Two landmark phase 3 trials published simultaneously in *The New England Journal of Medicine* and presented at the 2025 ASCO Annual Meeting have redrawn the treatment map for lung cancer, one for resectable non-small cell lung cancer, one for relapsed small cell lung cancer. Both answered survival questions that the field has been pursuing for years. Both produced results that are immediately and unambiguously practice-changing.
The first, CheckMate 816, delivered statistically significant overall survival benefit for neoadjuvant nivolumab plus chemotherapy before surgery in resectable NSCLC, the only phase 3 neoadjuvant-only chemoimmunotherapy trial to achieve this endpoint across any solid tumor type (Forde PM et al. *N Engl J Med.* 2025. doi:10.1056/NEJMoa2502931). The second, DeLLphi-304, showed that tarlatamab, a bispecific T-cell engager targeting DLL3, reduced the risk of death by 40% compared with chemotherapy in previously treated small cell lung cancer, establishing a new standard of care in a disease that has resisted meaningful therapeutic progress for decades (Mountzios G et al. *N Engl J Med.* 2025. doi:10.1056/NEJMoa2502099).
What CheckMate 816 Actually Showed
In the phase 3, open-label CheckMate 816 trial, patients with stage IB to IIIA resectable NSCLC were randomized to receive three cycles of neoadjuvant nivolumab plus platinum-based chemotherapy or chemotherapy alone, followed by surgery. Previous analyses had already confirmed significant improvements in event-free survival and pathological complete response. What had been missing was the final, definitive overall survival readout.
At a median follow-up of 68.4 months, the five-year overall survival rate was 65.4% in the nivolumab group compared with 55.0% in the chemotherapy-alone group, a 10% absolute improvement and a 28% reduction in the risk of death (HR 0.72; 95% CI 0.52–1.00; p=0.0485) (Forde PM et al. *N Engl J Med.* 2025). Pathological complete response was achieved in 24% of patients in the nivolumab group versus 2.2% in the chemotherapy group. Critically, the addition of nivolumab did not compromise surgical feasibility or increase perioperative complications.
This is now the only phase 3 neoadjuvant-only chemoimmunotherapy trial to demonstrate a statistically significant overall survival benefit across any resectable solid tumor type. The perioperative window alone three cycles before surgery, with no mandated adjuvant continuation was sufficient to produce durable systemic disease control at five years.
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Why the Presurgical Window Is Enough
One of the most debated questions in perioperative oncology has been whether adjuvant continuation of immunotherapy after neoadjuvant chemoimmunotherapy adds meaningful benefit. CheckMate 816 answers part of that question by showing that the neoadjuvant-only approach is not a lesser strategy, at least not for survival.
The biology is compelling. The presurgical setting provides an intact tumor antigen reservoir, enabling more potent immune priming than adjuvant therapy can achieve after resection. Three cycles of nivolumab plus chemotherapy appear sufficient to activate durable antitumor T-cell responses that persist long after treatment ends (Forde PM et al. *N Engl J Med.* 2025).
Trials of perioperative immunotherapy CheckMate 77T, KEYNOTE-671, AEGEAN add adjuvant immunotherapy after surgery and also show event-free survival benefits. Whether the adjuvant component adds independent survival value over and above the neoadjuvant phase remains the central unresolved debate in the field. That question is actively being pursued in ongoing adaptive trial designs.
pCR and ctDNA Clearance as Emerging Biomarkers
CheckMate 816 provided some of the clearest evidence to date that pathological complete response is a meaningful surrogate for long-term overall survival, not just a pathological curiosity. Patients who achieved pCR had significantly better long-term outcomes than those who did not (Forde PM et al. *N Engl J Med.* 2025).
Equally important was the circulating tumor DNA data. Presurgical ctDNA clearance was observed in 56% of patients receiving nivolumab plus chemotherapy compared with 35% receiving chemotherapy alone, and clearance independently predicted favorable overall survival regardless of treatment arm. As discussant Lizza Hendriks from Maastricht University Medical Center noted at ASCO 2025, these findings raise the prospect of using pCR and ctDNA to identify which patients could de-escalate or escalate treatment, a goal that several ongoing adaptive trials are now pursuing prospectively.
The subgroup analysis also showed that the overall survival benefit was most pronounced in patients of Asian ancestry, those with PD-L1 expression of 50% or greater, and those who received carboplatin-based doublets, providing the first granular data on patient selection within the eligible resectable population.
Tarlatamab: A New Mechanism Enters the SCLC Arena
While CheckMate 816 completed a story that had been building for years, DeLLphi-304 opened an entirely new chapter. Small cell lung cancer accounts for approximately 15% of lung cancer diagnoses but is responsible for a disproportionate share of lung cancer deaths, with a five-year survival across all stages of under 10% (Mountzios G et al. *N Engl J Med.* 2025). Relapse after platinum-based chemotherapy is nearly universal, and the second-line options like topotecan, lurbinectedin, amrubicin, produce modest response rates and median overall survival of approximately eight months.
