15.3. Reporting Adverse Events The Investigator will record all directly observed AEs and all AEs spontaneously reported by the study patient. In addition, each study patient will be questioned about any AEs they have experienced during each study visit . Each AE should be described in detail in the patient’s medical record and on the “Adverse Event ” CRF and SAEs on a “Serious Adverse Event ” form and include the following information: start and stop dates and times , CTCAE v. 4.03 grading, relationship to study medication, action taken, and outcome. AEs should be recorded from time of first dose up to 4 weeks following the last dose of study medication regardless of the causal relationship to the study medication. AEs considered related to study medication should be recorded at any time regardless of when they occurred. 15.4. Prompt Reporting of SAEs All SAEs, w hether or not considered related to study drug, must be reported within 24 hours to the Medical Monitor listed on page 2 of this protocol. During the initial report, the Medical Monitor will require the following patient information as available : • Patient i dentification, including patient study number, initials, and sex . • Date of first study drug dose . • Total dose and number of doses administered . • Date and amount of last study drug dose . • Whether the patient was taking study drug and which drug(s) at the time of the AE . • Date, duration, and description of AE . • Events and/or symptoms leading up to the AE . • Action taken, including whether patient was withdrawn from study due to the event . • Concomitant therapy (including doses, routes, a nd regimens) . • Pertinent laboratory data . • Medical history (including time on study prior to AE and history that might be related to the AE) . • Study drug status (e.g., interrupted, discontinued, dose changed) . Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 68 of 95 • In addition to the above information, the Medical Monitor will require the Investigator's assessment of the following: − Severity of the AE . − Relationship of the AE to study treatment . − Outcome of the AE . Any oral report of SAEs must be followed within 48 hour s by a detailed, written report signed by the Investigator. Any necessary follow -up must be submitted as soon as reasonably possible . The Sponsor will promptly report SAEs related to HS-110 or additional study drug to the FDA and other applicable regulator y agencies in accordance with 21 CFR 312.32 and local regulatory requirements. The Investigator should also comply with any applicable requirements related to the reporting of SAEs to the IRB/EC. The Medical Monitor will review each SAE report and evaluate the relationship of the SAE to study treatment and to underlying disease. Based on the Investigator’s and Medical Monitor ’s (Sponsor’s ) assessment of the SAE, a decision will be made concerning the need for further action. The primary consideration govern ing further action is whether new findings affect the safety of patients participating in the clinical study. If the discovery of a new SAE related to HS-110 and/or additional study drug raises concern over the safety of continued administration of study d rug to patients, the Sponsor will take immediate steps to notify the FDA and all Investigators participating in clin ical studies of HS-110. Further action that may be required includes the following: • Modification of the protocol . • Discontinuation or suspens ion of the study . • Modification of the existing consent form and informing current study participants of new findings . • Addition of any n ewly identified HS-110 related AEs to the list of expected AEs to the Investigator’s Brochure . 15.5. Study Review Committee and Data Monitoring Committee In the phase 1b portion of the study, a Study Review Committee provided ongoing safety evaluations and recommendation for advancement into phase 2. Moving forward, a fully constituted and independent Data Monitoring Committee (DMC) will review ongoing safety and efficacy of phase 2 patients . A full description of the membership, roles, and responsibilities of the DMC will be outlined in a separate charter. Ad-hoc meetings will also occur if the S ponso r, Medical Monitor, or Investigator believes a safety issue has arisen during the course of the trial that may warrant further review or trial alteration. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 69 of 95 16. STATISTICS 16.1. General Statistical Considerations Patients will be analyzed according to the following cohorts for Arm 5: • Cohort A, composed of all CPI naïve patients (n=40 , including 15 phase 1b patients ). • Cohort B, composed of all CPI progressor patients (n=60). Note that this cohort will be permitted to over -enroll. Patients will be analyzed according the following cohorts for Arm 6. Distribution will not be controlled within the two cohorts (n=up to 20 based on patient availability ): • Cohort C, composed of all patients receiving maintenance p embrolizumab • Cohort D, composed of all patients receiving maintenance pembrolizumab + pemetrexed Each cohort (A, B, C and D) will be analyzed including patients of all histolog y types , and then again including only adenocarcinoma patients. Analyses will be performed within each of the cohorts to identify differences in strata for each of the following factors if sufficient data exists : • Histology: a denocarcinoma and squamous cell carcinoma • PD-L1 status : negative ( <1% ) and positive (≥1%) based on tumor cell expression • TIL status : high (> 10%) and low (≤ 10%) • Tumor Mutation Burden : high (10 or more mutations) and low (less than 10 mutations) Additional factors, such as line of treatment or presence of injection site reactions, may be added to statistical model s used for analyses; the method of pooling and testing for interaction among the different factors will be described in detail in the SAP. The intent of this clinical investigation is to establish the ORR and quantify the duration of PFS across the various subsets in NSCLC patients who receive HS -110. Categorical variables will be summarized by frequency distributions (number and percentage of patients) , while continuous variables will be summarized by descrip tive statistics (mean, standard deviation, median, minimum and maximum). All binary clinical endpoints such as immune response, DCR and ORR will be presented as point estimates with 95% CI for each cohort. Time - to-event endpoints (PFS, OS) will be calculat ed using Kaplan -Meier methodology. TEAEs will be summarized in an overall summary of treatment -emergent adverse events (TEAEs) , as well as tables summarized all TEAEs (by SOC and PT), TEAEs related to HS-110, TEAEs related to the combination therapy (nivo lumab, pembro lizumab , or pembrolizumab /pem etrexed , serious TEAEs, serious TEAEs related to the combination therapy, and grade 3+ TEAEs. Listings of all TEAEs, serious TEAEs, and TEAEs leading to discontinuation will also be presented. 16.2. Sample Size Within Arm 5, Cohorts A and B are planned to enroll 40 and 60 patients , respectively . Note that Cohort B will be permitted to over -enroll based on patient availability. The phase 1b patients Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 70 of 95 (n=15) will be included in the sample size for Cohort A. The distributio n of patients, relative to enrollment, will not be controlled within Arm 6 (Cohorts C and D) but is planned to be up to 20 total based on patient availability . Response will be summarized for various combinations of factors in an exploratory manner. With a total enrollment into this clinical investigation of up to 120 patients, this study should provide sufficient precision to provide a characterization of the likely efficacy subsets to be used in a larger study. 16.3. Analysis Populations Study populations are defined as follows: Safety Population : defined as all patients who receive at least 1 dose of HS -110. Per-Protocol (PP) : defined as all patients who have received at l east 6 weekly doses of HS-110 in combination with either nivolumab ( given with every other HS-110 dose) or pembrolizumab (given with every third HS -110 dose during priming ), and who have a pre-treatment tumor assessment and at least one post -treatment tumor assessment. Adenocarcinoma Population : defined as all patients in the PP who had adenocarcinoma histology . Other sub -populations of patients for secondary and exploratory analyses may be defined at the time of statistical analysis and will be identified in any reporting of results.