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iRECIST: Modified RECIST for Immunotherapy

1. Welcome

1.1 iRECIST

Notes:

Hello and welcome to this MyLearning course on modified RECIST for immunotherapy, also known as iRECIST. My name is Greg Goldmacher. I am one of the radiologists in Merck's Translational Biomarkers group, and I will be walking you through these concepts today.


1.2 Why This Training?

Notes:

Why are you taking this course? The iRECIST paper was published in March of 2017 in Lancet Oncology and all new Merck immuno-oncology trials from this point forward will use these criteria. Therefore, teams working on our immuno-oncology trials need to know how iRECIST criteria work.

Before you start this course, you need to have a strong working knowledge of RECIST 1.1; otherwise, this course isn’t going to make any sense. That is, you need to understand how tumor burden is documented pre-treatment, at baseline, and how target and non-target lesions are defined. And you need to understand how after baseline response is assessed using a combination of target lesion response, non-target lesion response, and the appearance of new lesions.

If you don’t feel that you have a thorough understanding of RECIST 1.1, you have a couple of options:

You can click on the Resources link in the top right-hand corner of the slide and get a slide deck that reviews RECIST 1.1.

You can also search the myLearning course catalog for additional coursework that cover RECIST 1.1 and then return to this course.


1.3 Learning Objectives

Notes:

When you have finished this course, you should be able to:

Explain why iRECIST is used and how it is used;

Apply the concepts that distinguish iRECIST from RECIST 1.1 and describe the new response categories;

And you need to understand how response is assessed after an initial RECIST 1.1 progression.


1.4 Benefits for You

Notes:

If you understand iRECIST and how it works, it will help you improve in your job function- the specific tasks, of course, depend on the job function. Ultimately, understanding means that you can make decisions independently rather than following rigidly defined rules and respond to novel situations that you haven't encountered. Understanding these concepts and speaking the language of these criteria will also help you communicate with other teams.


1.5 Outline

Notes:

Here's what we're going to cover today.

We’ll discuss why iRECIST and all immunotherapy-related criteria are used and how we got to the point of iRECIST at this time.

We will then discuss the concepts and response categories that distinguish iRECIST from RECIST 1.1.

And we will describe the decision-making process that happens after you see initial RECIST progression.

We will conclude with some exercises to cement the knowledge in your mind.


2. Rationale and History

2.1 Rationale and History

Notes:

Let’s start by talking about the rationale and the history of development of iRECIST.


2.2 Rationale and Summary

Notes:

There is a well-described phenomenon of pseudoprogression, or flare, in response to immuno-oncology treatments. You have what looks like initial growth of tumor, and then the tumors respond. That can be either growth of existing tumors or even the appearance of new tumors. The thought behind that is that there may be microscopic tumor rests that are below the threshold of detection of the imaging technology being used to assess them, and then they enlarge enough that they become visible on the scan. Then this is followed by response.

The way that all immunotherapy-based criteria work, fundamentally, is that when you see initial progression, if the trial participant is clinically stable and doing well, the investigator may choose to continue treatment and obtain another scan some time later to see if that progression is confirmed. The various immune-based criteria describe what it means for the progression to be confirmed.


2.3 Early Pseudoprogression:

Notes:

Just to show you some examples of what this can look like, here is a case from one of our early Keynote trials of an advanced melanoma.

At baseline, you can see a skin lesion and on the CT, a lesion in the liver that's shown by the red circle.

Twelve weeks after treatment, there has been dramatic growth of the skin lesion and the lesion in the liver has grown as well.

And then, with no change in therapy over the course of weeks 24 and 52, you see that the liver lesion shrinks to where it's hard to see on the scan and there's also a remarkable response in the skin lesion.


2.4 Delayed Pseudoprogression:

Notes:

Here is another example, in a patient with gastric cancer, where the pseudoprogression happens a little bit later in the course of treatment. So you see, across the top, baseline, week 8, and week 16 CT scans of the chest, with 3 lesions seen on the scans. At week 16, this scan was called progression based on unequivocal progression of non-target lesions.

And again, you see with no change in therapy, the bottom row of scans-weeks 24, 28, and 32-shows a sustained decrease in the size of the lesions, with a partial response. And please note that this could not have been captured by RECIST 1.1 because after progression, it would have just been progression the rest of the way.


2.5 Flare with Pembro Seen In

Notes:

So this flare, or pseudoprogression phenomenon, has been seen with pembrolizumab in a number of solid tumor indications, including melanoma, non-small cell lung cancer, head and neck cancer, gastric, and bladder cancer, as well as others.


2.6 Brief History

Notes:

Now, let's briefly talk about how we got to iRECIST.

