Extended-Interval Tarlatamab Yields Comparable Exposure, Survival to Q2W Dose in Previously Treated SCLC

Extended-interval dosing of tarlatamab-dlle (Imdelltra) at 20 mg every 3 weeks (Q3W) or 30 mg every 4 weeks (Q4W) generated efficacy, safety, and pharmacokinetic profiles broadly consistent with the approved 10 mg every-2-week (Q2W) regimen in patients with small cell lung cancer (SCLC) that progressed on or recurred after first-line platinum-based chemotherapy, according to primary analysis data from the randomized phase 2 DeLLphi-309 trial (NCT06745323) presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC) in Seoul this week.¹^,²

At a data cutoff of May 7, 2026, the confirmed objective response rate (ORR) by blinded independent central review (BICR), was as follows for assessed doses:

• 39.8% (95% CI, 29.2 -51.1) with 10 mg Q2W (n = 83)
• 31.0% (95% CI, 21.3%-42.0%) with 20 mg Q3W (n = 84)
• 27.1% (95% CI, 18.0%-37.8%) with 30 mg Q4W (n = 85)

Descriptive odds ratios versus the Q2W arm were 0.68 (95% CI, 0.36-1.29) for Q3W and 0.56 (95% CI, 0.30-1.08) for Q4W. Investigator-assessed ORRs were 36.1%, 36.9%, and 30.6%, respectively. Analyses were descriptive, and no hypotheses were formally tested.¹

"These data suggest that the tarlatamab 20 mg every-three-week and 30 mg every-four-week regimens may offer treatment flexibility for patients with SCLC and that alternative dosing schedules for bispecific T-cell engagers may achieve outcomes consistent with an established regimen," lead study author Jonathan Goldman, MD, of UCLA Health, said in a release accompanying the new data.²

Rationale for DeLLphi-309

Tarlatamab is a DLL3-directed bispecific T-cell engager (BiTE). At 10 mg intravenously Q2W, the agent improved overall survival (OS) vs chemotherapy in the second-line SCLC setting in the phase 3 DeLLphi-304 trial, with a median OS of 13.6 months vs 8.3 months.¹

Investigators noted that less frequent dosing could enhance treatment flexibility, including for combination with chemoimmunotherapy — as is being explored in the phase 1b DeLLphi-303 and phase 3 DeLLphi-312 trials.

Route optimization is being assessed in parallel. Data from the phase 1B DeLLphi-308 trial (NCT06598306) presented at WCLC 2026 reported that 15 mg subcutaneous tarlatamab every 2 weeks achieved exposures comparable to the approved intravenous dose, with a 30% ORR and predominantly grade 1 cytokine release syndrome (CRS) in 60 patients with previously treated extensive-stage SCLC.³

In the first-line maintenance setting, tarlatamab plus durvalumab (Imfinzi) improved OS and progression-free survival (PFS) versus durvalumab alone in topline phase 3 results announced earlier this month.⁴

DeLLphi-309 Trial Design

The open-label trial enrolled adults with SCLC that progressed on or recurred after first-line platinum-based chemotherapy and an ECOG performance status of 0 or 1. Where first-line standard of care includes a PD-(L)1 inhibitor, patients must have failed or been ineligible for that therapy.¹

Patients (n = 252) were randomly assigned 1:1:1 to intravenous (IV) tarlatamab at 10 mg Q2W, 20 mg Q3W, or 30 mg Q4W, each following a 1 mg step dose on day 1. Randomization was stratified by first-line platinum sensitivity (≥90 days vs <90 days). Patients in the Q2W arm were monitored for 1 - 2 hours after the first 2 doses; those in the extended-interval arms were monitored for 6 - 8 hours after the first 3 doses.

The primary end point was confirmed ORR by BICR. Secondary end points included investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), PFS, OS, pharmacokinetics, and safety outcomes.

Median patient ages were 64, 63, and 67 years in the Q2W, Q3W, and Q4W arms, respectively, and brain metastases were present in 49%, 55%, and 47% of each arm. The Q4W arm had a numerically higher proportion of patients with an ECOG performance status of 1 (64% vs 57% and 56%), a larger median sum of target-lesion diameters (84 mm vs 70 mm and 69 mm), and a higher rate of liver metastases (46% vs 40% and 32%).

