Best of ASCO Dallas 2026: Small Cell Lung Cancer Updates
Presenter: Shiraj Sen, MD, PhD, NEXT Oncology – Texas Oncology; Dallas, Texas
Conference: Best of ASCO Dallas 2026
The Bottom Line
At ASCO 2026, emerging data in small cell lung cancer (SCLC) highlighted progress in two areas of substantial unmet need: treatment of patients with brain metastases and development of novel antibody-drug conjugates (ADCs) for relapsed/refractory disease. At the 2026 Best of ASCO Dallas conference presented by Total Health, Dr Shiraj Sen focused on three presentations: a post hoc analysis of the phase 3 DeLLphi-304 trial evaluating the intracranial activity of tarlatamab, and early-phase studies of two novel ADCs, DLL3-directed BL-M14D1, and the B7-H3–directed SYS6043.
The DeLLphi-304 analysis showed that tarlatamab reduced the risk of CNS progression or death by 60% compared with chemotherapy in previously treated patients with stable, asymptomatic brain metastases. Median overall survival (OS) among patients with baseline brain metastases was 13.9 months with tarlatamab versus 6.8 months with chemotherapy. Meanwhile, BL-M14D1 and SYS6043 were shown to produce objective response rates (ORRs) of 71.4% and 66.7%, respectively, in heavily pretreated SCLC populations. Although these phase 1 data remain preliminary, Dr Sen viewed DLL3 and B7-H3 as important targets in a rapidly evolving ADC landscape. Dr Sen’s overarching message was straightforward: “Clinical trials should be considered for all patients with refractory small cell lung cancer.”
Background
Dr Sen noted that patients with relapsed SCLC continue to have limited treatment options and poor outcomes, particularly when brain metastases are present. Historically, median OS with second-line chemotherapy in patients with SCLC and brain metastases has been approximately 4.5 to 6.6 months. Tarlatamab is a DLL3-targeted bispecific T-cell engager (BiTE). In the randomized phase 3 DeLLphi-304 trial, tarlatamab previously demonstrated superior OS and progression-free survival (PFS) versus standard chemotherapy among patients whose disease progressed during or after platinum-based therapy. Median OS was 13.6 versus 8.3 months (HR 0.60; P<.001), and median PFS was 4.2 versus 3.7 months (HR 0.71). The new post hoc analysis asked an especially relevant question for SCLC – that is does that benefit extend to the CNS?
At the same time, the therapeutic landscape is expanding beyond conventional chemotherapy and immune-based approaches. DLL3 and B7-H3 are emerging as targets for ADC development, with several compounds advancing through clinical trials. Dr Sen emphasized that these programs are progressing rapidly enough that clinicians treating SCLC should increasingly consider clinical trial availability when planning therapy for relapsed disease.
Trial Design and Patients
Intracranial Activity of Tarlatamab: DeLLphi-304
DeLLphi-304 randomized patients with SCLC progressing after first-line platinum-based chemotherapy, with or without anti–PD-(L)1 therapy, 1:1 to tarlatamab or chemotherapy. Patients with asymptomatic treated or untreated brain metastases were permitted. The post hoc CNS analysis used modified Response Assessment in Neuro-Oncology Brain Metastases (mRANO-BM) criteria with blinded independent central review. Dr Sen highlighted the clinical relevance of this methodology because mRANO-BM can capture lesions as small as 5 mm and incorporates absolute changes and volumetric measurements when possible, potentially providing a more practical assessment of the multiple small brain metastases frequently encountered in SCLC. The CNS efficacy population in the trial included 67 patients receiving tarlatamab and 56 receiving chemotherapy who had at least 1 baseline brain metastasis by mRANO-BM and at least 1 postbaseline scan. Importantly, 75% and 71%, respectively, had received previous radiotherapy and/or surgery for brain metastases.
