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Opening Talk: What Is Disease Control?

M. O'Brien (United Kingdom)

SlotAE-2 O'Brien, M.

Focus on the definition of disease control, its relevance in the metastatic setting and its evolving role in drugs development programs by the co-chairman Dr. Mary O’Brien


Good evening, thank you all for coming. 

What is disease control?  This is a term that has started to slip in and we therefore thought we would focus a little bit on it.

Question 1 – What is Disease Control?

To start off let’s see what you all interpret it as.  Is it the percentage of patients with stable disease?  Is it a summation of CR/PR and stable disease for a period of time?  Is it just CR/PR and stable disease?  Is it the percentage of patients with a CR/PR and stable disease lasting at least six months?  [Brief pause]

Full transcription

Full transcription

Good evening, thank you all for coming. 

What is disease control?  This is a term that has started to slip in and we therefore thought we would focus a little bit on it.

Question 1 – What is Disease Control?

To start off let’s see what you all interpret it as.  Is it the percentage of patients with stable disease?  Is it a summation of CR/PR and stable disease for a period of time?  Is it just CR/PR and stable disease?  Is it the percentage of patients with a CR/PR and stable disease lasting at least six months?  [Brief pause]

Okay, so most of you think it is for a period of time.  23%, probably the Breast doctors, think it has to be for six months. 

Disease Control

The right answer is it is for a period of time, so the definition does not make a specification on it at this point in time, according to the FDA website.

Disease control is one thing, but in the past we have been used to talking about CR/PR, stable disease and progressive disease, and we did this with our old palliative regimens in both breast cancer and lung cancer, because in those days it was all about symptom control, quality of life, we knew it prolonged life over not having treatment, but a lot of treatments give the same outcomes, so we did focus very much on the patient experience in the past. 

Maximum Symptom Improvement from Baseline for Patients with CR/PR vs. SD vs. PD (using LCSS)

We are quite familiar with the fact that the better your response is, a CR or a PR, the better your symptom control is, but we do accept that within the group of patients with stable disease quite a few of them will also have symptom improvement and, in general, progressive disease was associated with a deterioration in symptoms.

SD and PS – TRIALS over 20 years

Over the past 20 years things have changed, we slip into different ways of practice and practice evolves. 

Just to remind us that for trials we normally use the WHO criteria, which were originally developed in 1981, and this gives us the definition of a partial response and particularly progressive disease, and in between there was the stable disease. 

This then was modified again in 2000 with RECIST 1 and 2009 with RECIST 1.1 and since then we now have a RECIST mesothelioma and we have criteria for disease related and immune responses. 

I think, going back, we always thought that stable disease was something that did not last a long time, in general the patients would progress quite quickly or, indeed, with more treatment they would eventually get a response.  In stable disease patients normally had symptoms that were stable or sometimes improved. 

Then PS came into it as well.  In the days gone by actually PS0, patients with no symptoms, were not actually included in trials, we used to do a watch and wait policy and we did trials on that and we would not submit patients to toxic treatments unless they had symptoms.  That was particularly in lung cancer, breast cancer has always evolved slightly differently.

Then we started to note, particularly from some big US studies in lung cancer, that PS2 patients actually were getting more toxicity and were not very good, as a group, for drug development, so that you find most non small cell lung cancer and breast cancer drug trials are now in Performance Status 0 and 1 patients, there are some 2s included, but in general we now have changed the group of patients we select. 

Question 2 – What is the definition of PD from RECIST 1.1?

A little bit more on the factual, going from WHO to RECIST a few things changed, a few numbers changed.  Just to test you all, can you remember what the definition of PD from the most recent RECIST 1.1 is?  Is it a 25% increase in the sum of the lesions from baseline or a 20% increase, or is it a 25% increase in the sum from the best response or a 20% increase? 

I will give you 10 seconds to reply to that.  [Pause for responses]

Okay, so despite a tool that we should be using all the time there is quite a smattering of responses.

Question 2 - Answer

There is, of course, one correct answer and, yes, it is, I am afraid, from the RECIST 1.1 it is – 25% was WHO, RECIST was 20% and it is an increase in the sum from the best response from, what they call, the NADIR.  

New Paradigm: To transform Cancer into a Chronic Disease

With this paradigm of new treatments what we really want to do is think that we have cancer now into a chronic disease, where we basically can shrink a tumour and keep it shrunk, we accept we never get rid of it completely, but life goes on and life is good, of good quality, but patients remain on treatment.  Our old paradigm was that we would shrink as much as we could, but we did accept that the tumour eventually grew again and this area was our area of stable disease, and this big, black ball will be what we hear more about in our pharmacology talk.

Changing practice - DC

Now, changing practice, introduction of the term disease control – it is now possible to prolong therapies because we have oral therapies with acceptable toxicities, so we now can address these questions and we now have trials of maintenance therapies, and some of them are showing us survival benefits.  There has been a change of thinking, even with standard therapies, and that must be largely to do with a better selection of our patients, because many of our patients now are of better performance status. 

