A look forward: Targeted immuno-oncology in ES-SCLC treatment

By Naveed Saleh, MD, MS | Medically reviewed by Jeffrey A. Bubis, DO, FACOI, FACP
Published April 8, 2024

Key Takeaways

  • When treating small cell lung cancer (SCLC), targeting DLL3 via tarlatamab may improve overall survival and progression-free survival.

  • Attempts to target DLL3 with rovalpituzumab tesirine (Rova-T) have mostly fallen flat.

  • SEZ6 and enhanced GD2 strategies have shown promise in early stage research.

Recently, the addition of immunotherapy to chemotherapy regimens has demonstrated increased survival in patients with ES-SCLC, and immunotherapy plus chemotherapy is now standard of care. 

Let’s take a closer look at the future of this groundbreaking care for patients with this form of advanced lung cancer.

Related: Mastering toxicity in ES-SCLC: A case study with Dr. Jared Weiss


Tarlatamab (AMG 757) is a half-life extended, bispecific T-cell connector that targets CD3 and delta-like ligand 3 (DLL3). DLL3 is an atypical Notch ligand that is overexpressed in most forms of SCLC tumors but is not present in normal adult tissues.  

Tarlatamab functions independently of MHC-I expression to trigger immune responses, resulting in T-cell mediated tumor lysis, according to authors of a review in Frontiers in Oncology.[]  

Interim dose-exploration data from a phase 1 study in relapsed SCLC (NCT03319940) demonstrated preliminary evidence supporting the efficacy of tarlatamab, along with an acceptable safety profile.[]

In the dose-exploration and expansion cohorts (n=102; median age: 63 years; ECOG PS was 0-1 in 99%; median prior lines were 2.0; median treatment duration was 9.3 weeks), tarlatamab (0.003-100.0 mg) was given every 2 weeks with or without step dosing in SCLC patients who progressed after one or more platinum-based regimens.

Overall confirmed and unconfirmed ORR was 24.0%, whereas confirmed responses occurred in 18.8% of patients, including 2 complete responses and 16 partial responses. The median time to response was 1.79 months, and the median duration of response was 12.30 months. The median PFS was 3.5 months, and the median OS was 12.3 months.

Treatment-related AEs (TRAEs) of any grade occurred in 91.2% of patients; grade ≥ 3, 31.4%; grade ≥ 4, 7.8%; grade 5, 1.0%.

Investigators concluded, “Tarlatamab has an expected and manageable safety profile and delivers promising efficacy with excellent response durability amongst confirmed responders in this heavily pretreated SCLC population. The PFS/OS compares well to other therapies currently available for relapsed SCLC. A phase 2 study of tarlatamab in 3L+ SCLC (NCT05060016) is enrolling based on these results.”

As noted by the Frontiers in Oncology authors, a phase 1b trial is evaluating the efficacy and safety of atezolizumab and chemotherapy plus tarlatamab in treatment-naive ES-SCLC.


Clinical outcomes involving treatment with rovalpituzumab tesirine (Rova-T) have been disappointing, write researchers in the Journal of Thoracic Oncology.[] This has been the conclusion despite an initial fervor revolving around Rova-T monotherapy in early phase 1 trials in SCLC.

Rova-T is an antibody-drug conjugate that consists of a DLL3-targeting antibody bound to a cytotoxic agent pyrrolobenzodiazepine via a protease-cleavable linker. In the TAHOE trial, investigators examined the efficacy and safety of Rova-T vs topotecan as second-line (2L) therapy in patients with SCLC expressing high levels of DLL3; results were published in Journal of Thoracic Oncology.[]

In this RCT, Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles to 296 patients; two additional cycles were offered to patients who met protocol-defined criteria for continued dosing. Topotecan was administered to 148 patients. The median age of the patients was 64 years, and 77% had extensive disease at initial diagnosis.

The median OS was 6.3 months in patients receiving Rova-T vs 8.6 months in patients receiving topotecan (HR=1.46).

“Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC,” the authors wrote. 

"A considerable unmet therapeutic need remains in this population."

Authors, Journal of Thoracic Oncology

The use of Rova-T with immune checkpoint inhibitors, however, has shown evidence of efficacy. An open-label, phase 1/2 study assessed the safety and efficacy of Rova-T plus the immune checkpoint inhibitor nivolumab with or without ipilimumab in 42 patients with previously treated ES-SCLC.[] Antitumor activity was observed, albeit at the risk of an increase in treatment-emergent adverse events.

Related: Research insights: Managing neurologic events in ES-SCLC

Cohort 1 was administered 0.3 mg/kg Rova-T (every 6 weeks for two cycles) plus 360 mg nivolumab (two, 3-week cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1, along with 1 mg/kg nivolumab (four 3-week cycles) and 1 mg/kg ipilimumab (commencing week 4). Starting at week 10, both cohorts received 480 mg nivolumab every 4 weeks. The ORR was 30% (cohort 1, 27.6%; cohort 2, 36.4%). All responses were partial.

GD2 strategies

Disialoganglioside (GD2) is highly expressed on SCLC tumor cells and might be a good target for chimeric antigen receptor T cells (CART), according to an article in Cancer Research Communications.[]

Although GD2-directed CARTs (GD2-CART) kill various GD2-expressing tumors, they exhibit limited toxicity vs SCLC. This could change with recent innovations.

Researchers recently introduced GD2-CAR into induced pluripotent stem cells (iPSC)-derived rejuvenated cytotoxic T lymphocytes (GD2-CARrejT). GD2-CARrejTs are more aggressive against SCLC cells compared with GD2-CARTs.

Research has shown that dual blockade of TIGIT and programmed death-1 (PD-1) magnified the cytotoxicity of GD2-CARTs to a variable degree. This indicates that low TIGIT and PD-1 expression by GD2-CARrejTs is an integral factor for robust cytotoxicity against SCLC.

"Not only for robust cytotoxicity but also for availability as ‘off-the-shelf’ T-cell therapy, iPSC-derived GD2-CARrejTs are a promising novel treatment for SCLC."

Authors, Cancer Research Communications

Related: Advances in 2L treatment for ES-SCLC: Navigating the options


Seizure-related homolog protein 6 (SEZ6) is a transmembrane protein expressed in SCLC tumors that has shown promise in treating SCLC. ABBV-011 is an antibody-drug conjugate that takes aim at SEZ6 by leveraging a calicheamicin payload. This strategy has demonstrated antitumor activity in preclinical models of SCLC.[] 

Preliminary results involving monotherapy dose-escalation and dose-expansion cohorts of the first-in-human ABBV-011 study also demonstrated antitumor activities of this agent.

In this phase 1, open-center, multilabel trial (n=99), the maximum tolerated dose was not met, and the drug was well-tolerated at 1.0 mg/kg.

The confirmed ORR was 25%, with 10 partial responses. The median duration of response was 4.2 months. Median PFS was 3.5 months. The clinical benefit rate was 65% (10 partial responses; 16 stable disease).

What this means for you

Immunotherapy combined with chemotherapy has become the standard treatment for ES-SCLC. Though still in early trial stages, novel immunotherapy approaches will potentially improve the treatment landscape of ES-SCLC, targeting GD2, SEZ6, and DLL3.

Read Next: Palliation of dyspnea in ES-SCLC: Identifying etiology and targeted treatment
Share with emailShare to FacebookShare to LinkedInShare to Twitter