ALK patients with high PD-L1 expression and immunotherapy
Many of our members are wondering if immunotherapy with current checkpoint inhibitors may be a good idea for them if they have been diagnosed with a high PD-L1 expression. Spoiler alert: it is a bad idea for most. Read on to find out why.
Using immunotherapy with checkpoint inhibitors has invigorated the treatment and hopes of many lung cancer patients since 2015. Targeting PD-1 (antibodies called Nivolumab, Pembrolizumab) or its ligand, PD-L1 (antibodies called Atezolizumab and Durvalumab) has been found to be very effective against lung cancer, giving doctors a new tool in their ever-expanding arsenal of medicines. However, this may not be applicable to lung cancer patients with the ALK mutation.
In 2008, there was a brief report stating that a T cell lymphoma (cancer of the lymphatic system) where ALK was active also strongly expressed PD-L1. This expression was highly dependent on the activity of ALK through a downstream protein called STAT3. STAT3 can interact with PD-L1’s control area (or called promoter) to regulate PDL-1’s gene expression[1].
By 2015, the results of the previous group were confirmed by a Japanese group. They expressed EML-4/ALK fusion in a cell line (where ALK was always active)and found the expression of PD-L1 to be higher than normal. However, if the cells were treated with Alectinib, an ALK specific tyrosine kinase inhibitor (TKI), PD-L1 expression was reduced[2].
Around this time, there was a big push to learn more about the interaction between ALK and PD-1/PD-L1. A group in Mass General headed by Dr. Costa found that a higher PD-L1 expression may not occur in actual real-life data. Out of the 71 specimens that were examined, about 4 patients harbored the ALK mutation. From those four patients, only 1/4 of ALK patients had high PD-L1 expression[3].
A group in France published a report in mid-2017 about a clinical trial where patients were given immune checkpoint inhibitors (Nivolumab, Pembrolizumab, and Atezolizumab) compared to standard chemotherapy treatment. There was no benefit for ALK patients with immune checkpoint inhibitors[4].
A review was published in 2018 by a group in Spain focusing on immunotherapy and EGFR/ALK patients. In several clinical trials, there were not enough ALK patients to give a significant result. Also, there were clinical trials where ALK patients were excluded[5].
Just published by a Korean group in 2020, they wanted to investigate the reason for the lack of response of ALK patients to immune checkpoint inhibitors by using a mouse model. They had an EML4-ALK mutant mouse and treated the mouse with immune checkpoint inhibitors or Ceritinib (an ALK TKI). There was a lack of increase of effector T cell response that mediate anti-tumor activity[6]. Authors concluded that ALK-positive tumors progressing on Ceritinib are not immunogenic enough to respond to immune checkpoint inhibitors.
There was a report from France in August 2020 that there was a patient that had a durable response to monotherapy on Nivolumab after Ceritinib and platinum-based chemotherapy[7].
In our Facebook group, ALK Positive, there have been discussions on immunotherapy with checkpoint inhibitor since early 2016. Mirroring the scientific world, ALK-positives were very enthusiastic about this newly developing immunotherapy treatment. Several members reported the use of Keytruda (Pembrolizumab) or Opdivo (Nivolumab) as part of their treatment plan. There was a quote mentioning 5% to 10% effectiveness of immunotherapy on ALK patients as monotherapy. However, a push for combined immunotherapy was seen around the same time. By 2017, reports from members mentioned that MD Anderson (TX, USA) does not think ALK patients do well on single immunotherapy. A rush of discussion started to focus on how much % PD-L1 expression is important. Reports from our gurus, Dr. Shaw and Dr. Camidge, by 2019 showed less enthusiasm about immunotherapy as the next step for ALK patients if they have exhausted all available TKIs. They recommended going into a clinical trial or chemotherapy plus immunotherapy. Currently, it is believed that immunotherapy as a monotherapy is not advisable for ALK patients. However, immunotherapy can be a part of a combination therapy.
In conclusion, research is giving scientists some mixed results to be conclusive at best. Doctors’ personal observation of how immunotherapy affects their ALK patients can lead to a positive or a negative bias toward immunotherapy treatment. More studies needs to be done on how immunotherapy can affect ALK patients.
2008 https://www.pnas.org/content/105/52/20852.short [1]
2015 https://pubmed.ncbi.nlm.nih.gov/26019170/ [2]
2017 https://www.sciencedirect.com/science/article/pii/S155608641730014X# [3]
https://link.springer.com/article/10.1007/s11523-017-0510-9 [4]
2018: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074780/ [5] (review)
https://journals.sagepub.com/doi/full/10.1177/1758834017745012 (review)
2020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394300 [6]
https://www.sciencedirect.com/science/article/abs/pii/S016950022030427X [7]
AUTHOR: Alice Chou