Scenario:
patient was confirmed to have no brain lesions at baseline.  iUPD is assigned at timepoint 3 due to new liver lesions.  14 days later the patient has an unscheduled CT scan for new symptoms which shows a new lesion in new site.  4.5 weeks after the iUPD was first documented repeat imaging shows a further new liver lesion and increase in size of the original new lesion by more than 5mm.

Question:
Can the scan done after only two weeks be used to assign iCPD?

Answer:
in order to be consistent in the implementation of iRECIST, scans done prior to 4 weeks after 1^st iUPD (with a protocol defined variance permitted of a recommended +/- 2 days) should not be used to define iCPD UNLESS

• the scans were also performed to investigate a new clinical symptom or sign AND
• an (additional)new lesion is identified on scans done out of schedule. Increases in size of existing lesions (including new lesions identified at the time of iUPD) would not allow iCPD to be assigned and the scans should be repeated to fulfill the requirement of 4-8 weeks after the initial iUPD.

Scans done less than 4 weeks after the initial iUPD (for e.g.  in error or done for other reasons such as possible pulmonary embolus) should be disregarded and repeated as recommended 4-8 weeks after the initial iUPD.

iRECIST recommends that imaging be repeated 4-8 weeks after iUPD was detected.

Questions:
Scans were repeated 9 weeks after the iUPD was first detected, because of scheduling issues.  Can those scans not be used?

Answer:
In order to ensure that patients do not have real and continuing disease progression that requires a change in management, it is recommended that scans be done within 4-8 weeks.  However, if the scan cannot be done within 8 weeks (scheduling, comorbid illness etc.) then the next scan (i.e., in this scenario, the scan done at 9 weeks) can be used to confirm iCPD.

In the paper and as reproduced below, scenario B shows that the appearance of a new lesion (NL) does not preclude the next assessment (time-point, TP) being iPR (immune partial response, because of further shrinkage of target lesions after the new lesion is recorded), while in scenario D, iUPD (i-unconfirmed progressive disease) occurs at TP3 based on an increase in target lesion (T) size, which then shrinks, and meets the criteria for iPR at TP4. However, in scenario F the requirements for PR are met PRIOR to the iUPD being recorded (based on a new lesion), and the subsequent TP response is iUPD because no change was seen in any disease measurement.

While this may seem a little counterintuitive, the underlying concept is that in Scenario B, there is an initial appearance of a new lesion, which may not be truly indicative of tumour worsening, followed by shrinkage of lesion/s present at baseline. In Scenario F, there is initial tumour shrinkage allowing PR to be assigned, but then iUPD occurs, based on a new lesion. There is no further change; while it is possible that this may represent continued PR, it may also be indicative of slow progression (see Scenario Fa and Fb below).

The RECIST working group continues to strongly recommend the use of the current and published nomenclature, so that the former (continued shrinkage after iUPD) can be distinguished from the latter (shrinkage followed by iUPD with no further change) and formally examined during validation procedures to see whether they are equivalent and represent true benefit and PR

However, we believe that some clarifications are warranted as follows

1. iRECIST are recommendations for data handling rather than patient management. iRECIST are also not validated response criteria. Investigators will make treatment decisions with their patients, based on those individual patients, whatever the coding of the TP response for TP3 in scenario F, and likely discontinue treatment for A, but continue for B. These are subjective decisions that are not captured easily by data coding, but should be recorded on the case report form
2. Scenario F is likely to be rare
3. It may be appropriate, in exceptional circumstances and for some diseases (for example melanoma) to clearly define in the protocol how the impact of new lesions (and thus Scenario F TP3) will be handled. Suggestions are:
   1. As published – to ensure consistency across trials
   2. Consider prolonged iUPD (for example for 6 months) to be a separate category of response that could be included in a clinical benefit rate.
   3. Describe the circumstances under which TP3 may be considered to be iPR (similar methodology could be applied to iSD)
4. ‘No change’ is considered to be a change of less than 5 mm in the sum of measures (SOM) of baseline target lesions (or of new lesions; iSOM) to be consistent with RECIST 1.1. Using that clarification, Scenario F would be iPR at TP3 if the SOM decreased further by at least 5 mm, or the new lesions SOM decreased by at least 5 mm (or resolved)

Abbreviations. + = new lesion develops, NE= not evaluatedUNE= unequivocal progression INC = increased, NE= not evaluated

Per RECIST 1.1, in exceptional circumstances, unequivocal progression in non-target disease may result in RECIST 1.1 PD / iRECIST iUPD. Any increase in non-target tumour burden at the next assessment would allow iCPD to be confirmed; the increase does NOT have to be unequivocal (per RECIST 1.1) again.

