TARLATAMAB-DLLE

A new clinical trial partnership between Boehringer Ingelheim and BioNTech is looking to test two complementary immunotherapeutic mechanisms for patients battling one of the hardest-to-treat lung cancers.The collaboration pairs Boehringer's DLL3-targeting T‑cell engager obrixtamig with pumitamig, a PD‑L1/VEGF bispecific antibody co-developed by BioNTech and Bristol Myers Squibb, and will test the dual strategy in extensive-stage small-cell lung cancer (ES-SCLC). The Phase Ib/II trial will begin dosing patients in the second half."By uniting T-cell redirection against DLL3 with PD-L1 and VEGF pathway modulation, we aim to address two central barriers in SCLC – immune evasion and an immunosuppressive, pro-angiogenic microenvironment," said Itziar Canamasas, Boehringer's global head of oncology, said in a release Thursday.SCLC, which accounts for roughly 15% to 20% of lung cancers, is notorious for its aggressive growth, early metastasis and high relapse rates. Even with the advent of immune checkpoint inhibitors combined with chemotherapy, most patients progress within months and prognosis remains poor.Beyond ImdelltraThe only DLL3-targeting drug approved so far is Amgen's T-cell engager Imdelltra (tarlatamab-dlle). It was granted full FDA approval in November for ES-SCLC patients who have progressed on or after platinum-based chemotherapy based on data showing a 40% reduction in risk of death compared to chemotherapy in the Phase III DeLLphi-304 trial.The target has also drawn interest from AbbVie, which bet up to $1.2 billion recently for ex-China rights to ZG006 (alveltamig), a T-cell engager that binds two distinct DLL3 epitopes on tumour cells. That programme is advancing through several trials, including a Phase III study in relapsed SCLC.Boehringer says obrixtamig yielded promising early data when combined with chemotherapy and Roche's PD-L1 inhibitor Tecentriq (atezolizumab). In the Phase I DAREON 8 study, the triplet achieved a 68% objective response rate and disease control in 89% of patients, alongside a 52% rate of progression-free survival (PFS) at nine months. That combination is going to be tested in the Phase III DAREON-Lung-1 study, which will enroll around 670 advanced SCLC patients and is set to begin this week.PD L1/VEGF readoutsMeanwhile, two mid-stage readouts have hinted at pumitamig's potential in ES-SCLC. One showed a 76.3% confirmed response rate, 100% disease control, and PFS of 6.8 months, while a separate study conducted in China produced results that were broadly similar.The programme has advanced to the Phase III ROSETTA LUNG‑01 study that got under way last year in patients with untreated SCLC.PD‑L1/VEGF antibody candidates have attracted lots of attention, with much of it focused on Summit Therapeutics' ivonescimab, which is currently up for review at the FDA for EGFR-mutated non–small-cell lung cancer; a decision slated for later this year. The drug is also being investigated in Phase II for frontline ES-SCLC and in the Phase III HARMONi-9 trial in limited-stage SCLC.

Sweden-based biopharma Immedica revealed that lurbinectedin (Zepzelca) combined with atezolizumab has received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) as first-line maintenance therapy for extensive-stage small cell lung cancer, moving the combination closer to becoming the first approved regimen to improve survival beyond checkpoint inhibitor monotherapy in this setting. The opinion is based on data from the Phase III IMforte trial, a randomized, open-label study enrolling adults with ES-SCLC whose disease had not progressed following four cycles of induction therapy with atezolizumab, carboplatin, and etoposide. In IMforte, the lurbinectedin-atezolizumab combination reduced the risk of disease progression or death by 46% and the risk of death by 27% compared with atezolizumab maintenance alone. Measured from the point of randomization, median overall survival was 13.2 months versus 10.6 months (HR 0.73; 95% CI: 0.57–0.95; p=0.0174), and median progression-free survival by independent assessment was 5.4 months versus 2.1 months (HR 0.54; 95% CI: 0.43–0.67; p<0.0001). The data were presented at the 2025 ASCO annual meeting and published simultaneously in The Lancet. Safety was consistent with the known profiles of both agents. The CHMP opinion now passes to the European Commission for a final marketing authorization decision covering the EU. Before the FDA approved lurbinectedin plus atezolizumab in October 2025, the maintenance phase of ES-SCLC treatment was defined by continuation of a single checkpoint inhibitor — Roche’s PD-L1 target datezolizumab (Tecentriq) following the IMpower133 regimen, or AstraZeneca’s PD-L1 durvalumab (Imfinzi) following the CASPIAN regimen. Both approaches offered modest survival benefit over chemotherapy alone but left the maintenance window largely unchallenged. The IMforte control arm, with a median PFS of 2.1 months on atezolizumab alone, illustrates how quickly patients progressed even after responding to induction. Lurbinectedin is a marine-derived small molecule that inhibits RNA polymerase II-dependent transcription, suppressing oncogenic transcription programs in tumor cells and, according to PharmaMar’s characterization, also downregulating cytokine production in tumor-associated macrophages. The mechanistic rationale for pairing it with a PD-L1 inhibitor rests on the premise that transcription inhibition and immune checkpoint blockade address distinct and potentially complementary tumor escape mechanisms. Whether this dual targeting accounts for the observed survival benefit, or whether the cytotoxic activity of lurbinectedin is the primary driver, is not established from the press release data alone. The survival gain — approximately 2.6 months in median OS and 3.3 months in median PFS — is statistically significant and consistent across both endpoints, which strengthens the signal. The OS hazard ratio of 0.73, however, sits at the wider end of what oncologists typically consider a practice-defining benefit in a maintenance setting, and the confidence interval (0.57–0.95) approaches 1.0. The PFS benefit is more pronounced (HR 0.54), but PFS improvements in SCLC have not always translated proportionally to OS gains, and the absolute OS difference here is modest. The competitive framing is also shifting. Tarlatamab, a DLL3×CD3 T-cell engager developed by Amgen, is in Phase III evaluation in relapsed SCLC benchmarked against standard-of-care chemotherapy options that include lurbinectedin. That program operates in a different line of therapy and uses a mechanistically distinct approach — immune redirection rather than transcription inhibition — but it signals that the SCLC treatment landscape is being contested across multiple modalities simultaneously. Cross-trial comparisons are limited by differences in patient populations, lines of therapy, and trial design, and no head-to-head data exist between these approaches in any shared setting. For Immedica, the CHMP opinion covers its distribution territories in the Nordics, UK and Ireland, Central and Eastern Europe, and the Middle East and North Africa, under a partnership with PharmaMar, which originated the compound. Jazz Pharmaceuticals holds US rights and sponsored the FDA approval. The commercial structure means that the EU authorization, once granted by the European Commission, will be executed across multiple regional partners rather than a single entity — a distribution model that may affect how quickly the combination reaches patients in different healthcare systems. The content above comes from the network. if any infringement, please contact us to modify.