a study of anti-cancer therapies targeting the mapk pathway in patients with advanced nsclc

Conditions: Advanced Non-squamous Non-small-cell Lung Cancer

Summary: * to evaluate the safety and tolerability of escalating doses of eras-007 or eras-601 in combination with other cancer therapies in study participants with advanced non-small cell lung cancer (nsclc). * to determine the maximum tolerated dose (mtd) and/or recommended dose (rd) of eras-007 or eras-601 administered in combination with other cancer therapies. * to evaluate the antitumor activity of eras-007 or eras-601 in combination with other cancer therapies. * to evaluate the pk profiles of eras-007 or eras-601 and other cancer therapies when administered in combination.

this is a phase 1b, open-label, multicenter master protocol evaluating safety, tolerability, and antitumor activity of eras-007 or eras-601 in combination with other cancer therapies in study participants with advanced nsclc. the study will commence with the following dose escalation cohorts: eras-007 plus osimertinib in study participants with advanced nsclc harboring epidermal growth factor receptor-sensitizing mutation(s) (egfrm); eras-007 or eras-601 plus sotorasib in study participants with advanced nsclc harboring kirsten rat sarcoma g12c mutation (kras g12cm). dose expansion will follow and will evaluate eras-007 or eras-601 drug combinations administered at the rd identified from each respective dose escalation cohort in study participants with advanced egfrm or kras g12cm nsclc.

Eligibility criteria:
inclusion criteria: * age ≥ 18 years. * willing and able to give written informed consent. * have histologically or cytologically confirmed nsclc, with presence of egfr mutation(s) sensitive to egfr inhibitors, or kras g12c mutation. * measurable disease per response evaluation criteria in solid tumors (recist) v1.1. * adequate bone marrow and organ function. * have ecog performance status of 0 or 1. * willing to comply with all protocol-required visits, assessments, and procedures. * able to swallow oral medication. exclusion criteria: * concurrent treatment with any systemic anticancer therapy for nsclc, including any approved or investigational agent. * for participants with egfrm nsclc: prior therapy with a ras, raf, mek, or erk inhibitor. * for participants with kras g12cm nsclc: prior therapy with a shp2, erk, or kras g12c inhibitor (depending on which cohort is being considered for enrollment). * palliative radiotherapy within 7 days of enrollment. * history of unacceptable toxicity to treatment with osimertinib or sotorasib. * major surgery within the 28 days of enrollment. * unresolved toxicities from prior systemic therapy greater than nci ctcae grade 1 at time of enrollment, except for toxicities not considered a safety risk (eg, alopecia, vitiligo, and grade 2 neuropathy due to prior chemotherapy). * history of another malignancy ≤5 years prior to first dose, except for patients who are disease-free for \>2 years after treatment with curative intent or who have carcinoma in situ. * symptomatic and unstable brain metastases, or spinal cord compression, except for patients who have completed definitive therapy (surgery or radiotherapy), are not on steroids, and have a stable neurologic status for a least 2 weeks after completion of the definitive therapy and steroids. * history of or clinically active ild, drug induced ild, or radiation pneumonitis that required steroid treatment. * impaired cardiovascular function or clinically significant cardiovascular disease. * history or current evidence of retinal pigment epithelial detachment (rped), central serous retinopathy, retinal vein occlusion (rvo), or predisposing factors to rped or rvo. * any evidence of severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding that renders the patient inappropriate to participate in the study. * pregnant or breastfeeding women. * contraindication to osimertinib or sotorasib use as per local label.

Keywords: egfr epidermal growth factor receptor mutation biomarker nsclc tagrisso osimertinib erk mapk sotorasib lumakras kras g12c shp2 ptpn11 molecular alterations kirsten rat sarcoma non-small cell lung cancer lung neoplasms thoracic neoplasms eras-601 eras-007