1. Immune Related Response Criteria (irRC) Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors
Training Presentation v3.0

2. Rationale for Change

3. Wolchok Criteria
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune- related response criteria. Clin Cancer Res 2009; 15:

4. Index and Non Index Lesions
What to measure?
“Per the protocol, CT scans of the chest, abdomen and pelvis should be acquired at each imaging visit, therefore, measurable index lesions should be identified within these regions.”

5. Definition of Measurability per irRC
Note: at baseline, cutaneous disease identified by physical exam or imaging should
not be considered measurable. These lesions may be followed as non-index lesions.

6. Per Inclusion Criteria: must have at least one measureable lesion by RECIST 1.1
If lesion is not a node: Longest diameter must be ≥ 10 mm
( A is the longest diameter/B is short axis)
Example (A)12 mm x ( B) 8 mm
Measurable per protocol- YES
Example (A) 9 mm x ( B) 5mm
Measurable per protocol- NO
If lesion is a node: Short Axis must be ≥ 15 mm
(C is longest diameter/D is short axis)
Example (C) 20mm x (D) 16mm
Example (C) 11 m x (D) 10 mm
Measurable per protocol- No A B

7. Per IIOM: Lesion must also be measurable by irRC
Lesion should be measurable in two dimensions
If lesion is not a node: it must be ≥ 10 mm x ≥ 10 mm
(A is the longest diameter/B is short axis
Example (A)11 mm x (B) 9 mm
Measurable by irRC (per IIOM)- NO
Measurable by RECIST (per protocol)- YES
If the lesion is a node, it must be ≥ 15 mm x ≥ 15 mm
(C is longest diameter/D is short axis)
Example (C)17 mm x (D) 15 mm
Measurable by irRC (per IIOM)- YES

8. Measurable Disease by RECIST KEY POINTS
Per the Protocol- measurability is based on RECIST
However disease response on trial will be assessed using irRC
Therefore, it is ideal to enroll subjects that are measurable by RECIST and irRC
Non node ≥10mm (longest diameter) x ≥10mm (short axis)
Node ≥15mm (longest diameter) x ≥15mm (short axis)
If it is not possible to identify a lesion that is measurable by both irRC and RECIST, follow rules of RECIST

9. Baseline Assessment *
Note: at baseline, cutaneous disease identified by physical exam or imaging should
not be considered measurable. These lesions may be followed as non-index lesions.

10. Definition Non-Index Lesions

11. Definition – Non-measureable Lesions

12. Response Category Definition

13. Assessment of Disease Burden

14. Overall Disease Burden at Baseline

15. Examples of Index Lesion MeasurementsBL
TP2
TP3

16. Lymph Node Measurement
At baseline, lymph nodes will be considered index if they measure
≥15x15mm
At baseline, lymph nodes will be considered non-index lesions if they measure ≥10x10mm but <15x15mm
At baseline, lymph nodes will be considered “normal” if they are less than 10x10 mm
For “new” nodes to be included post baseline they must measure at least 15 mm in short axis.

17. How do I measure Lymph Nodes?

18. Additional Points – Lymph Nodes
Use best clinical judgment for new lymph nodes which do not meet the
>15x15 mm but do meet the threshold for pathologic and
non-measurable of >10x10 mm but <15x15 mm, and are indicative
of worsening disease
Following a PR or SD: a lymph node identified as target disease at baseline that falls below the measurable threshold at follow-up and then gets larger is not considered new. The sum of cross product measurement for the lymph node is added back into the SPD for overall tumor burden
Following a CR: a lymph node that was identified as target disease at baseline that falls below the measurable threshold at follow-up and then gets larger following a CR is automatically PD

19. Post Baseline Assessment
of New Measurable Lesions
Post Baseline Tumor Burden = SPD of index + SPD of new measureable lesions
The SPD of new, measurable lesions are to be added to the original index lesion SPD. To be considered new post baseline:
Non-nodal >5x5mm
Nodal >15x15mm
Reader will use their best clinical judgment for new lymph nodes which do not meet this threshold but are >10x10mm but <15x15mm, ad determine if they should be included in the SPD
Up to 10 new non-cutaneous(visceral) and 5 new cutaneous may be added post baseline. Cutaneous lesions may be tracked by physical exam

20. Post Baseline Assessment of
New, non-measurable lesions

21. Remember, New Lesions….
Do not define progression but will preclude complete response (irCR)
New, measureable lesions are only cause for progression if the tumor burden has increased at least 25% from nadir (lowest value) in two consecutive observations at least 4 weeks apart

