• Women or men with breast carcinoma
• Documented ER-positive and/or PR positive
• PIK3CA mutation
• Documented HER2-negative
• De-novo HR+, HER2- ABC, or alternatively relapsed HR+, HER2- ABC after at least 2 years of standard neoadjuvant/adjuvant endocrine therapy without disease progression during that treatment and disease-free interval of at least 1 year since the completion of that treatment
• Bilateral breast cancer is allowed if both HR+/HER2-
• Measurable disease
• ECOG PS 0-1
• No metaplastic breast cancer
• No known or untreated CNS mets. History of treated CNS mets allowed
• No active lung disease
• No history of IBD

• Histologically confirmed diagnosis of metastatic or unresectable NSCLC (squamous or nonsquamous) not a candidate for definitive therapy
• KRAS G12C mutation
• Known PD-L1 status (can enroll regardless of level)
• 1st line- no prior treatment for metastatic NSCLC
  • OK to have had radiosensitizing chemo >1 year prior
• ECOG PS 0-1
• Measurable disease
• No active CNS mets
• No XRT to the lungs within 6 months prior to first dose of study treatment
• No known autimmune disease

• Measurable disease by RECIST 1.1 criteria.
• Adequate bone marrow or organ function.
• Life expectancy of ≥ 3 months.
• Sufficient performance status.
• Confirmed NSCLC, without small cell lung cancer transformation with or without brain metastases.

• Disease progression following or intolerance of standard of care (excluding patients in the treatment-naïve non-classical driver cohort):

  • Cohort 1 (Non-Classical driver cohort): Advanced/metastatic NSCLC with a non-classical driver EGFR mutation (eg, G719X) following up to 2 lines of therapy with only 1 prior EGFR TKI regimen (third-generation preferred; other approved EGFR TKI acceptable).
  • Cohort 2 (Acquired resistance C797S cohort): Advanced/metastatic NSCLC with the acquired resistance C797S EGFR mutation following up to 2 lines of therapy, including only one EGFR TKI, which must be a third generation EGFR TKI (eg, osimertinib).
  • Cohort 3 (First-line non-classical driver cohort): Treatment-naïve advanced/metastatic NSCLC with a non-classical driver EGFR mutation (1 cycle of chemotherapy or immune checkpoint inhibitor are permitted). Patients with co-occurring L858R mutations and a non-classical mutation are eligible for inclusion.

• Identification of one (or more) of the following EGFR mutations by Next Generation Sequencing (NGS) as determined by a local assay performed in a validated laboratory in the absence of other known resistance mutations (eg, T790M, MET):

  • Non-classical driver EGFR mutations (eg, L861R, S768I, G719X).
  • EGFR acquired resistance mutation (eg, C797S) to a 3rd generation EGFR TKI.
  • For Phase 2, dose expansion, patients in Cohort 1 who received 3rd generation EGFR TKI (eg, osimertinib), the NGS report within 6 months prior to the start of Screening is acceptable. For patients in Cohort 2, the NGS report must be from the last disease progression on the immediate prior therapy. For patients in Cohort 3, the NGS report must be at the time of diagnosis.
• No known resistant mutations in tumor tissue or by liquid biopsy (eg T790m, MET)
• No more than one line of EGFR TKI tx
• No symptomatic CBS dz

• Histologically or cytologically confirmed, locally advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC not suitable for radical treatment (complete surgical resection, concurrent/sequential radio-chemotherapy) according to the Union for International Cancer Control and the American Joint Committee on Cancer (AJCC) TNM staging system (8th edition), and should meet the following criteria:

  1. Subjects without actionable genomic alterations (AGAs):

     • Subjects with non-squamous NSCLC must have documented negative test results for EGFR and ALK alterations. If no prior test results for EGFR and ALK are available, subjects must undergo EGFR and ALK testing at the study site. For subjects with squamous NSCLC, EGFR and/or ALK testing is not required prior to enrollment if their status is unknown;
     • No other known actionable genomic alterations, such as ROS1, NTRK, BRAF, MET exon 14 skipping, and RET;
     • Prior standard treatment failure of ≥ 1 line, including at least anti-PD-(L)1 antibody and platinum-based chemotherapy;

  2. Subjects with AGAs:

     • Previous test results confirming the presence of one or more actionable genomic alterations;
     • Prior standard treatment failure of ≥ 1 line, including at least targeted therapy for driver gene alterations (patients with EGFR mutations must be previously treated with EGFR inhibitors) and platinum-based chemotherapy;
• At least one measurable lesion as per RECIST 1.1 within 4 weeks prior to randomization;
• ECOG PS score of 0-1
• No small cell, neuroendocrine, or sarcomatoid
• No second malignancy within 2 years except early-stage that have received curative treatment
• No prior treatment with any topo-I targeting agent
• No severe lung disase
• No severe cardiac disease
• No steroids within 2 weeks
• No autoimmune disease except treated hypothyroidism or DM Type 1
• No active HIV, HBV, HCV

Inclusion Criteria:

• Participants with histologically/cytologically confirmed advanced recurrent or metastatic solid tumor malignancy
• Part 1 (dose escalation): Participants must have had disease progression on or following all available standard of care (SOC) therapies known to confer clinical benefit.
• Part 2 (dose expansion): Participants may be enrolled following disease progression that has progressed after at least 1 available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognized SOC.
• Measurable Disease

Exclusion Criteria:

• History of another malignancy within 2 years prior to the first trial intervention administration (unless the malignancy was treated with curative intent with low risk of recurrence [e.g., nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar] which are allowed to enroll).
• Therapy with Immunosuppressive doses of systemic medications, such as steroids (doses >10 mg/day prednisone or equivalent daily) within 2 weeks before trial intervention administration
• Have known active central nervous system (CNS) metastases and/or leptomeningeal disease (LMD).
• Active and clinically relevant bacterial, fungal, or viral infection that is not controlled or requires systemic antibiotics, antifungals, or antivirals, respectively.
• Ascites or pleural effusion that is symptomatic and/or requiring drainage within 2 weeks prior to the first trial intervention administration.
• Have active hepatitis B virus (HBV) or hepatitis C virus (HCV), or participants with human immunodeficiency virus (HIV).
• Any medical condition that, in the investigator's or sponsor's opinion, poses an undue risk to the participant's participation in the trial.

• Histologically confirmed locally advanced, recurrent, or metastatic incurable solid tumors
• Must have tumor specimen available
• Measurable disease
• ECOG PS 0-1
• Life expectancy at least 12 weeks
• Phase 1a- must have exhausted all standard therapies for their disease
• Phase 1b- must have disease that has progressed after at least one available standard therapy
• Some cohorts are tumor-type specific- please contact study team to see if tumor type is eligible at any time during the study
• No active HBV/HCV or chronic or acute EBV
• No history of autoimmune disease
• No symptomatic or actively progressing CNS mets