Tarlatamab Plus Durvalumab Cuts Risk of Death by 58% as First-Line Maintenance in ES-SCLC

Adding the bispecific T-cell engager tarlatamab-dlle (Imdelltra; Amgen) to durvalumab (Imfinzi; AstraZeneca) as first-line maintenance therapy extended median overall survival (OS) by more than 8 months in patients with extensive-stage small-cell lung cancer (ES-SCLC), according to interim results of the global phase 3 DeLLphi-305 trial (NCT06211036).

The findings were presented October 24, 2026, during the Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain, and published simultaneously in the New England Journal of Medicine (NEJM).¹⁻³

The combination offered a median OS of 21.1 months, compared with 12 to 13 months typically seen for first-line chemoimmunotherapy, the authors wrote. For patients with ES-SCLC, getting the regimen right in first-line maintenance is critical. “Many patients are unable to proceed to second-line therapy; therefore, improving first-line therapy represents an opportunity to improve outcomes.”¹

Study Design and Demographics

Between June 2024 and September 2025, investigators at 175 sites in 29 countries randomly assigned 563 patients 1:1 to tarlatamab-durvalumab (n = 282) or durvalumab alone (n = 281). Eligible adults had an Eastern Cooperative Oncology Group performance status of 0 or 1 and no progression after 4 cycles of platinum-etoposide, at least 3 given with durvalumab. Patients with asymptomatic treated or untreated brain metastases could participate. OS from randomization was the primary end point; progression-free survival (PFS) was the key secondary end point.¹

Black patients were underrepresented in the study relative to their presence in the overall US population and among those with ES-SCLC; federal data show 8% of those in the US with this type of lung cancer are Black.⁴ Hispanic patients, who account for 2.3% to 3% of patients with ES-SCLC, were underrepresented as well.⁴ The study population in the combination group was 57.8% White (163 patients), 38.7% Asian (109 patients), 1.4% Black (4 patients), and 1.8% other (5 patients). In the durvalumab group, the breakdown was 64.4% White (181 patients), 32.7% Asian (92 patients), 1.4% Black (4 patients), and 1.4% other (4 patients).¹

The authors wrote, “The trial population was broadly consistent with those of contemporary extensive-stage small-cell lung cancer trials and included patients with treated or untreated asymptomatic brain metastases, a clinically important population that often has a poor prognosis.”¹

Trial criteria that limited enrollment based on prior treatments affected who could participate, they noted, explaining, “our trial enrolled only patients without disease progression after initial chemoimmunotherapy, which underscores the need to evaluate tarlatamab earlier in the treatment course.”¹ This is taking place in the ongoing phase 3 DeLLphi-312 trial (NCT07005128).⁵

More reflective of recent trends was DeLLphi-305’s inclusion of never smokers. In the combination arm, 19.1% were current smokers (54 patients), with 9.2% never smokers (26 patients), 71.3% former smokers (201 patients); 1 patient had missing data (0.4%). In the durvalumab arm, 8.5% were never smokers (24 patients), 19.6% were current smokers (55 patients), 71.2% were former smokers (200 patients), with data missing for 2 patients (0.7%).¹

Survival Data

At median follow-up of 15.9 months for the combination and 16.1 months for the durvalumab arm, median OS was 21.1 months (95% CI, 20.8-not estimable) vs 12.7 months (95% CI, 11.2-14.8), for an HR of 0.42 (95% CI, 0.32-0.54; P < .001), which the authors noted crossed the interim efficacy boundary. OS at 12 months was 79.4% vs 53.3%.¹

Median PFS was 7.4 months vs 1.9 months (HR, 0.34; 95% CI, 0.28-0.42; P < .001), and 12-month PFS was 38.4% vs 9.5%. Among patients with measurable disease, the confirmed objective response rate was 26.4% vs 4.1% (risk ratio, 6.4), with median duration of response of 12.7 months vs 5.6 months. Benefits extended across prespecified subgroups, including patients with brain or liver metastases. Patients received the combination for a median of 45.9 weeks vs 8.1 weeks with durvalumab alone.¹

The authors cautioned that the median OS estimate “may evolve with longer follow-up owing to the extent of data censoring before the median.” They also noted that the open-label trial did not use lurbinectedin plus atezolizumab, evaluated in the phase 3 IMforte trial, as a comparator, which limits direct comparison with a more contemporary maintenance regimen.¹^,⁶

Safety

Grade 3 or higher adverse events (AEs) occurred in 46.8% of patients receiving the combination vs 40.6% of those receiving durvalumab, and serious AEs in 41.8% vs 31.7%. Fatal AEs were similar (4.6% vs 4.7%). Cytokine release syndrome (CRS) occurred in 49.6% of tarlatamab-treated patients, mostly grade 1 (41.8%) or grade 2 (7.4%), with 1 grade 3 event and no grade 4 or fatal events; median onset was 22.5 hours after dosing. Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 1.1%, with no grade 3 or higher events. Dysgeusia affected 48.9%. AEs led to tarlatamab discontinuation in 5.7%.¹

Amgen reported that grade 3 or higher treatment-related AEs occurred in 20.9% vs 10.8% of patients.²

