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

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 tumours but is not present in normal adult tissues.  

In May, the United States Food and Drug Administration (FDA) granted accelerated approval to tarlatamab-dlle after a phase 2 DeLLphi-301 study (NCT05060016) assessed the antitumor activity and safety of two different doses of tarlatamab in patients with relapsed ES-SCLC who had previously been treated with two or more lines of therapy.

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).

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.

 

Overall, 220 patients received tarlatamab. They received a step dose of 1 mg of tarlatamab on day 1 of cycle 1, after which they were administered a target dose of either 10 mg or 100 mg on days 8 and 15 of cycle 1 and then every 2 weeks thereafter in 28-day cycles until disease progression occurred.

Among patients assessed for antitumor activity and survival, median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% of the patients in the 10-mg group and in 32% of patients in the 100-mg group. Among those with an objective response, the duration of response was at least 6 months in 59% (40 out of 68 patients). Objective responses were ongoing at the time of data cutoff in 55% (22 out of 40 patients) in the 10-mg group and in 57% (16 out of 28 patients) in the 100-mg group.

In the 10-mg group, the median progression-free survival was 4.9 months; in the 100-mg group, it was 3.9 months. Overall survival estimates at 9 months were 68% and 66% of patients, respectively.

The most common treatment-related AEs (TRAEs) were cytokine-release syndrome, which occurred in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group. Other TRAEs included decreased appetite (in 29% and 44% of patients, respectively) and pyrexia (in 35% and 33% of patients, respectively). Only 3% of patients discontinued tarlatamab because of TRAEs.

Note: This trial only included ECOG 0 and 1 patient. 

 

Rova-T

 

Clinical outcomes involving treatment with rovalpituzumab tesirine (Rova-T) have been disappointing, wrote researchers in the 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.

This has been the conclusion despite an initial fervour 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 the 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).

"A considerable unmet therapeutic need remains in this population." — Authors, 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.

 

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, although all patients experienced one or more treatment-emergent adverse events.

 

Cohort 1 was administered 0.3 mg/kg Rova-T every 6 weeks for two cycles, plus 360 mg of IV-administered 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 of 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 tumour cells and is considered 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.

 

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 than 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

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.

 

 

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).

 

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 by 40 patients 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 and 16 stable disease).