What Are the Top Takeaways for Neuroendocrine Carcinoma From 2026 ESMO?

At the 2026 European Society for Medical Oncology (ESMO) Congress, investigators presented results from 3 trials evaluating bispecific antibodies that pair PD-L1 blockade with a second immune or angiogenic target in advanced neuroendocrine carcinoma (NEC), a disease with few effective options after first-line platinum-based chemotherapy.

Two of the presentations focused on opamtistomig (LBL-024), a PD-L1 × 4-1BB bispecific antibody engineered with high affinity for PD-L1 and attenuated 4-1BB binding, intended to localize T-cell activation to the tumor while limiting systemic toxicity. One reported pivotal phase 2b data (NCT05170958) with monotherapy in the third-line or later setting; the other reported updated phase 1b/2 data (NCT06157827) with the agent plus etoposide/platinum chemotherapy in the first line.^1,2 The third presentation reported first results from a phase 2 trial (NCT05879055) evaluating pumitamig (BNT327), a PD-L1 × VEGF-A bispecific antibody, combined with leucovorin, fluorouracil, and irinotecan (FOLFIRI) in the second line.³

Opamtistomig Across Lines of Therapy

LBA57: Opamtistomig (LBL-024) monotherapy in advanced extrapulmonary neuroendocrine carcinoma (EP-NEC) after ≥2 prior lines of therapy: results from a pivotal, registrational phase IIb study of a novel PD-L1×4-1BB bispecific antibody

In the pivotal phase 2b portion of the LBL-024-CN001 study, opamtistomig monotherapy produced an independent review committee (IRC)–assessed confirmed ORR of 26.0% (95% CI, 17.6%-36.0%) among 96 patients with EP-NEC who had received at least 2 prior lines of therapy. The lower bound of the CI exceeded the prespecified success threshold of 13%. This data was presented by Ming Lu, MD, chief physician at Peking University Cancer Hospital and Beijing GoBroad Hospital in Beijing, China.

Patients with central lab–confirmed EP-NEC received opamtistomig at the recommended phase 2 dose of 15 mg/kg intravenously every 3 weeks. The primary end point was IRC-assessed ORR per RECIST v1.1; secondary end points included investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), time to response, progression-free survival (PFS), OS, and safety.

The median patient age was 61 years (range, 30-78), 68.8% of patients were male, and 86.5% had an ECOG performance status of 1. Small cell NEC accounted for 55.2% of cases and large cell NEC for 44.8%. The most common primary sites of origin were gastric (24.0%), colorectal (17.7%), uterine (13.5%), and esophageal (9.4%). Nearly all patients (96.9%) had stage IV disease, 67.4% of those with metastases had liver involvement, and 25.0% had received 3 or more prior lines of treatment. Among 39 patients evaluable for PD-L1, 82.1% had a combined positive score (CPS) below 1.

As of the August 16, 2026, data cutoff and with a median follow-up of 16.3 months, the IRC-assessed best responses included a complete response (CR) in 3.1% of patients, partial response (PR) in 22.9%, stable disease in 9.4%, and progressive disease in 54.2%; the DCR was 35.4% (95% CI, 25.9%-45.8%). Investigator-assessed ORR was 29.2% (95% CI, 20.3%-39.3%).

Among the 25 IRC-confirmed responders, the median DOR was 9.8 months (95% CI, 4.4-not evaluable [NE]), and the 12-month DOR rate was 41.7% (95% CI, 21.6%-60.7%). Overall, 13 of 96 patients (13.5%) remained on treatment for more than 12 months, including 4 patients who stayed on therapy beyond 20 months, 3 of whom attained CRs. The median PFS was 1.4 months (95% CI, 1.4-2.1) per IRC assessment via RECIST v1.1 and 2.8 months (95% CI, 1.5-5.5) per investigator-assessed immunotherapy RECIST. The median OS among all patients was 8.7 months (95% CI, 6.1-11.7), with a 12-month OS rate of 39.4% (95% CI, 29.5%-49.1%).

ORRs were generally consistent across prespecified subgroups, including PD-L1 CPS below 1 (ORR, 28.1%) and at least 1 (ORR, 28.6%), and large cell (ORR, 27.9%) vs small cell (ORR, 24.5%) histology. Patients with liver metastases had a numerically lower ORR than those without (17.2% vs 43.8%), as well as shorter median PFS (1.4 vs 4.2 months) and median OS (7.0 vs 10.5 months). ORR was also higher among patients who developed anti-drug antibodies than among those who did not (58.3% vs 25.7%), a finding the investigators described as exploratory.

Treatment-emergent adverse events (TEAEs) occurred in 94.8% of patients, and 28.1% experienced grade 3 or higher treatment-related adverse events (TRAEs). The most common TRAEs were anemia (any grade, 40.6%; grade ≥3, 6.3%), increased aspartate aminotransferase (any grade, 32.3%; grade ≥3, 2.1%), and increased alanine aminotransferase (any grade, 31.3%; no grade ≥3 events). Liver enzyme abnormalities were mostly grade 1 or 2 and transient. Four treatment-related deaths (4.2%) occurred, attributed to infectious pneumonia, sepsis, septic shock, and an unspecified cause.