So the first set of immunotherapy criteria were published in 2009 by Jedd Wolchok and colleagues. And these criteria- these are called the irRC, or immune-related response criteria-these were based on the WHO criteria rather than on RECIST. So they measured lesions in two dimensions rather than just one dimension as with RECIST, and they used a different set of logic, closer to the WHO criteria logic. New lesions were measured and added to the baseline tumor burden and progression could only be based on the quantitatively described tumor burden, so there was no such thing as non-target progression. And they introduced the concept that progression has to be confirmed.

Now, people weren't happy with these criteria for a variety of reasons. There were gaps in them. So many people made the effort to combine irRC with RECIST, producing what they called irRECIST. The problem is that there were two completely different approaches to irRECIST.

One was to take the Wolchok irRC and just make them one-dimensional; that is, measure the legions in one dimension and set the thresholds for progression and response to be those of RECIST.

The other approach was to keep the logic of RECIST and then add a confirmation requirement and that is the approach that Merck took.


However, the problem is there were two different systems, both were being referred to as irRECIST, so it was difficult for investigators to compare results across trials or even to speak the same language to each other.

2.7 iRECIST Development

Notes:

In 2016 and ’17, there was a collaboration that developed to harmonize the different approaches to immune-based RECIST, which involved multiple pharmaceutical companies as well as academia and regulators, and this resulted in the form of iRECIST that we're discussing today.

Please note that these are considered guidelines rather than strict formal criteria. The idea is to enable the collection of data that will be uniform across trials, and analysis of multi-trial data in the future can lead to refinements and improvements in these guidelines.


3. New Concepts and Response Categories

3.1 New Concepts

Notes:

Now let's talk about the concepts that distinguish iRECIST from RECIST 1.1 and the new categories of response created in these guidelines.


3.2 RECIST 1.1 Until PD

Notes:

The first thing to understand is that until the initial progression seen by RECIST 1.1, there is no distinct iRECIST. That is, at baseline, you pick target and non-target lesions based on the same rules and the same definitions of what is measurable as RECIST 1.1, and the response categories and the thresholds for changes and some of diameters are exactly the same. It's just RECIST 1.1 until the time you see progression by RECIST 1.1.


3.3 Concept: Confirming PD

Notes:

The first concept that makes iRECIST different from RECIST 1.1 is that progression may needs to be confirmed. That is, when the subject first shows radiographic progression based on RECIST 1.1, the investigator makes a decision. If the subject is clinically stable-and that means stable performance status, no worsening signs or symptoms of disease (which can include laboratory abnormalities), and no progression that requires urgent intervention or change in treatment such as, for example, growth of a mass that impinges on the spinal cord requiring intervention-if all of those criteria for critical stability are met, the investigator can choose to continue treatment and then repeat a scan in 4 to 8 weeks to see whether progression is confirmed.

If it is not confirmed, it is considered pseudoprogression. The subject would then return to their ordinary imaging schedule as set out in the protocol.


3.4 Concept: New Lesion Assessment

Notes:

Another concept that makes iRECIST different concerns how new lesions are assessed when they first appear. When new lesions appear this is progression by RECIST1.1, but if the subject will be continued on treatment and assessed by iRECIST, new lesions can be classified as measurable or non-measurable based on the same size thresholds and rules about reproducibility as you would apply to lesions seen at baseline.

These new lesions can then be categorized as new lesion target or new lesion non-target. You can select up to 5 new legion targets -and then you measure them in the same way that you measure any target lesion: longest diameter for non-nodal lesions, short access measurement for lymph nodes-and then you add up these diameters to create a new lesion target sum of diameters (SOD). This is kept completely distinct from the sum of diameters for the baseline target lesions. Any other lesions are classified as new lesion non-targets.

Please note that this only applies the first time you see new lesions. If in the iRECIST assessment any additional new lesions appear later, these will all be new lesions non-targets only.


3.5 New Response Categories

Notes:

IRECIST defines new response categories, all of which are designated with the lower case ‘i’ preceding the name of the category. And these are all responses used in iRECIST-that is, at or after progression by RECIST 1.1-these can be applied to visit, or overall responses, or to lesion category responses. So the target lesion response can be an i__ response. So for example, iSD is stable disease scene after RECIST progression. And the other categories are iPR, iCR, and non-iCR/non-iUPD, which is the equivalent of non-CR/non-PD for non-target lesions.

The first response category that is really unique to iRECIST is iUPD-so unconfirmed progress disease. This is always the first visit response seen in iRECIST. Something distinct about iUPD is that iUPD can occur multiple times throughout the course of a patient's treatment and can even occur multiple times in a row as we will discuss shortly.

The other distinct category for iRECIST is iCDP-that is, confirmed progressive disease. And iCPD is only possible immediately iUPD. So you cannot get to iCPD without going through iUPD first. So again, iUPD: always the first iRECIST visit response; iCPD: only possible coming out of iUPD.


