The goal of this clinical research study is to find a safe and tolerable dose of navlimetostat in combination with pumitamig that can be given to patients with MTAP-deficient advanced non-small cell lung cancer (NSCLC). The effectiveness of the study drugs will also be studied.

Primary Objectives:

Phase I: To evaluate the safety of navlimetostat in combination with pumitamig. Phase II: To evaluate the efficacy of navlimetostat in combination with pumitamig.

Secondary Objectives:

• To evaluate toxicity and tolerability of navlimetostat in combination with pumitamig.
• To evaluate efficacy outcomes including disease control rate, progression-free survival, overall survival, and duration of response.
• To compare the efficacy of the combination in patients with prior ICI exposure and those without (treated with targeted therapy and/or chemotherapy).

Exploratory Objectives:

• To identify potential biomarkers of resistance and sensitivity including MTAP expression (IHC), ctDNA changes as a predictive biomarker for detecting early progression and/or poor response to therapy, and early changes in cytokines and circulating immune cells as markers of treatment response
• To investigate the TME in MTAP-deficient NSCLC before and after treatment

Inclusion Criteria:

General inclusion criteria

• Age ≥18 years. Because no dosing or adverse event data are currently available on the use of navlimetostat in combination with pumitamig in patients <18 years of age, children are excluded from this study.

• Have at least one measurable lesion as the target lesion based on RECIST v1.1. Lesions treated with prior local treatment (radiation, ablation, etc) are generally not considered target lesions. If the lesion with prior local treatment is the only target lesion, evidence must be provided to demonstrate disease progression.

• MTAP loss as defined by homozygous deletion on NGS and/or by absent MTAP protein expression by IHC. Test can be performed on an archival tissue. External testing by a commercial vendor (e.g. Foundation Medicine, Caris, BostonGene, Tempus) or internal assay (e.g. UT MD Anderson MAPP or IHC) is accepted.

• ECOG performance status 0-1.

• Histologically or cytologically confirmed non-small cell lung cancer (NSCLC).

• Patients must have previously received at least one course of systemic therapy for advanced or metastatic disease. Perioperative treatment is accepted if patient progresses within 6 months.

• Patients must have received at least one prior line of standard therapy. Prior exposure to anti-PD-1 or anti-PD-L1 therapies or other checkpoint inhibitors is permitted.

• Patients with actionable genomic alterations for which targeted therapy is considered standard front-line must have received appropriate targeted therapy EGFR, ALK, RET, NTRK, MET or ROS1). Patients may also have been treated with one or more lines of chemotherapy.

• Adequate organ and marrow function as defined below

  • Hemoglobin ≥9.0 g/dL with no packed red blood cell transfusions in the past 7 days.
  • Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L.
  • Platelet count ≥100,000 with no platelet transfusions in the past 7 days.
  • Total bilirubin ≤1.5 x institutional upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is ≤3 × ULN.
  • AST (SGOT)/ALT (SGPT) <3 x institutional ULN value unless liver metastases are present, in which case <5 x ULN.
  • Calculated creatinine clearance ≥45 mL/min (using Cockroft-Gault formula or 24-hour urine collection).
  • Urine protein < 2+ or 24-hour urine protein quantification < 1.0 g
  • Coagulation function: international normalized ratio (INR) or prothrombin time and activated partial thromboplastin time ≤ 1.5 x ULN unless the participant is receiving anticoagulation therapy as long as the prothrombin or activated partial thromboplastin is within therapeutic range of intended use of anticoagulant.

• Agree to follow the study protocol, including treatment, scheduled visits, and examinations, for the duration of the study.

Reproductive status

Note: The investigator or designee shall counsel individual of childbearing potential (IOCBP) participants (as defined in Appendix 3) and male (as assigned at birth) participants who are sexually active with IOCBP on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention present in seminal fluid to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant.

Note: The investigator or designee shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. • Female (as assigned at birth) participants Note: Individuals who are not of childbearing potential are exempt from contraceptive requirements.

o IOCBP must have a negative highly sensitive urine or serum (as required by local regulation) pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study intervention.

