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16 appendices 16.1 appendix a

| ECOG Performance Status Scale                                         |                                                                     |
|-----------------------------------------------------------------------|---------------------------------------------------------------------|
| Grade                                                                 | Descriptions                                                        |
| Normal activity. Fully active, able to carry on all pre-disease       |                                                                     |
| 0                                                                     | performance without restriction.                                    |
| Symptoms, but ambulatory. Restricted in physically strenuous          |                                                                     |
| l                                                                     | activity, but ambulatory and able to carry out work of a light or   |
| sedentary nature (e.g., light housework, office work).                |                                                                     |
| In bed <50% of the time. Ambulatory and capable of all self-care, but |                                                                     |
| 2                                                                     | unable to carry out any work activities. Up and about more than 50% |
| of waking hours.                                                      |                                                                     |
| In bed >50% of the time. Capable of only limited self-care, confined  |                                                                     |
| 3                                                                     | to bed or chair more than 50% of waking hours.                      |
| 100% bedridden. Completely disabled. Cannot carry on any self-care.   |                                                                     |
| 4                                                                     | Totally confined to bed or chair.                                   |
| Dead.                                                                 |                                                                     |
| s                                                                     |                                                                     |
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16.2 appendix b modified immune-related

This new classification is based on the recent learning from clinical studies with cancer immunotherapies that even if some new lesions appear at the beginning of a treatment or if the total tumor burden does not increase substantially, tumor regressions or stabilizations might still occur later. The irRC were created using bi-dimensional measurements (as previously widely used in the World Health Organization criteria). For this trial, the concepts of the irRC are combined with RECIST 1.1 to come up with the modified irRC.  
For modified irRC, only target and measurable lesions are taken into account. In contrast to the RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions
(minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and measurable new lesions does not increase by ≥ 20%.  
The same method of assessment and the same technique should be used to characterize each  
| Overall irCR:   |
|-----------------|
| Overall irPR:   |
| Overall irSD:   |
| Overall irPD:   |  
identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are displayed below.  
Modified immune-related response criteria are defined as follows:
New measurable lesions: Incorporated into tumor burden.  
New non-measurable lesions: Do not define progression but precludes (irCR).  
Sum of the longest diameters of target and new measurable lesions increases > 20% (compared to nadir), confirmed by a repeat, consecutive observations at least 4 weeks (normally it should be done at 6 weeks) from the date first documented.  
| Complete disappearance of all lesions (whether measurable or not) and no new    |
|---------------------------------------------------------------------------------|
| lesions. All measurable lymph nodes also must have a reduction in short axis to |
| 10 mm.                                                                          |
| Sum of the longest diameters of target and new measurable lesions decreases     |
| ≥ 30%.                                                                          |
| Sum of the longest diameters of target and new measurable lesions neither       |
| irCR, irPR, (compared to baseline) or irPD (compared to nadir).                 |  
| Measurable Response                                                                                      | Non-Measurable Response   | Overall Response   |       |
|----------------------------------------------------------------------------------------------------------|---------------------------|--------------------|-------|
| Using Modified irRC                                                                                      |                           |                    |       |
| Index and New, Measurable                                                                                | Non-Index Lesions         | New, Non-          |       |
| Lesions (Tumor Burden)¹                                                                                  | Measurable Lesions        |                    |       |
| Decrease 100%                                                                                            | Absent                    | Absent             | irCR² |
| Decrease 100%                                                                                            | Stable                    | irPR²              |       |
| Any                                                                                                      |                           |                    |       |
| Decrease 100%                                                                                            | Unequivocal progression   | Any                | irPR² |
| Decrease ≥ 30%                                                                                           | Absent / Stable           | Any                | irPR² |
| Decrease ≥ 30%                                                                                           | Unequivocal progression   | irPR²              |       |
| Any                                                                                                      |                           |                    |       |
| Decrease < 30% to increase <                                                                             | Absent / Stable           | Any                | irSD  |
| 20%                                                                                                      |                           |                    |       |
| Decrease < 30% to increase <                                                                             | Unequivocal progression   | Any                | irSD  |
| 2%                                                                                                       |                           |                    |       |
| Increase ≥ 20%                                                                                           | Any                       | Any                | irPD  |
| ' Decreases assessed relative to baseline                                                                |                           |                    |       |
| Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a second, consecutive |                           |                    |       |
| assessment at least 4 weeks apart (normally it should be done 6 weeks apart).                            |                           |                    |       |