9.4. Efficacy Analysis In this First-In-Patient study anti-tumor activity is a secondary objective. The main analysis populations will be based on mITT and EP (see Section Analysis Sets ). Disease response will be presented in the form of participant data listings that include, but are not limited to starting dose, disease response at each visit, and best overall response. In addition, progression date, death date, date of first response and last disease assessment date, and date of last contact will be listed. Summary of objective response rates (ORR) and clinical benefit rate (CBR) will be provided by descriptive statistics. Progression -free survival (PFS) is the time from start date to date of first documentation of progression, or death due to any cause. Progression is defined as the appearance of local, regional or distant disease of the same type after complete response or progression of pre-existing lesions. It does not include second primary malignancies of unrelated types. Overall survival (OS) is the time from start date to date of death due to any cause. Duration of Response (DOR) is defined as the duration of overall response measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Duration of Stable Disease (DOSD) is defined as stable disease measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. Clinical Benefit Rate (CBR) is defined as the proportion of participants who achieved anti- tumor responses of Complete Response (CR), Partial Response (PR), or Stable Disease for > 6 months (SD). The Kaplan--Meier methods will be used to analyze all time to event endpoints. Details of these endpoint analyses methods will be included in the Statistical Analysis Plan.CCI PF-06936308 C3621001 Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 1209.5.Safety Analysis The main anal yses of DLTs will be based on the Per Protocol anal ysis set. Participants not meeting the criteria for inclusion in the Per Protocol Analy sis set (ie, not evaluable for assessment of DLTs) will be replaced. Summaries and anal yses of other safety parameters will include all participants in the Safety Anal ysis Set (see Section Anal ysis Sets ). 9.5.1. Analysis of Primary Endpoint Dose L imiting Toxicity (DL T) is the primary endpoint of Part 1 of the study . The occurrence of DLTs observed in the dosing cohorts will govern the dose escalati on as described in Section 3.1. If a participant is withdrawn from study for any reason other than a DLT prior to completion of th e 28-day safet y observation period, a replacement participant will be assigned for the same dose as the replaced participant. The properties of the statistical methods for the anal yses of DLTs are described in section Statistical Methods and Properties . Adverse Events constituting DLTs will be listed per dose level. Adverse Events (AEs) will be graded b y the investigator according to the CTCAE version 5.0 and coded u sing the Medical Dictionary for Regulatory Activities (MedDRA). The focus of AE summaries will be on Treatment Emergent -Emergent Adverse Events, those with initial onset or increasing in severity after the first dose of study treatment. The number and pe rcentage of participants who experienced an y AE, SAE, treatment related AE, and treatment related SAE will be summarized according to worst toxicity grades. The summaries will present AEs both on the entire study period by dose and by cycle. 9.5.2. Analysis of S econdary Endpoints Laboratory Tests Abnormalities The number and percentage of participants who experienced laboratory test abnormalities will be summarized according to worst toxicity grade observed for each lab assay . The analyses will summarize labora tory tests both on the entire study period and by cycle (C ycle 1 and Cy cles bey ond 1). Shift tables will be provided to examine the distribution of laboratory toxicities. For laboratory tests without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. 9.5.3. ECG The anal ysis of ECG results will be based on participants in the safet y analysis set with baseline and on -treatment ECG data. Baseline is defined as the pre- dose ECG collected before the first dose of any component of t he study treatment. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safet y reasons after the nominal time -points will not be averag ed along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analy sis) as individual values obtained at unscheduled time points. PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 121QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, Frederica’s). Data will be summarized and listed for QT, HR, PR interval, QRS, and QTcF by cohort. Individual QT intervals will be listed by time and cohort. Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be used to summarize the absolute corrected QT interval and changes from baseline in corrected QT after treatment by cohort and time point. For each participant and by treatment, the maximum change from baseline will be calculated as well as the maximum post-baseline interval across time-points. Categorical analysis will be conducted for the maximum change from baseline in corrected QT and the maximum post-baseline QT interval. Shift tables will be provided for baseline versus worst on treatment corrected QT using Maximum CTC AE Grade. Shift tables will also be provided for ECG abnormality at baseline versus on treatment (yes, no, not done: (n, %)). Participants experiencing clinically -relevant morphological ECG changes will be summarized (including frequency and percentage). If applicable, the effect of relevant drug concentrations on corrected QT change from baseline will be explored graphically. Additional concentration -corrected QT analyses may be performed. Data may be pooled with other study results and/or explored further with PK/PD models. 9.6. Analysis of Pharmacokinetics 9.6.1. Analysis of Pharmacokinetics 9.6.1.1. Tremelimumab Pharmacokinetic AnalysisThe concentration -time data for tremelimumab will be summarized descriptively (n, mean, standard deviation, coefficient of variation (CV), median, minimum, maximum, geometric mean and its associated CV) by dose, and nominal time for both Part 1 and Part 2. For participants assigned to Cohorts 3A and 6A , the concentration -time data of tremelimumab after the first dose will be analyzed individually by noncompartmental methods to determine PK parameters. The PK parameters to be estimated will include the maximum plasma concentration (C max), time to maximum plasma concentration (T max), and area under the plasma concentration versus time curve following the first dose from time 0 to the last time point prior to the second tremelimumab dose (AUC last) and if data permit or if considered appropriate, area under the plasma concentration versus time curve from time 0 extrapolated to infinity (AUC inf), terminal elimination half-life- (t 1/2), apparent serum clearance (CL/F), apparent volume of distribution (V z/F). The PK parameters will be summarized descriptively (n, mean, standard deviation, coefficient of variation (CV), median, minimum, maximum, geometric mean and its associated CV) by dose. Individual participant and median profiles of the concentration time data, after the first tremelimumab dose, will be plotted by dose, using nominal times. Individual and median profiles will be presented on both linear-linear and log-linear scales.CCI PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 1229.6.1.2. Sasanlimab Pharmacokinetic Analysis The concentration -time data for sasanlimab will be summarized descriptively (n, mean, standard deviation, CV, median, minimum, maximum, geometric mean and its associated CV) by dose, and nominal time for both Part 1 and Part 2. For participants assigned to Cohorts 4A and 5A, the concentration -time data of sasanlimab after the first dose will be analyzed individually by noncompartmental methods to determine PK parameters. The PK parameters to be estimated will include the following: (a) the maximum plasma concentration (C max), (b) time to maximum plasma concentration (T max), and (c) area under the plasma concentration versus time curve following the first dose from time 0 to the last time point prior to the second sasanlimab dose (AUC last). If data permit or if considered appropriate, other analyses may include: (a) area under the plasma concentration versus time curve from time 0 extrapolated to infinity (AUC inf), (b) terminal elimination half-life (t 1/2), (c) apparent serum clearance (CL/F), and (d) apparent volume of distribution (Vz/F). The PK parameters will be summarized descriptively (n, mean, standard deviation, coefficient of variation (CV), median, minimum, maximum, geometric mean and its associated CV) by dose). Individual participant and median profiles of the concentration-time data after the first sasanlimab dose will be plotted by dose using nominal times. Individual and median profiles will be presented on both linear-linear and log-linear scales. 9.6.3. Analysis of Immunogenicity Data The percentage of participants with positive tremelimumab ADA and NAb will be summarized by each cohort. For participants with positive ADA or NAb, the magnitude (titer), time of onset, and duration of ADA or NAb response will also be described, if data permit. The percentage of participants with positive sasanlimab ADA and NAb will be summarized by cohort. For participants with positive ADA or NAb, and if data permits, the magnitude (titer), time of onset, and duration of ADA or NAb response will be described.CCI PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 1239.6.4. Population Pharmacokinetic Analysis or Pharmacokinetic/ (PK ) Modeling PK data from this study may be analyzed using modeling approaches and may also be pooled with data from other studies to investigate any association between tremelimumab or sasanlimab exposure or significant safety and/or efficacy endpoints. The results of these analyses, if performed, may be reported separately.