Based on these data, a biologics license application for opamtistomig has been accepted and granted priority review by China's National Medical Products Administration (NMPA). The FDA previously granted the agent fast track designation in EP-NEC in January 2026.⁴

2392O: Opamtistomig (LBL-024), a novel PD-L1×4-1BB bispecific antibody, combined with chemotherapy as first-line treatment for advanced extrapulmonary neuroendocrine carcinoma: results from a phase Ib/II trial

In the first-line setting, opamtistomig plus etoposide and cisplatin or carboplatin (EP/EC) yielded an ORR of 69.2% (95% CI, 56.6%-80.1%) and a confirmed ORR of 60.0% (95% CI, 47.1%-72.0%) among 65 efficacy-evaluable patients with treatment-naive EP-NEC in the phase 1b/2 LBL-024-CN002 trial. Results from the trial were presented by Panpan Zhang, MD, of the Early Drug Development Center Centre at Peking University Cancer Hospital & Institute.

The trial enrolled patients with histologically or cytologically confirmed NEC and no prior systemic therapy. Phase 1b escalated opamtistomig from 6 to 15 mg/kg with EP/EC; phase 2 randomly assigned patients 1:1 to receive either 6 mg/kg or 15 mg/kg, followed by a 15-mg/kg expansion cohort. All patients received EP/EC. Etoposide at 100 mg/m² on days 1 to 3 was given with cisplatin at 75 mg/m² or carboplatin area under the curve 5 on day 1 every 3 weeks for up to 6 cycles, and opamtistomig continued for up to 2 years. ORR per RECIST v1.1 was the phase 2 primary end point.

Between January and December 2024, 69 patients were enrolled: 23 at 6 mg/kg, 6 at 10 mg/kg, and 40 at 15 mg/kg. The median age was 60 years (range, 27-75), 71.0% of patients were male, 94.2% had a Ki-67 index of at least 50%, 71.0% had a PD-L1 CPS below 1, and 61.8% of those with metastases had liver involvement. Gastric (26.1%), esophagus (15.9%), and pancreas (11.6%) were the most common primary sites of origin.

As of a June 30, 2026, data cutoff and with a median follow-up of 21.2 months, overall, the CR rate was 4.6%, the PR rate was 64.6%, and the DCR was 90.8% (95% CI, 81.0%-96.5%). ORRs were similar across dose levels: 68.2% (95% CI, 45.1%-86.1%) at 6 mg/kg, 66.7% (95% CI, 22.3%-95.7%) at 10 mg/kg, and 70.3% (95% CI, 53.0%-84.1%) at 15 mg/kg. In the full analysis set, the median PFS was 5.7 months (95% CI, 5.5-8.6), the 18-month PFS rate was 21.0% (95% CI, 12.2%-31.4%), and the median DOR was 10.2 months (95% CI, 5.6-15.9). The median OS was not reached (95% CI, 12.5-NE), and the 18-month OS rate was 55.7% (95% CI, 43.1%-66.6%).

The median PFS was numerically longer at 6 mg/kg than at 15 mg/kg, being 9.5 months (95% CI, 5.1-17.1) vs 5.7 months (95% CI, 4.4-7.8), respectively. The investigators noted that baseline imbalances in liver metastases and PD-L1 status, along with small sample sizes, may account for the difference rather than dose itself. In subgroup analyses, ORR was higher among patients without liver metastases than those with them, at 70.4% (95% CI, 49.8%-86.2%) vs 47.6% (95% CI, 32.0%-63.6%). They were also higher among those with small cell vs large cell histology, at 67.7% (95% CI, 48.6%-83.3%) vs 34.8% (95% CI, 16.4%-57.3%). PFS trended longer among patients without liver metastases (HR, 0.598; 95% CI, 0.340-1.041) and those with PD-L1–positive disease (HR, 0.663; 95% CI, 0.340-1.305).

All patients experienced at least 1 TEAE, and grade 3 or higher TRAEs occurred in 79.7%; these were largely hematologic, including decreased neutrophil count (62.3%), decreased white blood cell count (36.2%), decreased platelet count (24.6%), and anemia (21.7%). Immune-related AEs occurred in 37.7% of patients and were grade 3 or higher in 17.4%, most often diabetes mellitus (2.9%) and immune-mediated myocarditis (2.9%); no grade 5 immune-related events occurred. TRAEs led to opamtistomig discontinuation in 5.8% of patients and to death in 2 patients (2.9%), both at 15 mg/kg.

