Tarlatamab active in previously treated small cell lung cancer
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Key takeaways:
- The agent induced durable objective responses, and researchers called survival outcomes “promising.”
- More than half of patients experienced cytokine release syndrome.
MADRID — Tarlatamab exhibited antitumor activity among patients with small cell lung cancer who received prior treatment, according to results of the DeLLphi-301 study presented at ESMO Congress.
The agent induced durable objective responses and researchers characterized survival outcomes as “promising.”
The results — simultaneously published in The New Engand Journal of Medicine — support the use of tarlatamab for patients with previously treated small cell lung cancer, researcher Luis Paz-Ares, MD, PhD, chair of the department of medical oncology at Hospital Universitario 12 de Octubre and head of the lung cancer unit at National Oncology Research Center in Madrid, said during a presentation.
“Small cell lung cancer is an aggressive disease with poor survival outcomes,” Paz-Ares said. “Treatment possibilities are really [limited] ... and no drugs have been approved for patients who have received three lines or more of therapy.”
Tarlatamab (AMG 757, Amgen) is a bispecific T-cell engager immunotherapy that targets delta-like ligand 3 (DLL3) and CD3.
A phase 1 study showed tarlatamab exhibited antitumor activity and a manageable safety profile, Paz-Ares said.
The phase 2 DeLLphi-301 study assessed tarlatamab for 220 patients with extensive-stage small cell lung cancer who had received at least two prior treatments, including platinum doublet. All patients had measurable disease, with ECOG performance status of 0 or 1. Patients with treated and stable brain metastases could enroll.
In part one, researchers assessed the efficacy and safety of IV tarlatamab administered every 2 weeks at doses of either 10 mg (n = 88) or 100 mg (n = 88). In a dose-escalation stage, 12 patients received 10 mg tarlatamab every 2 weeks. In part 3, 34 patients received 10 mg tarlatamab with a reduced inpatient monitoring period.
Objective response rate per blinded independent central review assessment, treatment-emergent adverse events and tarlatamab serum concentrations served as the primary endpoints. Secondary endpoints included duration of response, disease control rate, PFS and OS.
More than 70% of patients were men, more than 90% had a smoking history, more than one-third had received at least three prior lines of therapy, and more than 70% had prior anti-PD-1/anti-PD-L1 therapy.
Among patients evaluated for survival and antitumor activity, median follow-up was 10.6 months for those who received the 10-mg dose and 10.3 months for those who received the 100-mg dose.
Results showed objective response rates of 40% (97.5% CI, 29-52) in the 10-mg group and 32% (97.5% CI, 21-44) in the 100-mg group.
More than half (59%) of patients who responded to therapy remained in response for at least 6 months.
Researchers reported median PFS of 4.9 months (95% CI, 2.9-6.7) in the 10-mg group and 3.9 months (95% CI, 2.6-4.4) in the 100-mg group.
OS data had not matured; however, researchers reported median OS of 14.3 months (95% CI, 10.8 to not estimable) in the 10-mg group and not estimable (95% CI, 12.4 to not estimable) in the 100-mg group. Estimated 9-month OS rates were 68% in the 10-mg group and 66% in the 100-mg group.
Investigators observed no new safety signals. Toxicity generally appeared manageable and could be treated with supportive care, Paz-Ares said.
The most common adverse events included cytokine release syndrome (10 mg, 51%; 100 mg, 61%), decreased appetite (10 mg, 29%; 100 mg, 44%) and pyrexia (10 mg, 35%; 100 mg, 33%).
Most CRS cases occurred during the first treatment cycle, and the majority of events were grade 1 or grade 2.
Grade 3 CRS occurred among 1% of patients in the 10-mg group and 6% of those in the 100-mg group.
Immune effector cell-associated neurotoxicity occurred infrequently and predominantly was observed with the 100-mg dose, Paz-Ares said.
About one-third of patients experienced loss of appetite or fever, and about one-third of patients experienced constipation, Paz-Ares said.
Treatment-related adverse events prompted 3% of patients to discontinue tarlatamab.
Based on the efficacy-safety balance observed in the phase 2 trial, researchers selected 10 mg every 2 weeks as the dose to assess in the ongoing phase 3 DeLLphi-304 study, designed to compare the efficacy and safety of tarlatamab with standard chemotherapy.
Perspective
Back to TopPilar Garrido, MD, PhD
Tarlatamab 10 mg demonstrated encouraging results in a highly selected population, with durable anticancer activity and manageable safety in a setting of huge clinical need, but there are challenges ahead.
Small cell lung cancer is the most aggressive form of lung cancer. Patients typically have a very good response to chemotherapy, but most relapse within 6 months. In the United States, lurbinectedin (Zepzelca; Jazz Pharmaceuticals, PharmaMar) is approved for use as second-line therapy. No therapies are specially approved for the third-line setting or beyond and, to date, no targeted therapies are available. There are four major molecular subtypes but, despite molecular and clinical heterogeneity, small cell lung cancer is treated as a single entity.
DLL3 is an attractive emerging therapeutic target in small cell lung cancer. It is overexpressed on the surface of small cell lung cancer tumor cells, with minimal to no expression on normal cells. There are different DLL-3 targeted therapies in development.
This study obviously was conducted in a highly selected population. We did see some challenges related to toxicity. Currently this is in-patient administration only, and this is challenging when thinking about adherence and convenience for our patients. Another potential challenge is the limited experience managing CRS and neurological-related adverse events.
In terms of efficacy, we need to know the CNS activity. It’s important to have longer follow-up. We also need to identify the characteristics of patients most likely to respond. Researchers observed responses regardless of DLL-3 expression, so we need a better biomarker. It also will be important to know the details of the ongoing phase 3 trial.
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Paz-Ares L, et al. Abstract LBA92. Presented at: European Society for Medical Oncology Congress; Oct. 20-24, 2023; Madrid.
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