Overcoming the challenges of low PD-L1 lung cancer: The latest …

The addition of immune checkpoint inhibitors to lung cancer treatment has shown promising outcomes in terms of increasing survival rates. However, immune checkpoint inhibitors are not very effective against tumors that contain a low number of programmed death-ligand 1 (PD-L1) on them. Recently, a new immunotherapy regimen consisting of checkpoint inhibitors and other immunotherapy drugs has shown encouraging activity against low PD-L1 tumors.

Let’s delve deeper into a clinical trial exploring an immunotherapy combination in an effort to understand what benefit this combination holds for patients with low PD-L1 lung cancer.

Lung cancer is one of the major types of cancer and the leading cause of cancer-related deaths worldwide. In most cases, it results from uncontrolled growth in airways inside the lungs – called bronchi, or the air sacs – called alveoli. With time, cancer spreads to lymph nodes or other organs in the body, such as the brain in a process called metastasis.

Lung cancer can be of various types based on its site of origin in the lung and the mutations it harbors. Two major types are:

Small cell lung cancer

Non-small cell lung cancer (NSCLC), which makes up 80% to 85% of lung cancers and includes adenocarcinoma and squamous cell carcinoma

The standard treatment of localized lung cancer is surgery to remove the tumor followed by radiotherapy and/or chemotherapy. For metastasized lung cancer, radiotherapy and chemotherapy are given before the surgery [1]. Immune checkpoint inhibitor drugs are being increasingly added to the treatment of lung cancer as a means of improving survival rates.

Lung cancer

The immune system recognizes and destroys the mutant cells before they have the opportunity to become a tumor. However, some cancer cells acquire mutations that allow them to evade the immune response. One way that cancer cells do this is by inhibiting the immune cells, especially T-cells which are at the forefront of the body's fight against tumors. T-cells have a receptor on their surface called the anti–programmed death 1 (PD-1) which acts as a checkpoint meaning that it acts as a "brake" for these cells and prevents them from attacking healthy cells in the body.

Cancer cells exploit this mechanism by binding to the PD-1 receptor and avoiding being destroyed. To circumvent this problem, immune checkpoint inhibitors have been developed which are basically antibodies that attach themselves to the receptor on the T-cells [2]. Thus, they prevent cancer cells from coming into contact with this receptor and inhibiting T-cells. Durvalumab is one such immune checkpoint inhibitor that has been shown to be effective in lung cancer patients having a high number of tumor-infiltrating T-cells.

However, immune checkpoint inhibitors are not as effective against tumors having a PD-L1–low or PD-L1–negative profile. This presents a challenge in achieving the necessary immune response against cancer.

One potential solution lies in novel therapeutic regimens that can augment the immune checkpoint inhibitors. Tremelimumab, a humanized monoclonal antibody, is a promising candidate for these regimens. It targets CTLA-4, a protein found on the surface of T-cells, and enhances their ability to bind with other proteins, CD80 and CD86, which in turn results in diversification of T-cell responses and increased tumor infiltration.

When given together, tremelimumab and durvalumab work in a synergistic manner and support a sustained antitumor response. The addition of chemotherapeutic drugs further increases the exposure of tumor antigens to the immune system which results in better clinical outcomes.

Seeing its potential, tremelimumab plus durvalumab combination therapy has been evaluated in phase 3 clinical trial for metastatic NSCLC [3].

This clinical trial enrolled participants who had:

age 18 years or more.

Eastern Cooperative Oncology Group performance-status score of 0 or 1. This score reflects a patient's ability to carry out daily activities. It ranges from 0 (fully active) to 5 (dead).

measurable disease according to RECIST v1.1

not received any prior anti-cancer therapy.

no known EGFR mutations or ALK translocations.

All the participants were randomly divided into 3 groups which received:

Administered for up to four 21-day cycles.

Followed by durvalumab once every 4 weeks until progression.

One additional dose of tremelimumab was given.

Administered for up to four 21-day cycles.

Followed by durvalumab once every 4 weeks until progression.

Administered for up to six 21-day cycles.

This clinical trial found that:

Both experimental regimens; tremelimumab + durvalumab + chemotherapy and durvalumab + chemotherapy demonstrated higher 12-month progression-free survival and 24-month overall survival rates compared to chemotherapy alone [4].

Most of the adverse effects were related to the chemotherapy. They were low-grade and manageable within current guidelines.

And most importantly, patients having metastatic NSCLC with less than or equal to 1% PD-L1 appeared to gain survival from the addition of tremelimumab to durvalumab and chemotherapy.

This phase 3 clinical trial has shown that the addition of tremelimumab to the regimen increases the efficacy of immune checkpoint inhibitors against tumors that do not respond well to the immune checkpoint inhibitors alone due to lack of PD-L1 on them. While the advantage may be minor compared to the effect on tumors with high PD-L1 expression, it is still a step in the right direction. These findings offer hope for patients who were previously unresponsive to immune checkpoint inhibitors alone.

1. R. D. Neal, F. Sun, J. D. Emery, and M. E. Callister, “Lung cancer,” BMJ, vol. 365, p. l1725, Jun. 2019, doi: 10.1136/bmj.l1725.

2. S. Bagchi, R. Yuan, and E. G. Engleman, “Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance,” Annu Rev Pathol, vol. 16, pp. 223–249, Jan. 2021, doi: 10.1146/annurev-pathol-042020-042741.

3. AstraZeneca, “A Phase III, Randomized, Multi-Center, Open-Label, Comparative Global Study to Determine the Efficacy of Durvalumab or Durvalumab and Tremelimumab in Combination With Platinum-Based Chemotherapy for First-Line Treatment in Patients With Metastatic Non Small-Cell Lung Cancer (NSCLC) (POSEIDON),” clinicaltrials.gov, Clinical trial registration NCT03164616, Mar. 2023. Accessed: Mar. 16, 2023. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT03164616

4. M. L. Johnson et al., “Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study,” J Clin Oncol, vol. 41, no. 6, pp. 1213–1227, Feb. 2023, doi: 10.1200/JCO.22.00975.