Safety and Preliminary Anti-Tumor Activity of TYRA-430 in Advanced Hepatocellular Carcinoma and Other Solid Tumors With Activating FGF/FGFR Pathway Aberrations

Key Inclusion Criteria:

All Patients:

• Age ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.

• Adequate end organ function.

• Ability to swallow oral formulations.

• Ability to understand and willingness to sign the ICF.

Part A:

• Histologically confirmed locally advanced unresectable/metastatic HCC orhistologically confirmed advanced solid tumor with documented FGF/FGFR pathwayalterations

• For participants with histologically confirmed locally advanced or metastatic HCC:

• Barcelona Clinic Liver Cancer (BCLC) stage B that is not eligible forlocoregional therapy, or stage C.

• Child-Pugh Score class A

• Must have previously received SOC appropriate for their tumor type. Any number ofprior therapies, including FGFR inhibitors, are permitted.

• Agree to provide archival tumor tissue no older than 2 years from the time ofenrollment, if available. If an archived specimen is not available, a biopsy is notrequired.

Part B, Cohort 1:

• Histologically confirmed locally advanced/metastatic HCC who have previouslyreceived standard of care.

• Barcelona Clinic Liver Cancer (BCLC) stage B that is not eligible for locoregionaltherapy, or stage C.

• Child-Pugh Score class A

• Availability of an archival formalin-fixed paraffin-embedded (FFPE) tumor tissuespecimen obtained ≤2 years prior to screening for submission to sponsor-designatedcentral laboratory for FGF19 IHC testing.

• At least 1 measurable lesion by RECIST v1.1.

Part B, Cohort 2:

• Histologically confirmed advanced solid tumor except FGFR3-altered urothelialcarcinoma and primary central nervous system tumors who have previously receivedstandard of care. Note: Participants with confirmed diagnosis of locally advanced ormetastatic HCC are not eligible for Cohort 2.

• Must have an eligible activating gain-of-function alteration in the FGFR3 or FGFR4gene, or focal amplifications of FGF19

• Archival tumor tissue biopsy specimen no older than 2 years from the time ofenrollment, if available. If a tissue biopsy specimen is not available, a biopsy isnot required.

• At least 1 measurable lesion by RECIST v1.1.

Key Exclusion Criteria:

All Patients:

• Have disease that is suitable for local therapy administered with curative intent.

• Have not recovered from reversible toxicity of prior anticancer therapy to < Grade 1or baseline (except toxicities that are not clinically significant or not expectedto resolve, including but not limited to, alopecia, fatigue, skin discoloration, orGrade 1 neuropathy).

• Have received the following anticancer therapy:

1. Any immunotherapy or other antibody therapy within 28 days prior to the firstdose of the study drug.

2. A TKI < 5 days or 5X the terminal Phase elimination half-lives, whichever islonger, prior to the first dose of TYRA-430.

3. Other systemic therapy not listed above < 14 days prior to the first dose ofthe study drug.

• Participant discontinued a prior anti-FGFR therapy due to significant toxicity,defined as hepatotoxicity ≥ Grade 3 or any Grade 4 toxicity according to CTCAE v5.0.

• Has a serum phosphorus level > upper limit of normal (ULN) during screening thatremains >ULN despite medical management.

• History of or current uncontrolled cardiovascular disease.

• Active, symptomatic, or untreated brain metastases.

• Have a diagnosis of primary CNS malignancies.

• Gastrointestinal disorders that will affect oral administration or absorption ofTYRA-430.

• Females who are pregnant, breastfeeding, or planning to become pregnant and maleswho plan to father a child while enrolled in this study.

• Any reason that, in the view of investigator, would substantially impair the abilityof the participant to comply with study procedures and increase the risk to theparticipant.

Part B, Cohort 1:

• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

• Prior treatment with pan-FGFR inhibitors or FGFR4-selective inhibitors.

Part B, Cohort 2:

• Histologically confirmed locally advanced/metastatic HCC.

• Histologically confirmed urothelial cancer.