Immune Checkpoint Inhibitor Resistance: What To Do Next?

Immunotherapy, a type of treatment that helps the body’s own immune system fight cancer, is often discussed as a first line of treatment for people with metastatic non-small cell lung cancer (mNSCLC) without an actionable biomarker, like EGFR or ALK. Immunotherapy has been proven to provide better outcomes for most of this patient population, though treatment resistance can reduce effectiveness. So, what can be offered to people who develop resistance to the drugs used in immunotherapy, specifically immune checkpoint inhibitors?

Progression after immunotherapy

Many people with mNSCLC who experience disease progression after first-line immunotherapy treatment are often told by their doctor to try a different type of chemotherapy. As of April 2022, the National Comprehensive Cancer Network (NCCN) recommends this as a subsequent line of treatment for people with lung cancer who have already tried immunotherapy. This leaves many people with lung cancer feeling stuck and without options. While there is currently no consensus better choice than the NCCN recommendation, there is a universally understood need for more research into this area.

Many physician scientists are passionate about running clinical trials to find the next best treatment option for people with mNSCLC who progress after immunotherapy. Currently, there are different types of clinical trials studying the combination of already approved immune checkpoint inhibitors with other types of drugs to help increase the efficacy of the immune checkpoint inhibitors.

PD1/PDL-1 combination therapy research

Checkpoint inhibitors are a type of immunotherapy that block the body’s immune “checkpoints” so that the cancer cannot control them. One checkpoint that is commonly targeted for lung cancer is the PD-1/PDL-1 checkpoint, which is a major focus of clinical trial research right now. There are several combinations being studied:

• Priming the immune system
  One approach of these trials is to combine PD-1/PD-L1 inhibitors with other drugs that help prime the immune system to be more active and attempt to supercharge the efficacy of the PD-1/PD-L1 inhibitor.
• Controlling the tumor environment
  A second approach is to combine PD-1/PD-L1 inhibitors with drugs that can help to control the tumor environment such as VEGFR inhibitors. It is hypothesized that PD-1/PD-L1 inhibitors can sometimes stop working due to an “immune suppressive tumor environment” leading to tumor growth and/or resistance. This second approach intends to limit the effect of the tumor environment on the efficacy of PD-1/PD-L1 inhibitors.
• Combining checkpoint inhibitor treatments
  A third approach is to combine PD-1/PD-L1 inhibitors with inhibitors for other immune checkpoints. An example of this is the now FDA approved combination of Opdivo (a PD-1 inhibitor) and Yervoy (a CTLA-4 inhibitor). However, there are trials with other checkpoints ongoing with the hope of discovering more options for people with mNSCLC.

Despite promising research in this space, there is currently no clear best option. Clinical trials help researchers identify new and better treatment options – including immunotherapies. If you’d like to discuss whether a clinical trial is the right option for you or a loved one, please contact one of our LungMATCH navigators by calling our free HelpLine at 800-298-2436 or emailing support@go2.org.