•Laboratory abnormalities as characterized by type, frequency, severity, and timing. Secondary Objective(s): Secondary Endpoint(s): •To evaluate the PK of tremelimumab and of sasanlimab after SC administration. •To evaluate the anti-drug antibody (ADA) response of tremelimumab and sasanlimab after SC administration with the other components.•Tremelimumab and sasanlimab single-dose PK parameters, including the maximum concentration (C max), time to maximum concentration (T max), and if data permit, area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC0-∞); and trough concentrations after multiple dosing (C trough). •Incidence and titers of ADA and neutralizing antibodies against tremelimumab and against sasanlimab.CCI PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 57•To document any preliminary evidence of anti-tumor activity. •Objective tumor response, as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 by calculating the Objective Response Rate (ORR) and Progression-Free Survival (PFS). 2.2. Part 2: Dose Expansion Objectives and Endpoints Primary Objective(s): Part 2 Primary Endpoint(s): Part 2 •To document preliminary evidence of anti-tumor activity using the Clinical Benefit rate (CBR) in participants with NSCLC. •To assess safety and tolerability of VBIR-2 in participants with NSCLC.•CBR (proportion of participants who achieve Complete Response, Partial Response or Stable Disease for > 6 months) using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 (Appendix 3 ). •Adverse Events as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy. •Laboratory abnormalities as characterized by type, frequency, severity, and timing. Secondary Objective(s): Secondary Endpoint(s): •To document preliminary evidence of anti-tumor activity in participants with NSCLC. •To evaluate the PK of tremelimumab and of sasanlimab after SC administration. •To evaluate the anti-drug antibody (ADA) response of tremelimumab and sasanlimab after SC administration with the other components.•Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) using RECIST version 1.1 (Appendix 3 ). •Overall survival (OS). •Tremelimumab and sasanlimab trough concentrations after multiple dosing (C trough) at various time points. •Incidence and titers of ADA and neutralizing antibodies against tremelimumab and against sasanlimab.CCI PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 583. STUDY DESIGN 3.1. Study OverviewThis is a Phase 1, open label, multi-center, multiple dose, safety, PK, PD and immunogenicity study evaluating the components of VBIR-2 (PF-06936308), now solely in participants with advanced or metastatic NSCLC or TNBC. The study is divided into two parts, Dose Escalation (Part 1) in participants with NSCLC and TNBC without acceptable alternative treatment options, followed by Dose Expansion (Part 2) in participants with NSCLC who have progressed on or after treatment with platinum-based chemotherapy and treatment with ≤1 immune checkpoint inhibitor, given concurrently or sequentially with chemotherapy. Dose Escalation (Part 1)The Dose Escalation (Part 1) completed its determination of MTD after 6 cohorts. It enrolled 36 participants in Part 1. It included participants for whom no standard therapy was availablefor advanced or metastatic NSCLC or TNBC, without restrictions as to the prior number of lines of immunotherapy or chemotherapy. Six dose escalation cohorts were investigated: •AdC68 2 x 10 11VP +5 mg pDNA. •AdC68 6 x 1011VP +5 mg pDNA: •If needed – dose reduction of the AdC68 dose to 2 x 1011VP is allowed. •AdC68 6 x 1011VP +5 mg pDNA +40 mg tremelimumab.* •AdC68 6 x 1011VP +5 mg pDNA +40 mg tremelimumab +130 mg sasanlimab*: •AdC68 6 x 1011VP +5 mg pDNA +40 mg tremelimumab +300 mg sasanlimab;CCI PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 59•AdC68 6 x 1011VP +5 mg pDNA +80 mg tremelimumab +300 mg sasanlimab.* * If needed – dose reduction of the tremelimumab or sasanlimab dose is allowed. 3.1.1. Criteria for Dose Escalation The principles of modified toxicity probability interval (mTPI) design,140will be utilized for the dose escalation portion of the study. An mTPI design, targeting a DLT rate of 27.5% and an acceptable DLT equivalence interval (22.5% to 32.5%), will be utilized in the dose escalation phase. The dose levels to be evaluated are given in Figure 1 . If a high DLT rate is observed at the starting dose, the study may explore a lower dose or may be stopped. Each cohort would enroll 2 to 4 DLT evaluable participants and at least 6 and up to 12 participants would be enrolled at a dose level that is predicted to be the MTD as per the mTPI method. Dose cohorts with an acceptable safety profile may be expanded up to N=12 to further assess safety, pharmacokinetics, . Decisions to enroll additional participants at dose levels already cleared for safety