In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 3 TUMOR RESPONSE EVALUATION 3.1 Evaluation of Target Lesions Complete Res ponse (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must also have reduction in the short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions , taking as reference the baseline sum diameters.Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative incr ease of 20%, the sum must also demonstrate an absolute increase of at least 5 mm . (Note: The appearance of 1 or more new lesions is also considered progression.)Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. 3.1.1 Special Notes on the Assessment of Target Lesions 3.1.1.1 Lymph Nodes Lymph nodes merit special mention since they are normal anato mical structures that may be visible by imaging even if not involved by tumor. Pathological nodes that are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of ≥≥15 mm by CT scan . Only the short axis of these nodes will contribute to the baseline sum. Nodes that have a short axis < 10 mm are considered non-pathological and should not be recorded or followed. 3.1.1.2 Target Lesions That Become ‘ Too Small to M easure’ All lesions (nodal and nonnodal) recorded at baseline should have their actual measurements recorded at each subsequent evaluation. If the radiologist is able to provide an actual measurement, even if it is below 5 mm it should be recorded. Revised Protocol No.: 04 Date: 31-May-2019 184 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS However, when such a lesion becomes difficult to assign an exact measurement to then: •If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. •If the lesion or lymph node is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned =. This default value is derived from the 5-mm CT-slice thickness (but should not be changed with varying CT-slice thickness). 3.1.1.3 Target Lesions That Split or Coalesce on Treatment •When non-nodal lesion s ‘fragment’, the longest diameters of the fragmented portions should be added together to calculate the target lesion sum. •As lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter measurements of each individual lesion. If the lesions have truly co alesced such that they are no longer separable, the vector of the longest diameter in this instance should be the maximal longest di ameter for the ‘coalesced lesion’. 3.2 Evaluation of Non-Target Lesions While some non-target lesions may actually be measur able, they need not be measured and instead should be assessed only qualitatively at th e timepoints specified in the protocol. Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must also be nonpathological in size (< 10 mm short axis). Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) above the normal limits. Progressive Disease (PD): Unequivocal progression of existing non-target lesions. ( Note: The appearance of 1 or more new lesions is also considered progression.) 3.2.1 Special Notes on Assessment of Non-Target Lesions The concept of progression of non-target dis ease requires additional explanation. 3.2.1.1 When the Subject Also Has Measurable Disease •To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. •A modest ‘increase’ in the size of 1 or more non-target lesions is usu ally not sufficient to qualify for unequivocal progression status. 3.2.1.2 When the Subject Has Only Non-Measurable Disease •To achieve ‘unequivocal progression’ on th e basis of the non-target disease, there must be an overall level of substantial worsening such that the overall tumor burden has increased sufficiently to merit discontinuation of therapy. •A modest ‘increase’ in the size of 1 or more non-target lesions is usu ally not sufficient to qualify for unequivocal progression status. Revised Protocol No.: 04 Date: 31-May-2019 185 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS •Because worsening in non-target disease cannot be easily quantified as the lesions are nonmeasurable, a useful test that can be applied when assessing subjects for unequivocal progression is to consider if the increase in ove rall disease burden based on the change in non-measurable disease is comparable in magn itude to the increase that would be required to declare PD for target disease: that is, an increase in tumor burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase in diameter in a measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’ or an increase in lymphangitic disease from lo calized to widespread or may be described in protocols as ‘sufficient to require a change in therapy’. •If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD at that point. 3.2.1.3 Tumor Markers Tumor markers alone cannot be used to assess objective tumor responses. If markers are initially above the upper normal limit, however, they must normalize in order for a subject to be considered as having attained a CR. 3.3 New Lesions The appearance of new malignant lesions denotes PD. The finding of a new lesion should be unequivocal: that is, not attributable to differences in scanning technique, change in imaging modality, or findings thought to represent something other than tumor (eg, some ‘new’ bone lesions may be simply healing or a flare of pre-existing lesions). This distinction is particularly important when the subject’s baseline lesions show partial or complete response. For example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. A lesion identified on a follow-up study in an anatomical location that was notscanned at baseline is considered a new lesion and will indicate PD. An example of this is the subject who has visceral disease at baseline and while on study has a CT or MRI brain scan that reveals metastases. The subject’s brain metastases are considered to be evidence of PD even if he/she did not have brain imaging at baseline. If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then PD should be declared using the date of the initial scan. 3.3.1 FDG-PET Evaluation While [ 18F] fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of the qualitative assessment of FDG-PET scanning to complement CT scanning in assessment of PD (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: •Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD based on a new lesion. •No FDG-PET at baseline and a positive FDG-PET at follow-up: Revised Protocol No.: 04 Date: 31-May-2019 186 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS −If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. −If the positive FDG-PET at follow-up is not confirmed as a new site of disease by CT, additional follow-up CT scans are needed to determine if there is truly PD occurring at that site (if so, the date of PD will be the date of the initial positive FDG-PET scan). −If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 4 RESPONSE CRITERIA 4.1 Timepoint Response A response assessment should occur at each timepoint specified in the protocol.