A few weeks ago I had the chance to speak with Dr. Tony Mok, who is a professor in the Department of Clinical Oncology at the Prince of Wales Hospital in Hong Kong and the Chairman of the Hong Kong Cancer Therapy Society. He is also the principal investigator and lead author for the pivotal Iressa Pan ASian Study (IPASS), which was published in the New England Journal of Medicine in the fall of 2009. I started by telling him that I consider that study to be arguably the most influential over the last 5-10 years in the field of lung cancer, because it highlighted that molecular predictive factors trump clinical markers in determining who is likely to do best with a targeted therapy, specifically an EGFR tyrosine kinase inhibitor like Iressa (gefitinib) or Tarceva (erlotinib). Here's the first part of our conversation about what we've learned about how best to use these EGFR inhibitors and the potential differences in practice between Asia and the US.

Dr. Mok: Well, thank you for your kind comment. And I was just being lucky to be in the right place at the right time. You know that EGFR mutation is actually more common in East Asia, especially in the Chinese population. And so I just happened to be a lung cancer researcher, have been collaborating with the pharmaceutical in clinical trial research, so when gefitinib (Iressa) was taken off the market in the United States, they had to take these first line studies into Asia. So at that time that we actually looked at the situation knowing that each of our patients is the major biomarker that we can choose the patient, but we were not able to conduct a biomarker direct research simply for the fact that we did not have the technology back in 2005 to test all the patients and get the results quick enough. So we decided to enrich the population in the sense of a never-smoker adeno, such that we could capture the highest chance of the patient having this mutation. And of the 1,200 patients, the patients we did a mutation analysis, about 60% of them are EFGR-mutation positive. So with that we were able to prove the fact that with the mutation, you're a lot better with gefitinib than chemotherapy, and without the mutation chemotherapy is still the standard. Dr. West: Right. So that really indicated that you were potentially doing a disservice to patients who you might have selected just based on clinical markers, and then even if you're an Asian never-smoking woman with an adeno carcinoma, if you're one of the 40% who doesn't have an EGFR mutation, you are better off with chemotherapy. Dr. Mok: That's absolutely correct. For patients without the mutation, if you take gefitinib as a first line therapy, the response rate in the IPASS studies is only about 1%, as compared to chemotherapy, it's about 25%. So in other words, you will be a lot worse in terms of the clinical outcomes if you don't have the mutation and then you take gefinitib as a first-line treatment. So we actually have to know when a patient first arrives in the office, and then we have to make a treatment decision: we have to know whether they're mutation-positive or mutation-negative. So I think this is an example of what we call personalized therapy. Dr. West: You're practicing in Hong Kong, and obviously as you had mentioned, the incidence of an EGFR mutation and also probably an ALT rearrangement are considerably higher in Asian patients who are more likely to be never-smokers than in North America or in Europe. How common is it to do mutation testing for EGFR, KRAS, and ALK right from the beginning? And are you doing it on primarily never-smokers, or on everyone who comes through the door? Dr. Mok: Excellent question. The paradigm has been shifting with the availability of the data and of the different EGFR TKIs in the market. Basically we are trying to do mutation analysis in all patients with adenocarcinomas regardless of their smoking status. We do not do it routinely outside of adenocarcinoma, because the pick-up rate is probably about 3% and is most likely for the economic reason and cost-effectiveness. But all adenocarcinomas, we are testing them. Now that is only on the presumption that they have sufficient tissue. As you probably know well, a lot of the diagnoses are still made by cytology either from a pleural effusion or on an FNA (fine needle aspiration), so we are still influencing, changing the thinking of a lot of respirologists and the diagnostic radiologists to try to get better tissue. Dr. West: So this is really kind of changing in real-time and as we strive to get more tissue... Dr. Mok: Yes. And now I would say that close to about 70% to 80% of the time we will be able to do the molecular analysis. Still there