FDA Grants Breakthrough Therapy Designation to Sacituzumab Tirumotecan for EGFR+ NSCLC

The FDA has granted breakthrough therapy designation to sacituzumab tirumotecan (SKB264/MK-2870) for use as a potential option in patients with advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring EGFR mutations whose disease has progressed on or following a TKI and platinum-based chemotherapy.¹

The decision is based on findings from a phase 2 expansion cohort of a phase 1/2 study examining its use in patients with EGFR-mutated NSCLC and findings from two parts of a phase 2 study examining its use in patients with EGFR-mutated NSCLC who had previously received at least 2 lines of 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,” Scot Ebbinghaus, MD, vice president of global clinical development at Merck Research Laboratories, stated in a news release. “We believe antibody-drug conjugates [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 TROP2-directed ADC has a proprietary pyrimidine-thiol linker conjugated to a novel topoisomerase I inhibitor at DAR 7.4.² The agent was examined in the nonrandomized phase 2 OptiTROP-Lung01 study (NCT05351788), which enrolled patients with locally recurrent or metastatic NSCLC without actionable genomic alterations. Patients could not have previously received systemic treatment. They were also required to have an ECOG performance status of 0 or 1.

Those included in cohort 1A received sacituzumab tirumotecan at 5 mg/kg every 3 weeks plus KL-A167 at 1200 mg every 3 weeks; those in cohort 1b were given sacituzumab tirumotecan at 5 mg/kg every 2 weeks plus KL-A167 at 900 mg every 2 weeks. Treatment continued until progressive disease or intolerable toxicity. The primary end point of the study was investigator-assessed objective response rate (ORR) and secondary end points included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety.

Data from the study were shared at the 2024 ASCO Annual Meeting and had a data cutoff date of January 2, 2024. At a median follow-up of 14.0 months in cohort 1A (n = 40), the ORR with the combination was 48.6% (95% CI, 31.9%-65.6%), which included a confirmed partial response (PR) of 43.2%. The DCR was 94.6% and the median DOR was not reached (NR; 95% CI, 8.3-not evaluable [NE]). The median PFS was 15.4 months (95% CI, 6.7-NE), and the 6-month PFS rate was 69.2% (95% CI, 51.2%-81.6%).

The median follow-up in cohort 1B was 6.9 months. The combination elicited an ORR of 77.6% (95% CI, 64.7%-87.5%), with a confirmed PR of 69.0%. Moreover, the DCR was 100% and the median DOR was NR (95% CI, 6.6-NE). The median PFS was NR (95% CI, 8.4-NE) and the 6-month PFS rate was 84.6% (95% CI, 71.4%-92.1%).

Subgroup analyses were also done in cohort 1B. In those with a PD-L1 tumor proportion score (TPS) of less than 1% (n = 21), the ORR was 63.2%, with a confirmed PR rate of 57.9%. The DCR was 100% and the PFS rate at 6 months was 82.2% (95% CI, 54.3%-93.9%). In those with a TPS ranging from 1% to 49% (n = 19), the ORR was 81.3%, which included a confirmed PR rate of 68.8%. The DCR in this group was also 100% and the 6-month PFS rate was 76.6% (95% CI, 41.2%-92.3%). In the last group of patients, with a TPS of 50% or higher (n = 23), the ORR was 87.0%, with a confirmed PR rate of 78.3%. The DCR was 100% and the PFS rate at 6 months was 91.3% (95% CI, 69.5%-97.8%). In those with nonsquamous histology (n = 34), the ORR with the regimen was 72.7%, with a confirmed PR rate of 63.6%. The DCR was 100% and the 6-month PFS rate was 93.8% (95% CI, 77.3%-98.4%). In those with squamous histology (n = 29), the ORR was 84.0%, with a confirmed PR rate of 76.0%. The DCR was 100% and the 6-month PFS rate was 73.5% (95% CI, 49.9%-87.2%).

In terms of safety, in cohort 1A, 95.0% of patients experienced treatment-related adverse effects (TRAEs), 42.5% of which were grade 3 or higher. TRAEs resulted in dose reduction or interruptions for 17.5% and 25.0% of patients, respectively; 2.5% of patients experienced TRAEs that led to discontinuation of any drug. Serious TRAEs occurred in 10% of patients. In cohort 1B, 96.8% of patients experienced TRAEs, 54.0% of which were grade 3 or higher. These effects led to dose reduction for 31.7% of patients and interruption for 50.8% of patients; 3.2% of patients experienced TRAEs that led to treatment discontinuation. Serious TRAEs occurred in 22.2% of patients. No patients experienced TRAEs that proved fatal.

The most common TRAEs experienced by at least 20% of patients were anemia, decreased neutrophil count, decreased white blood cell count, alopecia, rash, nausea, reduced appetite, increased alanine aminotransferase, stomatitis, increased aspartate aminotransferase, decreased platelet count, and fatigue.

Sacituzumab tirumotecan is under exploration in combination with pembrolizumab (Keytruda) in 3 clinical trials: as first-line treatment in patients with NSCLC and a PD-L1 TPS of 50% or higher (NCT06170788), as maintenance treatment in those with metastatic squamous NSCLC (NCT06422143), and as post-operative treatment in those with resectable NSCLC who did not achieve a pathologic complete response (NCT06312137).

In October 2024, the National Medical Products Administration (NMPA)’s Center for Drug Evaluation accepted for review a new drug application seeking the approval of sacituzumab tirumotecan for use in adult patients with EGFR-mutant locally advanced or metastatic NSCLC who experienced disease progression after EGFR TKIs.³ In November 2024, the NMPA approved the use of the agent in adult patients with unresectable locally advanced or metastatic triple-negative breast cancer who have previously received at least 2 systemic therapies, including at least 1 in the advanced or metastatic setting.⁴

References

1. FDA grants breakthrough 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. News release. Merck. December 3, 2024. Accessed December 3, 2024. https://www.merck.com/news/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-ca/
2. Fang W, Wang O, Cheng Y, et al. Sacitizumab tirumotecan (SKB264/MK-2870) in combination with KL-A167 (anti-PD-L1) as first-line treatment for patients with advanced NSCLC from the phase II OptiTROP-Lung01 study. J Clin Oncol. 2024;42(suppl 16):8502. doi:10.1200/JCO.2024.42.16_suppl.8502
3. Kelun-Biotech's TROP2-ADC SKB264 (sac-TMT) Third NDA Accepted by NMPA, locally advanced or metastatic EGFR-mutant NSCLC. News release. Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. October 31, 2024. Accessed December 3, 2024. https://en.kelun-biotech.com/newsCenter.aspx?mid=18
4. Kelun-Biotech’s TROP2 ADC sacituzumab tirumotecan (sac-TMT, 佳泰莱) approved for marketing by NMPA Of China for 2L+ advanced or metastatic TNBC. News release. Sichuan Kelun-Biotech Biopharmaceutical. November 27, 2024. Accessed December 3, 2024. https://en.kelun-biotech.com/newsCenter.aspx?mid=18