First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors

Abstract

Purpose Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This Phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers. Experimental Design Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed. Results Twenty-five patients (52-60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (N=7), 10 (N=6), 12 (N=9), and 18 (N=3) mg/kg. Neutropenia was dose-limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (N=3), neutropenia (N=2), diarrhea (N=1), and leukopenia (N=1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16-36 weeks; 6 survived 15-20+ months. No pre-selection of patients based on tumor Trop-2 expression was done. Conclusion Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for Phase II studies.

Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

“…ELISA monitoring of IgG in the serum found that it clears more slowly, staying in the circulation for a longer period. Similar results are being found in patient samples (34)(35)(36)(37), where (i) the IgG component clears more slowly than the conjugate, (ii) >95% of the total SN-38 in the serum is bound to the IgG, (iii) the amount of free SN-38G in the serum is only a fraction of the free SN-38, and (iv) there is no evidence of glucuronidation of SN-38 bound to IgG. Analysis of serum samples taken from patients given 8 to 10 mg/kg of IMMU-132 on days 1 and 8 of 21-day cycles has found free SN-38 concentrations at levels of about 100 ng/mL 30 minutes after the end of a 2-to 3 h-infusion, whereas the total SN-38 levels average about 4,000 ng/mL (34).…”

“…IMMU-132 was found to deliver much higher levels of SN-38 to tumors than irinotecan and, importantly, all of the SN-38 delivered to the tumor by IMMU-132 is released in its most potent form. In relationship to gastrointestinal toxicity, the much lower amounts of SN-38G in the serum and significantly lower amounts of SN-38/SN38G in the intestine with IMMU-132 are expected to reduce the risk for severe diarrhea in patients, which is confirmed in clinical studies (34)(35)(36)(37)(38). Thus, IMMU-132 is an ADC that appears to have unique properties that combine to make an effective therapeutic agent in the solid cancers tested.…”

“…Because SN-38G levels in the serum are also very low with IMMU-132, we suspect that this reduces the pool of drug available for enterohepatic recirculation. These 2 factors likely combine to explain the lower incidence and severity of diarrhea observed clinically with IMMU-132 than other agents delivering SN-38 (34)(35)(36)(37).…”

Combining ABCG2 Inhibitors with IMMU-132, an Anti–Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers

“…As such, IMMU-132 provides a paradigm change that contrasts the prevailing approach of conjugating a low level of an ultratoxic payload (picomolar potency) with a stable linker to an antibody capable of internalization upon target engagement (38,39). Importantly, the ongoing phase II studies with IMMU-132 as a single agent in patients with metastatic triplenegative breast cancer (mTNBC) who had received a median of 5 (range ¼ 2 to 12) prior lines of therapy have shown an interim objective response rate of 31% by RECIST 1.1 in 58 evaluable patients (40), thus extending the results obtained in phase I trials, which indicated IMMU-132 had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat solid cancers (25). Promising initial results have also been reported for IMMU-132 administered to patients with platinum-resistant urothelial carcinoma (26).…”

“…IMMU-132 departs from most ADCs in its use of a moderately, not ultratoxic drug, its high drugto-antibody ratio (DAR) without impairing target affinity and pharmacokinetics, and its selection of a pH-sensitive, cleavable linker to confer cytotoxicity to both tumor and bystander cells (22)(23)(24). This novel ADC is currently in clinical trials for patients with advanced triple-negative breast cancer (25), urothelial bladder cancer (26), and other solid cancers. As these patients were all heavily pretreated with chemotherapy, the presence of acquired resistance with the expression of MDR genes is highly likely, which may affect the therapeutic outcome of IMMU-132.…”