22. Adding New Lesions Post Baseline
POST baseline, newly appearing lesions which had not
been previously observed must measure >5x5mm
before it can be added to SPD. These cannot be a
previously recorded non-index which increased in size.
Example: from 3 to 5mm
If recorded previously as a non-index lesion cannot be
added to the SPD until it reaches 10x10mm
Example: a non-nodal recorded at BL as 6x4mm but
now measures 8x8mm cannot be added to the SPD until
it reaches 10x10mm
But, a brand new lesion never before seen measuring 5x5mm may be added

23. “New” Baseline
The tumor burden value at the first regularly scheduled post baseline time point will replace the baseline SPD value if the SPD increases for any reason
This will become the “new” baseline reference value on which to base later assessments

24. Examples – “New” Baseline
A timepoint will qualify as a “new baseline” if all of the following conditions are met:
1) The timepoint is within the first regularly scheduled timepoint (+/-7 days) of treatment
2) The timepoint has the largest SPD of all timepoints
3) The timepoint has no index lesions that have an assessment of NE
Baseline
Timepoint 2
Wk12
irSD +9% from BL
No confirmatory scan required because it is SD
(becomes new BL/nadir)
Timepoint 3
Wk24
irSD % from new BL TP2

25. How Do I Measure Coalescing Lesions?
If initially separate lesions coalesce, record the resulting longest diameter for one of the original index lesions (or short axis for two target lymph nodes) and Zero mm measurements be attributed for the other target(s)

26. Brain Scans History of treated brain metastases:
1) Stability of treated brain metastases must be documented (required) by MRI before the patient may be considered eligible for the study; these lesions should not be selected as index lesions or non-index lesions at baseline and follow-up imaging should not occur unless patient becomes symptomatic
2) Prescreening images are assessed at the site and whether positive or negative are not currently submitted to ICON, but may be sent for comparison if follow-up brain imaging is acquired due to patient developing symptoms

27. Brain Scans continued
No history of brain metastases, but clinical symptoms of brain metastases develop during the study:
1) brain MRI should be performed as clinically indicated and images sent to ICON
2) at follow up time points, if the patient has clinical symptoms suggestive of new or worsening disease in the brain and MRI reveals measurable ((≥5x5mm) brain lesions these should be added to the SPD according to irRC. Brain imaging must then be performed at every follow-up time point and the brain lesions must continue to be added to the SPD

28. Brain Scans continued
No history of brain metastases, no clinical symptoms of brain metastases:
1) Brain CTs or MRIs are not required at baseline or during study follow-up.

29. Cutaneous Lesions
Cutaneous lesions and other superficial/palpable lesions assessed only by physical exam are not considered measurable for the purposes of this protocol, but may be considered non-target lesions for tumor assessments by investigators.
If identification of a cutaneous lesion occurs at baseline, the lesion(s) may be tracked as non-target disease and that lesion must be obtained and submitted at all subsequent timepoints.

30. Sub-cutaneous Lesions
Subcutaneous lesions should not be selected as target unless the following conditions apply: a) there is no other target disease b) it meets measurability criteria c) it can be reproducibly measured d) it will be imaged at all timepoints consistent with anatomy defined (ie. chest abdomen and pelvis).

31. Immune-Related Complete
Response - irCR
Complete disappearance of all index and non-index lesions
Any lymph nodes must have returned to non-pathological size
(<10 mm x 10 mm)
No new lesions appearing at that visit
Must be confirmed in two consecutive observations not less than
4 weeks apart

32. Immune-Related Partial Response – irPR
> 50% decrease in tumor burden compared with baseline
Must be confirmed by a second assessment at least 4 weeks after
first documentation
Presence of new lesions is permitted as long as inclusion of
the product of diameters of the new lesions still results in at least
a 50% decrease in the tumor burden
Persistence of one or more non-index lesion(s) and/or presence
of one or more new non-index lesions

33. Immune-Related Stable Disease – irSD
Neither a 50% decrease in tumor burden compared with baseline nor a 25% increase compared to nadir can be established
Persistence of one or more non-index lesions and/or
presence of one or more non-index lesions is
permitted
Does not require confirmation

