A Phase II Study of Ivonescimab as Monotherapy or in Combination With Platinum/Pemetrexed Chemotherapy in Patients With Advanced Non-small Cell Lung Cancer (NSCLC) Harboring Actionable Genomic Alterations (AGAs)
The goal of this clinical trial is to assess the efficacy of ivonescimab monotherapy in patients with advanced non-small cell lung cancer harboring actionable genomic alterations who have received prior targeted therapies and chemotherapy. This clinical trial also aims to assess the efficacy of ivonescimab plus carboplatin/pemetrexed chemotherapy in patients with advanced non-small cell lung cancer harboring actionable genomic alterations other than epidermal growth factor receptor mutations who have received prior targeted therapies but no chemotherapy. The main questions it aims to answer are: * Will ivonescimab alone or together with carboplatin/pemetrexed chemotherapy shrink tumors in the clinical trial's patients? * Will ivonescimab alone or together with carboplatin/pemetrexed chemotherapy effectively influence if the patients' cancer grows, how long the treatment takes to start working, how long the treatment keeps working after it first starts to help, how long the treatment keeps the cancer from getting worse, and overall survival of patients? * How many patients receiving ivonescimab alone or together with carboplatin/pemetrexed chemotherapy will experience treatment-emergent, treatment-related, immune-related, and especially interesting side effects? Patients receiving ivonescimab alone will receive an intravenous infusion of ivonescimab every 3 weeks for up to 24 months. Patients receiving ivonescimab together with carboplatin/pemetrexed chemotherapy will receive separate intravenous infusions of ivonescimab, pemetrexed, and carboplatin every 3 weeks for 4 cycles (each cycle is 21 days). These patients will continue to receive infusions of ivonescimab and pemetrexed every 3 weeks for up to 24 total months.
• Histologically or cytologically confirmed advanced or metastatic non-squamous NSCLC not amenable to curative resection or radiation.
• AGA requirements as follows:
‣ Ivonescimab monotherapy: Tumor harboring classical EGFR sensitizing mutation (i.e., L858R, exon 19 deletion), or ALK, ROS1, RET, or NTRK1-3 fusion, per local testing. Note: The number of patients with EGFR mutation-positive NSCLC enrolled will be capped at maximum of 10 (in order to ensure the assessment of non-EGFR disease subsets). Ivonescimab plus carboplatin/pemetrexed: Tumor harboring ALK, ROS1, RET, or NTRK1-3 fusion, per local testing.
• Prior therapy requirements as follows:
• a. Prior genotype-specific standard-of-care targeted therapy must have included at least one genotype-appropriate TKI(s) specified below: i. EGFR sensitizing mutation: a third-generation EGFR TKI such as osimertinib or lazertinib ii. ALK fusion: a third- or fourth-generation ALK TKI such as lorlatinib or neladalkib (NVL-655) iii. ROS1 fusion: crizotinib, entrectinib, repotrectinib, or taletrectinib iv. RET fusion: selpercatinib or pralsetinib v. NTRK1-3 fusion: entrectinib, larotrectinib, or repotrectinib Ivonescimab monotherapy: Must have received platinum/pemetrexed chemotherapy. No limitations on the number of prior lines of systemic therapy including the number of lines of chemotherapy or TKI(s). Ivonescimab plus carboplatin/pemetrexed: May not have received any prior chemotherapy. No limitations on the number of prior TKI(s).
• At least 1 measurable lesion as assessed by investigator per the RECIST v1.1 criteria for both cohorts.
• Participants must be willing to undergo the mandatory pre-treatment and post-progression tissue biopsies. If archival pre-treatment tissue is available from within 6 months of study enrollment, with no new intervening systemic therapy since the biopsy, a repeat pre-treatment biopsy may be omitted upon discussion with the principal investigator. On-treatment tissue biopsy (obtained within 7 days prior to Cycle 2 Day 1) will be mandatory for patients in Cohort 1 and optional for patients in Cohort 2. In select cases, if medically deemed unsafe/not feasible, exception may be granted upon discussion with the principal investigator.
• Clinically asymptomatic treated or untreated brain metastases are allowed if they have not required increasing doses of steroids within 2 weeks prior to study entry for CNS symptoms.
• Age ≥18 years old.
• ECOG performance status of 0 or 1.
• Adequate Organ Function:
• a. Hematology (no blood transfusions or growth factor therapy used within 7 days of the screening CBC): i. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L ii. Platelet count ≥ 100 × 109/L iii. Hemoglobin ≥ 9.0 g/dL b. Kidneys: i. Creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gault formula (Cohorts 1 and 2) or estimated glomerular filtration rate (eGFR) value ≥ 60 mL/min (for Cohort 1) or ≥30 mL/min (for Cohort 2) using the Cockcroft-Gault formula or estimated glomerular filtration rate (eGFR) ii. Urine protein \< 2+ or 24 hour urine protein quantification \< 1.0 g c. Liver: i. Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); for patients with liver metastases or confirmed/suspected Gilbert syndrome, TBIL ≤3 × ULN ii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
⁃ 2.5 × ULN; for patients with liver metastases, AST and ALT ≤ 5 × ULN d. Coagulation: prothrombin time (PT) or international normalized ratio (INR)
⁃ 1.5 x ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy). This applies only to patients who are not on therapeutic anti-coagulation. Patients receiving therapeutic anti-coagulation should be on a stable dose for at least one month prior to study enrollment.
• Female patients of childbearing age must have negative serum pregnancy test results before first ivonescimab drug dose or per region-specific guidance documented in the informed consent and a negative urine pregnancy test on the day of first dose prior to dosing.
• Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 90 days after the last dose of the ivonescimab and until 6 months after the last doses of carboplatin and pemetrexed.
• Unsterilized male patients having sex with a female partner of childbearing potential, or a pregnant or breastfeeding partner must agree to use barrier contraception (male condom) for the duration of the treatment period until 90 days after the last dose of ivonescimab and until 90 days after the last doses of carboplatin and pemetrexed. Male patients with female partners of childbearing potential must have the female partner agree to use at least 1 form of highly effective contraception for the duration of the treatment period until 90 days after the last dose of ivonescimab and until 90 days after the last doses of carboplatin and pemetrexed.