Non-small cell lung cancer, pancreatic, or colorectal cancer (SIRB-22-0045)

5.1. Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

Age and Sex:

1. Participants aged ≥18 years (or the minimum age of consent if >18 in accordance with local regulations) at Screening who have signed informed consent.

a. A female participant is eligible to participate if she is not pregnant or breastfeeding.

b. Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants. Disease Characteristics:

2. Documented histologic or cytologic diagnosis of NSCLC, PANC, or CRC receiving standard of care (which may include systemic therapy).

3. Cachexia defined by Fearon criteria of weight loss as (See Section 8.1.1 for details if the participant’s body weight is unavailable from medical record): BMI 2% within 6 months prior to Screening; or  involuntary weight loss of >5% within 6 months prior to screening irrespective of BMI.

4. Serum GDF-15 concentrations of ≥1.5 ng/mL (as measured using the Investigational Use Only Roche Elecsys GDF 15 assay) 10 at Screening. 090177e19baba084\Approved\Approved On: 28-Oct-2022 01:42 (GMT) Ponsegromab (PF-06946860) Protocol C3651003 Final Protocol Amendment 1 27 October 2022 PFIZER CONFIDENTIAL CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022) TMF Doc ID: 164.01 Page 49

5. Participants who are assessed by the investigator to be able to participate for Part A with ECOG PS ≤3.

Other Inclusion Criteria:

6. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.

5.2. Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions:

1. Current active reversible causes of decreased food intake, as determined by the Investigator. These causes may include, but are not limited to:

 NCI CTCAE Grade 3 or 4 oral mucositis;  NCI CTCAE Grade 3 or 4 GI disorders (nausea, vomiting, diarrhea, and constipation);  Mechanical obstructions making patient unable to eat.

2. Receiving tube feedings or parenteral nutrition (either total or partial) at the time of Screening or Randomization.

3. Cachexia caused by other reasons, as determined by the investigator, including, but not limited to:  Severe COPD requiring use of home O2;  NYHA class III-IV heart failure;  AIDS.

4. Undergoing major surgery (central venous access placement and tumor biopsies are not considered major surgery) within 4 weeks prior to randomization. Patient must be well recovered from acute effects of surgery prior to Screening. Patient should not have plans to undergo major surgical procedures during the study.

5. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study. 090177e19baba084\Approved\Approved On: 28-Oct-2022 01:42 (GMT) Ponsegromab (PF-06946860) Protocol C3651003 Final Protocol Amendment 1 27 October 2022 PFIZER CONFIDENTIAL CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022) TMF Doc ID: 164.01 Page 50

6. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody (IgG protein) or molecules made of components of monoclonal antibody. Prior/Concurrent Therapy:

7. Initiation of new treatment with systemic glucocorticoids within the 4 weeks prior to the first dose of study intervention through Week 16; stable (ie, no significant change to dosage or frequency of administration in prior 4 weeks) steroid therapy eg, dexamethasone as part of pre-medication or daily oral prednisone is permissible. Refer to Section 6.9 and Appendix 10.

8. Concurrent administration with anamorelin hydrochloride (eg, within 30 days prior to the first dose of study intervention through Week 16). Refer to Section 6.9 and Appendix 10. Prior/Concurrent Clinical Study Experience:

9. Concurrent investigational products (including drug, biologic agents, or vaccines) are not permitted within 30 days (or as determined by the local requirement) or 5 half-lives (whichever is longer) of the first dose of study intervention through the duration of the study (including both Part A and B). Refer to Section 6.9 and Appendix 10.

10. Enrollment in a previous study with ponsegromab. Diagnostic Assessments:

11. History of severe liver disease or cirrhosis, unrelated to metastatic cancer. Potential study participants with the following liver function test abnormalities will also be excluded:  Total bilirubin ≥1.5 × ULN (except for Gilbert’s syndrome)  AST >3 × ULN (AST > 5X ULN if there is liver involvement by the tumor)  ALT >3 × ULN (ALT >5X ULN if there is liver involvement by the tumor)  Alkaline phosphatase >3 x ULN (Alkaline phosphatase >5X ULN in case of bone metastases).