Immutep's LAG-3 Therapy Significantly Boosts Response Rate of Keytruda in NSCLC and HNSCC

Recently, Immutep announced that its soluble LAG-3 fusion protein eftilagimod alpha (efti, also known as IMP321), in combination with Merck & Co.’s blockbuster PD-1 inhibitor Keytruda, achieved positive interim results in a Phase 2 clinical trial. As a first-line treatment for patients with non-small cell lung cancer (NSCLC), the combination therapy demonstrated an overall response rate (ORR) of 47%. In contrast, Keytruda monotherapy yields an ORR of only 20% in NSCLC patients when not selected for high PD-L1 expression. Additionally, the combination therapy achieved an ORR of 33% in the second-line treatment of patients with head and neck squamous cell carcinoma (HNSCC).

LAG-3 protein can regulate the signaling pathways of T lymphocytes and antigen-presenting cells (APCs), playing an important role in adaptive immune responses. Soluble LAG-3 binds to major histocompatibility complex class II (MHC II) molecules on the surface of APCs, thereby activating these cells. This activation leads to an increase in the number and activation status of cytotoxic CD8-positive T cells. Through this mechanism, soluble LAG-3 protein enhances the immune response against cancer antigens.

Image source: Immutep official website

Although Keytruda has been approved for the treatment of patients with non-small cell lung cancer (NSCLC), PD-L1 expression levels significantly influence whether patients can benefit from this therapy. Statistics show that the objective response rate to Keytruda monotherapy is nearly 40% in NSCLC patients with PD-L1 expression >50%, whereas it is only 15–20% in those with PD-L1 expression levels of 1–49%. Patients who do not express PD-L1 are expected to have an even lower response rate. Expanding the patient population that benefits from Keytruda therapy is one of MSD’s key research priorities. Soluble LAG-3 protein may enhance the efficacy of Keytruda by activating immune cell responses.

▲ Targeting LAG3 can treat a variety of diseases (Image source: Immutep official website)

Eftilagimod alpha is a soluble LAG-3 fusion protein. In the Phase 2 clinical trial named TACTI-002, it was used in combination with the PD-1 inhibitor Keytruda to treat patients with different types of non-small cell lung cancer (NSCLC) and patients with squamous cell carcinoma of the head and neck. In Part 1 of the trial, Cohort A consisted of NSCLC patients who had never received PD-1/PD-L1 inhibitor therapy. Patients enrolled in the trial were not required to meet any specific PD-L1 expression level criteria. The trial results showed that among the 17 treated patients, the objective response rate (ORR) reached 47%. Moreover, responses were observed across all three categories of patients with varying PD-L1 expression levels; among the 8 patients who achieved a response, 5 had PD-L1 expression levels <50%.

▲ PD-L1 Expression Levels and Clinical Responses in NSCLC Patients of Cohort A (Image source: Reference [1])

Dr. Frederic Triebel, Chief Scientific Officer and Chief Medical Officer at Immutep, stated: “The results of the TACTI-002 study are highly encouraging. A response rate of 47% was observed in patients with first-line non-small cell lung cancer (NSCLC), whereas the typical response rate for Keytruda monotherapy is around 20% when patients are not preselected for high PD-L1 expression. This indicates that the combination therapy can be effective in patients who do not respond to monotherapy.”

He added, “It is also exciting that patients with head and neck squamous cell carcinoma receiving second-line therapy achieved an overall response rate of 33%. The expected response rate for Keytruda monotherapy is typically 15–18%. Moreover, three patients in this cohort have yet to be evaluated.”

Based on the positive clinical results from TACTI-002, Immutep has initiated the second phase of this clinical trial to enroll more patients and evaluate the efficacy of this combination therapy.

References:

[1] Immutep Reports Positive TACTI-002 Data. Retrieved February 18, 2020, from https://www.immutep.com/files/content/investor/press-release/2019/2030895.pdf

[2] Immutep. Retrieved February 18, 2020, from https://www.immutep.com/

Flash Update | LAG-3 Therapy Significantly Improves Keytruda Response Rate in First-Line Treatment of Non-Small Cell Lung Cancer

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