We started to change our thinking before immune therapy, we started to change our thinking with targeted therapy, when we had targeted agents and we invented this term of treatment beyond progression and oncogene addiction, where parts of the tumour responded and parts did not, and if you withdrew your treatment to the target you could actually get a flare.  We started to think the textbooks, that we had all read and learnt, were not telling us the whole story and now, with immuno therapies, it is all coming again, where we both have, not even what we are calling progression, we are calling it pseudo progression and we are also getting tumour flare.  The way we practice and the way we think has changed.

Disease Control immune therapy 2015

A lot of this disease control and immune therapy related criteria assessment started 10 years ago from a workshop of 200 oncologists, immunologists and regulatory doctors and was published in 2007.  This was the first mention that perhaps with immune therapy we may need to change our criteria. 

For example, they stated that maybe antitumor activity takes longer than with chemotherapy, that responses may occur even if part of the disease is progressing and when would you stop, especially if you can get clinically insignificant progression, in other words small lesions that were not visible before when other lesions were responding.  Also this impression of a very durable stable disease and that they would maybe call that antitumor activity.  Really putting that all together has influenced where we are with standard treatments.

Pembrolizumab: NSCLC Clinical Activity

For example, I explained about disease control, but we now have the widely used disease control rate, when you introduce the rate you should really say at a certain time point, because it is a rate, but nevertheless we will not dwell on that.

Here are, of course, the figures that we are very familiar with, this is the use of pembrolizumab in squamous-cell lung cancer with very impressive disease control rates, which incorporate both responses, CRs and PRs, and, of course, selection for a group that gets a better response. 

It is with these new drugs now that we are finding these new terminologies and ways of reporting. 

Treatment Exposure and Response Durationa (RECIST v1.1, Investigator Review)

A few things, this is the swimmer plots, again we see the best swimmers have little red triangles which were the partial responses, but very good swimmers are also in yellow, and they are the patients with stable disease. 

Just another point, here is the point where there was the first assessment and in fact documentation of response can occur early with immune therapies, so some of the things they were saying in 2007 have not panned out. 

LUME-Lung 1 in adenocarcinoma patients: Tumour response and disease control – secondary endpoint

It is not just with immuno therapy that this term of disease control rate has slipped in.  This is the last drug we have had licensed in lung cancer treatment and that is nintedanib, which is a multi-targeted kinase inhibitor, and this drug in second-line non small cell adds and improves survival in certain groups over docetaxel alone, and the results are reported in this way of both stable disease but now disease control rate.  Again, we are getting similar figures and much bigger percentages than we have been previously used to.

Example of Disease Control with Chemotherapy: Oral Vinorelbine in NSCLC

We can also look at other data in other situations and describe it in the same way. 

For example, oral vinorelbine in non small cell, we can look at disease control rate and, indeed, it is a way of making things look very much better than we usually see in non small cell lung cancer, and you will hear more about this later. 

Example of Disease Control with Chemotherapy: Oral Vinorelbine in MBC

Indeed, in breast cancer we are also doing the same thing, except breast cancer doctors are a little bit more strict and they are saying ‘For how long the stable disease should last,’ and, of course, with breast cancer patients I think you can say this because they are much more optimistic about getting a long stable disease period.  Again, more about this shortly.


How can we sort this all out?  Will imaging sort it out?  It probably will sort out some of it, because we know that imaging in itself can predict early response, we now have a RECIST set of criteria for PET responses, but depending on your isotope and your imaging and including other modalities, like diffusion-weighted MRI, we can both image to show an inflammatory response and, indeed, apoptosis.  I think imaging will help sort out some of the problem. 

Case Report

Indeed, here is the sort of thing we get with a targeted therapy, like an EGFR-mutant patient who is treated with a targeted agent, has a very brisk response with a lesion disappearing, but we get small areas of increased activity in the lung, which could either be pseudo progression, progression or inflammatory changes. 

Disease Control Rate as predictor of survival?

Is it a predictor of survival, disease control rate?  Yes, it is, there is evidence in non small cell and in metastatic breast cancer. 

Options to optimize disease control with chemotherapy

Can we optimize disease control?  This evening you are going to hear about maintenance therapy and metronomic schedules. 

SATURN Trial: OS According to Response to First-line CT (ITT Population)

Just to remind you that one of the maintenance studies that approved the drug erlotinib as a maintenance therapy in non small cell lung cancer did show that those patients who had stable disease as their best response to first-line treatment were the patients who went on to get further survival benefit with their maintenance therapy, and the patients who had responded really got nothing more out of this treatment, so just to show you again that within the stable disease is a group of patients waiting for more treatment.

Metronomic Chemotherapy

Metronomic chemotherapy you will hear about, it is an innovative approach, it allows us to deliver active chemotherapy in a different way and is a potential way of improving this disease control rate.

DC Challenges

But there are challenges.  First of all, the magnitude of the benefit, if we have more active treatments we will have more PRs, more CRs, less stable disease and more disease control therefore.  Currently for designing your trials and developing your drugs and licensing them it is not a recognised endpoint with the FDA or the EMEA.  We also have spent very little time with modern, new drugs and new tools to assess the actual value to the patient and one thing we always have to remember, while we hang around in this space now, because we want these new treatments to work and to do things we have never seen before, is with this disease control and this delay are we delaying other active treatments that patients could really be getting on with?

I now would like to introduce my colleague, Professor Milano, who will take you through some aspects of the pharmacology.