BL-M14D1
BL-M14D1 is a novel DLL3-directed ADC consisting of an anti-DLL3 monoclonal antibody linked through a stable enzyme-cleavable linker to a topoisomerase I inhibitor payload. DLL3 is reported to be overexpressed in up to 80% of SCLC, with relatively low expression in normal tissues. The phase 1 study enrolled patients with relapsed/refractory SCLC, neuroendocrine carcinoma, and other solid tumors who had received standard therapy and had ECOG performance status 0-1. The SCLC population was heavily pretreated: among 87 patients, 64.4% had received at least 2 previous lines of therapy, 85.1% had received prior immunotherapy, and 28.7% had baseline brain metastases. However, patients with active or untreated brain metastases were excluded.
SYS6043
SYS6043 is a next-generation B7-H3–targeted ADC carrying a topoisomerase I inhibitor payload. Its design includes a silenced Fc region intended to reduce off-target toxicity. The multicenter, open-label phase 1/2 trial conducted in China enrolled patients with previously treated advanced or metastatic solid tumors and ECOG performance status 0-1. Across the overall 627-patient population, the median number of prior treatment lines was 2; 77.0% had received platinum-based chemotherapy and 55.3% had received immunotherapy.
Main Trial Results
Tarlatamab Demonstrates Intracranial Activity
Among patients with brain metastases evaluable by mRANO-BM, median CNS PFS was 6.5 months with tarlatamab versus 4.2 months with chemotherapy (HR 0.40; 95% CI, 0.24-0.66). Thus, tarlatamab reduced the risk of CNS progression or death by approximately 60%. The OS findings were also notable. Among patients with baseline brain metastases by investigator-assessed RECIST, median OS was 13.9 months with tarlatamab versus 6.8 months with chemotherapy (HR 0.51; 95% CI, 0.34-0.74), corresponding to a 49% reduction in the risk of death. In patients without brain metastases, median OS was 13.6 versus 9.6 months, respectively. Dr Sen noted that the survival curves for tarlatamab-treated patients with and without brain metastases were remarkably similar: “The benefit of tarlatamab seems to be preserved in patients with small cell lung cancer, whether they have [brain] mets or not.” He noted that the data have practical implications but should not be extrapolated indiscriminately to symptomatic CNS disease. Dr Sen contrasted a patient with large brain metastases and vasogenic edema, where radiation and/or neurosurgical evaluation would remain important, with a patient experiencing widespread extracranial progression and a single asymptomatic 3-mm brain lesion. In the latter situation, he suggested that tarlatamab with close CNS monitoring could potentially be considered when local treatment is not feasible or appropriate.
BL-M14D1 Produced Deep Responses in Pretreated SCLC
Among 84 evaluable patients with SCLC treated with BL-M14D1, the ORR was 71.4% (95% CI, 60.5%-80.8%), confirmed ORR was 60.7%, and disease control rate (DCR) was 94.0%. Median duration of response was 7.4 months and median PFS was 7.1 months, with a 6-month PFS rate of 57.3%. Activity was observed regardless of the number of prior lines. At the 4.0-mg/kg dose, ORRs were 78.6% after 1 prior line and 70.0% after 2 or more lines; at 4.5 mg/kg, corresponding ORRs were 75.0% and 69.2%. Tumor reductions were frequently substantial in the trial: At 4.0 mg/kg, 94.1% of patients experienced tumor shrinkage, with a median reduction of 52.5%. At 4.5 mg/kg, 94.7% experienced shrinkage, with a median reduction of 46.4%. Dr Sen emphasized why this degree and duration of activity attracted attention: “These responses continue on in many cases for four, six, eight… months, which again in patients with second- or third-line small cell lung cancer is not something that we've historically been able to do with standard-of-care therapies.” He noted, however, that these results derive from a nonrandomized early-phase study conducted in an East Asian population, and whether comparable efficacy will be observed in broader Western populations remains to be established.