3.6 iRECIST Begins at RECIST PD

Notes:

So here is a graphic representation of this idea. So you start with a scan of baseline and we'll just call that Visit 0 here. And then however many visits you have in RECIST 1.1 with whatever responses you have-in this case, let's just say there's one visit-and then at Visit 2, there is progression by RECIST 1.1. That RECIST 1.1 PD becomes the beginning of iRECIST and, again, the first iRECIST visit response is always iUPD. If the subject is continued on, evaluation would proceed by iRECIST, and you could proceed onto iCPD or to something else, and we'll discuss that in a minute. Any further responses by RECIST 1.1 in this subject would automatically be progressive disease.


3.7 InForm Data Entry

Notes:

A word here about entering data into InForm. The lesion data for both RECIST and iRECIST is entered on the lesion form LSNIR. Now the responses-target lesion response, non-target lesion response, presence of new lesions, and overall or visit response-those are entered on the response form called ORIR. Initially, the responses are entered on the top portion of the form, which is the recessed portion, and that portion of the form has RECIST 1.1 response categories. At the point of RECIST 1.1 progression, for that one visit, both the top and the bottom portions of the form are completed. The bottom portion is the iRECIST portion of the visit response for that one visit, and iRECIST, remember, will always be iUPD. And then following that point, responses are entered only in the bottom portion of the form.


Top1 (Slide Layer)

Top2 (Slide Layer)


Bottom 1 (Slide Layer)

Bottom 2 (Slide Layer)


4. Response Assessments after PD by RECIST 1.1

4.1 Response Assessments after PD by RECIST 1.1

Notes:

Now let's get into the heart of iRECIST: how to assess response once RECIST 1.1 has shown progression.


4.2 “Cause” of PD

Notes:

Now, in the discussion that follows, I'm going to use the term “a cause of PD,” and I want to make sure you understand what I mean by that. A cause of PD is when any category of lesion shows the change that would drive progression in RECIST 1.1. So if target lesions show growth of at least 20% relative and at least 5 mm absolute increase from the nadir, that would be RECIST 1.1 progression based on target lesions, and so here Target Legions would be a cause of PD. For non-target lesions, of course, that would mean unequivocal progression, or the appearance of new lesions. Any of those three things can be a cause of PD.

A quick note on terminology here: the iRECIST paper uses the term “sum of measurements,” or SOM, to represent the target tumor burden. But because RECIST 1.1 uses “sum of diameters” (SOD), we’re going to stick with sum of diameters for our discussion.


4.3 Possibilities After Initial iUPD

Notes:

So you see progression by RECIST 1.1 and you decide to continue the patient on treatment and scan again 4 to 8 weeks later. That RECIST 1.1 PD by iRECIST is now called iUPD. Let's talk about the possible outcomes on that confirmation scan and what it takes for those outcomes to occur.

One possibility is that progression is confirmed, leading to a visit response of iCPD. In order for that to happen, one of two things has to occur. Either any of the original causes of progression have to show worsening-and, by the way, I know I haven't defined worsening yet, I will define it in detail in a minute. For now let's just have a placeholder concept for worsening. So either any original cause of progression shows worsening or another cause of progression appears.

So, for example, if the initial RECIST progression, iRECIST iUPD, was caused by growth of target lesions and appearance of new lesions, then you would get iCPD on the confirmation scan if either the target lesions or new lesions showed worsening, or if another cause of PD appeared-that is, if you saw unequivocal progression of the non-target lesions.

Another possible outcome would be continuation of iUPD. When would this happen? It would happen if target lesions were a cause of the initial progression-that is, on that initial iUPD had exceeded the PD threshold. And on the


confirmatory scan, they are still above the PD threshold, but have not shown worsening, and no other factor has appeared to drive iCPD-that is, no new cause of regression or worsening of an existing cause.

The third possibility is that the iUPD resolves into iSD or iPR. In order for that to happen, whether the target lesions were initially a cause of iUPD or not, on this confirmatory scan they have to be below the PD threshold. So if the target lesions show SD-that is, there is not 30% decrease from baseline but not 20% increase from nadir-that is iSD; and if the target lesions are actually 30% decreased from baseline that would be iPR. And no other factor that would drive the outcome along the iCPD track can have happened, so there can be no new cause of progression and no worsening of existing causes.

Something critical to note here: target lesions are weighted more heavily in determining the overall response. That is, if you have iUPD that involves both target lesions and some other cause of iUPD (or RECIST progression), then only the target lesion progression has to resolve in order to achieve iSD or iPR. For example, if you had at iUPD a partial response in the target lesions -that is, let's say they were 50% of baseline-but you had unequivocal progression of non-target lesions and new lesions had appeared, and then nothing changed so that target lesions still show PR and there had been no worsening of the non-target lesions or new lesions, that would be iPR. So iPR would be driven here by the target lesions and the lack of worsening of the other causes.

