Transcript:Daniel Heng, MD, MPH, FRCPC: All right. Now we’re going to talk about what happens after first-line therapy. Carlos, why don’t you take it away and just talk about when do you start thinking about second-line therapy. What is resistance?

Carlos H. Barrios, MD: Well, I think that resistance raises a very important point in the management of kidney cancer and I think it’s one of the major unmet needs in this area. We do not understand the mechanisms of resistance in order to make rational choices in our second-line therapy. So that’s a very important aspect of what we have been doing in clinical research. So that’s an initial concept that I pose to all of you.

The second concept is that the definition of progression when we use targeted agents is not necessarily the same or as easy as we have been used to with the progression that we obtain with chemotherapy, in oncology in general. Chemotherapy progression has been clearly established in clinical practice and in clinical research with the RECIST criteria that apply, in general, to the benefit for treatment with chemotherapy.

However, in the targeted era, we have been finding that some patients did not necessarily apply to the RECIST criteria as properly as we would like. So there are patients that sometimes do continue deriving a benefit from therapy even though the radiologic criteria of progression are met. So we still are struggling at finding out exactly what the best way of dealing with this is, and I guess my opinion in that regard is that we need to be very careful and recognize that there are some patients that, while still benefiting from therapy, may actually have X-rays or CT scans with some degree of progression.

And what we all have been doing is that if clinical benefit is there, we tend to continue with the targeted agents, hoping that sometimes what’s happening is that the rate of progression seems to be lower than if we essentially remove the drug from the clinical setting. So I think that this is a challenge for all of us and we need to perform more trials in order to [elaborate on] this. Later we’ll talk about immunotherapy and the same thing essentially will happen in that arena.

Paul Nathan, MBBS, PhD, FRCP: I entirely agree with that. I think the one other influence on us is availability of other lines of treatment.

Carlos H. Barrios, MD: Definitely.

Paul Nathan, MBBS, PhD, FRCP: So it depends on where you are in the world, but if you’ve got very limited access to subsequent treatments, obviously you have no choice but to tease out as much benefit from your first line of treatment before switching. And so inevitably we’re influenced by what reimbursement decisions are taken locally but also what trials you have available.

Carlos H. Barrios, MD: And nevertheless, as we’re not curing anybody with kidney cancer, making the best of every line of therapy and probably prolonging some degree of the control of the disease is certainly a good objective.

Nizar M. Tannir, MD, FACP: So Danny and I guess, Paul, you mentioned that in the UK you only have two lines reimbursed. You can just use two drugs. Which one you start with is up to you between pazopanib or sunitinib. You have axitinib and everolimus for second-line therapy, but you cannot use them more than once each of these four. Danny, we’re all aware of the data for re-challenge and reusing the drug that you used previously. In other words, if you use, for example, sunitinib first and then you went to everolimus and then the patient progressed, can you go back and re-challenge with sunitinib? Because obviously there are data published in Cancer by the Americans showing that this strategy does work for some patients. And when you don’t have other drugs you can use except those two, it makes perfect sense to try again to re-challenge that patient with a drug, especially in clear cell RCC where we know that VEGF is the driver.

Daniel Heng, MD, MPH, FRCPC: Or go on a clinical trial.

Nizar M. Tannir, MD, FACP: If there’s no clinical trial.

Paul Nathan, MBBS, PhD, FRCP: This is where there’s a gap between what makes clinical sense and what the reimbursement decisions are often based on. So, as a kidney cancer doctor, I’m in no doubt that sequential use and sometimes revisiting TKIs make sense, and I have a cohort of patients who have had significant benefit from that strategy. However, the reality is that in my world, the NHS makes decisions about what’s available and we’re limited by that, which means the vast majority of my patients who have multiple lines of treatment do so because they take part in clinical trials.

Nizar M. Tannir, MD, FACP: Sure, sure. Danny, I think the way I looked at the question of second-line therapy is whether the patient is sensitive to a first-line VEGFR TKI or not. And I think as you well know, about 20% or 30% of patients are outright refractory, so they’re not going to respond to any VEGFR TKI. Those patients pose a real challenge because, as you published from your IMDC data, if they did not respond to a first-line VEGFR TKI, they are unlikely to respond to another VEGFR TKI or an mTOR inhibitor. Changing tracks doesn’t seem to really benefit them. So there’s something inherent about the biology of RCC that if they progress right through your best first-line VEGFR TKI, it’s a challenge to treat them. So I think we will be talking about immunotherapy later and maybe these are the patients who would be best treated with a novel agent rather than putting them through the sequence of VEGFR TKI and mTOR inhibitors.

Carlos H. Barrios, MD: Again, you’re raising an important point in that regard, in the sense that I feel that there is a lack of rationale, because we have not been biopsying these patients. Like we have been doing in other diseases, we have not been collecting or analyzing the blood for tumor- circulating DNA in order to find out what are the new mutations, what are the new molecular changes that actually happened that may be responsible for the resistance. Even though we have a number of different alternatives, we have not been able to sequence them in the best way using a rational approach because it’s a new diagnosis. How I’m going to decide on the treatment of second-line based on a biopsy that was performed four or five years ago, even longer than that?

Transcript Edited for Clarity