I was introduced to Dr. Chen, the only Heme/Onc physician at Taipei Hospital, when he was almost done with his rounding. Though I only got to see two of his patients, Dr. Chen gave a lengthy and detailed history lesson on the primary medications used to treat lung adenocarcinoma, which I will detail here.
To start off with, we classify lung cancers broadly into two categories: small-cell lung carcinoma (SCLC) vs. non-small-cell lung carcinoma (NSCLC). SCLC is chemotherapy sensitive, heavily associated with smoking, and has over 20 subtypes. NSCLC has three major subtypes: squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Most of the targeted therapy used to treat NSCLC came out in the early 2000’s. Primarily, the two most common targeted therapies involve Erlotinib and Gefitinib. Erlotinib is still being used today for lung cancer in general: it was shown to be effective in patients with or without the Epidermal Growth Factor Receptor (EGFR) mutation. As a reminder, EGFR is a receptor tyrosine kinase that is part of the ErbB/Her family, and is often found to be mutated in lung cancers. Targeted therapy therefore involves inhibiting EGFR if it is mutated.
When these two drugs first came out, all of the different subtypes of lung cancers were not differentiated, since phenotyping was not possible at the time. We will focus on Gefitinib, since its history is not as straightforward as Erlotinib, which is still approved for use today for lung cancers in the U.S. and in Asia. As with any new drug, Gefitinib was put through clinical trials, which revealed that the response rate to Gefitinib was low. However, these trials revealed that response was very effective in a certain subgroup of patients. We now know this subgroup to be EGFR (+) patients. Gefitinib was approved by the FDA in 2003 for NSCLC treatment, but the FDA withdrew approval in 2005 due to lack of evidence that it was actually beneficial for patients. However, it was not taken off the market in Asia; studies in Asia found that over 70% of Asian non-smokers responded positively to it. As a side note, the studies also found that if patients had a skin rash as a symptom as well, the response was more likely to be positive.
Further studies in Asia compared the use of Gefitinib and chemotherapy on a patient’s condition 6 months post-diagnosis and treatment. It revealed that Gefitinib was more beneficial in patients with the EGFR mutation. Therefore, Dr. Chen’s conclusion was to use targeted therapy if the patient has the EGFR mutation. With no mutation, chemotherapy is more effective; with the mutation, Gefitinib is better than chemotherapy since it is less toxic. Thus, Gefitinib is used in Asia for patients with the EGFR mutation, but is not approved for use by the FDA in the U.S. for treatment of NSCLC.
There were a couple of side comments that Dr. Chen made which I found intriguing. There are no drugs at the moment approved for k-ras targeted therapy; they are all in phase 2 of clinical trials, and none are in phase 3. Targeted therapies all target oncogenes; there are none for tumor suppressors. Therefore, since researchers have been unable to find an oncogene for squamous cell carcinoma, there is no targeted therapy for this subtype.
UPDATE July 13, 2015: Gefitinib has just been approved by the FDA for treatment of EGFR(+) NSCLC!
College of Osteopathic Medicine in 台灣 (Taiwan) 