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.

 

 

Tarlatamab

 

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.  

 

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.

Borghaei H, Paz-Ares L, Johnson M, et al. OA12.05 phase 1 updated exploration and first expansion data for DLL3-targeted T-cell engager tarlatamab in small cell lung cancer. J Thorac Oncol. 2022;17(9 suppl S33).

 

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.

 

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.

 

Rova-T

 

 

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.

Blackhall F, Jao K, Greillier L, 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.

 

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.

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.

Malhotra J, Nikolinakos P, Leal T, 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.

Antitumor activity was observed, albeit at the risk of an increase in treatment-emergent adverse events.

 

 

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.

Kinoshita S, Ishii M, Ando J, et al. Rejuvenated iPSC-derived GD2-directed CART cells harbor robust cytotoxicity against small cell lung cancer. Cancer Res Commun. 2024;4(3):723–737.

 

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.

 

 

SEZ6

 

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.

Morgensztern D, Ready NE, Johnson ML, 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 cancer [Abstract 3002]. J Clin Oncol. 2023;41(16 suppl).

 

 

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).