Note: If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Note: The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of an individual with an undetected pregnancy.

• IOCBP participants must agree to follow instructions for method(s) of contraception as described below and included in the ICF.

  • IOCBP are not permitted to use hormonal contraceptive methods alone as a highly effective method of contraception and must use an additional nonhormonal highly effective method of contraception (as described in Appendix 3).

    o A female (as assigned at birth) is eligible to participate if they are not pregnant or breastfeeding and at least 1 of the following conditions applies:

  • Is not an IOCBP OR

  • Is an IOCBP using a combination of a hormonal and a non-hormonal contraceptive method or a non-hormonal method alone that is highly effective (with a failure rate of < 1% per year), as described in Appendix 3, during the intervention period and for at least 6 months after the last dose of study intervention. IOCBP participants must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period. If needed, IOCBP participants should be advised to seek advice about egg donation and cryopreservation of germ cells before treatment.

• Male (as assigned at birth) participants:

Note: Azoospermic males are not exempt from contraceptive requirements and will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant.

• Male (as assigned at birth) participants will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant or breastfeeding. Male (as assigned at birth) participants should continue to use a condom during the intervention period and for at least 6 months after the last dose of study intervention.
• IOCBP partners of male (as assigned at birth) participants should be advised to use a highly effective method of contraception during the intervention period and for at least 6 months after the last dose of study intervention for the male participant. IOCBP partners are not permitted to use hormonal contraceptive methods alone as a highly effective method of contraception and must use an additional non-hormonal highly effective method of contraception (as described in Appendix 3).
• Male (as assigned at birth) participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, oral), even if the participant has undergone a successful vasectomy, during the intervention period and for at least 6 months after the last dose of study intervention.
• Male (as assigned at birth) participants must refrain from donating sperm during the intervention period and for at least 6 months after the last dose of study intervention. If needed, male (as assigned at birth) participants should be advised to seek advice about sperm donation and cryopreservation of germ cells before treatment.
• Breastfeeding partners of male (as assigned at birth) participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms. • Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Prior treatment with PRMT5 and/or MAT2A inhibitors.

• Prior treatment with anti-PD-1/VEGF or anti-PD-L1/VEGF bispecific antibodies

• Exposure to systemic anticancer therapy within 21 days or 5 half-lives (whichever is longer) prior to trial enrollment is not permitted.

• Significant risk of pulmonary hemorrhage (per investigators clinical judgement) indicated by the following criteria:

  • Tumors with clear radiographic evidence of major blood vessel invasion, as demonstrated by any of the following radiological features: luminal irregularity, discontinuity, distortion or truncation, intraluminal mass formation or any other abnormal imaging funding assessed by the investigator to indicate risk of bleeding.
  • Tumor lesions with clear invasion of major airways (such as tracheal invasion) or vital organs (such as the heart, pericardium, and esophagus)
  • At least one major cavitation posing hemorrhage risk
  • Clinically significant hemoptysis defined as coughing up or expelling ≥ 1 teaspoon (5 mL) of blood or small blood clots within 4 weeks prior to study treatment initiation. Note: participants with blood in the sputum are allowed to be enrolled.

• Recent (within 3 months) history of intracranial/spinal or GI bleed, vascular disease with a risk of rupture, or therapeutic anticoagulation/antiplatelet treatment within 10 days before initiation of treatment. Participants receiving anticoagulation at a stable dose may be eligible if their PT and aPTT values are stable and within the intended therapeutic range, and if hemorrhagic risk is assessed as low per investigator's clinical judgement.

• Have any of the following hypertension or diabetic conditions prior to trial treatment:

  • Uncontrolled hypertension (systolic BP ≥ 160mmHg and/or diastolic BP

    ≥ 100mmHg) while on antihypertensive medication

  • Those with a history of hypertensive crisis or hypertensive encephalopathy

  • Poorly controlled diabetes (fasting blood glucose ≥ 13.3mmol/L / 240 mg/dL or HgA1c ≥ 8.5%)

• Has a known additional malignancy that is progressing or requires active treatment.