will be based on clinical judgment. The mTPI method relies upon a statistical probability algorithm, calculated using all participants treated in the current dose level to determine one of the following dose-finding decisions: the subsequent dose should be escalated, maintained at the current dose, or de-escalated in the next cohort of 2 to 4 participants, or the trial should be terminated. It is currently envisaged that AdC68 6 x 10 11VP +5 mg pDNA +150 mg tremelimumab +300 mg ANTI-PD-1 (PF-06801591) will potentially be the highest dose level. Table 3 .Decision Rules Number of participants treated at current dose #DLTs 1 2 3 4 5 6 7 8 9 10 11 12 0 E E E E E E E E E E E E 1 D S S S E E E E E E E E 2 U D S S S S S S S E E 3 U U D D S S S S S S 4 U U U U D S S S S 5 U U U U U D S S 6 U U U U U U U • Columns indicate number of participants in the cohort and rows indicate number of participants with DLTs • E=Escalate to the next higher dose; S: Stay at the same dose; D: De-escalate to the previous lower dose; U:De-escalate to the previous lower dose and the current dose will never be used again in the trial CCI CCI PF-06936308 C3621001 Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 60If a participant discontinues close to Day 28for reasons other than toxicity and due to an evident non drug -related event , the participant may be deemed evalu able for safet y if safet y assessments have been unremarkable and the investigator and sponsor’s medical monitor both agree that the participant is evaluable for DLT safet y observation. The dose escalation Part 1 of the study will stop if any of the followi ng criteria is met: The maximum sample size has been achieved (approximately 36 participants in total as per the current dosing schedule); 6 to 12 participants have been enrolled at a dose level that is predicted to be the MTD according to Table 3; All dose levels explored appear to be overly toxic, and the MTD cannot be determined; All candidate dose levels have been tested and deemed safe. As an example, if the total n umber of participants (cumulative in the study) treated at the current dose is 4, the following dosing rules are applied: 0-1 DLT -> escalate; 1 DL T -> remain at the same dose; 2 DL Ts -> De -escalate to the previous or intermediate lower dose; 3-4 DLTs -> De-escalate and consider current dose as intolerable. Activation of each cohort will occur no sooner than 28 days after the first 2 -4 participants receive the first AdC68 vaccination, but may occur later if the sponsor and investigators determine additiona l safety data is needed. The Pfizer clinical team and investigators will review all available safety data from the previous and current cohorts prior to making a decision to dose escalate. If no safety issues that would prohibit dose escalating are obser ved, the next cohort of participants would be open for accrual. If dose escalation continues up to a predefined Maximum Feasible Dose (MFD), the escalation is halted without a maximum tolerated dose (MTD) estimate. In those circumstances, the MFD may be the recommended Phase 2dose (RP2D). 3.1.2. Dose Expansion (Part 2) The Expansion Phase will enroll participant s in 1 cohort of participants with metastatic or locally -advanced NSCLC who have previousl y received treatment with a platinum -based chemotherap y regimen and not more than one treatment with an immune checkpoint inhibitor regimen either concurrently or sequentially with the chemotherapy . PF-06936308 C3621001Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 61Participants will participate in the active treatment period of the study for approximately 9 months. This includes a 28 day screening period followed by 2 cycles of vaccine treatment, totaling 8 months in duration. After completion of the active treatment phase (vaccine prime, pDNA boosts, checkpoint inhibitor support), participants will then enter the maintenance phase of the study (pDNA boosts only with checkpoint inhibitor support). Treatment will continue until: disease progression, unacceptable toxicity, death or participant’s or investigator’s decision occurs. Since the treatment effect of cancer immunotherapy can often be delayed, participants will be encouraged to continue on study treatment for at least 24 weeks before an investigator considers removing the participant due to disease progression, as long as (a) Participant and investigator agree; (b) Participantcontinues to meet all other study protocol eligibility criteria; (c) Toxicity remains acceptable; and (d) No deterioration of participant performance status. Disease progression will be confirmed with 2 consecutive timepoints at least 4-8 weeks apart in the absence of rapid clinical deterioration. Participants who demonstrate clinical benefit with manageable toxicity and who are willing to continue receiving