To reiterate, however, if the radiologist is able to provide an actual measure, that should be recorded, even if it is below 5 mm. 2.1.1.3 Lesions that split or coalesce on treatment When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be added together to calculate the target lesion sum. Similarly, 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 coalesced such that they are no longer separable, the vector of the longest diameter in this instance should be the maximal longest diameter for the ‘coalesced lesion’. 2.2 Evaluation of Non-Target Lesions This section provides the definitions of the criteria used to determine the tumor response for the group of non-target lesions. While some non-target lesions may actually be measurable, they need not be measured and instead should be assessed only qualitatively at the time points specified in the protocol. •Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (< 10mm short axis). •Non-CR/Non-PD: Persistence of one or more non-target lesion(s) •Progressive Disease (PD): Unequivocal progression (see below) of existing non-target lesions. 2.2.1 Special Notes on Assessment of Progression of Non-Target Disease The concept of progression of non-target disease requires additional explanation as follows: 2.2.1.1 When the patient also has measurable disease In this setti ng, to achieve ‘unequivo cal 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 presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy (see examples in Appendix 2 and further details below). A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status. Pleu ral effusions, pericardial e ffusions and ascites will not be followed as target or non-target lesions and will not contribute to response or progression. The designation of overall progression solely on the basis of change in non-target disease in the faceof SD or PR of target disease will therefore be extremely rare. 2.2.1.2 When the patient has only non-measurable disease This circumstance arises in some trials when it is not a criterion of study entry to have measurable disease. The same general concepts apply here as noted above, however, in this instance there is no measurable disease assessment to factor into the interpretation of an increase in non-measurable Revised Protocol No.: 04 Date: 31-May-2019 224 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS disease burden. Because worsening in non-ta rget disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for unequivocal progression is to consider if the increase in overall disease burden based on the change in non-measurable disease is comparable in magnitude to the increase that would be required to declare PD for measurable disease: i.e., an increase in tumor burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). Examples include, an increase in lymphangitic disease from localized to widespread, or may be described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient should be considered to have had over all PD at that point. While it would be ideal to have objective criteria to apply to non-measurable diseas e, the very nature of that disease makes it impossible to do so; therefore the increase must be substantial. 2.2.2 New Lesions New bone lesions New bone lesions s hould be evaluated as per PCWG3 criteria. Bone lesions will be assessed by radionuclide bone scan only. Radiographic progression on bone scan is defined by the following criteria: •At least 2 new lesions on the first posttreatment bone scan, with at least 2 additional lesions on the next scan (performed at least 6 weeks late r) as compared to first posttreatment bone scan. Date of progression is then the date of first post-treatment scan, •For scans after the first post-treatment scan, at least 2 new lesions relative to the first post-treatment scan AND confirmed on a subsequent scan (performed at least 6 weeks later). Date of progression is the date of the scan that first documents at least 2 new lesions relative to the first post-treatment scan. New soft tissue lesions The appearance of new malignant soft tissue lesions denotes disease progression; therefore, some comments on d etection of new lesions are important. There are no specific criteria for the identification of new radiographic lesions; however, the finding of a new lesion s hould be unequivocal: ie, not attributable to differences in scanning technique, change in imaging modality or findings thought to represent something other than tumor. This is particularly important when the patient’s baseline lesions show partial or comp lete 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. NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be considered new lesions and will not contribute to response or progression. In the event a new fluid collection is seen on a post-baseline imaging ex am, a comment may be made, but the appearance of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression. An example of this is the patient who has visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. The patient’s brain metastases ar e considered to be evidence of PD even if Revised Protocol No.: 04 Date: 31-May-2019 225 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).