FDA Grants Breakthrough Therapy Designation to Sacituzumab Govitecan for Second-Line ES-SCLC

The FDA has granted breakthrough therapy designation to sacituzumab govitecan-hziy (Trodelvy) for patients with extensive-stage small cell lung cancer (ES-SCLC)) whose disease has progressed on or after platinum-based chemotherapy.¹

The decision is supported by findings from the ES-SCLC cohort of the phase 2 TROPiCS-03 trial (NCT03964727), which demonstrated antitumor activity and safety with the agent in both platinum-resistant and platinum-sensitive ES-SCLC.

Updated data from TROPiCS-03 were presented at the 2024 IASLC World Conference on Lung Cancer in September 2024.² At data cutoff of March 8, 2024, with a median follow-up of 12.3 months (range, 8.1-20.1), the investigator-assessed overall response rate (ORR) with sacituzumab govitecan was 41.9% (95% CI, 27.0%-57.9%), consisting entirely of confirmed partial responses. Stable disease and progressive disease were observed in 41.9% vs 9.3% of patients, respectively; 7.0% of patients were not assessed. The disease control rate was 83.7% (95% CI, 69.3%-93.2%), and the clinical benefit rate (CBR) was 48.8% (95% CI, 33.3%-64.5%). The median duration of response (DOR) was 4.7 months (95% CI, 3.5-6.7), with 48.2% of responders (95% CI, 23.9%-68.9%) maintaining a response at 6 months. The median time to response was 1.4 months (range, 1.2-4.2).

Based on these data, further evaluation of sacituzumab govitecan in a phase 3 trial of patients with ES-SCLC is planned.¹

TROPiCS-03 Overview

The ongoing TROPiCS-03 trial enrolled patients with metastatic or locally advanced solid tumors.² In the ES-SCLC cohort, eligible patients are required to have histologically confirmed ES-SCLC with measurable disease per RECIST 1.1 criteria, an ECOG performance status (PS) of 0 or 1, and progression following 1 or fewer prior lines of platinum-based chemotherapy and PD-L1-directed therapy. Patients with stable, treated brain metastases were also allowed.

Patients with ES-SCLC received intravenous sacituzumab govitecan at 10 mg/kg on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.

Among the 43 patients enrolled onto the study, the median age was 67 years (range, 48-83), with most patients being current or former smokers (97.7%) and having an ECOG PS of 1 (81.4%). Liver and brain metastases were present in 30.2% and 11.6% of patients, respectively. Responses to prior therapy included complete response/partial response (55.8%) and stable/progressive disease (37.2%).

The study’s primary end point was investigator-assessed ORR, with secondary end points including DOR, CBR, progression-free survival (PFS), overall survival (OS), and safety. 

Safety Data With Sacituzumab Govitecan in ES-SCLC

In the ES-SCLC cohort, the safety profile for sacituzumab govitecan was consistent with that from prior studies in other approved indications. All patients reported treatment-emergent adverse effects (TEAEs), with 74.4% experiencing grade 3 or higher TEAEs. 

The most commonly observed TEAEs included diarrhea (any-grade, 67%; grade ≥3, 9%), fatigue (58%; 2%), neutropenia (12%; 44%), constipation (42%; 0%), nausea (40%; 0%), alopecia (30%; 0%), anemia (26%; 5%]), decreased appetite (23%; 0%), abdominal pain (19%; 0%), vomiting (16%; 0%), hypomagnesemia (16%; 0%), and rash (16%; 0%). 

Serious TEAEs occurred in 51.2% of patients, and 37.2% of patients experienced TEAEs necessitating dose reductions. No TEAEs led to treatment discontinuation, though 3 patients experienced TEAEs resulting in death, with 1 case deemed related to the study drug.

Current and Potential Indications

Sacituzumab govitecan, a TROP-2-directed antibody-drug conjugate, is approved in over 50 countries for second-line or later treatment of patients with metastatic triple-negative breast cancer (TNBC) and in more than 40 countries for certain patients with pretreated hormone receptor (HR)–positive, HER2-negative metastatic breast cancer.¹

In the United States, sacituzumab govitecan is indicated for use in patients with unresectable locally advanced or metastatic TNBC who have received at least 2 prior systemic therapies, with at least 1 therapy for metastatic disease; and patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer (immunohistochemistry score of 0 or 1+, or 2+ with negative in situ hybridization) who previously received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. 

The agent is currently under investigation for other tumors with high TROP-2 expression, including SCLC and first-line metastatic non–small cell lung cancer, where it has shown clinical activity in both TROPiCS-03 and the phase 2, proof-of-concept EVOKE-02 study (NCT05186974), respectively. Additional studies are ongoing in head and neck cancers and gynecologic malignancies.

References

1. U.S. FDA grants breakthrough therapy designation to Trodelvy® (sacituzumab govitecan-hziy) for second-line treatment of extensive-stage small cell lung cancer. News Release. Gilead. December 17, 2024. Accessed December 17, 2024. https://www.gilead.com/news/news-details/2024/us-fda-grants-breakthrough-therapy-designation-to-trodelvy-sacituzumab-govitecan-hziy-for-second-line-treatment-of-extensive-stage-small-cell-lung-cancer
2. Dowlati A, Chiang AC, Cervantes A, et al. Sacituzumab govitecan as second-line treatment in patients with extensive-stage small cell lung cancer. J Thoracic Oncol. 2024;19(suppl 16):OA04.04. doi:10.1016/j.jtho.2024.09.034