The phase I/II IMMU-132-01 trial has previously reported efficacious results with the antibody-drug conjugate sacituzumab govitecan (SG) in various advanced epithelial cancers. In an updated analysis of this trial, SG was found to have manageable adverse events comparable to chemotherapy, and showed efficacy in colorectal, endometrial, oesophageal, pancreatic, castration-resistant prostate and small cell lung cancers.
“This molecule is increasingly making its mark in several cancer types. This is particularly the case in patients with metastatic TNBC and urothelial carcinoma for whom further line treatment options are limited. This agent has the potential to address this medical need.”
Patients with metastatic epithelial tumours who experience disease progression typically have a poor prognosis. Antibody-drug conjugates (ADCs) are able to deliver a targeted cytotoxic payload with a lower toxicity than an unconjugated, non-specific cytotoxic agent. ADCs have already proven efficacious in this setting, with several registered compounds for the treatment of metastatic urothelial cancer, breast cancer and haematological malignancies. Recently, the phase I/II IMMU-132-01 trial reported promising efficacy data of the ADC sacituzumab govitecan (SG) at a dose of 10 mg/kg in patients with various advanced epithelial cancers. Now, final safety data is reported of the overall safety population (OSP), as well as additional efficacy data from colorectal (CRC), endometrial, oesophageal, pancreatic, castration-resistant prostate cancer (CRPC) and small cell lung cancer (SCLC) cohorts.
The OSP cohort of this single-arm, open-label, multicentre phase I/II trial included 495 patients with metastatic epithelial cancer, who had relapsed or were refractory to at least one prior standard therapeutic regimen. Patients received intravenous infusions of SG at 8, 10, 12 or 18 mg/kg on days 1 and 8 in 21-day cycles until disease progression of unacceptable toxicity, death, or withdrawal of consent. UGT1A1 genotyping was performed but was not an eligibility requirement.
Overall, two third of patients in the OSP cohort were female and the median age in the study was 61 years. Almost all patients enrolled in the study (98.6%) had stage IV disease. The most common cancer types in this cohort were triple-negative breast cancer (TNBC) (29.1%), HR+/HER2- BC (13.7%) and SCLC (12.5%). At a median follow-up of 8.97 months, treatment was ongoing in 2.4% of patients, while 97.6% had permanently discontinued therapy. The most common reason for treatment discontinuation was progressive disease (67.7%), while adverse events (AEs) were responsible for 8.3% of treatment discontinuations. Overall, a median of 11 doses of SG were administered with a median treatment duration of 3.7 months. AEs were experienced by 97.6% of the cohort, with the most common treatment-related AEs (TRAEs) being nausea (62.6%) (grade ≥3: 3.6%), diarrhoea (56.2%) (Grade ≥3: 7.9%), fatigue (48.3%) (Grade ≥3: 6.3%), alopecia (40.4%, no grade 3 events) and neutropenia (57.8%) (Grade ≥3: 42.4%). Neutropenia had a median onset of 19 days, with a median duration of 8.5 days. The incidence of febrile neutropenia was low, at 5.5%, with grade ≥3 febrile neutropenia occurring at a rate of 5.2%. Grade ≥3 anaemia occurred in 10.3% of patients. Treatment-related serious AEs occurred in 15.2% of patients, consisting of febrile neutropenia (4.0%), diarrhoea (2.8%), vomiting and neutropenia (both 1.4%) and nausea (1.2%). AEs led to treatment interruption in 51.7% of patients in the OSP cohort, and 56.8%, 49.5%, 88.9% and 100% of patients in the 8mg/kg, 10mg/kg, 12mg/kg and 18mg/kg cohorts, respectively. Dose reductions were required in 32.3% of patients. Discontinuations due to AEs occurred in 9.9% and 8.0% of patients in the 8mg/kg and 10mg/kg groups, respectively. AE patterns and frequencies were broadly similar in heterozygous and wild-type UGT1A1 patients. In contrast, patients with homozygous UGT1A1 mutations were more likely to experience neutropenia compared to heterozygous and wild-type patients (60.9% vs. 38.3% and 33.3%, respectively). The same was true for diarrhoea (60.9% vs. 51.7% and 54.8%) and anaemia (50.0% vs. 31.7% and 37.3%).
With respect to efficacy, this updated analysis confirmed the previously reported promising activity in patients with TNBC (N= 108; overall response rate [ORR]: 33.3%; median progression-free survival [PFS]: 5.6 months, median overall survival [OS]: 13.0 months) metastatic urothelial carcinoma (N= 45; ORR: 28.9%; median PFS: 6.8 months; median OS: 16.8 months) non-small cell lung cancer (NSCLC) (N= 54; ORR: 16.7%; median PFS: 4.4 months; median OS: 7.3 months). For patients with colorectal cancer (CRC; N= 31), oesophageal (N=19) and pancreatic ductal adenocarcinoma (PDA; N= 16) overall response rates (ORR) were low, at 3.2%, 5.3% and 0%, respectively. According to the study investigators, this low response rate may be related to the high rate of patients with prior irinotecan exposure. The median PFS in the CRC, PDA and oesophageal cancer patients were reported at 3.9, 2.0 and 3.4 months, respectively, with a corresponding median OS of 14.2, 4.5 and 7.2 months. Among patients with SCLC (N= 62), the clinical activity of SC was more pronounced with an ORR of 17.7% (all partial responses), with a corresponding median PFS and OS of 3.7 and 7.1 months, respectively. Of these patients, 34% had previous irinotecan exposure. Also in patients with endometrial cancer (N= 18) a promising ORR was found at 22.2% (median PFS: 3.2 months. OS: 11.9 months). Finally, an ORR of 9% was reported in patients with CRPC (N= 9), including 1 complete response.
This updated analysis SG confirms the toxicity profile of this agent with an AE profile that is fairly similar to that of chemotherapy. Efficacy was seen in several cancer cohorts, validating Trop-2 as a broad target in solid tumors.
Bardia A et al., Sacituzumab Govitecan, a Trop-2-Directed Antibody-Drug Conjugate, for Patients with Epithelial Cancer: Final Safety and Efficacy Results from the Phase 1/2 IMMU-132-01 Basket Trial. Annals of Oncol. 2021: S0923-7534(21) 00883-8. [epub].