Small Cell Lung Cancer: New Drugs on the Horizon! Tarlatamab and Ceralasertib
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Why Is It Difficult, and Why Now?
Because of rapid proliferation and early spread, extensive-stage small cell lung cancer (ES-SCLC) is a disease that progresses rapidly and relapses early . The current standard, adding a PD-L1 inhibitor to platinum–etoposide chemotherapy, provides only ~2–2.5 months of modest improvement in median overall survival (OS) over chemotherapy alone. This clearly highlights the need for new first-line strategies producing deeper, more durable responses. ESMO 2025presented two studies potentially addressing this gap: tarlatamab in a triplet combination and ceralasertib + durvalumab maintenance.
Tarlatamab + Chemotherapy + PD-L1: An Early Signal of Deep Responses
DeLLphi-303 (phase Ib, open-label) evaluated the efficacy and safety, in extensive-stage small cell lung cancer (ES-SCLC), of first-line tarlatamab + platinum–etoposide + a PD-L1 inhibitor . Patients subsequently continued in maintenance with tarlatamab + a PD-L1 inhibitor (n=96). This approach attracted attention for its high early response rate and potential for lasting disease control.
Abstract
The main aim was to determine the tarlatamab combination’s safety profileand characterize tolerability within the dose-limiting toxicity (DLT) window. Secondary objectives included efficacy measures such as objective response rate (ORR), progression-free survival (PFS) and duration of response (DOR) as clinical outcomes.
- ORR: 71%
- Median PFS: 10.3 months
- Median DOR: 11.0 months
- 12-month OS: 81%; median OS: not yet reached
Presentation Details
Presentation: Abstract 2757O — “Tarlatamab with first-line chemoimmunotherapy for extensive-stage small-cell lung cancer (ES-SCLC): DeLLphi-303 study”
Presenter: Prof. Dr. Martin Wermke (University Hospital Carl Gustav Carus, Dresden, Germany)
Congress: ESMO Congress 2025, Berlin (October 17–21, 2025)
Ceralasertib + Durvalumab Maintenance: Encouraging Survival Curves
After platinum-based chemoimmunotherapy without progression, extensive-stage small cell lung cancer (ES-SCLC) patients entered a phase II multicenter study (n=30) evaluating maintenance with ceralasertib (ATR inhibitor) + durvalumab . The aim was to maintain the response achieved after chemotherapy and strengthen long-term disease control.
Abstract
In this phase II study, after completing platinum-based chemoimmunotherapy, patients were randomly assigned to durvalumab + ceralasertib maintenance with follow-up. The primary endpoint was objective response rate (ORR) ; secondary endpoints included progression-free survival (PFS), duration of response (DOR) and overall survival (OS) as outcomes.
- ORR: 73.3% (complete responses: 2 patients)
- Median PFS: 6.1 months
- Median DOR: 6.6 months
- 12-month OS: 68% | 24-month OS: 59%
Presentation Details
Presentation: Abstract 2761O — “Chemo-immunotherapy followed by durvalumab and ceralasertib in treatment-naïve patients with extensive-stage small-cell lung cancer”
Presenter: Dr. Muhammad Furqan (University of Iowa, US)
Congress: ESMO Congress 2025, Berlin (October 17–21, 2025)
Comparing Two Maintenance Approaches
Both studies involved patients with extensive-stage small cell lung cancer without progression after platinum-based chemoimmunotherapy (ES-SCLC). However, agents, mechanistic targets, sample sizes, and survival outcomes differ substantially.
| Parameter | DeLLphi-303 (Tarlatamab + PD-L1) | Durvalumab + Ceralasertib (ATRi) |
|---|---|---|
| Treatment Phase | Maintenance after 1L chemoimmunotherapy | Maintenance after 1L chemoimmunotherapy |
| Treatment Combination | Tarlatamab (DLL3 BiTE) + PD-L1 inhibitor (Atezolizumab / Durvalumab) | Durvalumab (PD-L1) + Ceralasertib (ATR inhibitor) |
| Sample (n) | 88 patients (Atezolizumab arm n=48, Durvalumab arm n=40) | 30 patients |
| Primary Endpoint | Dose-limiting toxicity (DLT), safety, and tolerability | Objective response rate (ORR) |
| Secondary Endpoints | PFS, OS, ORR, DOR, immune biomarker correlations | PFS, DOR, OS, safety |
| ORR | 71% | 73.3% (2 complete responses) |
| Median PFS | 10.3 months | 6.1 months |
| 12 / 24-month OS | 81% / — (mOS not reached) | 68% / 59% |
| Grade ≥3 TRAEs | 78%; treatment discontinuation 6% | 23.3% treatment-related; total SAEs 46.7% |
| Key Toxicities | CRS (% low-to-moderate grade), ICANS (% rare), fatigue | Anemia, leukopenia, gastrointestinal problems |
| Mechanism / Rationale | DLL3-targeted T-cell engagement → immune effector activation | ATR inhibition → increased DNA damage and immunogenicity |
| Presenter | Prof. Dr. Martin Wermke (Germany) | Dr. Muhammad Furqan (US) |
| Overall Clinical Impact | High early response, well-managed toxicity → an ‘immune reactivation’ strategy | Sustained long-term OS signal → a ‘sensitization through DNA repair suppression’ strategy |
DROZDOGAN Academy Commentary
- Early deep response + maintenance rationale: High ORR with T-cell engagers such as tarlatamab supports early tumor-burden reduction and continued immune surveillance through PD-L1 maintenance.
- Targeting the DNA damage response: Ceralasertib, an ATR inhibitor, combined with immunotherapy offers potential for increasing tumor immunogenicity ; 12–24-month OS rates are promising.
- Patient selection is critical: Broad expression of tarlatamab’s target may provide a rare ES-SCLC biomarker-like anchor. Nevertheless, CRS/ICANS management and center experience determine success.
- Steps needed: Randomized phase II/III multiarm designs (e.g., biomarker-directed arms) should include early intermediate endpoints (PFS2, treatment-specific OS) and quality-of-life measurements as support.
- Impact on practice today: These data are hypothesis-generating; referral to clinical trials and encouraging eligible patients’ trial participation are the most appropriate steps.
- Looking ahead: Current findings strengthen the prospect of including tarlatamab in first-line combinations . This could change the ES-SCLC treatment paradigm.
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