Mechanisms of Resistance to EGFR TKI and New Treatment Strategies
Second Generation Lung Cancer Therapy Targeted to EGFR Mutations May Help Patients Live Longer
Experimental drug delays cancer growth by more than five months compared to currently available medication, study shows
By Don Rauf
Medically Reviewed by Sanjai Sinha, MD
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For patients with advanced non-small cell lung cancer (NSCLC), a new treatment option may offer better results than a drug commonly used to stop or slow tumor growth.
In a recent phase 3 clinical trial — the last stage before drugs are submitted to the FDA for approval — the investigational drug, dacomitinib, beat Iressa (gefitinib) in treating NSCLC that carries epidermal growth factor receptor (EGFR) mutations.
"Dacomitinib is a second generation of EGFR inhibitor drugs, which are in general thought to be more effective than first generation drugs such as gefinitinib," says Nagashree Seetharamu, MD, a medical oncologist at Northwell Health Cancer Institute in Lake Success, New York. "These second generation medications, however, are associated with a higher incidence of side effects, which need to be weighed against the drug's efficacy. Risks and benefits need to be discussed in detail with patients before prescribing."
In the study, scientists randomly assigned 452 patients who were newly diagnosed with stage IIIB or IV, EGFR-positive NSCLC to receive either dacomitinib or Iressa. Dacomitinib cut the risk of cancer growth by 41 percent compared to Iressa.
The cancer did not worsen for a median of 14.7 months for the dacomitinib patients, compared to 9.2 months for those on gefitinib—a difference of 5.5 months.
"This study proves that more potent EGFR inhibition is associated with long progression-free survival," said lead study author Tony Mok, MD, a professor and chair of the Department of Clinical Oncology at the Chinese University of Hong Kong.
The results, presented at the 2019 American Society of Clinical Oncology Annual Meeting, are the first phase 3 trials involving a head-to-head comparison of a second-generation EGFR inhibitor to a first-generation inhibitor.
The EGFR Advantage
Approximately 80 to 85 percent of all lung cancers are NSCLC, according to the American Cancer Society. About 10% of those patients have tumors that carry too much of the protein EGFR, which can trigger faster growth of the cancer.
The recognition of mutations such as EGFR have been a major breakthrough in the treatment of lung cancer in the past 15 years, offering scientists a treatable target and NSCLC patients whose tumors carry the mutation better odds of survival.
In addition to Iressa, EGFR inhibitors currently used for NSCLC include Tarceva (erlotinib) and Gilotrif (afatinib). These drugs can be used alone, without chemotherapy, as the first treatment for advanced NSCLCs. All are taken in pill form.
Second Generation EGFR Inhibitors: More Powerful, More Side Effects?
In the study from University of China in Hong Kong, dacomitnib’s increased potency did come with a price — 14 percent of patients developed severe acne and 8 percent developed diarrhea. Iressa’s most common side effect was liver enzyme abnormalities.
What’s more, the dose of dacomitinib administered by the researchers— 45 milligrams (mg) — had to be reduced in more than 66 percent of the patients because of side effects.
"To me, it will be a better idea to start with 30 mg and dose increase to 45 mg if well-tolerated," says Dr. Mok.
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