, for body scans). Use of MRI remains a complex issue. MRI ha s excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image 64 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow -up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath -hold scanning techniques, if possible. 6.3.4 Response Criteria All the scans performed at Baseline and other imaging performed as clinically required (other supportive imaging) need to be repeated at subsequent visits. In general, lesions detected at Baseline need to be followed using the same imaging methodology and preferably the same imaging equipment at subsequent tumor evaluation visits. Brain CT / MRI scan should be performed, if clinically indicated by development of new specific symptoms or on the discretion of the Principal Investigator. For each subject, the Investigator will designate 1 or more of the following measures of tumor status to follow for determining response: CT or MRI images of primary and / or metastatic tumor masses, physical examination findings, and the results of other assessments. All available images collected during the trial period will be considered. The most appropriate measures to evaluate the tumor status of a subject should be used. The measure(s) to be chosen for sequential evaluation during the trial have to correspond to the measures used to document the progressive tumor status that qualifies the subject for enrollment. The tumor response assessment will be assessed and listed according to the Study Calendar 3.5. The foreseen treatment duration is until disease progression verified by a scan subsequent to the initial documentation of PD, unacceptable toxicity, or any criterion for withdrawal from the trial occurs (see Section 6.3). Before stopping the treatment, progressive disease should be confirmed by imaging 4 to 6 weeks (preferably 6 weeks, but not later) after progression has been diagnosed according to RECIST 1.1 [ 36]. If progression is based on the occurrence of a new lesion in an area not scanned at Baseline, a further on- study scan 6 weeks later should be considered before performing the 28- Day Safety Follow -up visit. Treatment may be continued despite progression according to RECIST 1.1 at any time if: • There are no new or concerning symptoms. • There i s no decrease in ECOG PS. • The Investigator does not consider it necessary to administer a salvage therapy. The treatment should be stopped immediately, if the subject does not tolerate M7824 or if therapeutic failure occurs, which requires urgent treatment with an additional drug or results in clinically significant progression / deterioration. Tumor responses to treatment will be assigned based on the evaluation of the response of target, non-target, and new lesions according to RECIST 1.1 (all measurements should be recorded in metric notation). 65 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 •To assess objective response, the tumor burden at baseline will be estimated and used for comparison with subsequent measurements. At baseline, tumor lesions will be categorized in target and non-target lesions according to RECIST 1.1. Results for these evaluations will be recorded with as much specificity as possible so that pre-and post-treatment results will provide the best opportunity for evaluating tumor response. Any CR or PR should be confirmed according to RECIST 1.1. In the case of a PR or CR, a confirmatory CT or MRI scan should be done no sooner than 4 weeks (preferably at the scheduled 6-week interval). The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if the Investigator suspects PD. As an exploratory endpoint antitumor activity will also be evaluated according to iRECIST [ 37]. Using iRECIST criteria the following will be incorporated into assessment: 1. An increase in the sum of target lesions of more than 20%, unequivocal increase in non- target lesions or new lesions result in iUPD (unconfirmed progressive disease); iUPD can be assigned multiple times as long as iCPD (confirmed progressive disease) is not confirmed at the next assessment. 2. Progression is confirmed in the target lesion category if the next imaging assessment after iUPD (4 –8 weeks later) confirms a further increase in sum of measures of target disease from iUPD, with an increase of at least 5 mm. Progression is confirmed in the non- target lesion category if subsequent imaging, done 4–8 weeks after iUPD, shows a further unequivocal increase in non- target lesions. Progression is confirmed in the new lesions category if at next assessment additional new lesions appear or an inc rease in size of previously seen new lesions is seen (≥5 mm for sum of new lesion target). 3. However, the criteria for iCPD (after iUPD) are not considered to have been met if complete response, partial response, or stable disease criteria (compared with baseline and as defined by RECIST 1.1) are met at the next assessment after iUPD. The statu s is reset (unlike RECIST 1.1, in which any progression precludes later complete response, partial response, or stable disease). iCR, iPR, or iSD should then be assigned; and if no change is detected, then the timepoint response is iUPD. 6.3.5 Response Criteria by RECIST 1.1 6.3.5.1 Evaluation of Target Lesions Complete Response (CR) : Disap pearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in 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 of 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 increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). 66 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 Stable Disease (SD) : Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. 6.3.5.2 Evaluation of Non-Target Lesions Compl ete Response (CR) : Dis appearance of all non -target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a par ticipants to be considered in complete clinical response. Non-CR/Non -PD: Per sistence of one or more non -target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD) : Appeara nce of one or more new lesions and/or unequivocal progression of existing non- target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of “non- targe t” lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investiga tor). 6.3.5.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The participant 's best response assignment will depend on the achievement of both measurement and confirmation criteria. For P articipants with Measurable Disease (i.e., Target Disease) Target Lesions Non-Target Lesions New Lesions Overall Response Best Overall Response when Confirmation is Required* CR CR No CR >4 wks. Confirmation** CR Non- CR/Non -PD No PR >4 wks. Confirmation** CR Not evaluated No PR PR Non- CR/Non - PD/not evaluated No PR SD Non- CR/Non - PD/not evaluated No SD Documented at least once >4 wks. from baseline** 67 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 Target Lesions Non-Target Lesions New Lesions Overall Response Best Overall Response when Confirmation is Required* PD Any Yes or No PD no prior SD, PR or CR Any PD*** Yes or No PD Any Any Yes PD * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. ** Only for non-randomized trials with response as primary endpoint.