Sacituzumab Govitecan Generates Responses With Manageable Safety Profile in ES-SCLC

Afshin Dowlati, MD

Treatment with sacituzumab govitecan-hziy (Trodelvy) in the second-line setting yielded antitumor activity in patients with extensive-stage small cell lung cancer (ES-SCLC), including those with platinum-resistant or -sensitive disease, according to updated findings from the ES-SCLC cohort of the phase 2 TROPiCS-03 trial (NCT03964727), which were presented at the 2024 IASLC World Conference on Lung Cancer.¹

At a data cutoff date of March 8, 2024 and a median follow-up of 12.3 months (range, 8.1-20.1), the investigator-assessed overall response rate (ORR) was 41.9% (95% CI, 27.0%-57.9%); all responses were confirmed partial responses (PRs). Other best overall responses included stable disease (SD; 41.9%) and progressive disease (PD; 9.3%). Notably, 7.0% of patients were not assessed for response. The disease control rate (DCR) 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), and 48.2% of patients (95% CI, 23.9%-68.9%) were still responders at 6 months. The median time to response was 1.4 months (range, 1.2-4.2).

“Almost all responses were brisk, with the first scan done at 6 weeks; some of these responses are durable,” lead study author Afshin Dowlati, MD, stated during the presentation. “Efficacy, when evaluated independently, was consistent with the investigator-assessed response rate.”

Dowlati is a professor in the Department of Medicine in the Division of Hematology and Oncology at the Case Western Reserve University School of Medicine, as well as the associate director for Clinical Research and a member of the Developmental Therapeutics Program at the Case Comprehensive Cancer Center in Cleveland, Ohio.

Reflecting on Prior Findings from TROPiCS-03

The ongoing, open-label, multicohort TROPiCS-03 trial is investigating sacituzumab govitecan in patients with metastatic or locally advanced solid tumors. Patients in the ES-SCLC cohort needed to have histologically confirmed ES-SCLC with measurable disease per RECIST 1.1 criteria, an ECOG performance status (PS) of 0 or 1, and disease progression following no more than 1 prior line of platinum-based chemotherapy and PD-L1-directed therapy. Patients with stable, treated brain metastases were permitted to enroll.

Overall, 43 patients were enrolled in the ES-SCLC cohort and received intravenous sacituzumab govitecan at 10 mg/kg on days 1 and 8 of 21-day cycles until PD or unacceptable toxicity. Investigator-assessed ORR served as the primary end point. Key secondary end points included DOR, CBR, and progression-free survival (PFS) per investigator assessment; ORR, DOR, CBR, and PFS per blinded independent central review; overall survival (OS); and safety.

Patients had a median age of 67 years (range, 48-83), a minority were male (46.5%), and most had an ECOG PS of 1 (81.4%) and were current or former smokers (97.7%). In total, 30.2% and 11.6% of patients had liver and brain metastases, respectively. Best responses to last prior anticancer therapy included complete response/PR (55.8%) and SD/PD (37.2%).

Preliminary data from evaluable patients in the ES-SCLC cohort (n = 30) were previously reported at the 2023 ESMO Congress, and demonstrated an investigator-assessed ORR of 37% (95% CI, 20%-56%), including best overall responses of PR (37%), SD (50%), and PD (10%).² The median DOR was 6.3 months (95% CI, 2.7-not reached [NR]).

Confirming the Benefit of Sacituzumab Govitecan in ES-SCLC

Updated data showed that the median duration of treatment was 4.4 months (range, 0.03-18.04), and patients received a median of 7 treatment cycles (range, 1-25).1 In total, 83.7% of patients discontinued sacituzumab govitecan; disease progression was the most common reason for treatment discontinuation and occurred in 72.1% of patients. No patients discontinued treatment due to adverse effects (AEs).

A total of 76.7% of patients experienced tumor shrinkage, and 48.8% of patients had a target lesion diameter reduction of greater than 30%.

The median PFS was 4.40 months (95% CI, 3.81-6.11), and the 8-month PFS rate was 36.6%). The median OS was 13.60 months (95% CI, 6.57-14.78), and the 12-month OS rate was 50.3%.

Among the subgroup of patients with platinum-resistant disease (n = 20), the ORR was 35.0% (95% CI, 15.4%-59.2%); all responses were confirmed PRs. Other best overall responses included SD (35.0%) and PD (20.0%); 10.0% of patients were not assessed for response. The DCR was 70.0% (95% CI, 45.7%-88.1%), and the CBR was 40.0% (95% CI, 19.1%-63.9%). The median DOR was 6.3 months (95% CI, 1.5-6.9), and 57.1% of patients (95% CI, 17.2%-83.7%) were still in response at 6 months. The median PFS was 3.8 months (95% CI, 1.4-7.6), and the median OS was 6.6 months (95% CI, 4.7-17.7).

Among the subgroup of patients with platinum-sensitive disease (n = 23), the ORR was 47.8% (95% CI, 26.8%-69.4%) and entirely comprised confirmed PRs. In total, 47.8% of patients had SD, and 4.3% of patients were not assessed for response. The DCR was 95.7% (95% CI, 78.1%-99.9%), and the CBR was 56.5% (95% CI, 34.5%-76.8%). The median DOR was 4.4 months (95% CI, 3.0-NR), and 41.6% of patients (95% CI, 13.1%-68.4%) were still in response at 6 months. The median PFS was 5.0 months (95% CI, 4.1-7.4), and the median OS was 14.7 months (95% CI, 7.7-NR).

Contextualizing Safety and Preparing for the Future

All patients in the ES-SCLC cohort reported any-grade treatment-emergent (TEAEs), and 74.4% had grade 3 or higher TEAEs. The most common any-grade TEAEs were diarrhea (grade 1/2, 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.

In total, 37.2% of patients had TEAEs leading to dose reductions. No patients had TEAEs leading to treatment discontinuation. Three patients had TEAEs leading to death, 1 of which was deemed related to the study drug.

“The safety profile was very similar to [that seen in] prior sacituzumab govitecan studies in diseases for which this drug is currently under use. These encouraging data are leading to a randomized phase 3 study in relapsed ES-SCLC,” Dowlati concluded.

References

1. Dowlati A, Chiang AC, Cervantes A, et al. Sacituzumab govitecan as second-line treatment in patients with extensive-stage small cell lung cancer. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract OA04.04.
2. Dowlati A, Cervantes A, Babu S, et al. Sacituzumab govitecan (SG) as second-line (2L) treatment for extensive stage small cell lung cancer (ES-SCLC): preliminary results from the phase II TROPiCS-03 basket trial. Ann Oncol. 2023;34(suppl 2):S1061-S1062. doi:10.1016/j.annonc.2023.09.1221