Navigating a paradigm shift; food and drug administration approved Tarlatamab-dlle redefining the landscape of small cell lung cancer therapy

Sir,

Small cell lung cancer (SCLC) constitutes 10% of lung cancer.¹ It is the leading cause of death due to cancer in men and the second most prevalent cause of cancer related death in women worldwide.² It is an extremely hostile tumor with early development, spread, and fatal as it is typically found too late. Early-stage patients are usually treated with chemotherapy and thoracic radiation and surgery is rarely used to treat this malignancy. The addition of immunotherapy to first-line chemotherapy has improved survival for the first time in the decennary. It has demonstrated promise in producing significant, long-lasting responses. The disease is still challenging to treat but adding radiation therapy to a patient's care at certain intervals may enhance illness control. Platinum-based chemotherapy is initially quite effective, eliciting prompt and often substantial responses, however, they are transient effects, and when SCLC recurs, treatment resistance is strong.³

The specific biology of SCLC has been revealed in recent years, due to the rapid development of modern molecular biology tools.¹ Lurbinectedin inhibition may reduce the proliferation of cancer cells, mainly by preventing mitosis. It is an inhibitor of RNA polymerase II, which is commonly hyperactivated in SCLC, resulting in excessive transcription in tumor cells.⁴ Ipilimumab is a human anti-CTLA-4 monoclonal antibody that stimulates T cell activation and proliferation by blocking CTLA-4 and its ligands (CD80/CD86).⁵ It has shown long lasting suppression in multiple tumor types.^6,8 Atezolizumab and pembrolizumab are humanized monoclonal antibodies. Atezolizumab is an inhibitory ligand that binds to the PD-1 receptor and adversely controls T cell activation and proliferation. However, pembrolizumab binds to the PD-1 receptor and prevents the negative signaling that is brought about by the interaction of PD-1 with its ligands.^9,10 Another humanized monoclonal antibody that targets PD-L1 is Durvalumab.¹¹ A completely human PD-1 immune checkpoint inhibitor antibody, nivolumab is safe and effective in SCLC patients.^12,13

Drug resistance and cancer cell’s resistance to genotoxic stimuli have been linked with overexpression of poly (ADP-ribose) polymerase (PARP).¹⁴ The PARP enzyme is substantially expressed in SCLC in comparison to normal lung epithelial cells and other histologic subtypes of lung cancer.¹⁵ For the past 10 years, platinum-etoposide chemotherapy has been the accepted standard of care. However, persistent thoracic lesions are seen in 75% of the patients, and these lesions frequently reoccur in the first year.¹⁶ Brain metastasis (BM) is quite common in patients with SCLC. According to prior research, 50% of SCLC patients had a chance of developing BM following systemic medication. Whole-brain radiation therapy (WBRT) is the usual course of treatment for BM in SCLC. Nevertheless, WBRT worsens quality of life and cognitive function.¹⁷

Amgen researchers have developed a first in class immunotherapy called IIMDELLTRA. It binds to CD3 on T cells and DLL3 on tumor cells, causing T cells to become activated and destroy DLL3-expressing SCLC cells. As a result, the cancer cell is lysed and a cytolytic synapse is formed.^18,19 DLL3 is an interesting target since it is a protein that is expressed on the surface of SCLC cells in approximately 85-96% of patients with SCLC but is little expressed on normal healthy cells.^20,21

In pivotal DeLLphi-301 study in the DeLLphi-301 trial IIMDELLTRA showed an impressive 40% objective response rate, 9.7-month median duration of response, and 14.3-month median. Overall survival, the patients responded well to tarlatamab treatment in 40% of cases, with a median overall survival of 14.3 months. These effects were exceptionally long-lasting, signifying a significant shift in the paradigm for treating SCLC.²²

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22. 22. FDA approves IMDELLTRATM (Tarlatamab-DLLE), the first and only T-cell engager therapy for the treatment of extensive-stage small cell lung cancer. Amgen. 2024. Available at: https://www.amgen.com/newsroom/press-releases/2024/05/fda-approves-imdelltra-tarlatamabdlle-the-first-and-only-tcell-engager-therapy-for-the-treatment-of-extensivestage-small-cell-lung-cancer. Accessed on 31 May 2024.