study treatment will be given the opportunity to continue treatment upon agreement between the investigator and sponsor. When the participant discontinues treatment, they will then enter a 6 month post-dose follow-up period to assess safety The end of the study is the last participant last visit. The overall design is presented in Figure 1 below:Figure 1. Study Design CCI PF-06936308 C3621001 Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 623.2.DLT Definition Severity of adverse events (AEs) will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For the purpose of dose escalation, any of the following AEs occurring in the first 28 day s following the first AdC68 vaccination that are considered possibly related to study treatment andare not considered related to disease/progression willbeclassified asDLTs: Hematologic: Grade ≥3 neutropenia lasting >7 day s. Febrile neutropenia (febrile neutropenia is defined as an absolute neutrophil count <1.0 × 109/Lwith a single temperature of >38. 3C, or 101F, or a sustained temperature of 38C , or 100. 4F, for more than one hour). Grade 3 neutropenic infection. Grade 3 thrombocy topenia with ≥ Grade 2 clinically significant bleeding (for bleeding events with no grading available, clinic ally significant bleeding is defined as requiring hospitalization or urgent medical intervention). Grade 3anemia lasting more than 7 days. Grade 3 lymphopenia lasting more than 14 days. Nonhematologic: Grade ≥3 AEs that are considered non -hematologic, non-hepatic major organ toxicity (excluding alopecia of any grade; Grade 3 nausea/vomiting or diarrhea <72 hours with adequate antiemetic and other supportive care; ≥ Grade 3 electroly te abnormality that lasts <24 to 72 hours, is not clinically complicated , and resolves spontaneously or responds to conventional medical interventions). Grade 3 flu -like sy mptoms lasting greater than 3 days with adequate treatment. Fever of >40.0°C, or 104.0°F, lasting for more than 3 day s with adequate treatment. Concurrent aspartate aminotransferase (AST) or alanine aminotransferase ( ALT) >3xupper limit of normal (ULN) and tota l bilirubin >2x UL N (potential Hy’s law case). Nonhematologic laboratory abnormalities: Grade ≥3 laboratory abnormalities either associated with s ymptoms or associated with worsening of an existing condition or that suggests a new disease process or that requires additional active management (eg,discontinuation of the drug, close observation, more frequent follow -up PF-06936308 C3621001 Final Protocol Amendment 2, 22 Dec 2020 PFIZER CONFIDENTIAL Page 63assessments, further diagnostic inve stigation or specific treatment).In addition, clinically important or persistent toxicities that are not included in the above criteria may be considered a DLT following review by Pfizer and the investigators. All DL Ts need to represent a clinically signi ficant shift from baseline. The following AEs will not be adjudicated as DLTs: Isolated Grade 3 laboratory abnormalities that are not associated with clinical sequelae and are corrected with supplementation/appropriate management within 72hours of onset. 3.3.MTD Definition The MTD is defined as the highest dose with true toxicity probabilities in the equivalence interval (EI) where the EI is defined as (22.5%, 32.5%). Even though the mTPI model may select an MTD with an incidence of DLTs that is higher than 32.5% since mTPI decision rules are based on unit probability mass (UPM) and not on point estimates of the DLT rate (see Section 9.2.1 ), doses with an incidence of DLT >32.5% (eg, 3 out of 9) cannot be declared as the MTD. In practice, model recommendations may be overridden b y clinical judgment, and MTD with an incidence of DLTs that is higher than 32.5% will not be considered accepta ble to be selected as MTD. 3.4. Toxicities Observed in the Expansion Phase Adverse events that meet the same grading criteria as the DLT criteria listed above will be discussed promptly by Pfizer and Investigators during the next available Safety meeting. At the meeting, the details of the toxicity will be presented, and actions to be taken (if any ) will be discussed, which may involve individual participants, or the Expans ion Cohort as a whole. 3.5. Recommended Part 2 Expansion Dose Definition The RP2D is the dos e chosen for further investigation based on Phase 1 study results. If the MTD proves to be clinically feasible for long- term administration in a reasonable number of participants, then this dose usually becomes the RP2D. Further experience with the MTD may result in a RP2D dose lower than the MTD. The Expansion Dose recommended for Part 2 is: AdC68 6 ×1011VP, 5 mg of pDNA, 80 mg of tremelimumab and 300 mg of sasanlimab. 4.PARTICIPANT ELIGIBIL ITY CRITERIA This study can fulfill its objectives only if appr opriate participants are enrolled.