A preclinical study of non-small cell lung cancer has found that triple therapy with trametinib, palbociclib, and radiation can inhibit the growth of tumours harboring a KRAS mutation. There are currently no therapies that specifically target this mutation in non-small cell lung cancer, providing a basis for future clinical trials.
What is Non-Small Cell Lung Cancer?
Non-small cell lung cancer (NSCLC) makes up between 85-90% of all lung cancers. While the cause of NSCLC remains unknown, some of the risk factors include smoking, exposure to radon, exposure to asbestos, air pollution, and a family history of lung cancer. There are three distinct subtypes of NSCLC:
- Adenocarcinomas – these cancers are typically found in the outer part of the lungs.
- Squamous cell carcinomas – these cancers typically form in the centre of the lungs, close to the bronchus.
- Large cell carcinomas – these cancers are found in all parts of the lung. They differ from the other two sub-types in that they are faster growing.
Symptoms of NSCLC can include chest pain, cough and shortness of breath, fatigue, and coughing up of blood. Whereas later stages of the disease can produce symptoms such as bone and joint pain, difficulty swallowing, facial swelling, and general weakness.
What are current treatments available for NSCLC?
Standard treatment options for NSCLC include surgery, radiotherapy, and chemotherapy. Targeted therapies are also being developed, including immunotherapy. Treatment typically depends on the stage of the tumour at diagnosis, with earlier stages typically being treated with surgery and radiotherapy or chemotherapy. Patients diagnosed with later, more difficult to treat stages of the disease, which include cancers that have spread outside the lungs, are typically candidates for other targeted therapies and may be eligible to participate in a clinical trial. Targeted forms of therapy aim to specifically target key molecules that are involved in growth of NSCLC cells. There are two key cellular proteins that are currently targets for NSCLC therapy, these are EGFR and ALK.
Some NSCLC tumours contain alterations in the EGFR gene. In these tumours, certain drugs that inhibit EGFR may be effective. These drugs include erlotinib, gefitinib, and afatinib.
In tumours that contain an ALK gene mutation, drugs such as crizotinib, ceritinib, or alectinib, which target the ALK gene, may be effect forms of treatment.
While there are targeted treatments for both EGFR and ALK mutations, there is another subset of tumours that have been found to have a mutation in the KRAS gene. This subset of tumours are also resistant to current forms of therapy, however there is no a specific targeted therapy currently available.
Pre-Clinical Study of Trametinib and Palbociclib
A group of researchers from Thomas Jefferson University has recently reported on a study that investigated the effect of combining trametinib with palbociclib on NSCLC cells and animal models with a KRAS-mutation.
Trametinib – is a drug that inhibits the signalling of MEK1 and MEK2 proteins. These proteins are involved in the RAS/RAF/MEK/ERK signalling cascade that regulates cell growth.
Palbociclib – is a drug that inhibits CDK4 and CDK6 proteins, which leads to the inhibition of cell growth.
The researchers found that treatment with trametinib and palbociclib in combination was able to sensitize the cancer cells to subsequent radiation therapy. This was achieved in cells that were initially resistant to trametinib, suggesting that a combination of targeting both signalling pathways disabled the cells enough for radiation therapy to become effective. The study provides a basis for further clinical testing of this combination in patients who have tumours with the KRAS mutation. The preclinical data demonstrates positive results, and while neither of the drugs are currently approved for treating NSCLC, further research is clearly warranted.
Clinical Trial of Combination Trametinib and Palbociclib
The pharmaceutical companies GlaxoSmithKline and Pfizer are currently recruiting participants in Texas, Massachusetts, and Tennessee, to take part in a trial of combination trametinib and palbociclib for treatment of solid tumours.
The study will be made up of three distinct parts. Part 1 of the study will be a Phase I trial that will investigate the appropriate doses and schedules to be used for trametinib in combination with palbociclib in patients with solid tumours. An initial dose of 75mg of palbociclib for 21 days, followed by 7 days with no palbociclib, in addition to 1.5mg of trametinib once per day, for a combined 28-day cycle will be administered. Subsequently, increasing doses will be tested until the optimal dose is found. Part 2 of the study will enroll additional participants to assess the effect of this combination of tumours with various tumour biomarkers, in addition to anti-tumour activity. Part 3 of the trial will go ahead only if parts 1 and 2 are successful at finding sufficient anti-tumour activity. It will be a Phase II clinical trial of the drug combination in patients with solid tumours. Participants will be eligible to take part in the trial if they are over the age of 18, with a confirmed diagnosis of a solid tumour that has not responded to the current standard of therapy. Patients who have been previously treated with either a MEK inhibitor or a CDK4/6 inhibitor, or who are positive for the BRAF600 mutation may not be eligible to participate.
Non-Small Cell Lung Cancer Fact Sheet, Available from: https://www.nlm.nih.gov/medlineplus/ency/article/007194.htm Last Accessed: January 5, 2015.
American Cancer Society Non-Small Cell Lung Cancer Information for Patients, Available from: http://www.cancer.org/cancer/lungcancer-non-smallcell/ Last Accessed: January 5, 2015.
Jefferson University News Release: “Three Hits to Fight Lung Cancer”, Available from: http://www.newswise.com/articles/view/645271/?sc=mwhn Last Accessed: January 5, 2015.
Tao, Z, Le Blanc, JM, Wang, C, Zhan, T, Zhuang, H, Wang, P, Yuan, Z, Lu, B. “Coadministration of Trametinib and Palbociclib Radiosensitizes KRAS-Mutant Non–Small Cell Lung Cancers In Vitro and In Vivo” Clinical Cancer Research January 1, 2016 22; 122
Clinicaltrials.gov “A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Anti-Cancer Activity of Trametinib in Combination With Palbociclib in Subjects With Solid Tumors” Available from: https://www.clinicaltrials.gov/ct2/show/NCT02065063?term=NCT02065063&rank=1 Last Accessed: January 5, 2015.
Written by Deborah Tallarigo, PhD