Exceptions include basal cell carcinoma of the skin, ductal carcinoma in situ, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• Major surgery within 21 days of starting treatment is not permitted. Patients must have recovered from the effects of any major surgery.

• Patients with an average QTc (using Fridericia correction) >470 msec are excluded.

• Patients with clinically significant uncontrolled medical conditions are excluded, including: active infection requiring IV antibiotics; significant cardiovascular disease (including uncontrolled hypertension or heart failure, ventricular arrythmia, unstable angina or MI within 6 mo prior to study treatment initiation); extensive bilateral interstitial lung disease; psychiatric illness that limits compliance; history GI/non-GI fistula, GI perforation, or intraabdominal abscess within 6 mo prior to initiation on study; evidence or history of bleeding diathesis or coagulopathy considered a safety risk as per investigatory clinical judgement including history of thromboembolic or major hemorrhagic events within 6 months of initiation on study; or any other condition deemed high risk by the Investigator.

• Known central nervous system (CNS) metastases or leptomeningeal disease is exclusionary unless adequately treated and the patient is no longer on steroids or anticonvulsants. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.

• Patients unable to swallow oral medication or with gastrointestinal disorders likely to interfere with drug absorption are excluded.

• Pregnant or breastfeeding women are excluded.

• Ongoing need for a medication with a known risk of Torsade's de Pointes or known as a strong inhibitor or strong inducer of CYP3A4 and/or P-glycoprotein or a proton-pump inhibitor that cannot be switched to alternative treatment prior to study entry. The following drug interaction databases and other literature can be utilized to determine the CYP3A4/Pgp inhibitors and inducers:

  o https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-anddruginteractions-table-substrates-inhibitors-and-inducers https://druginteractions.medicine.iu.edu/MainTable.aspx

• Active viral hepatitis, including the following:

  • Any positive test result for hepatitis B virus (HBV) indicating presence of virus, e.g., HBV DNA positive would be excluded. Participants with negative HBV viral load are eligible to enroll, as are participants with anti-HBs positive in line with prior vaccination or resolved infection.
  • Any positive test result for hepatitis C virus (HCV) indicating presence of active viral replication (detectable HCV RNA).
  • Participants with positive HCV antibody and an undetectable HCV RNA are eligible to enroll.

• Known human immunodeficiency virus (HIV) positive with an AIDS-defining opportunistic infection within the last year, or a current CD4 count < 350 cells/μL. Participants with HIV are eligible if they have received established antiretroviral therapy (ART) for at least 4 weeks prior to study treatment initiation and continue on ART as clinically indicated while enrolled on study. Viral serology only to be conducted if locally mandated and, if done, must be performed within 28 days of study treatment initiation.

• Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy ≤ 7 days prior to the first dose of study intervention.

• Live/attenuated vaccine received within 30 days of first treatment. The use of inactivated seasonal influenza vaccines (e.g., Fluzone®) will be permitted on study without restriction.

• Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) intended to treat the disease under study within 2 weeks prior to treatment. The concurrent use of any botanical preparation is not permitted while on study.

• Prior organ allograft.

• History of allergy to study intervention or any of its components.

• History of severe (Grade ≥3) irAEs observed with previous PD-1/PD-L1 checkpoint inhibitors that led to treatment discontinuation and rechallenge with ICI was not possible.

• Active, known autoimmune disease. Note: participants with endocrine disorders treated with hormone replacement (e.g. Type I DM, hypothyroidism only requiring hormone replacement), skin disorders not requiring systemic therapy or conditions not expected to recur are allowed.

• Advanced/clinically significant lung disease (e.g. pneumonitis requiring systemic steroids, uncontrolled COPD or asthma, restrictive lung disease or pulmonary hypertension) within 6 mo prior to study treatment initation, or any history of ILD or pneumonitis requiring treatment with systemic steroids (>/= G2), or who have current or suspected ILD or pneumonitis.

• History of peripheral artery disease (e.g., claudication, Leo Beuerger's Disease).

• Any condition for which, in the investigator's opinion, participation would not be in the patient's best interest (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

• Participation in another interventional clinical tria