SUMMARY: The FDA on May 16, 2024, granted accelerated approval to IMDELLTRA® (Tarlatamab-dlle) for Extensive Stage-Small Cell Lung Cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 13-15% of all lung cancers. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis. Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.
Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. Second-line treatment options are limited, and the response duration is short varying from 3-5 months, with Overall Survival rarely exceeding 8 months. There are presently no approved therapies for third line and beyond and these patients face a dire prognosis.
Delta-like protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 85-96% of the SCLC tumors), making this a a potential target in the treatment of Small Cell Lung Cancer.
Tarlatamab is a first-in-class 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.
The present FDA approval was based on the efficacy of Tarlatamab in the open-label, global, multicenter, multi-cohort, Phase 2 DeLLphi-301 trial, which included patients with Relapsed/Refractory Extensive Stage Small Cell Lung Cancer with disease progression after platinum-based chemotherapy. In this Phase 2 study, patients received a step dose of Tarlatamab 1 mg IV on day 1 of cycle 1, after which they received the target dose of either 10 mg or 100 mg on day 8 and day 15 of cycle 1 and every 2 weeks thereafter in 28-day cycles (two doses per cycle) until disease progression or unacceptable toxicity. Overall 134 patients received Tarlatamab 10 mg IV, the median age in this group was 64 years and the median duration of treatment in this group was 5.1 months. Positivity for DLL3 expression on tumor cells was not required for trial entry and patients with symptomatic brain metastases, interstitial lung disease or non-infectious pneumonitis, and active immunodeficiency were excluded.
The Primary end point was Objective Response Rate (Complete or Partial Response), as assessed by Blinded Independent Central Review. Secondary end points included Duration of Response, Progression-Free Survival and Overall Survival. Efficacy was evaluated in 99 patients with disease progression enrolled in this study, who received Tarlatamab 10 mg IV, following platinum-based chemotherapy.
The Objective Response Rate was 40% and median Duration of Response was 9.7 months. The researchers noted that this Objective Response Rate far exceeded the historical control benchmark of 15% for the Primary end point. Of the 69 patients with available data regarding platinum sensitivity status, the ORR was 52% in 27 patients with platinum-resistant Small Cell Lung Cancer (defined as progression less than 90 days after last dose of platinum therapy) and 31% in 42 patients with platinum-sensitive Small Cell Lung Cancer (defined as progression 90 or more days after last dose of platinum therapy). The median Overall Survival was 14.3 months, with final and complete survival data still not mature. The most common adverse reactions were Cytokine Release Syndrome (CRS), fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, and constipation, anemia and nausea.
It was concluded that Tarlatamab represents a new immunotherapeutic approach for Small Cell Lung Cancer. It is the first and only DLL3-targeting Bispecific T-cell Engager therapy, establishing itself as an effective and innovative treatment option for patients with previously treated Small Cell Lung Cancer.
Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. Ahn M-J, Cho BC, Felip E, et al. for the DeLLphi-301 Investigators. N Engl J Med 2023;389:2063-2075
