FDA Grants Breakthrough Therapy Designation to Sacituzumab Tirumotecan (sac-TMT) for the Treatment of Certain Patients With Previously Treated Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer With EGFR Mutations
First breakthrough therapy designation for investigational sac-TMT in the U.S.
RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to sacituzumab tirumotecan (sac-TMT) for the treatment of patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations (exon 19 deletion [19del] or exon 21 L858R) whose disease progressed on or after tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy. Sac-TMT is an investigational trophoblast cell-surface antigen 2 (TROP2)-directed antibody drug conjugate (ADC) being developed in collaboration with Kelun-Biotech. This designation is based on data from the Phase 2 expansion cohort of a Phase 1/2 study evaluating sac-TMT in patients with EGFR-mutated NSCLC, which were presented at the 2023 American Society of Clinical Oncology Annual Meeting, as well as data from two parts of a Phase 2 study evaluating sac-TMT in patients with EGFR-mutated NSCLC who have been treated with at least two lines of prior therapy.
“This designation by the FDA highlights the importance of developing novel therapeutic options for patients living with EGFR-mutated nonsquamous non-small cell lung cancer,” said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. “We believe ADCs are an important modality in the treatment of cancer and are rapidly advancing the clinical development of sacituzumab tirumotecan, with the goal of meaningfully improving upon current standards of care in certain cancers.”
The FDA’s Breakthrough Therapy designation is granted to expedite the development and review of medicines that are intended to treat serious or life-threatening conditions. To qualify for this designation, preliminary clinical evidence must indicate that the product may demonstrate substantial improvement over currently available options on at least one clinically significant endpoint. The benefits of this Breakthrough Therapy Designation include more intensive guidance from the FDA on an efficient development program, access to a scientific liaison to help accelerate review time and potential eligibility for Priority Review if relevant criteria are met.
Merck is rapidly advancing the global clinical development program evaluating sac-TMT as a monotherapy and in combination with KEYTRUDA® (pembrolizumab) with 10 ongoing Phase 3 studies across various solid tumors. Two of these ongoing trials include TroFuse-004, which is evaluating sac-TMT versus chemotherapy (docetaxel or pemetrexed) in patients with previously treated NSCLC with EGFR mutations or other genomic alterations, and TroFuse-009 which is evaluating sac-TMT versus doublet chemotherapy (pemetrexed and carboplatin) in certain patients with previously treated EGFR-mutated NSCLC. These are the only Phase 3 trials evaluating a TROP2 ADC in previously treated EGFR-mutated NSCLC.
Sac-TMT recently received its first marketing authorization in China from the National Medical Products Administration (NMPA) for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received at least two prior systemic therapies (at least one of which is for advanced or metastatic stage), based on results from the Phase 3 OptiTROP-Breast01 study. Under a collaboration agreement, Kelun-Biotech maintains the rights to develop, manufacture and commercialize sac-TMT in Greater China (which includes Mainland China, Hong Kong, Macau and Taiwan).
About sacituzumab tirumotecan (sac-TMT)
Sac-TMT is an investigational ADC that consists of three components: 1) a TROP2-targeting monoclonal antibody, sacituzumab, 2) a cytotoxic payload from the topoisomerase 1 inhibitor class and 3) a novel, irreversible but hydrolyzable linker, which joins the monoclonal antibody and the cytotoxic payload leveraging proprietary linker conjugation technology. The average drug-to-antibody ratio of sac-TMT is 7.4. TROP2 is highly expressed in a variety of epithelial-derived tumors and can promote tumor cell proliferation, invasion and metastasis. TROP2 ADCs specifically target TROP2-expressing tumor cells to deliver cytotoxic effects and have shown encouraging anti-tumor activity in clinical studies.
Sac-TMT was developed by Kelun-Biotech. Kelun-Biotech (6990.HK) is a holding subsidiary of Kelun Pharmaceutical (002422.SZ), which focuses on the R&D, manufacturing, commercialization and global collaboration of innovative biological drugs and small molecule drugs. Under a collaboration agreement, Kelun-Biotech has granted Merck the exclusive rights to develop, manufacture and commercialize sac-TMT in all territories outside of Greater China (which includes Mainland China, Hong Kong, Macau and Taiwan).
About lung cancer
Lung cancer is the leading cause of cancer death worldwide. In 2022 alone, there were approximately 2.4 million new cases and 1.8 million deaths from lung cancer globally. Non-small cell lung cancer is the most common type of lung cancer, accounting for about 80% of all cases. Epidermal growth factor receptor mutations occur in 14% to 38% of all NSCLC tumors worldwide. In 2024, the overall five-year survival rate for patients diagnosed with lung cancer is 25% in the United States. Improved survival rates are due, in part, to earlier detection and screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:
- Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
- metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (
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