The investigators selected 15 mg/kg every 3 weeks as the recommended phase 3 dose, citing linear pharmacokinetics from 6 to 15 mg/kg, a steady-state half-life of 8.9 days, a trend toward higher response with greater exposure, and no exposure-related toxicities. A randomized, double-blind, placebo-controlled phase 3 trial of opamtistomig plus chemotherapy in first-line EP-NEC is ongoing (NCT07720193).

PD-L1 × VEGF-A Blockade in the Second Line

2393O: First results from a phase 2 trial of second-line pumitamig (PD-L1 × VEGF-A bsAb) plus chemotherapy in unresectable neuroendocrine neoplasms

Pumitamig plus FOLFIRI achieved a confirmed ORR of 40.0% and a median PFS of 5.5 months in patients with unresectable NEC whose disease progressed on first-line platinum-based chemotherapy. These results from a phase 2 trial were presented by Jianming Xu, PhD, of the department of Gastrointestinal Oncology at the Fifth Medical Center of Chinese PLA General Hospital in Beijing, China. The investigators described it as the first trial of a PD-(L)1 × VEGF-A bispecific antibody in NEC.

Pumitamig is designed to block PD-L1 while neutralizing VEGF-A, with the aim of reversing T-cell suppression, normalizing tumor vasculature, and concentrating both effects in the tumor microenvironment. In this single-arm, open-label, multicenter study conducted in China, adults with grade 3 neuroendocrine tumors or NEC with a Ki-67 index of at least 55% (excluding small cell lung cancer), an ECOG performance status of 0 or 1, and progression following first-line platinum-based chemotherapy received pumitamig at 20 mg/kg plus FOLFIRI intravenously every 2 weeks for up to 2 years. The co-primary end points were confirmed ORR per RECIST v1.1 and TRAEs.

Among 31 enrolled patients, the median age was 59 years (range, 32-74), 51.6% were female, 64.5% had liver metastases, and 61.3% had a PD-L1 CPS of at least 1. Small cell histology accounted for 61.3% of cases and large cell for 29.0%. The most common primary sites of tumor were stomach or gastroesophageal junction (25.8%), colorectal (22.6%), esophageal (16.1%), cervical (12.9%), and hepatobiliary or pancreatic (12.9%).

As of an August 3, 2026, data cutoff and with a median follow-up of 10.0 months (range, 1.4-23.9), all 12 confirmed responses among 30 evaluable patients were PRs; 46.7% had stable disease and the confirmed DCR was 86.7%. The median time to response was 1.4 months (range, 1.1-2.6), and the median DOR was 5.9 months (95% CI, 3.7-8.0). In the overall population, the median PFS was 5.5 months (95% CI, 3.1-7.1); the median OS was 12.8 months (95% CI, 8.3-14.0), with 6- and 12-month OS rates of 80.6% and 51.1%, respectively.

Responses varied by PD-L1 expression: the confirmed ORR was 57.9% in patients with a CPS of at least 1 (n = 19) vs 10.0% in those with a CPS below 1 (n = 10), with a median PFS of 6.74 (95% CI, 3.12-9.59) vs 5.49 months (95% CI, 1.54-8.25), respectively. Responses were observed across most primary tumor sites, although none occurred among 4 patients with a hepatobiliary or pancreatic primary tumor site.

Grade 3 or higher TRAEs occurred in 83.9% of patients, most commonly decreased neutrophil count (41.9%), decreased white blood cell count (22.6%), and asthenia (12.9%). TRAEs led to dose interruption in 74.2% of patients and permanent discontinuation in 12.9%. VEGF-related events occurred in 54.8% of patients and were grade 3 or higher in 16.1%, including upper gastrointestinal hemorrhage in 2 patients. Immune-related AEs occurred in 25.8%, with no grade 3 or higher events. One treatment-related death (3.2%) resulted from intracranial hemorrhage attributed to disease progression.

References

1. Lu M, Zhang P, Chen J, et al. Opamtistomig (LBL-024) monotherapy in advanced extrapulmonary neuroendocrine carcinoma (EP-NEC) after ≥2 prior lines of therapy: results from a pivotal, registrational phase IIb study of a novel PD-L1×4-1BB bispecific antibody. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA57.
2. Zhang P, Lu M, Liu B, et al. Opamtistomig (LBL-024), a novel PD-L1×4-1BB bispecific antibody, combined with chemotherapy as first-line treatment for advanced extrapulmonary neuroendocrine carcinoma: results from a phase Ib/II trial. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 2392O.
3. Xu J, Ye S, Niu Z, et al. First results from a phase 2 trial of second-line pumitamig (PD-L1 × VEGF-A bsAb) plus chemotherapy in unresectable neuroendocrine neoplasms. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 2393O.
4. Global development accelerates: Leads Biolabs' PD-L1/4-1BB bispecific antibody granted fast track designation by FDA. News release. Nanjing Leads Biolabs. January 15, 2026. Accessed October 27, 2026. https://tinyurl.com/4mstbjvd