Tarlatamab works through a fundamentally different mechanism. It is a bispecific T-cell engager that simultaneously binds delta-like ligand 3 (DLL3) on the surface of SCLC tumor cells and the CD3 epsilon subunit on cytotoxic T cells, physically bridging tumor and immune effector cells to trigger direct killing. DLL3 is expressed on the surface of SCLC cells in approximately 85–96% of patients but is minimally expressed on normal adult tissues, a therapeutic window that makes targeted immune engagement feasible without broad systemic toxicity (AJMC 2025).
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The DeLLphi-304 Results in Numbers
The phase 3 DeLLphi-304 trial enrolled 509 patients with SCLC who had progressed during or after first-line platinum-based chemotherapy, with or without a PD-(L)1 inhibitor. Patients were randomized 1:1 to tarlatamab or investigator’s choice of chemotherapy. The population was clinically demanding: 71% had received prior anti-PD-(L)1 therapy, 44% had a chemotherapy-free interval below 90 days consistent with chemoresistant disease, and nearly 45% had baseline brain and/or liver metastases (Mountzios G et al. *N Engl J Med.* 2025).
At a median follow-up of 11.2 months, tarlatamab produced a median overall survival of 13.6 months compared with 8.3 months for chemotherapy, a 40% reduction in the risk of death (HR 0.60; 95% CI 0.47–0.77; p<0.001). Progression-free survival also significantly favored tarlatamab. The survival benefit was consistent across all prespecified subgroups, including patients with chemoresistant disease (HR 0.60) and baseline brain metastases (HR 0.45), the latter being a particularly striking finding (ASCO Post 2025).
Perhaps equally important from a daily practice perspective: grade ≥3 adverse events occurred in 54% of tarlatamab-treated patients versus 80% of those receiving chemotherapy. Patient-reported symptoms of dyspnea and cough also improved with tarlatamab versus chemotherapy.
Managing the New Toxicity Profile
The safety profile of tarlatamab requires specific institutional preparation. Cytokine release syndrome occurred in 55% of patients, though grade 3–4 CRS was observed in only 1.6%, within the manageable range when appropriate monitoring protocols are in place (AJMC 2025). Immune effector cell-associated neurotoxicity syndrome occurred in 47% of patients, with grade 3 events in 10%.
These toxicities are mechanistically expected consequences of T-cell engagement and differ substantially from the immune-related adverse events seen with PD-(L)1 inhibitors. They require institution-specific protocols for recognition, grading, and management that are distinct from those used for checkpoint inhibitor toxicity. As presenter Charles Rudin from Memorial Sloan Kettering Cancer Center noted at ASCO 2025, the data from DeLLphi-304 make tarlatamab “the preferred choice over chemotherapy” for previously treated metastatic SCLC, a statement that should accelerate development of institutional pathways for its outpatient and inpatient use.
The DeLLphi program is now systematically moving tarlatamab upstream: DeLLphi-305 is evaluating first-line maintenance in extensive-stage SCLC, DeLLphi-306 is investigating its use after concurrent chemoradiotherapy in limited-stage SCLC, and DeLLphi-312 is ongoing.
What This Means for Clinical Practice
For clinicians in thoracic oncology, both results carry immediate implications. Every patient with stage IB to IIIA resectable NSCLC should now be evaluated for neoadjuvant chemoimmunotherapy before surgical planning, not as an experimental option but as a regimen with level 1 evidence for overall survival benefit. Every patient with SCLC relapsing after platinum-based chemotherapy should be considered for tarlatamab, regardless of prior immunotherapy exposure, brain metastasis status, or chemotherapy-free interval.
Multidisciplinary teams should have active protocols for ctDNA monitoring in the perioperative setting, institutional pathways for BiTE-associated toxicity management, and real-time awareness of the sequential questions now driving the next generation of trials: how to use pCR and ctDNA to personalize neoadjuvant intensity, and how to sequence tarlatamab, PD-(L)1 inhibitors, and future combination strategies in the SCLC treatment continuum.
The Bottom Line
CheckMate 816 and DeLLphi-304 represent two distinct biological advances, neoadjuvant immune priming via checkpoint blockade, and direct T-cell redirection via bispecific antibody engineering, that have now both demonstrated phase 3 survival benefits in the two major subtypes of lung cancer. Together, they confirm that the era of lung cancer being treated with surgery or chemotherapy as isolated modalities is over.
The era of biologically integrated, immunologically driven, biomarker-guided lung cancer treatment is here.