34. Immune-Related Progressive
Disease - irPD
At least a 25% increase in tumor burden compared with nadir (minimum recorded tumor burden) in 2 consecutive observations no less than 4 weeks apart
Unequivocal progression of existing non-index lesions + global deterioration of health
Note: appearance of new lesions without global deterioration of health status is NOT automatically considered progression

35. Objective: How we measure progression?
lesion
size
(cm)
+25%
-50% SD PR PD 1 2 3 4 5 6 7 8
Baseline
Time points
PD is at 6 months in this hypothetical example. It is 25 % greater tumor diameter as compared to nadir (even though it is still same size as baseline)

36. Objective: How we measure progression?
lesion
size
(cm)
+25%
+25%
-50% PD SD SD SD PD PD 1 2 3 4 5 6 7
Time points
Baseline
What if the SPD increases at time point 1 but doesn’t persist
ie. “flare”?
Answer: Time point 1 becomes the new baseline or nadir

37. New, measureable lesion
Case Studies –
New, measureable lesion

38. New, measureable lesion
Case Studies –
New, measureable lesion

39. Immune-Related Progressive
Disease – irPD Additional Point – Brain Lesion
Question from site: New brain lesion per irRC: An off protocol brain scan was acquired because patient is now symptomatic for brain mets. We generally qualitatively assess for PD. Is qualitative assessment done per irRC? Would these brain lesions factor into SPD if they were considered measureable even though it is off-protocol imaging?
Response: If a new brain lesion is imaged, even though it may be off protocol, these new lesions in the brain will be assessed qualitatively and not added to the total SPD.

40. Site Questions
Question:  If a new scan has a new lesion,  the new lesion is a lymph node
>15 x 15mm, but the total sum of measurement is decreased by 21%.  Is the Overall Response SD or PD? 
Response: Per irRC it is SD. New lesions do not automatically equate to PD like they do for RECIST; but if measureable, they are to be added to the SPD which must show a 25% increase from nadir to be PD.
Question: What happens if an index lesion is surgically removed or not imaged because they forgot, FOV too small, improper positioning etc.?
Response: If an index lesion was not imaged for whatever reason, it will become “Not Evaluable” and the SPD of remaining index lesions will be calculated. If the SPD is indicative of PD, then PD will be specified for index lesion assessment. Otherwise, the SPD will be disregarded and the response assessment will be NE.

41. Site Questions
Question: What if an unscheduled visit occurs before the 1st regularly scheduled visit and there is an increase in SPD, does this become the new baseline?
Response: In the example below, if a patient has an unscheduled visit before the first regularly scheduled visit, even though there is an increase in SPD it does not become the “new” baseline. The 1st scheduled follow-up visit at Week 9 would become the new baseline.
BL = 100
TP2 = 121 (unscheduled)
TP3 = 124 (wk 9 regularly scheduled visit)

42. Examples Example 1 Example 2 Example 3 Remember:
Baseline
5980.4
Timepoint 2
3186.3
irSD -46% from BL
Timepoint 3
2283.5
irPR -61% from BL requires confirmation 4 weeks later
4 weeks later
1124.7
irPR -81% from BL
confirmed
Baseline
186.4
Timepoint 2
96.9
nadir
irSD -48% from BL
(becomes nadir)
Timepoint 3
88.0
irPR -52% from BL
(becomes new nadir)
4 week confirmatory scan
102.9
irSD -44% from BL, +16% from nadir TP3
Timepoint 5
102.7
irSD -44% from BL 
+16% from nadir TP3
Timepoint 6
75.0
New nadir
irPR -59% from BL
(becomes new nadir) requires confirmation
92.3
irPR -50% from BL
+23% from nadir TP6
Confirmed
Example 3
Baseline
707.2
Timepoint 2
1390.3
irPD +96% from BL
PD triggers 4wk confirmatory scan (new baseline)
4 week confirmatory scan
1104.0
irSD
-20% from new BL
(new Nadir)
Timepoint 4
1912.8
irPD +73.2% from new nadir (TP3); triggers 4wk confirmatory scan
Remember:
Use nadir for progression
Use baseline for response

43. eCRF Completion
Follow instructions provided in the “eCRF Entry Guidelines” and IIOM for recording your measurements and response assessments
on the:
Lesion Evaluation irRC (LSNEI) eCRF
-if a lesion responds and is too small to accurately measure
eg. less than 5mm a default value of 5mm should be entered
Immune Related Oncologic Response – Solid Tumor (IROR) eCRF

44. Thank You
Any other questions?