And then of course the final possibility: if all the legions completely resolve, everything goes away, then that would be called iCR.


4.4 Concept of “Worsening”

Notes:

So what do we mean when we talk about a particular cause of progression showing worsening? Well, before we get into the technical definition, remember something you may have encountered in your statistics and probability classes or in epidemiology called Bayes Rule. And without getting into the math of it, a Bayesian approach to determining how likely it is, for example, for a patient to have a disease, is that you take some prior knowledge about the disease-for example, its prevalence-and then you take the new information that comes in from some medical tests and you combine those two to give the post-test likelihood that the patient has the disease.

So, if you already have a high suspicion that the patient has the disease, you need less new data or less convincing new data to decide that yes, they do in fact have it. So in this context, the idea is that if some cause of progression has already manifested target lesion growth, non-target lesion growth, the appearance of new lesions, that factor is highly suspicious and it doesn't take a lot more growth for the suspicion to tip over into certainty. That is, if you already have progression by target lesions, just a little bit more growth in the target lesions means yes, that really is PD. So high suspicion plus a little bit more growth equals certainty of PD confirmation. And this is what we mean when we say that there is a low bar that an existing cause of PD has to clear in order to serve as the basis for confirming PD.


4.5 “Worsening” = Low Bar for iCPD

Notes:

So based on that, here are the actual functional definitions for worsening based on this low bar.

For target lesions: if target lesions had already showed you iUPD, then worsening is really just a little bit more increase. And by little bit we mean at least 5 mm increase in the sum of diameters from an existing iUPD-you don't need to have another 20% increase from the iUPD, you just need 5 mm of increase, just a little bit more growth, from iUPD to take you to target lesion iCPD.

For non-target lesions, it's really any more growth. It's, of course, subjective as things are with non-target lesions, but you don't need to have the sort of massive dramatic growth from iUPD by non-target lesions to trigger iCPD by non-target lesions. A little more growth, as subjectively assessed by an experienced reviewer, is enough to confirm the progression.

For new lesions, either the number of new lesions increases so more new lesions appear, or the size of the new lesions that had appeared and triggered that initial RECIST PD (or iRECIST iUPD); size increase means for new lesion targets that new lesion sum of diameter (SOD) increases by at least 5 millimeters, or for new lesion non-targets, it’s any significant growth. Again, for new lesions, any time they appear, they cause the iUPD condition, so any more growth from them is


enough to confirm progression.

So that’s what we mean by worsening.

4.6 What Happens After iUPD

Notes:

So what happens once the confirmatory scan is done?

If progression is confirmed-that is, if on the confirmatory scan the overall response is iCPD-treatment should be stopped as a general rule. Individual trial protocols may provide exceptions for when treatment can be continued if the investigator believes that the subject is still driving clinical benefit from a therapy.

If the confirmation scan shows continued iUPD, therapy should be continued and the iUPD resolution process should be repeated-that is, another scan is performed four to eight weeks later and the same confirmation process is repeated with the possible results of iCPD, iUPD, or iSD/iPR and so forth.

Finally, if the iUPD resolves into iSD, iPR, or iCR, treatment is continued, the subject returns to the regular imaging schedule, and the bar is reset for progression; that is, we are no longer at a heightened suspicion for the subject


overall and the next incidence of progression that is seen will result in another iUPD, which must then be confirmed again before iCPD can be called.

4.7 Progression After iSD/iPR/iCR

Notes:

What does it take to have radiographic progression after iSD, iPR, or iCR?

For target lesions, the sum of diameters (SOD) would have to cross the PD threshold, either for the first time, or once again. The PD threshold is always based on the nadir value; that is, the smallest value ever seen. Remember that resetting the bar for progression does not mean resetting the baseline, or resetting the nadir. The nadir is the smallest value ever seen; 20% increase from that is the PD threshold; and if target lesions cross that threshold, then you have another incidence of progression, which is called iUPD.

For non-target lesions, they either have to show unequivocal progression for the first time, or if non-target lesions had previously shown unequivocal progression leading to iUPD, and then they didn't worsen enough to trigger iCPD but they have not regressed, then our index of suspicion for them is still high, it's still a low bar situation, so any significant growth of non-target lesions would then trigger


another iUPD.

4.8 Progression After iSD/iPR/iCR (Cont.)

Notes:

For new lesions to trigger another progression, either new lesions would have to appear for the first time, which would, of course, be RECIST progression, or additional new lesions would have to appear. Or, if there had been new lesions as part of the prior progression, and they are still present, then any growth would trigger another iUPD. So for new lesion targets, that would be at least a 5 mm increase in the sum of diameters (SOD), or for new lesion non-targets, it would be visible growth, significant visible growth assessed qualitatively.

