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Tarlatamab Shows Promise in Patients with Previously Treated Small-Cell Lung Cancer

Findings from the DeLLphi-301 study
31 Oct 2023
Immunotherapy
Small Cell Lung Cancer

In a phase II DeLLphi-301 study, tarlatamab had durable antitumour activity in patients with heavily pretreated small-cell lung cancer (SCLC). The study was designed to compare two active doses, which is consistent with the US Food and Drug Administration Project Optimus initiative to reform the dose-optimisation and dose-selection paradigm in the development of drugs in oncology. The 10 mg dose was selected for subsequent tarlatamab studies because it had a more favourable benefit-to-risk profile than the 100 mg dose, with an objective response in 40% of the patients and a median overall survival (OS) of 14.3 months (the median duration of response was not evaluable). The objective response of 40% far exceeded the historical control benchmark of 15% for the primary endpoint.

The findings from this study, which include data on patient-reported outcomes, are promising relative to the outcomes of clinical studies of current standard-of-care second-line treatment options. The study findings were presented by Prof. Luis Paz-Ares of the Hospital Universitario 12 de Octubre in Madrid, Spain on 20 October at the ESMO Congress 2023 along with a simultaneous publication in the NEJM.

Tarlatamab is a bispecific T-cell engager immunotherapy that directs the patient’s T cells to cancer cells expressing delta-like ligand 3 (DLL3), independent of major histocompatibility complex (MHC) class I. Tarlatamab binds to both DLL3 on cancer cells and CD3 on T cells, leading to T-cell–mediated lysis of cancer cells. DLL3, a protein that inhibits Notch signalling, is typically localised intracellularly in normal cells but is abnormally expressed on the surface of SCLC. DLL3 is expressed in 85-94% of patients with SCLC. A phase I dose-exploration study of tarlatamab in patients with previously treated SCLC showed encouraging antitumour activity, with a median duration of response of 12.3 months. 

In the phase II DeLLphi-301 study, the antitumour activity and safety of two different doses of tarlatamab were assessed in patients with previously treated extensive-stage SCLC. Tarlatamab was administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated SCLC. The primary endpoint was objective response (complete or partial response), as assessed by blinded independent central review according to the RECIST v1.1.

Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumour activity and survival, the median follow-up was 10.6 months in the 10 mg group and 10.3 months in the 100 mg group. An objective response occurred in 40% (97.5% confidence interval [CI] 29 to 52) of the patients in the 10 mg group and in 32% (97.5% CI 21 to 44) of those in the 100 mg group.

Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cut-off were ongoing in 22 of 40 patients (55%) in the 10 mg group and in 16 of 28 patients (57%) in the 100 mg group. The median progression-free survival (PFS) was 4.9 months (95% CI 2.9 to 6.7) in the 10 mg group and 3.9 months (95% CI 2.6 to 4.4) in the 100 mg group; the estimates of OS at 9 months were 68% and 66% of patients, respectively.

The most common adverse events were cytokine-release syndrome (CRS) in 51% of the patients in the 10 mg group and in 61% of those in the 100 mg group, decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). CRS occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 CRS occurred less frequently in the 10 mg group (in 1% of the patients) than in the 100 mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events.

The authors concluded that tarlatamab represents a new immunotherapeutic approach for SCLC, a tumour type that is characterised by an immunosuppressive microenvironment. Given the mechanism of action of tarlatamab, the safety profile included a risk of CRS and ICANS and associated neurologic events, which are adverse events commonly associated with T-cell immunotherapies. 

Longer follow-up of patients in DeLLphi-301 study will give more information about the long-term durability of the response and the long-term survival benefits. The continuation of PFS beyond 9 months in approximately one quarter of the patients and a median OS duration of more than 14 months are encouraging observations. In the ongoing phase III DeLLphi-304 study, investigators are comparing tarlatamab 10 mg every 2 weeks with standard care in patients with previously treated extensive-stage SCLC.

The study was funded by Amgen.

References

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