Continued from part 1 Dr. West: You have a huge portion of your patients who have an EGFR mutation and we know that over time patients develop acquired resistance. So how do you approach the patients who have a great response initially, have a known EGFR mutation, and then you see that slipping away at slow progression? Do you continue the EGFR inhibitor? Do you add something to it? Do you change the dose? How do you approach that? Dr. Mok: I think this is one area where we still have a lot to learn. First of all, let's define resistance, or progression. If you use the Jackman criteria (Jackman, J Clin Oncol 2010), that still incorporates the RECIST criteria, which mean if the lesion that has increased by about 30%, then it's progression. But then one factor we didn't look into was in the rate of progression within this definition. The second concern is about the occurrence of a new lesion that's also progression. Now, whether this is directly applicable to a targeted like Tarceva or another EGFR TKI or not, I have some doubts, because simply from your experience and my experience, some of these patients get a new nodule, but they can take a long time to grow and the patient lives a normal life. And we also know the fact that if we take them off the TKI, the disease can progress rapidly. So some of these are slow progressors, then we just keep them on a TKI.

Dr. West: Right. Dr. Mok: Now eventually we have to get them off, but then -- when? And then is it better to put them on chemotherapy for a while first and then go back on TKI or not? We don't know that. So actually, one of the important studies we have to do in the future -- if we can get support for it -- is a post-progression extended study, which is a patient who got progression by RECIST criteria, randomized to continuation versus chemotherapy. We have not done that yet. So we are doing what we do by common sense, but we are not using any data to support our practice. And secondarily is the concept of the reversible TKI. The LUX Lung-1 trial with afatinib came out with some interesting data, in a sense that there are some responses in the population that have progressed on TKI, but then there's no overt survival benefit, while the progression-free survival is 3.3 months versus 1.1 month. So, the direction is not clear because in a sense, this particular study used overall survival as a primary endpoint, so it's unlikely that the drug will be registered for this indication in the near future. Then another irreversible TKI is that PF-299, and a phase III study is actually still ongoing; we don't have the data on it as of yet. So we're hoping that a newer class of drugs, or the newer class of EGFR TKIs, will be able to give us some better results, but for the time being, we don't have that information. So we can go to the chemotherapy, which we do all the time. And what I usually do is that I will kind of keep them on TKI as long as I can, and only when it's clearly they're progressing quickly, or if their progression is likely going to have a significant effect on something major like an airway or a vessel, or there is an increasing pleural effusion, then I will stop the TKI and put them on chemotherapy. Some other groups, like the Sloan-Kettering group, keep the TKI and start on chemotherapy. Personally, due to the four randomized studies, I am a little bit reluctant to give them concurrently, but what I may do is after chemotherapy to eventually put them back on the TKI. Future directions? Well I think there are a few. Number one, there are multiple ongoing clinical trials right now in this group of patients, but I think in the field we still probably have to re-biopsy the patient and treat them according to their so-called resistance mechanisms. T-790M? Maybe it has to be an irreversible TKI. I mean in those negative studies, so far we don't have the biomarker translations to that; we hopefully will get that information at ASCO this year. c-MET? we may have a number of c-MET inhibitors coming up. And others, hopefully there will be others that we will have in the future. Dr. West: So do you routinely advocate re-biopsies at this point? And is there any information that you get from that that can help you practically manage your patients today? Dr. Mok: At this moment, no -- because we don't have a target drug available or a clinical trial, so to justify re-biopsy is going to be a bit difficult. There are some easier biopsies that we can convince the patient to do as compared to a more invasive procedure that we will be a bit more reluctant, so it's not been set in clinical practice as yet, but certainly I think in the future we should develop a clinical trial that is based on the re-biopsy result. Dr. West: You'd said that you go back sometimes to either the same EGFR inhibitor or a different one. Certainly I'd seen a few gratifying responses. Can you speak to any clinical experience? Dr. Mok: Yes. For any patient who had progressed on gefitinib, there had been about two to three smaller studies, or retrospective studies to show that if you fail, you can put them on Tarceva (erlotinib). You may still have approximately 10% response rate, one small set are from Japan, and then another from Korea, both showing similar kind of phenomenon. Could it be just a dose effect or whether it is a different molecule effect? I cannot say, but interestingly enough is the fact that some of the patients who get a so-called secondary response to another TKI, the duration control is usually short. So personally I trust that it's more likely to be a dose effect rather than a molecular effect. Dr. West: But you don't dose escalate someone from 250 mg of gefitinib up to 500? Dr. Mok: Yes, you can, but you double the price. Dr. West: Yeah. That's a fair point. That's exactly why I was thinking while asking that. Culturally in the U.S. more and more we're seeing lots and lots of patients and caregivers going to "Dr. Google" and looking for as much information as they can find online, some on GRACE and some in various other places, and there's a wide range of information out there, some of it great. Dr. Mok: Oh you are provider of such, my friend. Dr. West: Well, thank you. I think it's a good thing to have patients become very educated and be able to participate. In Hong Kong, in China, in Asia in general, is your sense that patients are also eagerly obtaining as much information as they can and coming to their doctor to have a discussion? Or is it more of a unilateral presentation from doctor to their patient? Dr. Mok: Well, obviously that depends on the age group of the patient. I mean the older patient, they basically still listen to their doctor and without asking too much questions. As for the younger patient or the younger family of the patient, they would come in with a pile of questions or information. So as you said, they do Dr. Google, but they also Google doctors. So they look for their doctor through Google and so they get multiple opinions. So quite often when they come to see me, they already have seen two or three doctors; they just want me to tell them one's more my opinion of the circumstances, so-called the doctor shopping. So this is actually quite common. It's probably due to the proliferation of electronic information, plus the fact that in general we have a better-educated population in Hong Kong. I am not 100% sure whether this is the same in the entire China because the education level is still fluctuating from one city to another. Dr. West: And then finally, can you tell us a bit about the lung cancer research consortium that you run? Dr. Mok: It's not a formal consortium per se. We actually started almost 10 years ago when we did not have any infrastructure. We're just a group of us, about six or seven of us from Korea or Taiwan, and Australia or China. We group together so that we can do trials together as a collaborative group, but we did not have the money and the support to do a centralized database, so we are a lot to do in collaboration with the pharmaceutical company. So the status has not changed: we just work kind of loosely as a group that we discuss and we work together, but not so much as a group like United States with central funding, like ECOG or SWOG So there's quite a bit of difference with sort of the so-called collaboration that we have. The other group that is actually running quite strong is called CTOG, for Chinese Thoracic Oncology Group. And this group is based in China, and they have about 16 centers right now, all quality centers that were participants in the IPASS study. This is the good thing about running a major international clinical trial study in Asia/China, because the process helps us to build up the infrastructure of all those centers, because we need to produce high-quality centers. AstraZeneca was able to fund a lot of the studies, so we kind of built up infrastructure. And now, even after the study, the quality of the group, and their ability to do good trials, is still at a very high level. And now they are working together as a collaborative group called CTOG. The OPTIMAL study is such a product: it's actually called CTOG study number 002. This is one of example of how a national study was helped by the infrastructure of a prior clinical trial in a recently developed country. Dr. West: That's great. Well thanks so much. Dr. Mok: Thank you, Jack, for inviting me.