Now, for new lesions, it is important to keep track of the nadir value for the new target lesion sum of diameters and for the total number of new lesions. The purpose of this will become clear in a moment.


4.9 Resolving Second iUPD

Notes:

When you see another progression, that is, once again iUPD, and the process for resolving the iUPD is almost the same as the first time iUPD was seen.

You get another scan 4 to 8 weeks later, and the decision tree for this confirmatory scan is almost the same as before. There is just one small additional rule.

As before, if any of the existing causes of progressions that triggered this iUPD worsens or another cause of progression appears, that is iCPD.

The subject will stay in iUPD if there is no factor that drives iCPD and either of these two things occur: either the iUPD involved target lesions, going above the PD threshold, and they are still above the PD threshold without worsening, that's just like the first time we saw iUPD.

Or, and here's the small difference, if new lesions had already been present and if they then worsened, increased in size or number from their nadir values, to get you into this second iUPD; then unless that worsening of new lesions resolves you cannot exit iUPD and get back to iSD or iPR. So this is different from the first instance of iUPD where new lesions had just appeared and as long as they didn’t


worsen enough to cause iCPD they didn’t preclude you from dropping back out of iUPD into iSD or iPR, but in this case new lesions were already present and they worsened to cause this iUPD and that worsening would have to clear to resolve it. So the subject can drop back into iSD or iPR if the target lesions are not above the PD threshold, if there is no persistent worsening of previously worsening new lesions, and nothing else has happened that would drive you into iCPD.

Of course, if all the lesions resolve completely that gives you iCR.

5. Case Examples

5.1 Case Examples

Notes:

Now let's try applying these rules to some sample cases.


5.2 Case Preview

Notes:

Each of these cases will be a virtual subject. The subject will be represented by a single slice on a CT scan, which we’ll look at in a moment. In each of these cases, the very first visit after baseline will show progression by RECIST 1.1-just telling you that right in advance-and our task here will be to assess responses using the rules of iRECIST. These cases will start very simple and then increase in complexity. In the first three cases, the only changes will be in the target lesions, and in later cases, target, non-target, and new lesions will contribute to the response assessment.


5.3 Baseline For All Examples

Notes:

Here is a slice of a CT scan that represents our entire patient for all the sample cases. As you can see, this is an axial CT image through the upper abdomen, using both oral and IV contrast. There are two target lesions in the liver measuring 24 and 21 mm; there are two target lesions in the spleen measuring 32 and 23 mm; and there are four small non-target lesions in the liver. For these cases we are going to assume that the subject has no lesions anywhere else, and if there are any new lesions that appear, they will appear on this slice.


6. Case 1

6.1 Case 1

Notes:

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6.2 Case 1 – Baseline

Notes:

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6.3 Case 1 – Visit 1

(Pick One, 10 points, 1 attempt permitted)


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD

Feedback when correct:

The nadir SOD is 100, so the threshold for PD is 120. This is above that threshold, so it is PD by

RECIST 1.1, so by iRECIST it is iUPD.

Feedback when incorrect:

The nadir SOD is 100, so the threshold for PD is 120. This is above that threshold, so it is PD by

RECIST 1.1, so by iRECIST it is iUPD.

Notes:

{no audio}


Correct (Slide Layer)

Incorrect (Slide Layer)




Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD


There has been an increase of at least 5 mm from an existing iUPD, which is worsening of an

existing cause of progression, and thus iCPD.





Notes:

{no audio}




7. Case 2

7.1 Case 2

Notes:

{no audio}



Notes:

{no audio}


Notes:


{no audio}



Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


Because there has been no worsening, this is not iCPD.


Because the target lesion SOD is still above the PD threshold, this cannot resolve to iSD.

Therefore, the response remains iUPD.




Therefore, the response remains iUPD.

Notes:

{no audio}






Correct Choice

iCR


iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD







Notes:

{no audio}


8. Case 3

8.1 Case 3

Notes:

{no audio}



Notes:

{no audio}


Notes:


{no audio}



Correct Choice

iCR

iPR

X iSD

non-iCR/non-iUPD

iUPD

iCPD



The SOD has fallen below the threshold for progression (120 mm), so the target lesion response

is iSD. This leads to a “resetting of the bar”, so that another iUPD is needed before iCPD can

occur.



is iSD. This leads to a “resetting of the bar”, so that another iUPD is needed before iCPD can

occur.

Notes:

{no audio}






Correct Choice

iCR


iPR

X iSD

non-iCR/non-iUPD

iUPD

iCPD


Since the bar has been reset, the target lesions would have to grow enough to trigger

progression again, rather than just grow by at least 5 mm. The threshold for PD by target lesions

is 120, and the SOD has not increased enough to trigger PD.


