Matching-Adjusted Indirect Comparison of Tarlatamab for Patients with Platinum-Refractory or Platinum-Resistant Extensive-Stage Small-Cell Lung Cancer

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Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive cancer that is traditionally associated with poor survival outcomes, particularly among individuals with platinum-refractory or platinum-resistant disease. In the phase 3 DeLLphi-304 trial (NCT05740566), tarlatamab showed significant clinical benefit compared with single-agent chemotherapies (topotecan, lurbinectedin, or amrubicin) as second-line (2L) therapy for ES-SCLC. Paclitaxel and a combination of cyclophosphamide, doxorubicin, and vincristine (CAV) are alternative 2L treatments for platinum-refractory or platinum-resistant ES-SCLC that were not evaluated in the DeLLphi-304 trial. To address the lack of head-to-head evidence, unanchored matching-adjusted indirect comparisons (MAICs) were conducted to compare the efficacy of tarlatamab versus paclitaxel and CAV. The analyses leveraged individual-level patient data from DeLLphi-304 (tarlatamab) and published aggregate-level data from Owonikoko 2020 (NCT02038647; paclitaxel) and GFPC 0501 (NCT00418743; CAV). Analyses were restricted based on chemotherapy-free interval (CFI) to align with the eligibility criteria of Owonikoko 2020 (CFI < 180 days) and GFPC 0501 (CFI < 90 days). Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR). Unanchored MAIC was used to estimate the relative treatment effect after adjusting for baseline imbalances. Measures of effect included hazard ratios (HRs) and odds ratios (ORs). After MAIC reweighting, tarlatamab was associated with longer OS versus paclitaxel [HR (95% CI): 0.35 (0.23, 0.52), p < 0.001] and CAV [HR: 0.48 (0.32, 0.70), p < 0.001]. Tarlatamab was also associated with improved PFS, ORR and DCR relative to paclitaxel (p < 0.05). There were no significant differences between tarlatamab and CAV with respect to PFS, ORR, or DCR (p > 0.05). These results suggest that tarlatamab may increase survival relative to paclitaxel and CAV among individuals with platinum-refractory or platinum-resistant ES-SCLC in the 2L setting. These findings are subject to residual confounding and should be interpreted with caution. DeLLphi-304 ClinicalTrials.gov identifier, NCT05740566. Extensive-stage small cell lung cancer (SCLC) often spreads quickly and is difficult to treat. Many patients experience disease progression during or within a few months of completing initial treatment with standard chemotherapy. When this happens, the disease is called “platinum-refractory” or “platinum-resistant”, and treatment options are limited. Tarlatamab is a new treatment for this condition that was recently shown to provide better survival outcomes relative to standard of care chemotherapy (topotecan, lurbinectedin, or amrubicin) in the DeLLphi-304 trial. Paclitaxel and a combination of cyclophosphamide, doxorubicin, and vincristine are two additional treatment options for platinum-refractory or platinum-resistant extensive stage SCLC that were not directly assessed in the DeLLphi-304 trial. To address this limitation, we indirectly compared the efficacy of tarlatamab relative to these treatment options. Since the treatments were assessed in separate clinical trials, the tarlatamab patient data from DeLLphi-304 was re-weighted so that the baseline characteristics matched that of the comparator trials. After re-weighting patients, we found that individuals who were treated with tarlatamab tended to live longer than those treated with paclitaxel or a combination of cyclophosphamide, doxorubicin, and vincristine. These results suggest that tarlatamab may improve survival outcomes relative to paclitaxel or a combination of cyclophosphamide, doxorubicin, and vincristine for people with platinum-refractory or platinum-resistant extensive-stage SCLC. Since the treatments were indirectly compared using data from different clinical trials, these results are susceptible to bias and should be interpreted with caution.

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