iRECIST guidelines
for immunotherapy

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

• 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
• Scenario F is likely to be rare
• 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:
  • As published – to ensure consistency across trials
  • Consider prolonged iUPD (for example for 6 months) to be a separate category of response that could be included in a clinical benefit rate.
  • Describe the circumstances under which TP3 may be considered to be iPR (similar methodology could be applied to iSD)
• ‘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

Scenario B
	Baseline	TP1	TP2	TP3	TP4	TP5
T lesions (sum)	100	125	50	50	50	120
NT lesions	PRESENT	NC	NC	NC	NC	NC
New lesions		+	NC	NC	++	+*
TP response (R)		PD	PD	PD	PD	PD
TP response (iR)		iUPD	iPR**	iPR**	iUPD	iCPD
* some new lesions resolve. ** iPR despite non-resolution of new lesions detected at TP2. RECIST 1.1 has PD at TP1. iRECIST has iUPD at TP1 and TP4, iCPD at TP5 and iBOR of iPR. iCPD is based on RECIST 1.1 defined PD in T disease. iPD date = TP4

Scenario D
	Baseline	TP1	TP2	TP3	TP4	TP5
Target lesions (sum)	100	50	50	75	50	50
Non target lesions	PRESENT	NC	NC	NC	NC	NC
New lesions		ABSENT	ABSENT	+	ABSENT	ABSENT
TP response (R)		PR	PR	PD	PD	PD
TP response (iR)		iPR	iPR	iUPD	iPR	iPR
RECIST 1.1 has PD at TP3. iRECIST has iUPD at TP3 and iBOR of iPR. iUPD is based on new lesions (Target and Non target lesions) which subsequently resolve. iPD date = not occurred

Scenario F
	Baseline	TP1	TP2	TP3	TP4	TP5
Target lesions (sum)	100	50	50	50	NE	NE
Non target lesions	PRESENT	NC	NC	NC	NE	NE
New lesions		ABSENT	+	UC	NE	NE
TP response (R)		PR	PD	PD	NE	NE
TP response (iR)		iPR	iUPD	iUPD	NE	NE
RECIST 1.1 has PD at TP2 and BOR of PR. iRECIST has iUPD (based on new lesions) at TP2 and iBOR of iPR. iPD date = TP2 even though never confirmed; CRF should collect reason why not reassessed.

Scenario F : A
	Baseline	TP1	TP2	TP3	TP4	TP5
Target lesions (sum)	10	5	5	5	5	5
Non target lesions	Bulky	INC but not Unequivocal PD per RECIST	INC but not UNE	INC but not UNE	INC but not UNE	INC but not UNE
New lesions		Multiple large new	NC	NC	NC	NC
TP response (R)		PD	PD	PD	PD	PD
TP response (iR)		iUPD	This likely represents progression rather than iPR

Scenario F : B
	Baseline	TP1	TP2	TP3	TP4	TP5
Target lesions (sum)	100	5	5	5	5	5
Non target lesions	Minimal	NC	NC	NC	NC	NC
New lesions		Single 10 mm	NC	NC	NC	NC
TP response (R)		PD	PD	PD	PD	PD
TP response (iR)		iUPD	This likely represents true clinical benefit rather than disease progression TP2 (and subsequent TPs] may be considered iPR, if these rules are clearly defined in the protocol.