Since the bar has been reset, the target lesions would have to grow enough to trigger

progression again, rather than just grow by at least 5 mm. The threshold for PD by target lesions

is 120, and the SOD has not increased enough to trigger PD.

Notes:

{no audio}


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


The SOD has now reached the PD threshold, so this is progression, which means another iUPD.


The SOD has now reached the PD threshold, so this is progression, which means another iUPD.

Notes:


{no audio}






Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD








Notes:

{no audio}




9. Case 4

9.1 Case 4

Notes:

{no audio}



Notes:

{no audio}


Correct Choice

Select a response, then select Submit.

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD




Therefore, the target lesion response remains iUPD.




Therefore, the target lesion response remains iUPD.

Notes:

{no audio}


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


As there has been no other cause of PD, the overall response is also iUPD.


As there has been no other cause of PD, the overall response is also iUPD.

Notes:


{no audio}






Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD


The target lesions continue to shrink, but still above the PD threshold, so the target lesion

response remains iUPD.


The non-target lesions show dramatic enlargement, enough to be considered unequivocal

progression. This is a new cause of PD, and since the prior visit response was iUPD, this triggers

iCPD.


The target lesions continue to shrink, but still above the PD threshold, so the target lesion

response remains iUPD.

The non-target lesions show dramatic enlargement, enough to be considered unequivocal

progression. This is a new cause of PD, and since the prior visit response was iUPD, this triggers

iCPD.

Notes:

{no audio}




10. Case 5

10.1 Case 5

Notes:

{no audio}



Notes:

{no audio}


Correct Choice

iCR

iPR

X iSD

non-iCR/non-iUPD

iUPD

iCPD



is iSD.



is iSD.

Notes:

{no audio}


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD


New lesions have appeared, so from an existing iUPD at visit 1, we have added a new cause of

progression, which means the overall response is iCPD.


New lesions have appeared, so from an existing iUPD at visit 1, we have added a new cause of

progression, which means the overall response is iCPD.


Notes:

{no audio}




11. Case 6

11.1 Case 6

Notes:

{no audio}



Notes:

{no audio}




Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


There is progression by target lesion growth, and a new lesion has appeared. The new lesion is

large enough to be measurable, so it is a new lesion target. The overall response is progression

by RECIST 1.1, and the first iRECIST response, at the point of RECIST progression, is always iUPD.





Notes:

{no audio}


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD


The SOD for baseline target lesions has fallen below the threshold for progression (120 mm), so

the target lesion response is iSD. However, there has been at least 5 mm of growth in the NL-

SOD, which is worsening of new lesions. Worsening of an existing cause, starting from an iUPD,

is iCPD.



The SOD for baseline target lesions has fallen below the threshold for progression (120 mm), so

the target lesion response is iSD. However, there has been at least 5 mm of growth in the NL-

SOD, which is worsening of new lesions. Worsening of an existing cause, starting from an iUPD,

is iCPD.

Notes:

{no audio}




12. Case 7

12.1 Case 7

Notes:

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Notes:

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Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD










Notes:

{no audio}






Correct Choice

iCR


X iPR

iSD

non-iCR/non-iUPD

iUPD

iCPD


The SOD for the baseline target lesions has decreased, and is now more than 30% decreased

from baseline. The target lesion response is therefore iPR.


The SOD for the baseline target lesions has decreased, and is now more than 30% decreased

from baseline. The target lesion response is therefore iPR.

Notes:

{no audio}


Correct Choice

iCR

X iPR

iSD

non-iCR/non-iUPD

iUPD

iCPD


There is no other factor that would indicate progression, so the overall response is the same as

the target lesion response.





Notes:

{no audio}






Correct Choice

iCR

iPR

X iSD

non-iCR/non-iUPD

iUPD

iCPD


The nadir SOD for baseline target lesions is 60 mm. A 20% increase from 60 mm would be 72

mm. The target lesion SOD has not reached this PD threshold, so it is not iUPD. At the same time,

the SOD is no longer at least 30% decreased from baseline, so it is no longer iPR. By exclusion,

this is iSD.



The nadir SOD for baseline target lesions is 60 mm. A 20% increase from 60 mm would be 72

mm. The target lesion SOD has not reached this PD threshold, so it is not iUPD. At the same time,

the SOD is no longer at least 30% decreased from baseline, so it is no longer iPR. By exclusion,

this is iSD.

Notes:

{no audio}






Correct Choice

iCR


iPR

X iSD

non-iCR/non-iUPD

iUPD

iCPD







Notes:

{no audio}


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


The baseline target SOD has now crossed the PD threshold of a 20% increase from nadir, so the

target lesion response is iUPD.