B7-H3 Emerges as Another Promising ADC Target
SYS6043 demonstrated an ORR of 66.7% in the SCLC cohort, with many patients experiencing substantial tumor shrinkage. PFS and OS were immature at the time of presentation. Although the absence of mature survival data and randomized comparison precludes conclusions regarding clinical benefit relative to existing therapies, the findings reinforce B7-H3 as another potentially important therapeutic target in SCLC. Dr Sen also placed SYS6043 within a broader development landscape that includes multiple DLL3- and B7-H3–directed ADCs, some already progressing into later-phase studies and combination strategies with PD-1 inhibitors or tarlatamab.
Adverse Events and Toxicities
Tarlatamab
Among patients with brain metastases, tarlatamab had a more favorable overall safety profile than chemotherapy. Grade ≥3 treatment-emergent adverse events occurred in 54.1% versus 87.1%, while grade ≥3 treatment-related adverse events occurred in 25.5% versus 65.6%, respectively. Treatment-related adverse events led to discontinuation in 2.0% versus 6.5%. Neurologic events excluding dysgeusia occurred at similar rates (45.9% vs 44.1%). Dysgeusia was more frequent with tarlatamab (23.5% vs 3.2%), whereas neutropenia was substantially less frequent (7.1% vs 32.3%).
BL-M14D1
Toxicities with BL-M14D1 were predominantly hematologic, particularly anemia, leukopenia, and thrombocytopenia. Despite these adverse events, treatment-related toxicity resulted in discontinuation in only 2.4% of patients. One treatment-related grade 3 interstitial lung disease (ILD) event occurred at 6.0 mg/kg, and 1 treatment-related death from sepsis occurred at 4.5 mg/kg. Two dose-limiting toxicities occurred at 6.0 mg/kg, and 5.0 mg/kg was identified as the maximum tolerated dose.
SYS6043
Across the 627-patient SYS6043 study population, 37.2% experienced grade ≥3 treatment-related adverse events, 19.1% experienced serious treatment-related events, and 3.5% discontinued therapy because of treatment-related toxicity. Hematologic events, including anemia, leukopenia, and neutropenia, were prominent. ILD occurred in 23 patients (3.7%), including 3 grade 5 events. Five treatment-related deaths were reported overall, attributed to sepsis (n=2), respiratory failure (n=2), and an unknown cause (n=1). These findings underscore the need for careful toxicity characterization as B7-H3 ADCs move into larger trials.
Conclusions and Faculty Insights
The ASCO 2026 SCLC presentations as reviewed by Dr Sen point toward a treatment landscape that may become substantially broader over the next several years.
For tarlatamab, the DeLLphi-304 post hoc analysis provides evidence that the benefit observed over chemotherapy extends to patients with stable, asymptomatic brain metastases. The 60% reduction in the risk of CNS progression or death is particularly relevant given the frequency and clinical consequences of CNS involvement in SCLC. Interpretation of the results, however, requires recognition that the analysis was post hoc, involved a relatively small CNS-evaluable population, and approximately three quarters of patients had already received CNS-directed therapy.
For ADCs, both DLL3 and B7-H3 appear promising. BL-M14D1 generated responses in more than 70% of evaluable patients despite substantial prior treatment, while SYS6043 produced responses in approximately two thirds of patients with SCLC. Nonetheless, both datasets are early-phase, nonrandomized, derived from East Asian populations, and exclude active or untreated brain metastases. The high response rates therefore should not yet be interpreted as establishing either agent as a new standard of care. Rather, Dr Sen viewed the findings as evidence of the extraordinary pace of therapeutic development in SCLC: “These drugs really are coming and can be quite effective.”
For clinicians, Dr Sen believes the immediate implication is clinical trial awareness and referral. Multiple DLL3- and B7-H3–directed ADCs are advancing through development, and combinations with immunotherapy and tarlatamab are being explored. In a disease where treatment options can narrow quickly after progression, identifying an appropriate trial before a patient's clinical status deteriorates may be particularly important.
Speaker Disclosure Information: Dr Sen reported no relevant disclosures for this presentation.