Lung cancer is the most common cause of cancer-related deaths in the United States resulting in more than 158,000 deaths each year. With a 5-year survival rate at only 18 percent, the development of new and improved treatment options is needed.
Tumor cells develop mechanisms to evade detection by the immune system by expressing a protein called PD-L1. PD-L1 binds to its receptor found on immune cells to down regulate their activity. Additionally, immune cells express a molecule called CTLA-4 that inhibits their activation.
Imfinzi (Durvalumab) and tremelimumab are drugs that block the PD-1/PD-L1 and CTLA-4 pathways, respectively, and function to re-stimulate the immune system to target tumor cells. Both drugs are active as single-agents in several tumor types, and research suggests combining these two drugs may result in added clinical benefit.
Tremelimumab is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4 which enhances T-cell activation and primes the bodies immune response to cancer fostering cancer cell death. Tremelimumab is being evaluated in clinical trials programs in combination with Imfinzi in NSCLC, SCLC, bladder, and liver cancer.
Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering a cancers immune-evading tactics and releasing the inhibition of immune responses.
Researchers initially evaluated 102 patients with advanced NSCLC in a phase 1b study to evaluate Imfinzi and tremelimumab combination therapy. The researchers found that Imfinzi combined with tremelimumab resulted in manageable side effects. The most common were diarrhea, fatigue, and itching. Most toxicities could be reversed by administration of immunosuppressive drugs.
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They also reported that Imfinzi plus tremelimumab has significant anti-tumor activity in advanced NSCLC patients - 23% of whom achieved either a complete or a partial response to treatment. The drug combination was active in patients with and without tumor expression of PD-L1.
Pivotal Trial Confirms Benefit
According to study results released at the September 2021 World Lung Congress, and updated in October 2022 Imfinzi and tremelimumab, when added to platinum-based chemotherapy, demonstrated an improvement in overall survival and delayed cancer progression compared to chemotherapy alone when used as the initial treatment of stage IV (metastatic) NSCLC.
The POSEIDON clinical trial directly compared Imfinzi plus platinum-based chemotherapy or Imfinzi, tremelimumab and chemotherapy to chemotherapy alone as the initial treatment of 1,013 patients with either non-squamous or squamous NSCLC. The trial excluded patients with certain epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions.
Patients treated with a short course of five cycles of tremelimumab over 16 weeks in addition to Imfinzi and chemotherapy improved overall survival by 25% compared to chemotherapy alone. An estimated 25% of patients treated with the combination were alive at three years versus 13.6% for those treated with chemotherapy alone. Results appeared more pronounced with in patients with non-squamous NSCLC histology. An estimated 31.4% of patients with non-squamous NSCLC treated with the combination were alive at three years versus 17.3% for those receiving chemotherapy alone.
- Moffitt Cancer Center news release. (2016.) Retrieved from:
- Peters S, et al. Association Between KRAS/STK11/KEAP1 Mutations and Outcomes in POSEIDON: Durvalumab ± Tremelimumab + Chemotherapy in mNSCLC. Presented at IASLC 2022 World Conference on Lung Cancer, 9-13 September 2022.
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