The baseline target SOD has now crossed the PD threshold of a 20% increase from nadir, so the

target lesion response is iUPD.


Notes:

{no audio}






Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


An additional new lesion has appeared. Both this, and the target lesion growth, indicate

progression. Since the bar was reset by the iPR, this means the overall response must be iUPD.



An additional new lesion has appeared. Both this, and the target lesion growth, indicate

progression. Since the bar was reset by the iPR, this means the overall response must be iUPD.

Notes:

{no audio}






Correct Choice

iCR


iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


The baseline target SOD has not increased by at least 5 mm from a prior iUPD, so the target

lesion response remains iUPD.


The baseline target SOD has not increased by at least 5 mm from a prior iUPD, so the target

lesion response remains iUPD.

Notes:

{no audio}


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD


Another new lesion has appeared. This is worsening of new lesions (an increase in number),

from a prior iUPD, which indicates iCPD.


Another new lesion has appeared. This is worsening of new lesions (an increase in number),

from a prior iUPD, which indicates iCPD.


Notes:

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13. Case 8

13.1 Case 8

Notes:

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Notes:

{no audio}


Notes:


{no audio}


Notes:

{no audio}




Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


The baseline target lesion SOD is no longer in PR, but has not shown the 20% growth from nadir

(60 mm) that would indicate progression, so this response in iSD.

The new lesion previously seen had not resolved. Therefore, new lesion worsening would

indicate progression. There has been at least a 5 mm increase in the new lesion target SOD from

its nadir (12 mm), which is worsening. Because the iPR at the previous visit “reset the bar” for

overall response, the next scan that shows progression is again iUPD.



The baseline target lesion SOD is no longer in PR, but has not shown the 20% growth from nadir

(60 mm) that would indicate progression, so this response in iSD.

The new lesion previously seen had not resolved. Therefore, new lesion worsening would

indicate progression. There has been at least a 5 mm increase in the new lesion target SOD from

its nadir (12 mm), which is worsening. Because the iPR at the previous visit “reset the bar” for

overall response, the next scan that shows progression is again iUPD.

Notes:

{no audio}





(Pick Many, 10 points, 1 attempt permitted)

Correct Choice

iCR


iPR

X iSD

non-iCR/non-iUPD

iUPD

iCPD


The target lesion response is still iSD.


The target lesion response is still iSD.

Notes:

{no audio}





(Pick Many, 10 points, 1 attempt permitted)


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


The new lesion has shrunk by one millimeter, but the NL-SOD is still at least 5 mm above its

nadir value, which means that the overall response cannot revert to iSD, and must remain iUPD.


The new lesion has shrunk by one millimeter, but the NL-SOD is still at least 5 mm above its

nadir value, which means that the overall response cannot revert to iSD, and must remain iUPD.


Notes:

{no audio}






Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


The baseline target lesion SOD has now grown to exceed the PD threshold, so this is iUPD.


The baseline target lesion SOD has now grown to exceed the PD threshold, so this is iUPD.


Notes:

{no audio}






Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD


An additional new lesion has appeared, which indicates new lesion worsening. The last visit was

iUPD, and there has been both a new cause of PD (target lesions) and worsening of an existing

cause (new lesions). Therefore, this is iCPD.



An additional new lesion has appeared, which indicates new lesion worsening. The last visit was

iUPD, and there has been both a new cause of PD (target lesions) and worsening of an existing

cause (new lesions). Therefore, this is iCPD.

Notes:

{no audio}




14. Case 9

14.1 Case 9

Notes:

{no audio}



Notes:

{no audio}




Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


The non-target lesions show growth dramatic enough to be have been called "unequivocal

progression". Because this is the first incidence, this is PD by RECIST 1.1, and iUPD by iRECIST.


The non-target lesions show growth dramatic enough to be have been called "unequivocal

progression". Because this is the first incidence, this is PD by RECIST 1.1, and iUPD by iRECIST.


Notes:

{no audio}






Correct Choice

iCR

iPR

iSD

X non-iCR/non-iUPD

iUPD

iCPD


The non-target lesions have not grown further. They are still markedly enlarged from baseline,

but slightly smaller than at the last visit. iRECIST does not allow non-target lesions to remain in

iUPD over multiple visits. Therefore, even though they are still increased from their baseline size,

they are called non-iCR/non-iUPD at this visit.



The non-target lesions have not grown further. They are still markedly enlarged from baseline,

but slightly smaller than at the last visit. iRECIST does not allow non-target lesions to remain in

iUPD over multiple visits. Therefore, even though they are still increased from their baseline size,

they are called non-iCR/non-iUPD at this visit.

