Targeted therapy drugs have made a positive impact on treating various cancers by inducing dramatic disease remissions; however, many patients find themselves facing another challenge—drug resistance.
Jeffrey Engelman, MD, PhD, director of thoracic oncology and molecular therapeutics, and Alexandra Wanat, RN, CPHON, a thoracic oncology clinical research nurse, both from Massachusetts General Hospital in Boston, presented drug resistance issues among the lung cancer patient population at the Oncology Nursing Society’s (ONS) 40th Annual Congress in Orlando, Florida, April 23-26, 2015.
Targeted therapy drugs that target lung cancer tumors with the epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK) mutation, for example, may initially provide exceptional benefit, but over time tumors can develop resistance, causing recurrence. Dr. Engelman and colleagues have undertaken this research effort to understand how cancers become resistant to targeted therapy drugs and to develop new treatment options for those patients experiencing resistance.
Considering many cancer treatments are transitioning from chemotherapy to targeted therapies, it is important to understand why patients become resistant, and to also develop additional therapies that are more effective and less toxic.
For starters, Dr. Engelman has implemented a repeat biopsy program in which lung tumor biopsies are obtained before and after resistance occurs. These tumors are collected and genetic analysis is performed in order to help develop more laboratory models for discovery.
Through previous studies, researchers discovered a mutation now known as T790M. Many patients with acquired resistance to gefitinib or erlotinib have the T790M mutation. This discovery eventually led to the TIGER clinical trial program and the development of rociletinib (CO-1686), an oral targeted therapy drug designed to selectively target both the initial activating EGFR mutations and the T790M resistance mutation.
Although the CO-1686 investigational drug has shown promise in lung cancer patients experiencing drug resistance, many patients have experienced the problematic side effect of hyperglycemia. As a result, patients need to be strictly monitored, including obtaining C-peptide blood levels before beginning CO-1686 therapy. Considering this side effect could be an issue for some patients, administering metformin or pioglitazone may help to control glucose levels. Aside from hyperglycemia, the most common side effects are diarrhea, nausea, and rash.
CO-1686 could eventually become a first-line treatment in non-small cell lung cancer (NSCLC) patients with activating EGFR mutations, as well as a second-line treatment in NSCLC patients who become resistant to EGFR-directed therapy due to the emergence of the T790M secondary mutation.
Another drug currently in clinical trials (AURA trial) is AZD9291, a once-daily, selective, irreversible EGFR tyrosine kinase inhibitor designed to target patients with advanced EGFR-positive NSCLC who also have the T790M resistance mutation. AstraZeneca is currently investigating AZD9291 as first-line therapy for EGFR-positive NSCLC patients, and in combination with MEDI4736 (anti-PDL1 immunotherapy), selumetinib (MEK inhibitor), and AZD6094 (MET inhibitor) in NSCLC.
The presenters of this session also noted that patients who experience resistance to a particular targeted therapy drug should not be treated with the same drug again, as it could make their resistance to the drug worse. Also, they said that it is important to continuously monitor patients for side effects and address quality-of-life issues when administering targeted therapy drugs, including oral therapies.
Both CO-1686 and AZD9291 have received breakthrough therapy designation by the US Food and Drug Administration (FDA) and are still currently being tested in clinical trials.