The same is true for new lesions. A new lesion results in iUPD; if the new lesions are non-target, any increase in size at the next assessment allows iCPD to be assigned – the increase does not need to be unequivocal as defined by a RECIST 1.1

Lesions designated as non-target disease should be categorised on the case record form as for example

• no change from baseline or nadir (NC)
• increased from baseline or nadir (INC)
• no change from last assessment (NCLA)
• further increase from last assessment (INCLA)
• unequivocal increase (UNE)

Assessments with NC, UNE, NCLA can then be differentiated in the database from NC, UNE, INCLA with the former being iUPD/iUPD and the latter iUPD/iCPD

‘New’ progression in other disease categories such as target disease, or another new lesion can of course also confirm progression.

New lesions by themselves may define iUPD (when they appear), or iCPD when they increase in size (5mm or more if they are target, or any increase if non target), or another lesion appears.

However, as noted, the rules of RECIST1.1 always apply – if new lesions appear but then decrease in size or stay stable there are 2 scenarios possible

• each subsequent TP response remains iUPD. Here, any subsequent increase in size of the new lesions (5mm or more* for target or any for non-target new lesions) would allow ICPD to be defined. The TPR would be iUPD, iUPD, iUPD, iCPD for example
• Subsequent TP response is iSD, iPR. Here, the new lesions would result in a new iUPD in the following circumstances
  • Further new lesions develop
  • The NLT meet RECIST 1.1 criteria for PD (20% or more increase in SOM from ‘baseline’ or nadir)
  • The NLNT meet RECIST 1.1 criteria for PD (unequivocal increase equating to a 73% overall increase in tumour burden)

* Note: sequential increases are additive; thus a 4mm increase at one assessment, followed at the next assessment by a further 2mm increase meets the criteria for iCPD.

In the Lancet publication, in the section on Timepoint and best overall response  it is stated that

“The protocol should establish how missing response assessments will be handled. Assessments that are not done or are not evaluable should be disregarded. For example, an iUPD followed by an assessment that was not done or not evaluable, and then another unconfirmed progressive disease, would be indicative of iCPD.” 

Does this mean that the if there is a missing evaluation the NEXT assessment confirms iCPD even if no change had occurred?

Answer: The requirements of ICPD must still be met as detailed in the publication (for example, a further new lesion, an increase in iSOM (target new lesions) by at least 5mm, increase in size of non-target-new lesions, or new RECIST 1.1 PD in other categories

iDOR is defined as the time from the date of the first response iCR/iPR (whichever is first recorded) to the date of PD (iUPD confirmed as iCPD.  iDOR is only defined for subjects who have best overall response of iCR or iPR.  If a patient has  iPR (#1) followed by a iUPD (#1) which is not confirmed, then a iPR (#2) followed by a iUPD  (#2) which is confirmed at the next assessment, then the iDOR is from iPR1 › iUPD2.

RECIST 1.1 principles should be followed.  In general, when a lesion cannot be assessed the entire timepoint assessment should be considered to be not evaluable (NE).  RECIST 1.1 describes how to manage lesions that have become so small they cannot be measured.

iRECIST adds an additional element, as progression is only confirmed at the “next assessment”, and so the question arises of whether iCPD can be assigned If there is an intervening NE between iUPD and what would be iCPD.  iRECIST recommends that the NE TP assessments be disregarded, and the next evaluable assessment be considered the ‘next assessment’.  Clearly, this does not apply to scenarios where lesions are NE because of massive increases in size, the development of large effusions, are an increase in size leading to lobar collapse (for lung lesions).

In RECIST 1.1 the usual principle used is that once a PR has been assigned, and confirmed (if required), then the best response is always PR even is subsequent TP measurements no longer quite meet the criteria (providing that the criteria for PD are not met).  The same principles hold for iRECIST as shown below.