TRODELVY Powder for solution for infusion Ref.[28090] Active ingredients: Sacituzumab govitecan

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies and antibody drug conjugates, other monoclonal antibodies
ATC code: L01FX17

Mechanism of action

Sacituzumab govitecan binds to Trop-2-expressing cancer cells and is internalised with the subsequent release of SN-38 from a hydrolysable linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death.

Clinical efficacy and safety

The efficacy and safety of sacituzumab govitecan was assessed in ASCENT (IMMU-132-05), an international Phase 3, multicentre, open-label, randomised study conducted in 529 patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who had relapsed after at least two prior chemotherapies (no upper limit) for breast cancer. Earlier adjuvant or neoadjuvant therapy for more limited disease qualified as one of the required prior regimens if the development of unresectable, locally advanced or metastatic disease occurred within a 12-month period of time after completion of chemotherapy. All patients received previous taxane treatment in either the adjuvant, neoadjuvant, or advanced stage unless they had a contraindication or were intolerant to taxanes. Poly-ADP ribose polymerase (PARP) inhibitors were allowed as one of the two prior chemotherapies for patients with a documented germline BRCA1/BRCA2 mutation.

Patients were randomised (1:1) to receive sacituzumab govitecan 10 mg/kg as an intravenous infusion on Day 1 and Day 8 of a 21-day treatment cycle or Treatment of Physician’s Choice (TPC) which was dosed based on body surface area and per the approved product information. TPC was determined by the investigator before randomisation from one of the following single-agent regimens: eribulin (n=139), capecitabine (n=33), gemcitabine (n=38), or vinorelbine (except if patient had ≥ Grade 2 neuropathy, n=52). Patients with stable brain metastases (pre-treated, non-progressive, without antiseizure medicinal products and on stable corticosteroid dose for at least 2 weeks) were eligible. Magnetic resonance imaging (MRI) to determine brain metastases was required only for patients with known or suspected brain metastases. Patients with known Gilbert’s disease, bone-only disease, known history of unstable angina, myocardial infarction, or congestive heart failure, active chronic inflammatory bowel disease or gastrointestinal (GI) perforation, human immunodeficiency virus (HIV), active hepatitis B or C infection, live vaccine within 30 days, or who have previously received irinotecan were excluded.

Patients were treated until disease progression or unacceptable toxicity. The primary efficacy endpoint was progression-free survival (PFS) in patients without brain metastases at baseline (i.e. BMNeg) as measured by a blinded, independent, centralised review (BICR) group of radiology experts using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria. Secondary efficacy endpoints included PFS by BICR for the overall population, including all patients with and without brain metastases, overall survival (OS), objective response rate (ORR) and duration of response (DOR).

The primary analysis included 235 BMNeg patients in the sacituzumab govitecan group and 233 BMNeg patients in the TPC group. The analysis of the overall population included 267 patients in the sacituzumab govitecan group and 262 patients in the TPC group.

The demographics and baseline characteristics of the overall population (n=529) were: median age of 54 years (range: 27–82 years) and 81% <65 years; 99.6% female; 79% White; 12% Black; median number of prior systemic therapies was 4; 69% had previously received 2 to 3 prior chemotherapies; 31% had previously received >3 prior chemotherapies; 42% had hepatic metastases; 12% had present or a history of brain metastases. 8% were BRCA1/BRCA2 mutational status positive; BRCA status was available for 339 patients. At study entry, all patients had an ECOG performance status of 0 (43%) or 1 (57%). The median time from diagnosis of Stage 4 to study entry was 16.2 months (range: -0.4 to 202.9 months). The most frequent prior chemotherapies were cyclophosphamide (83%), anthracycline (83%) including doxorubicin (53%), paclitaxel (78%), carboplatin (65%), capecitabine (67%), gemcitabine (36%), docetaxel (35%), and eribulin (33%). Overall, 29% of patients had received prior PD-1/PD-L1 therapy. Thirteen percent of patients in the sacituzumab govitecan group in the overall population received only 1 prior line of systemic therapy in the metastatic setting.

The efficacy results in the BMNeg population showed a statistical significant improvement of sacituzumab govitecan over TPC in PFS and OS with hazard ratios (HR) of 0.41 (n=468; 95% CI: 0.32, 0.52; p-value: <0.0001) and 0.48 (n=468; 95% CI: 0.38, 0.59; p-value: <0.0001), respectively. The median PFS was 5.6 months vs 1.7 months; the median OS was 12.1 months vs 6.7 months, in patients treated with sacituzumab govitecan and TPC, respectively.

The efficacy results in the overall population were consistent with the BMNeg population in the prespecified final analysis (11 March 2020 cut-off date) and are summarised in Table 3.

Table 3. Efficacy endpoints (overall population) - Pre-specified Final Analysis:

¹ PFS is defined as the time from the date of randomization to the date of the first radiological disease progression or death due to any cause, whichever comes first.
² Stratified log-rank test adjusted for stratification factors: number of prior chemotherapies, presence of known brain metastases at study entry, and region.
³ Based on Cochran-Mantel-Haenszel test.
CI = Confidence Interval

In an updated efficacy analysis (final database lock 25 February 2021), results were consistent with the pre-specified final analysis. The median PFS by BICR was 4.8 months vs 1.7 months, in patients treated with sacituzumab govitecan and TPC, respectively (HR of 0.41; 95% CI: 0.33, 0.52). The median OS was 11.8 months vs 6.9 months, respectively (HR of 0.51; 95% CI: 0.42, 0.63). KaplanMeier curves for updated PFS by BICR and OS are presented in Figures 1 and 2.

Figure 1. Progression free survival (overall population; final database lock 25 February 2021) by BICR:

Figure 2. Overall survival (overall population; final database lock 25 February 2021):

Sub-group analysis

In subgroup analyses, improvements in PFS and OS in patients treated with sacituzumab govitecan compared to TPC were consistent across patient subgroups irrespective of age, race, BRCA status, prior number of systemic therapies overall (2 and >2, 2-3 and >3) and in the metastatic setting (1 and >1), prior therapy with anthracycline or PDL1, and liver metastases.

Brain metastases

An exploratory analysis of PFS and OS in patients with previously treated, stable brain metastases showed a stratified HR of 0.65 (n=61; 95% CI: 0.35, 1.22) and 0.87 (n=61; 95% CI: 0.47, 1.63), respectively. The median PFS was 2.8 months vs 1.6 months; the median OS was 6.8 months vs 7.5 months, in patients treated with sacituzumab govitecan and TPC, respectively.

Trop-2 expression

Additional subgroup analyses were conducted to evaluate the efficacy by tumour Trop-2 expression levels and the results were consistent across the different scoring methods used. In patients with low Trop-2 levels using membrane H-score by quartiles, benefit of sacituzumab govitecan over TPC was shown for both PFS (HR 0.64; 95% CI: 0.37, 1.11) and OS (HR of 0.71; 95% CI: 0.42, 1.21).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with sacituzumab govitecan in all subsets of the paediatric population for the treatment of breast cancer (see section 4.2 for information on paediatric use).