Merck, known as MSD outside the United States and Canada, has announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to sacituzumab tirumotecan (sac-TMT). This investigational antibody-drug conjugate (ADC) targets trophoblast cell-surface antigen 2 (TROP2) and is under development in collaboration with Kelun-Biotech. The designation specifically applies to sacituzumab tirumotecan’s potential for treating advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) with specific epidermal growth factor receptor (EGFR) mutations—exon 19 deletion (19del) or exon 21 L858R—after progression on tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy.

This decision is grounded in data from multiple clinical trials, including the Phase 2 expansion cohort of a Phase 1/2 study, and two parts of a Phase 2 trial that evaluated sacituzumab tirumotecan in patients with EGFR-mutated NSCLC who had undergone at least two prior lines of therapy. These findings, which were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, highlight the potential of sac-TMT as a promising new therapy.

The Significance of Breakthrough Therapy Designation

The FDA grants Breakthrough Therapy designation to therapies intended for serious or life-threatening conditions when preliminary clinical evidence indicates a significant improvement over existing treatments on at least one clinically meaningful endpoint. Benefits of this designation include more intensive FDA guidance during development, a dedicated scientific liaison to facilitate the process, and potential eligibility for Priority Review. These measures aim to accelerate the availability of innovative treatments for critical medical conditions.

Dr. Scot Ebbinghaus, vice president of global clinical development at Merck Research Laboratories, emphasized the importance of ADCs in advancing cancer care, stating, “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.”

Sac-TMT in the Clinical Development Pipeline

Merck is conducting a robust global clinical development program for sacituzumab tirumotecan. This includes its evaluation as a monotherapy and in combination with the immunotherapy KEYTRUDA® (pembrolizumab). Currently, there are ten ongoing Phase 3 trials exploring sac-TMT’s efficacy across a variety of solid tumors.

Two notable trials are:

TroFuse-004: Comparing sac-TMT with chemotherapy (docetaxel or pemetrexed) in patients with previously treated NSCLC and EGFR mutations or other genomic alterations.

TroFuse-009: Comparing sac-TMT with doublet chemotherapy (pemetrexed and carboplatin) in patients with previously treated EGFR-mutated NSCLC.

These are the only Phase 3 studies investigating TROP2-directed ADCs in this patient population, signaling sac-TMT’s unique position in the field.

International Approval and Broader Applications

Sac-TMT recently gained its first marketing authorization in China for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) in adult patients who have received at least two prior systemic therapies. This approval by the National Medical Products Administration (NMPA) is based on the Phase 3 OptiTROP-Breast01 study results. Kelun-Biotech retains the rights for sac-TMT’s development and commercialization in Greater China.

Commentary by YourDailyFit Columnist Alice Winters

The FDA’s Breakthrough Therapy designation for sacituzumab tirumotecan (sac-TMT) reflects the growing prominence of antibody-drug conjugates in cancer therapy. ADCs like sac-TMT represent a nuanced approach, combining precise tumor targeting with potent cytotoxic agents. This specificity not only aims to improve efficacy but also reduces systemic toxicity—a critical challenge in cancer treatment.

From a clinical perspective, sac-TMT’s focus on EGFR-mutated NSCLC patients with prior treatment failures is a strategic choice. This subset of patients faces limited options, and current standards such as TKIs and platinum-based chemotherapy often fail to deliver durable responses. Sac-TMT’s TROP2-targeting mechanism positions it uniquely to address these challenges.

The dual-trial approach of TroFuse-004 and TroFuse-009 underscores Merck’s commitment to establishing sac-TMT as a versatile option. Notably, its combination with pembrolizumab in ongoing trials could leverage synergies between ADCs and immunotherapies, potentially redefining treatment paradigms.

Another striking aspect is the international traction of sac-TMT, particularly its approval in China for TNBC. This signals the adaptability of the ADC platform across multiple tumor types, enhancing its global market potential. However, success in the competitive landscape of oncology depends on more than clinical results; pricing strategies, manufacturing scalability, and real-world efficacy will play decisive roles.

While the FDA designation is promising, sac-TMT’s broader adoption will hinge on Phase 3 results, particularly against chemotherapy. Questions about long-term safety, resistance mechanisms, and its effectiveness across diverse patient populations remain unanswered. Additionally, sac-TMT’s development emphasizes the importance of global partnerships, with Kelun-Biotech playing a pivotal role in its progress in Asian markets.

In conclusion, sac-TMT exemplifies the cutting-edge innovation driving modern oncology. If the ongoing trials corroborate its preliminary success, sac-TMT could emerge as a cornerstone therapy for NSCLC and beyond, with potential implications for ADCs’ role in cancer care.