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 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT01631552.

Figure 1. Response assessment following treatment with sacituzumab govitecan.

(A) Composite schematic showing best response determined from target lesion measurements according to RECIST 1.1 (y-axis) and time-to-progression measured from first dose until CT documentation of progression as per RECIST (z-axis; TTP expressed in months). Best response bars are color-coded to identify the 4 starting dose levels. Four of the 25 patients (numbers 6, 9, 14, and 23; 2 PDC, 1 GC and 1 SCLC) who were classified by RECIST with disease progression are not shown because either they did not have a follow-up CT with measurement of target lesions or they had new lesions despite having stable target lesions measurements. A bar break (//) shown for two PD patients denotes target lesions increased >30%, whereas TTP values in the boxes at top of the graph show the patients who exceeded 9 months. The number of prior therapies (in parentheses) and the patients who received prior topoisomerase I therapy (asterisks) are indicated below the graph. (B) Graph showing the patients sorted according to survival, showing also their TTP. Survival data were unavailable for 2 PDC patients (numbers 6 and 17 with TTP 1.0 and 2.9 months).

Figure 2. CT studies in 2 patients showing treatment response.

Panel A and B (patient #22). 65-year-old woman with poorly differentiated SCLC (Trop-2 expression by immunohistology, 3+) who received 2 months of carboplatin/etoposide (topoisomerase-II inhibitor) and 1 month of topotecan (topoisomerase-I inhibitor) with no response, followed by local radiation for 6 weeks (3000 cGy), but continued to progress. Four weeks later, the patient started sacituzumab govitecan at 12 mg/kg (2 doses), which was reduced to 9.0 mg/kg (1 dose), and finally to 6.75 mg/kg for 9 doses. The sum of the longest diameters (SLD) of the target lesions at study entry was 19.3 cm. The largest lesion is shown at baseline (A). After 4 doses, the SLD had reduced by 38%, including a substantial reduction in the main lung lesion (5.8 to 2.7 cm; panel B). Panel C and D (patient #3). 62 year-old woman, who 5 months after her initial diagnosis and surgery for colon cancer had a hepatic resection for liver metastases and then received 7 months of treatment with FOLFOX and 1 month of only 5-fluorouracil. She entered the study with multiple lesions, primarily in the liver (panel C). Immunohistology showed a 2+ staining of her primary cancer; her plasma CEA was 781 ng/mL. Therapy was initiated at 8 mg/kg and 6 treatments later (12 weeks), the 3 target lesions had reduced from a sum of 7.9 cm to 5.0 cm (−37%; PR). The response was confirmed 6.6 weeks later (after ten doses), with additional shrinkage to 3.8 cm (−52%). Panel D shows the target lesion 32 weeks from the start of treatment and after receiving 18 doses when there was a 59% reduction in the sum of the diameters of all target lesions. The patient continued therapy, achieving a maximum tumor reduction of 65% 44 weeks after treatment was initiated (28 doses). Plasma CEA decreased to 26.5 ng/mL after 18 doses, but thereafter began to increase despite continued radiological evidence (target and non-target lesions) of additional disease reduction or stabilization. Approximately 1 year from the start of treatment (31 doses given), one of the 3 target lesions progressed.

Figure 3. Concentrations of IgG and sacituzumab govitecan (IMMU-132) by ELISA and SN-38 (Total and Free) in serum samples (patient 15).

The top panel shows the concentrations of hRS7 IgG and sacituzumab govitecan as determined by ELISA in the peak (P) and trough (T) samples of a TNBC patient. C1D1 and C1D2 represent the first and second dose in cycle 1; data for 7 cycles are shown. The protein dose of sacituzumab govitecan for each treatment is provided above the bars. The bottom panel shows the concentrations of SN-38, either unbound (Free) or Total (acid-hydrolyzed sample) for 4 samples over the course of treatment.