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

Rationale for Change

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; 15:7412-7420.

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.”

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.

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

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

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

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.

Definition Non-Index Lesions

Definition – Non-measureable Lesions

Response Category Definition

Assessment of Disease Burden

Overall Disease Burden at Baseline

Examples of Index Lesion Measurements BL TP2 TP3

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.

How do I measure Lymph Nodes?

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

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

Post Baseline Assessment of New, non-measurable lesions

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

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

“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  

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 10581.7 Timepoint 2 Wk12 10677.6 irSD +9% from BL No confirmatory scan required because it is SD (becomes new BL/nadir) Timepoint 3 Wk24 12268.7 irSD +14.9% from new BL TP2

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)

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

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

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.

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.

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).

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

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

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

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

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)

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

New, measureable lesion Case Studies – New, measureable lesion

New, measureable lesion Case Studies – New, measureable lesion

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.

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.

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)

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

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

Thank You Any other questions?