Additional Efficacy and Pharmacokinetic Data Reported

Complete responses by BICR occurred in 4.8% of patients in each of the Q2W and Q3W arms and none in the Q4W arm; DCR was 60.2%, 70.2%, and 56.5%, respectively. Median DOR was 8.3 months (95% CI, 5.6 - not estimable [NE]) with Q2W, 5.6 months (95% CI, 4.1 - NE) with Q3W, and NE (95% CI, 4.2 - NE) with Q4W.

Median PFS by BICR was 4.2 months (95% CI, 2.6 - 5.6) with Q2W, 4.1 months (95% CI, 2.8 - 4.7) with Q3W (HR, 1.03; 95% CI, 0.73 - 1.47), and 2.7 months (95% CI, 1.6-4.2) with Q4W (HR, 1.23; 95% CI, 0.87 - 1.75). At a median follow-up of approximately 9 months, median OS was 11.2 months (95% CI, 9.4 - NE) in the Q2W arm and NE in both extended-interval arms (Q3W HR, 0.59; 95% CI, 0.34-1.03; Q4W HR, 1.03; 95% CI, 0.62 - 1.69). Six-month OS rates were 72%, 85%, and 69%, respectively.

Investigators attributed the numerically lower ORR in the Q4W arm to the baseline imbalance in higher-risk disease characteristics and a higher rate of discontinuation before the first post-baseline scan (12.9% vs 7.2% and 4.8%), noting that DOR and OS were maintained. Geometric mean steady-state trough concentrations were 0.425, 0.406, and 0.383 µg/mL, respectively, indicating substantial overlap in exposure across schedules.

Safety Profile of Extended-Interval Tarlatamab

Treatment-related adverse events (TRAEs) of any grade occurred in 91.6%, 92.9%, and 92.9% of patients in the Q2W, Q3W, and Q4W arms, respectively, and grade ≥3 TRAEs in 27.7%, 20.2%, and 25.9%. Serious TRAEs (27.7% vs 39.3% and 40.0%) and TRAEs leading to discontinuation (1.2% vs 7.1% and 4.7%) were numerically higher with extended-interval dosing. One treatment-related death occurred in the Q4W arm.

Treatment-related CRS occurred in 60.2%, 70.2%, and 64.7% of patients, respectively, and was grade ≥3 in 2.4%, 1.2%, and 2.4%. No CRS events were fatal. Treatment-related immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 6.0%, 6.0%, and 11.8% of patients and was grade 3 or higher in 1.2%, 3.6%, and 1.2%.

One grade 3 ICANS event in the Q4W arm had a fatal outcome; the investigator determined the cause of death was likely cardiac arrhythmia in the setting of metabolic and electrolyte abnormalities.

Investigators concluded that safety was broadly comparable across regimens and that the 20 mg Q3W and 30 mg Q4W schedules may offer treatment flexibility for patients with SCLC.

References

1. Goldman J, Rothschild S, Korantzis I, et al. Tarlatamab extended-interval dosing regimens in patients with SCLC: the randomized phase 2 DeLLphi-309 study. Presented at: International Association for the Study of Lung Cancer 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, Republic of Korea. Abstract OA05.01.
2. Extended-interval tarlatamab dosing shows consistent activity and safety in previously treated small cell lung cancer. News release. International Association for the Study of Lung Cancer. September 12, 2026. Accessed September 12, 2026.
3. Kunzmann K. Subcutaneous Tarlatamab Shows Consistent Tolerability and Preliminary Activity in Previously Treated ES-SCLC. OncLive. Published September 12, 2026. Accessed September 12, 2026. https://www.onclive.com/view/subcutaneous-tarlatamab-safe-active-against-es-sclc-tumors-phase-1b-es-sclc-trial
4. Rosa K. Durvalumab Plus Tarlatamab Boosts Survival as First-Line ES-SCLC Maintenance. OncLive. Published September 8, 2026. Accessed September 12, 2026. https://www.onclive.com/view/durvalumab-plus-tarlatamab-boosts-survival-as-first-line-es-sclc-maintenance