Tarlatamab Maintenance Combo Extends Survival in Extensive-Stage SCLC

First-line maintenance therapy with tarlatamab-dlle (Imdelltra) plus durvalumab (Imfinzi) significantly prolonged overall survival (OS) and progression-free survival (PFS) compared with durvalumab alone in patients with extensive-stage small cell lung cancer (ES-SCLC) who had not progressed after initial chemoimmunotherapy, according to results from the phase 3 DeLLphi-305 trial (NCT06211036) presented at the 2026 European Society for Medical Oncology (ESMO) Congress and simultaneously published in The New England Journal of Medicine.^1,2

What were the survival outcomes?

At a median follow-up of 15.9 months, the estimated median OS was 21.1 months (95% CI, 20.8-not estimable [NE]) with tarlatamab plus durvalumab vs 12.7 months (95% CI, 11.2-14.8) with durvalumab alone (HR, 0.42; 95% CI, 0.32-0.54; P <.001). The tarlatamab combination reduced the risk of death by 58% vs durvalumab alone, with OS rates of 91.5% and 79.4% at 6 and 12 months, respectively, vs 74.6% and 53.3% with durvalumab.

The median PFS was 7.4 months (95% CI, 5.6-9.1) with tarlatamab plus durvalumab vs 1.9 months (95% CI, 1.9-2.0) with durvalumab alone, corresponding to a 66% reduction in risk of progression or death (HR, 0.34; 95% CI, 0.28-0.42; P <.001). PFS rates with the combination were 53.4% and 38.4% at 6 and 12 months, respectively, vs 17.2% and 9.5% with durvalumab.

“We do this work not to improve everybody’s survival by a few months, but to improve it by years,” said Jacob Sands, MD, of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, in his presentation. “From this data, we see at the 1-year time point, 38% of patients are progression free in the tarlatamab plus durvalumab arm, compared with the 10% in the durvalumab arm.”

The OS benefit was consistent across all prespecified subgroups, including patients with brain or liver metastases and those with only stable disease after initial therapy. Similar subgroup benefits were observed with the combination in terms of PFS.

What was the objective response and durability?

Among patients with measurable disease at randomization, a confirmed objective response occurred in 26.4% (95% CI, 20.9%-32.5%) of the tarlatamab/durvalumab group vs 4.1% (95% CI, 2.0%-7.4%) of the durvalumab group (risk ratio, 6.4; 95% CI, 3.4-12.2; P <.001). The median duration of response was 12.7 months (95% CI, 7.4-NE) vs 5.6 months (95% CI, 3.6-NE), and 51.8% of responders in the combination group maintained their response at 12 months vs none in the durvalumab group. As of the data cutoff, 43.6% of patients in the tarlatamab/durvalumab group remained on treatment vs 11.4% in the durvalumab group.

Sands noted that, as with other immunotherapies, some progression events reflected oligoprogression that could be locally treated while patients continued to benefit from therapy. He added that the OS data remain immature. “The median follow-up is about 16 months, so this is not the final median [OS]. Please stay tuned as data matures,” he said.

What was the safety profile?

Grade 3 or higher adverse events (AEs) occurred in 46.8% of patients receiving tarlatamab plus durvalumab vs 40.6% of those receiving durvalumab alone, and serious AEs occurred in 41.8% vs 31.7%. Fatal events were balanced between the groups (4.6% vs 4.7%), with no treatment-related fatalities in the combination arm, and AEs led to tarlatamab discontinuation in 5.7% of patients. Cytokine release syndrome (CRS) occurred in 49.6% of the combination group vs 1.4% of the durvalumab group and was predominantly grade 1 (41.8%) or grade 2 (7.4%), with a single grade 3 event (0.4%) and no grade 4 or fatal events; the median time to onset was 22.5 hours, and most events resolved with supportive care, including glucocorticoids (21.6%), tocilizumab (Actemra; 3.9%), and low-flow oxygen (1.4%). Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 1.1% of patients, with no grade 3 or higher events.

What is the trial design, and what are the implications?

DeLLphi-305 is a phase 3, international, open-label, randomized trial that enrolled 563 patients with ES-SCLC who had not progressed after an initial 4 cycles of platinum-etoposide, at least 3 of which were concurrent with durvalumab, across 175 sites in 29 countries. Patients were randomly assigned 1:1 to tarlatamab at 10 mg every 2 weeks, following step-up dosing plus durvalumab at 1500 mg every 4 weeks (n = 282) or durvalumab alone (n = 281), and patients with asymptomatic treated or untreated brain metastases were eligible.

The primary end point was OS; the key secondary end point was PFS, followed by objective response, tested in a prespecified hierarchy. Additional secondary end points included duration of response, patient-reported outcomes, and safety. The results reflect a prespecified interim analysis (data cutoff, July 7, 2026).

“DeLLphi-305 has demonstrated unprecedented outcomes in both median [OS] and median [PFS], along with durability for a substantial subset of patients, all with a toxicity profile that appears manageable,” Sands said, concluding that the findings support tarlatamab plus durvalumab as “a new standard of care in the treatment of [ES-SCLC].”

References

1. Sands J, Yoshida T, Ahn MJ, et al. Tarlatamab plus durvalumab vs durvalumab as first-line maintenance therapy following first-line durvalumab, platinum, and etoposide in extensive-stage small cell lung cancer: primary analysis of the phase 3 DeLLphi-305 trial. Presented at: European Society for Medical Oncology (ESMO) Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA3.
2. Pérol M, Yoshida T, Ahn MJ, et al. Tarlatamab–durvalumab maintenance for extensive-stage small-cell lung cancer. N Engl J Med. Published online October 24, 2026. doi:10.1056/NEJMoa2609482