Notes:

{no audio}






Correct Choice

iCR


iPR

X iSD

non-iCR/non-iUPD

iUPD

iCPD


Because there is no new cause of progression and no worsening of existing causes, and the

target lesions show stable disease, the overall response is iSD.


Because there is no new cause of progression and no worsening of existing causes, and the

target lesions show stable disease, the overall response is iSD.

Notes:

{no audio}


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


The non-target lesions have shown additional growth. Since they had previously shown

progression, and have not resolved, this is worsening sufficient to indicate progression, thus

triggering iUPD again.



The non-target lesions have shown additional growth. Since they had previously shown

progression, and have not resolved, this is worsening sufficient to indicate progression, thus

triggering iUPD again.

Notes:

{no audio}






Correct Choice

iCR


iPR

iSD

non-iCR/non-iUPD

X iUPD

iCPD


The prior iSD at the visit level meant that we “reset the bar” for overall response, so this

progression is again iUPD.


The prior iSD at the visit level meant that we “reset the bar” for overall response, so this

progression is again iUPD.

Notes:

{no audio}


Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD


The non-target lesions have shown further growth. Since they had started at iUPD on the prior

scan, this is worsening from iUPD, which indicates iCPD.


The non-target lesions have shown further growth. Since they had started at iUPD on the prior

scan, this is worsening from iUPD, which indicates iCPD.


Notes:

{no audio}






Correct Choice

iCR

iPR

iSD

non-iCR/non-iUPD

iUPD

X iCPD


Worsening of an existing cause of progression from the prior iUPD means that this is iCPD.


Worsening of an existing cause of progression from the prior iUPD means that this is iCPD.


Notes:

{no audio}




15. Summaries and Conclusions

15.1 Summaries

Notes:

Now that you have had a chance to practice applying these rules, let's briefly recap them.


15.2 Recap of iUPD

Notes:

iUPD converts to iCPD if there is any new cause of progression seen on the confirmatory scan or if any of the existing causes of progression show worsening. So for any of the quantitative target lesions, that's an additional 5 mm of growth, and for any of the non-target lesions, it's any visually significant growth.

The subject stays in iUPD on the confirmatory scan if the target lesions were involved in the progression and are still above the PD threshold, but without showing any worsening, or on any subsequent iUPD-that is, after an initial iUPD has resolved-if new lesions that had contributed to the initial progression are above their nadir values by 5 mm for the new lesion target sum of diameters or the number of new lesions is greater than its nadir.

iUPD resolves to iSD or iPR if the target lesions are below the PD threshold, if on a subsequent iUPD the new lesions are not above their nadir, thus preventing the resolution to iSD or iPR, and for both the iSD/iPR and iUPD, assuming that no other factors have appeared which would have caused iCPD (a new cause or worsening of an existing cause).


15.3 PD After Flare

Notes:

If the confirmatory scan shows iSD, iPR, or iCR, we reset the bar, meaning that before you can get to iCPD, you need to have another iUPD. Another iUPD happens when there's another instance of RECIST progression, which means either target lesions crossing the PD threshold for the first time or again, or non-target lesions and new lesions either showing PD for the first time or, if they have appeared but not resolved, showing worsening (again with a low bar, because if they have already shown progression initially, they are still highly suspicious).

Resetting the bar does not mean rebaselining. The baseline value for sum of diameters stays the same and PR is always measured relative to that, and of course progression is always measured relative to the nadir, which is the smallest sum of diameters ever seen, pre-progression or post-progression.


15.4 Endpoint Determination

Notes:

Finally, let's touch briefly on how the endpoints are determined based on iRECIST.

The date of progression by iRECIST would be the date of the first iUPD that eventually was confirmed that was followed by an ICPD without interval resolution to iSD, iPR, or iCR, so without an interval resetting of the bar.

The best overall response according to iRECST or the iBOR would be the best, or most favorable, response seen since iUPD, and the protocol should specify whether confirmation of PR or CR is required as it is in our RECIST 1.1 endpoints.


15.5 Conclusions

Notes:

This concludes our review of iRECIST. Remember the key takeaway points here are that:

iRECIST appears at the moment of RECIST 1.1 progression, and the first visit response is always iUPD. A rescan at 4 to 8 weeks is required to see whether the progression is confirmed.

At that confirmatory scan, iUPD can be confirmed-that is, can turn into iCPD, or can stay at iUPD, or can regress back to iSD, iPR, or iCR.

Confirmation requires either a new cause of progression or worsening of any existing cause of progression, and if the initial progression is shown to be flare or pseudoprogression-that is, if the confirmatory scan reverts back to iSD, iPR, or iCR-there is a resetting of the bar; that means another RECIST progression is required and that also has to be confirmed by applying these same rules.


15.6 Thank You

Notes:

Thank you for your attention throughout this course. I hope that it will help you master these challenging concepts.

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