DLL3 Emerges as an Actionable Target in Small Cell Lung Cancer

In small cell lung cancer (SCLC), the protein DLL3 is a promising target in the development of emerging therapies. In particular, DLL3-targeted therapies have been integral in antibody-drug conjugates, T-cell engagers, and chimeric antigen receptor T-cell therapies.

During a presentation at the 2025 Immune Cell Effector Therapy Conference, Daniel R. Carrizosa, MD, MS, FACP, discussed current and emerging trials of T-cell engagers in SCLC.¹

About the DeLLphi-300 Trial

The first-in-human phase 1 DeLLphi-300 trial (NCT03319940) demonstrated manageable safety and response durability in patients with relapsed/refractory SCLC.²

Between December 26, 2017, and April 28, 2022, 107 total patients had been treated, 73 of whom were treated in dose exploration cohorts ranging from 0.003 mg to 100 mg intravenously every 2 weeks. Starting from the 3-mg dose cohort, there was a day 1 run-in dose of 1 mg followed by the target dose on day 8, on day 15, and every 2 weeks afterward.

An additional 34 patients received the 100-mg dose in a dose expansion cohort. The patient population had a median of 2 prior lines of therapy (range, 1-6); anti–PD-1/PD-L1 therapy was previously received in 49.5% and prior radiotherapy in 79%.

The primary end point was safety, and secondary end points included pharmacokinetics, pharmacodynamics, objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) and overall survival (OS) rates. The investigators reported an ORR of 23.4% (95% CI, 15.7%-32.5%), and exploratory analysis suggested that patients with increased DLL3 expression could have increased clinical benefit from this treatment. The disease control rate was 51.4% (95% CI, 41.5%-61.2%). Responses were observed with doses as low as 0.3 mg, and higher rates of response were generally seen with doses of 3 mg and above. Tumor shrinkage of at least 30% in target lesions was observed in 39 patients (36.4%).

The median OS was 13.2 months (95% CI, 10.5not evaluable [NE]), and the median PFS was 3.7 months (95% CI, 2.1-5.4). The median time to response was 1.8 months (range, 1.2-7.4), and the median DOR was 12.3 months (95% CI, 6.6-14.9).

About the DeLLphi-301 Trial

In previously treated patients with SCLC, tarlatamab demonstrated a positive risk-benefit profile according to patient-reported outcomes (PROs) in the phase 2 DeLLphi-301 study (NCT05060016).³

In a cohort of 100 PRO-evaluable patients receiving the target dose of 10 mg tarlatamab, the agent demonstrated manageable and sustained tolerability. Clinically meaningful reductions in dyspnea symptom burden (≥ 10-point improvement) were observed, particularly in later treatment cycles. Chest pain and cough symptoms remained stable. Further, the median time to deterioration (TTD) surpassed 6 months for both cough and dyspnea, while TTD for chest pain was not estimable.

Patients were given tarlatamab intravenously every 2 weeks at a dose of 10 mg, which is the regulatory approved dose, or 100 mg until progression or loss of benefit.

Investigators reported that the ORR was 40.0% (97.5% CI, 29.0%-52.0%), the median OS was 14.3 months (95% CI, 10.8NE), and the median PFS was 4.9 months (95% CI, 2.9-6.7).

About the DeLLphi-304 Trial

Second-line treatment with tarlatamab-dlle (Imdelltra) demonstrated statistically significant and clinically meaningful improvements in PFS and OS vs chemotherapy, according to data from the phase 3 DeLLphi-304 trial (NCT05740566).^4,5

At a median follow-up of 11.2 months for patients treated with tarlatamab (n = 254) and 11.7 months for those given chemotherapy (n = 255), tarlatamab led to a median OS of 13.6 months compared with 8.3 months for chemotherapy (HR, 0.60; 95% CI, 0.470.77; 2-sided P <.001).1 In the tarlatamab arm, the 6- and 12-month OS rates were 76% and 53%, respectively. These respective rates were 62% and 37% in the chemotherapy arm.

In the trial, patients were randomly assigned 1:1 to receive tarlatamab or chemotherapy comprising lurbinectedin (n = 47), topotecan (n = 185), or amrubicin (n = 23).

The primary end point was OS, and secondary end points were PFS and PROs. The median DOR was 6.9 months in the tarlatamab arm, compared with 5.5 months in the chemotherapy arm. The respective 6- and 12-month DOR rates were 56% and 41% for tarlatamab, compared with 29% and 13% for chemotherapy.

At data cutoff, response was ongoing in 47% of patients in the experimental group vs 15% of the control group.

Emerging DLL3 Therapies

With a solid group of trials evaluating monotherapy DLL3 therapies, combination therapy trials are also emerging.

For example, the phase 1, first-line DeLLphi-303 trial (NCT05361395) is evaluating the agent in combination with standard of care and the phase 3 DeLLphi-305 trial (NCT06211036) is exploring tarlatamab plus durvalumab vs durvalumab alone in the f irst-line setting.

Although tarlatamab is approved in the second line, “the agent could move into earlier lines of therapy and other SCLC indications,” Carrizosa concluded.

REFERENCES:

1. Carrizosa DR. Developments of T-cell engager therapies in lung cancer: taking a BiTE out of small cell: precision DLL3 therapies. Presented at: 2025 National Immune Cell Effector Therapy (ICE-T) Conference; July 26, 2025; Orlando, FL.

2. Paz-Ares L, Champiat S, Lai WV, 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. doi:10.1200/JCO.22.02823

3. Hummel HD, Ahn MJ, Blackhall F, et al. Patient-reported outcomes for patients with previously treated small cell lung cancer receiving tarlatamab: results from the DeLLphi-301 phase 2 trial. Adv Ther. 2025;42(4):1950-1964. doi:10.1007/s12325-025-03136-4

4. Rudin CM, Mountzios GS, Sun L, et al. Tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): primary analysis of Ph3 DeLLphi-304. J Clin Oncol. 2025;43(suppl 17):LBA8008. doi:10.1200/JCO.2025.43.17_suppl.LBA8008

5. Mountzios G, Sun L, Cho BC, et al. Tarlatamab in small-cell lung cancer after platinum-based chemotherapy. N Engl J Med. 2025;393(4):349-361. doi:10.1056/NEJMoa2502099