“For a disease where durable survival has remained extremely difficult to achieve, the magnitude and consistency of benefit in DeLLphi-305 are striking,” said international coordinating investigator Jacob Sands, MD, of Dana-Farber Cancer Institute. “Importantly, the benefit was seen across clinically relevant groups, including patients with brain metastases.”²^,³

Leora Horn, senior vice president, late development oncology, at AstraZeneca, said, “Imfinzi-based induction therapy followed by maintenance treatment with Imfinzi plus tarlatamab will redefine treatment standards for patients with extensive-stage small cell lung cancer.”³

Current Indication and Administration

Tarlatamab is FDA approved for adults with ES-SCLC with disease progression on or after platinum-based chemotherapy. It received accelerated approval in May 2024, converted to full approval in November 2025 based on the phase 3 DeLLphi-304 trial (NCT05740566).⁷ Updated DeLLphi-304 data at ESMO showed median OS of 13.6 months vs 8.4 months with chemotherapy (HR, 0.62; 95% CI, 0.51–0.76).²

Tarlatamab is given as a 60-minute intravenous infusion: a 1-mg step-up dose on day 1 of cycle 1, then 10 mg on days 8 and 15 and every 2 weeks thereafter. In DeLLphi-305, durvalumab was given at 1500 mg every 4 weeks.¹ The label carries a boxed warning for CRS and neurologic toxicity, including ICANS. In September 2026, the FDA shortened recommended monitoring after the first 2 doses from 22 to 24 hours to 6 to 8 hours.⁸ DeLLphi-305 required just 1 to 2 hours of on-site monitoring after the first 2 doses (6 to 8 hours in Europe).¹

Path to FDA Approval

As of mid-November, Amgen had not announced a regulatory submission for the combination. “We are moving with urgency to share these results with regulatory authorities worldwide,” said Jay Bradner, MD, executive vice president of research and development, artificial intelligence and data at Amgen.² On its third-quarter earnings call, Amgen said it was working to rapidly file worldwide, estimated that a first-line maintenance indication could reach 23,000 US patients, and said the shorter monitoring used in DeLLphi-305 could support outpatient administration.⁹

A statistically significant OS benefit at a prespecified interim analysis, published in a peer-reviewed journal, gives the companies a strong basis for a filing. Questions for regulators may include the open-label design and the trial’s restriction to patients who did not progress after durvalumab-based induction. Meanwhile, the phase 3 DeLLphi-312 trial is testing tarlatamab with durvalumab, carboplatin, and etoposide in untreated ES-SCLC, has completed enrollment.¹^,¹⁰

References

1. Pérol M, Yoshida T, Ahn MJ, et al; DeLLphi-305 Investigators. Tarlatamab–durvalumab maintenance for extensive-stage small-cell lung cancer. N Engl J Med. Published online October 24, 2026. doi:10.1056/NEJMoa2609482
2. Imdelltra in combination with Imfinzi reduced risk of death by an unprecedented 58% in first-line extensive stage small cell lung cancer. News release. Amgen. October 24, 2026. Accessed November 12, 2026. https://www.amgen.com/newsroom/press-releases/2026/10/imdelltra-in-combination-with-imfinzi-reduced-risk-of-death-by-an-unprecedented-58-in-firstline-extensive-stage-small-cell-lung-cancer
3. Imfinzi plus Imdelltra reduced the risk of death by 58% in 1st-line extensive-stage small cell lung cancer in the DeLLphi-305 phase III trial. News release. AstraZeneca. October 24, 2026. Accessed November 12, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/imfinzi-plus-imdelltra-reduced-the-risk-of-death-by-58-pct-in-1st-line-extensive-stage-small-cell-lung-cancer-in-the-dellphi-305-phase-iii-trial.html
4. Tapan U, Furtado VF, Qureshi MM, Everett P, Suzuki K, Mak KS. Racial and other healthcare disparities in patients with extensive-stage SCLC. JTO Clin Res Rep. 2021;2(1):100109. doi:10.1016/j.jtocrr.2020.100109
5. A study comparing tarlatamab, durvalumab, carboplatin, and etoposide versus durvalumab, carboplatin, and etoposide in first-line extensive stage small-cell lung cancer (ES-SCLC) (DeLLphi-312). ClinicalTrials.gov. Updated July 16, 2026. Accessed November 12, 2026. https://clinicaltrials.gov/study/NCT07005128
6. Paz-Ares L, Borghaei H, Liu SV, et al. Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2025;405:2129-2143. doi:10.1016/S0140-6736(25)01011-6
7. FDA grants traditional approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. November 19, 2025. Accessed November 12, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
8. FDA approves reduced monitoring time for first two doses of Imdelltra (tarlatamab-dlle). News release. Amgen. September 14, 2026. Accessed November 12, 2026. https://www.amgen.com/newsroom/press-releases/2026/09/fda-approves-reduced-monitoring-time-for-first-two-doses-of-imdelltra
9. Amgen Inc. (AMGN) Q3 FY2026 earnings call transcript. Yahoo Finance. Accessed November 12, 2026. https://finance.yahoo.com/quote/AMGN/earnings/AMGN-Q3-2026-earnings_call-723944.html
10. Amgen reports third quarter 2026 financial results. News release. Amgen. Accessed November 12, 2026. https://investors.amgen.com/news-releases/news-release-details/amgen-reports-third-quarter-2026-financial-results