolizumab in patients with recurrent small cell lung cancer. J Clin Oncol 2024; 42(16_Suppl): TPS8130.

66.

Schmitz

Zhang

Pannucci

, et al. Abstract 606: the PLK1 inhibitor, onvansertib, synergizes with paclitaxel in small cell lung cancer. Cancer Res 2024; 84(6_Suppl): 606.

67.

Byers

Heymach

Gibbons

, et al. 697 A phase 1 study of AMG 119, a DLL3-targeting, chimeric antigen receptor (CAR) T cell therapy, in relapsed/refractory small cell lung cancer (SCLC). 37th Annual Meeting of the Society for Immunotherapy of Cancer. Regular and Young Investigator Award Abstracts. J Immunother Cancer 2022; 10(Suppl_2): A1–A1603.

68.

Sands

Schoenfeld

Schwarzenberger

, et al. 702 Phase 1 study of DLL3-directed chimeric antigen receptor T-cells in subjects with extensive stage small cell lung cancer. 2023 SITC abstract 702. J Immunother Cancer 2023; 11(Suppl_1): 797.

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

0.03 MB