Are immunotherapies and combination treatments the future of lung cancer?

Some cancers are more closely associated with the immune system, and these cancers are called "immunogenic cancers" . The best-known members of this group used to be malignant melanoma, a skin cancer, and kidney cancer. However, studies in recent years have shown that lung cancer, previously thought not to be immunogenic, also belongs to this group. The new generation of immunotherapy drugs, "immune checkpoint inhibitors", offer new avenues in the treatment of non-small cell lung cancer (NSCLC), once thought to have weak immunogenic potential.

In lung cancer, the current state of immunotherapies, the rationale for immunotherapy, ongoing studies and possible paths in this field were presented in a report published in The Oncologist.

- Related topic: Immunotherapy and Cancer Vaccines

Among patients with advanced (stage 4.) lung cancer who had previously received chemotherapy, data from a series of studies now show that PD-1/PD-L1 inhibitors (nivolumab and pembrolizumab) increase survival times.

The fact that only some patients obtain positive results with these treatments shows that we need to make greater efforts to identify biomarkers that determine who may benefit from them. This could protect patients from possible drug toxicity (side effects) and the high costs of these drugs.

In the report, the researchers noted that, in the recently conducted CheckMate-057 study, PD-L1 markers predicted that Nivolumab, a checkpoint inhibitor, would improve overall survival, while the immunohistochemistry of the biomarkers was “incomplete”.

PD-L1, a cell membrane protein, is an immune-suppressing molecule produced in various immune cells and some cancer cells. The tumors we call PD-L1-positive tumors produce high levels of this protein. This molecule is used to silence immune cells. PD-L1 is not present at the same density in every tumor. Tumors containing more PD-L1 are known to respond better to immune checkpoint inhibitors.

According to the researchers, Another point of debate about PD-L1 markers is that this biomarker can change over time. However, the greatest debate about PD-L1 is that it is not binary. In lung cancer, we are accustomed to binary biomarkers that are clearly either present or absent. In contrast, PD-L1 expression positivity is more of a continuous variable, so we do not know the correct cutoff point. Some studies regard positivity greater than %1, others greater than %5, and even a small number greater than %50 for PD-L1 as "truly positive".

In the study discussed, the researchers examined studies analyzing the efficacy of Pembrolizumab, an anti-PD-1 inhibitor, including KEYNOTE-001 and 010 , as well as a study investigating the tolerability of Durvalumab, an anti-PD-L1 inhibitor. KEYNOTE-024 analyzes the efficacy of Pembrolizumab as first-line treatment for patients with NSCLC.

The researchers also highlighted the potential of other combination treatments that pair PD-L1 inhibitors with other checkpoint inhibitors, costimulatory checkpoints, immunomodulatory molecules, chemotherapy, vaccines and radiation.

The report also highlights the combination of PD-1/PD-L1 inhibitors with CTLA-4, which is promising for the future according to early clinical trial data. Results of ongoing studies including CheckMate-026 and KEYNOTE-024 are “eagerly awaited”.

In selected patient subgroups, such as those with high PD-L1 levels, PD1 inhibitors are expected to become the standard of care even in first-line lung cancer treatment. What role combination treatments will play in this situation is another important issue.