I'm fortunate to practice at Moffitt, where Dr. Gerold Bepler and Dr. George Simon pioneered a molecularly directed approach to front-line chemotherapy in NSCLC. Data from the phase II clinical trial demonstrated impressive median survival for a platinum-based doublet: 13.3 months. The schema of the MADeIT clinical trial is shown below and I'm happy to say that I am able to put many of my patients on this clinical trial. Dr. West recently posted a podcast featuring Dr. Simon, where he describes the trial in more detail. (click on image to enlarge) The testing for ERCC1 and RRM1 is performed at Moffitt and turnaround time is typically around a week or less. I consider this a very reasonable interval since patients are unlikely to experience progression or declines in their performance status in a week. A sample from a prior biopsy can be used and fresh tissue is not required. Even when we have to obtain tissue from another institution, we can usually get the patient started in a very reasonable time frame. Right now, we only perform testing as part of the clinical trial. I think this is the right thing to do: although our hypothesis is that molecularly-directed therapy will be superior, we don’t know that for sure yet.

So what about the never-smoker who comes for an opinion about front-line treatment? Would I send off EGFR mutation testing and treat accordingly? Would I empirically treat with Tarceva? The answer is it depends and I'll use some real cases to illustrate how I think about the options prior to recommending a course of action to a patient.

A 32 year old never-smoker presented with cough and was found to have a large left upper lobe mass. It was resected and her staging was T2NO, stage IB adenocarcinoma. A trial of adjuvant cis/nav was undertaken but because of substantial toxicity, she received only 2 cycles of therapy. Two years later, as part of a routine CT scan, she is found to have multiple bilateral lung nodules, all a centimeter or less in size. They show slight interval growth on follow-up CT and a biopsy is performed, demonstrating recurrent adenocarcinoma. She came to see me for a second opinion. She was asymptomatic from her cancer. As a single mom, she really wanted to avoid chemotherapy because it had made her so sick previously. Because her cancer had been shown to be slowly progressive and she was asymptomatic, I felt we could wait for EGFR mutation testing prior to starting any therapy. She really didn't want chemotherapy and didn't want to start Tarceva unless we were pretty convinced she'd benefit. So we waited about a month for the test to return. Unfortunately, her EGFR mutation testing was negative. Although she was very nervous about chemotherapy, I was able to convince her to try single-agent Alimta and she has had some shrinkage of her tumors followed by prolonged stable disease. I don't think it would have been wrong to give a trial of Tarceva in this patient - I have many colleagues who would have. But the patient did not want to do it without molecular testing and I didn't see a compelling reason to try to change her mind. A 54 year old never-smoking woman presented with severe shortness of breath and was found to have a large pleural effusion as well as a pericardial effusion and liver metastases. She had undergone a pericardial window and a pleurodesis but was already having some reaccumulation of the fluid around her lung and had had a 5 lb wt loss. Although she was up and about for most of the day, she’d had a precipitous drop in her activity level (previously played tennis daily). She had done some research on EGFR mutation testing and was interested in having it done. We sent this patient's tumor off for testing but started chemotherapy quickly while waiting for the results to return. I didn't feel that this patient could wait without therapy for the results. I also felt that, if she was mutation negative, she might have enough of a slip in her functional status if she progressed on Tarceva so that it might have been difficult or impossible for her to receive chemotherapy later. Her tumor was ultimately found to be positive for an EGFR mutation: she did very well with 4 cycles of chemotherapy and then started on Tarceva as a maintenance treatment and continues to do well. My current practice is to send off EGFR mutation testing at diagnosis on patients (male and female) who are light or never-smokers and have an adenocarcinoma. However, I don't necessarily wait for that information to start treatment. Since patients with EGFR mutant tumors are more likely than others to respond to chemotherapy, I still feel like front-line chemotherapy is a valid treatment choice in most patients. In the absence of mutation testing, I don’t feel great about starting Tarceva as initial therapy. I’m constantly reminded that even in a population of patients with many of the clinical characteristics associated with EGFR mutations, a large proportion will not have one (as noted in the IPASS trial). However, I do feel that these patients should be exposed to Tarceva earlier rather than later in their treatment course. If I send off the testing at diagnosis, I have this information immediately available to guide my choice of a maintenance or second-line regimen. EGFR mutation testing is now proving useful in another way: negative testing in a light- or never-smoker helps to identify someone more likely to have an ALK mutation. So I can keep the new Pfizer trial in mind for those patients when second-line therapy is needed. Ultimately, many of my patients with clinical characteristics that I wouldn’t usually associate with EGFR mutations (heavy smoking history, squamous cell histology) get EGFR mutation testing done as part of second-line or later clinical trials. So far, I haven’t had any surprise EGFR mutations in patients I hadn’t tested.