is about 20% to 30% of cases that we don't have adequate tissue. Dr. West: And patients are largely willing, even if it might mean an extra biopsy? Dr. Mok: I had actually one case I can share with you. This one young lady who's a teacher, she actually had a left lower lobe lung nodule and a pleural nodules, and then they did FNA of the lung nodule. It turned out to be an adequate sample for histology, showing adenocarcinoma, but not sufficient for EGFR mutation analysis. So what choice do I have? We would have to cut into the lobe or biopsy the pleural nodule, but the pleural nodules are kind of flat; it's very difficult to get tissue. So what we end up doing for this lady, she was a never-smoker with an adenocarcinoma, so we actually did a VATS to do a pleural nodule biopsy and it turned out what? EGFR mutation negative. So imagine a never-smoker female with an adeno, if we just close our eyes and put her on an EGFR TKI, we would not have done her a favor. But taking a relatively aggressive step to biopsy the pleural nodule, we actually proved the fact that she should receive chemotherapy first. Dr. West: Well, this is a situation where even a negative result is very informative. It changes your management no matter what the result is. Dr. Mok: Definitely. Dr. West: You've had Iressa available for years now, so how does Tarceva (erlotinib) fits in compared with Iressa in Asia? Dr. Mok: Well, both drugs are available. Both drugs initially have been approved as a second or third line treatment, and this is a research we started earlier almost closer to ten years ago when we had to expand access program and then subsequently the drug got approved. And Tarceva had been approved since the BR.21 trial, so both drugs have been around for quite a while. In mutation-positive patients, in a sense it's that the current data do not show a major distinguisher between the two. Of course there are some variations in progression-free survival, but that's not a direct comparison and the patient groupa are a bit different. So at this moment in time, with the current data, Iressa have been approved for each mutation-positive patient as a first-line therapy by the Health Authority. Tarceva (erlotinib) has not been approved yet because right now we've only got the OPTIMAL study, which is from China. The registrational study EURTAC is ongoing, enrollment hopefully showing data within the next year. But then the fact of the matter is that people who kind of use it interchangeably because it's available. In terms of market share, I think it's something around 60%/40%. Dr. West: 60% for Iressa? Dr. Mok: Yes, and 40% for Tarceva. Dr. West: Is the preference because of more history with Iressa, or toxicity, or...? Dr. Mok: No, it's price. Let's be realistic: price is important for the patient. In Hong Kong, patients still have to pay for it. And there is about a 20% difference in price, so if you get the same result, but a different price, patients make their choice. Secondly, the skin rash is a little bit more with the Tarceva compared to Iressa, and for mutation-positive patients, you know the response rate is 70% with Iressa, so you're quite confident you're going to get an outcome with the better tolerated drug. Dr. West: Do you think there are relevant differences between Iressa and Tarceva for mutation-negative patients? Dr. Mok: I think we can only speak based on two things: one is the pharmacodynamics, and the second is from the concrete data. Now as you probably are fully aware that the maximum tolerated dose (MTD) for Iressa is about 700 milligrams daily, and right now we're using 250, and MTD for Tarceva is 150 mg, which we're using as the standard dose. So potentially you may argue that it's actually a higher dose intensity with Tarceva. Now let's go into their so-called concept of EGRF inhibition. The cell may be truly "addicted" to the EGRF signal, which is the case for mutation-positive patient. As for the non-mutant "wild type", they actually do not depend entirely on it. So in principal, if you give a stronger or higher dose intensity, you may have greater suppression of the cancer cells. And in the BR-21 study, you can see that the patients who actually has stable disease have a survival benefit: they did not have a dramatic response like the mutation-positive patients, but the wild type patients, they actually have stabilization of the disease and they have longer overall survival and progression-free survival, so the benefits are there. At this moment we can only extrapolate from what we know biologically and from some of the existing clinical trials. Certainly I don't think we have definitive data to say one way or the other. (to be continued)