Sacituzumab Tirumotecan (MK-2870) Versus Pemetrexed and Carboplatin Combination Therapy in Participants With Epidermal Growth Factor (EGFR)-Mutated, Advanced Nonsquamous Non-small Cell Lung Cancer (NSCLC) Who Have Progressed on Prior EGFR Tyrosine Kinase Inhibitors (MK-2870-009)

The purpose of this study is to evaluate sacituzumab tirumotecan versus pemetrexed in combination with carboplatin for the treatment of epidermal growth factor receptor (EGFR)-mutated advanced non-squamous non-small cell lung cancer (NSCLC). Participants in this study have NSCLC that has continued to progress on prior treatment with EGFR tyrosine kinase inhibitors (TKIs).

The primary hypotheses of this study are that sacituzumab tirumotecan is better than platinum-based doublet chemotherapy (pemetrexed and carboplatin) in regard to progression-free survival (PFS) and overall survival (OS).

Participants will be randomized 1:1 into two arms:

* Sacituzumab tirumotecan
* Pemetrexed plus Carboplatin

Participants will receive treatment until any of the criteria for discontinuation of study intervention are met.

Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of advanced-stage nonsquamous non-small cell lung cancer (NSCLC).
* Participants who have adverse events (AEs) due to previous anticancer therapies must have recovered to Grade \<1 or baseline.
* Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load.
* Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable.
* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy.
* Life expectancy of at least 3 months.

Exclusion Criteria:

* Predominantly squamous cell histology NSCLC.
* History of second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years.
* Grade \>2 peripheral neuropathy.
* History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing.
* Active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease.
* Uncontrolled, or significant cardiovascular disease or cerebrovascular disease.
* Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids.
* Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
* Received radiation therapy to the lung that is \>30 Gray within 6 months of the first dose of study intervention.
* Known active central nervous system metastases and/or carcinomatous meningitis.
* Active infection requiring systemic therapy.
* History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
* Concurrent active HBV and HCV infection.
* History of allogeneic tissue/solid organ transplant.
* Participants who have not adequately recovered from major surgery or have ongoing surgical complications.