Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I–inhibiting Antibody–Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan

Abstract

We evaluated a Trop-2-targeting antibody conjugated with SN-38 in metastatic small cell lung cancer (mSCLC) patients. Sacituzumab govitecan was studied in patients with pretreated (median, 2; range, 1-7) mSCLC who received either 8 or 10 mg/kg i.v. on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR); duration of response, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Sixty percent of patients showed tumor shrinkage from baseline CTs. On an intention-to-treat basis ( = 50), the ORR was 14% (17% for the 10-mg/kg group); the median response duration, 5.7 months; the clinical benefit rate (CBR ≥4 months), 34%; median PFS, 3.7 months; and median OS, 7.5 months. There was a suggested improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients who were sensitive to first-line therapy, but no difference between first-line chemosensitive versus chemoresistant patients in the overall population. There was a statistically significant higher OS in those patients who received prior topotecan versus no topotecan therapy in a small subgroup. Grade ≥3 adverse events included neutropenia (34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not required for patient selection. No antibodies to the drug conjugate or its components were detected on serial blood collections. Sacituzumab govitecan appears to have a safe and effective therapeutic profile in heavily pretreated mSCLC patients, including those who are chemosensitive or chemoresistant to first-line chemotherapy. Additional studies as a monotherapy or combination therapy are warranted. .

Sacituzumab govitecan, an antibody‐drug conjugate targeting trophoblast cell‐surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo

“…Consistent with our preclinical in vitro and in vivo results in biologically aggressive endometrial cancer, results from a phase I/II clinical study reported acceptable toxicity and encouraging therapeutic activity of SG against multiple recurrent human epithelial cancers including urothelial cancers and lung cancers (Bardia et al, 2019;Faltas et al, 2016;Gray et al, 2017;Heist et al, 2017;Starodub et al, 2015). Moreover, our group has recently reported an impressive clinical response to SG in a 74-year-old woman with recurrent/chemotherapy-resistant endometrial serous tumor overexpressing Trop-2 (66% reduction of target lesions by RECIST 1.1 criteria for over 10 months of followup) (Han et al, 2018).…”

IMMU-140, a Novel SN-38 Antibody–Drug Conjugate Targeting HLA-DR, Mediates Dual Cytotoxic Effects in Hematologic Cancers and Malignant Melanoma

“…In particular, the same conjugation method has been used to create an anti-Trop-2 SN-38-ADC (sacituzumab govitecan, IMMU-132) that targets Trop-2 on solid tumors, and likewise has been shown to be superior to parental antibody both in vitro and in vivo (18,19,31). Further, it has demonstrated efficacy in heavily pretreated metastatic triple-negative breast cancer, as well as small-cell and non-small-cell lung cancer patients (14)(15)(16), suggesting that IMMU-140 may prove to be superior to its parental antibody clinically.…”

Antibody-Drug Conjugates for the Therapy of Thoracic Malignancies

“…Preclinical xenograft models have shown that sacituzumab govitecan could effectively deliver much higher doses of SN-38 to the tumor cell compared to irinotecan. 94 In the first-in-human phase I study, sacituzumab govitecan was given to heavily pretreated patients with metastatic solid tumors including SCLC and NSCLC. Patient selection was not based on tumor Trop2 expression.…”

“…The disease control and survival benefit from sacituzumab govitecan were observed even in patients with chemoresistant disease to first-line chemotherapy and patients who had previously received topotecan. 94 In another phase II trial, sacituzumab govitecan was also evaluated in a similar design in patients with pretreated NSCLC. The overall response rate among 47 evaluable patients was 19% with a median duration of 6.0 months.…”