Patients with small-cell lung cancer who relapse after platinum-based chemotherapy face poor outcomes. In a multinational, randomized, open-label phase 3 trial (DeLLphi-304), researchers evaluated the efficacy and safety of tarlatamab—a bispecific T-cell engager targeting delta-like ligand 3—compared with standard second-line chemotherapy.
A total of 509 patients with disease progression during or after first-line platinum-based therapy were randomly assigned to receive tarlatamab (n = 254) or chemotherapy (n = 255; topotecan, lurbinectedin, or amrubicin depending on geographic region).
Survival Outcomes
Median overall survival was 13.6 months (95% CI, 11.1 to not reached) with tarlatamab vs 8.3 months (95% CI, 7.0–10.2) with chemotherapy (hazard ratio [HR], 0.60; 95% CI, 0.47–0.77; P < .001). At 12 months, the overall survival rate was 53% for tarlatamab vs 37% for chemotherapy; at 6 months, 76% vs 62%, respectively.
Progression-free survival also favored tarlatamab. Although the median progression-free survival was 4.2 months (95% CI, 3.4–4.5) vs 3.7 months (95% CI, 2.9–4.2), the proportional hazards assumption was not met. The 12-month restricted mean progression-free survival time was 5.3 months with tarlatamab and 4.3 months with chemotherapy (P = .002).
Tumor Response
Objective response rates were 35% (95% CI, 29–41) in the tarlatamab group and 20% (95% CI, 16–26) in the chemotherapy group (risk ratio, 1.73; 95% CI, 1.29–2.33). Median duration of response was 6.9 months (95% CI, 4.5–12.4) vs 5.5 months (95% CI, 4.2–5.7), respectively. Among responders, 47% in the tarlatamab group and 15% in the chemotherapy group remained in the trial without progression or death at data cutoff.
Patient Characteristics
Among trial participants, 71% had received prior anti–PD-1 or anti–PD-L1 therapy, 44% had platinum-resistant disease (defined as progression <90 days after chemotherapy), and 45% had brain metastases. DLL3 was expressed in 95% of tumors with available data.
Patient-Reported Outcomes
At week 19, tarlatamab was associated with significantly greater reductions in dyspnea (mean between-group difference, −9.14; 95% CI, −12.64 to −5.64; P < .001) and cough (odds ratio, 2.04; 95% CI, 1.17–3.55; P = .01) compared with chemotherapy. Changes in chest pain were not statistically significant. Improvements in physical functioning and global health scores were observed numerically (10.35 and 8.93 points, respectively), but were not formally tested due to the hierarchical analysis design.
Safety and Adverse Events
Grade ≥3 adverse events occurred in 54% of patients treated with tarlatamab vs 80% with chemotherapy. Treatment-related discontinuation rates were lower with tarlatamab (5% vs 12%).
Cytokine release syndrome (CRS) occurred in 56% of patients receiving tarlatamab, primarily after the first two doses. Most CRS events were grade 1 (42%) or 2 (13%), with only 1% being grade 3. Median resolution time was 2 days.
Neurologic events were more common in the tarlatamab group (56% vs 35%), with dysgeusia as the most frequent (24%). Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 6%, including 1 patient who experienced a grade 5 event.
At data cutoff, 27% of patients in the tarlatamab group and 7% in the chemotherapy group remained on treatment.
Conclusion
Tarlatamab significantly prolonged overall survival and improved patient-reported symptoms with fewer high-grade toxicities than standard chemotherapy. It may represent a viable second-line option for relapsed or refractory small-cell lung cancer, including in patients with platinum resistance or brain metastases. Additional trials are underway to explore earlier-line use.
Disclosures and trial details are available in the full study report.
Source: NEJM