Rami Manochakian, MD, FASCO, on Tarlatamab vs Chemotherapy for Second-Line Treatment of SCLC: Expert Point of View

DELPHI-304 trial is a randomized controlled phase 3 trial comparing tarlatamab to chemotherapy in the second-line treatment of patients with small cell lung cancer who had disease progression after first-line chemotherapy, with or without a checkpoint inhibitor. Tarlatamab is a bispecific T-cell engager that targets DLL3 and CD3 and was approved in the second-line treatment and beyond of advanced small cell lung cancer based on DELPHI-301, which showed a very good response rate. DELPHI-304, of which the results were reported by the investigators at the ASCO 2025 Annual Meeting, also had an associated manuscript published in the New England Journal of Medicine. The study showed impressive, significant improvement in overall survival—statistically significant and, more importantly, meaningful clinical improvements. The hazard ratio was 0.6. There was a median overall survival improvement of more than five months, from 8.3 to 11.6 months. Other clinical outcomes that were reported included a response rate of about 35%. There was also improvement in progression-free survival. Kudos also to the investigators who reported patient outcomes, and there was a significant improvement in patient symptoms, particularly dyspnea and cough, with tarlatamab. When it comes to safety profile, tarlatamab had overall a better safety profile. There were significantly fewer grade 3 or above adverse events compared to chemotherapy. When it comes to the unique side effects—CRS (cytokine release syndrome) and ICANS—they were mostly grade 1 or 2 and managed fairly well with minimal issues, except maybe one case of ICANS. Why is this study important? Very important, because it's the first study ever to show a drug that has a better overall survival benefit compared to chemotherapy in the second-line setting treatment of small cell lung cancer. This is a standard-of-care treatment. From now on, if not already, I will be using it in clinic. I'm already using it. A couple of things to make sure we address on this drug, tarlatamab. We do know that there are some logistics to administering the drug—maybe in the hospital for the first couple of doses, as was done initially in the trial, and then it was adjusted. The reason is to watch for those side effects. Although they're rare—the reactions, the CRS—it requires some extra time of observation after the infusion. But I think as we evolve, we're seeing that has been more doable, and the study itself showed that actually observing in outpatient is doable. And then of course, more importantly, even though the percentage of higher-grade adverse events was lower with tarlatamab, we still owe it to our patients to monitor closely, to optimize and do everything to support them, and to treat those in a timely manner.