Summary Basis of Decision for Trodelvy

 

This New Drug Submission (NDS) for Trodelvy was reviewed as a Project Orbis Type-B submission as described above.

Clinical Pharmacology

The Canadian review of the clinical pharmacology was based on a critical assessment of the United States Food and Drug Administration (FDA) review, referring to the data package submitted to Health Canada as necessary, as per Method 2 of the foreign review approach described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Trodelvy (sacituzumab govitecan) is a first-in-class antibody-drug conjugate (ADC) directed at the protein trophoblast cell surface antigen-2 (Trop-2). Trodelvy has three components:

1. the humanized monoclonal antibody sacituzumab (hRS7 immunoglobulin G1κ [IgG1κ]), which binds to Trop-2;
2. the drug SN-38, a topoisomerase I inhibitor; and
3. a hydrolysable linker called CL2A, which links the humanized monoclonal antibody to the drug SN-38.

Trophoblast cell surface antigen-2 is a transmembrane calcium signal transducer that is overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC). The humanized monoclonal antibody component of Trodelvy, sacituzumab, targets and binds to Trop-2-expressing cancer cells and is internalized. The drug SN-38, a topoisomerase I inhibitor, is linked to the humanized monoclonal antibody by CL2A, a hydrolyzable linker. Upon release, SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting deoxyribonucleic acid (DNA) damage leads to apoptosis and cell death of cancer cells. Trodelvy therapy delivers cytotoxic chemotherapy to tumours, including adjacent cancer cells, in concentrations that are higher than those with standard chemotherapy and may reduce toxic effects in normal tissues that do not express the target.

The pharmacokinetic profiles of sacituzumab govitecan and its released active metabolite SN-38 were characterized in two clinical studies. Due to the apparent instability of the linkage between the carrier antibody and the payload drug (SN-38), the intravenous administration of sacituzumab govitecan resulted in a consistently high plasma level of the released cytotoxic drug, SN-38. At the recommended dose for Trodelvy, the plasma levels of SN-38 exceeded the maximum levels of SN-38 observed in patients treated with irinotecan (prodrug of SN-38), causing severe neutropenia. As a precaution, dose reduction/discontinuation has been adequately discussed in the Trodelvy Product Monograph. The recommended dose was primarily supported by relevant efficacy and safety data in TNBC patients. The sponsor agreed to submit updated reports of population pharmacokinetics and exposure-response analyses at a later stage for a confirmatory evaluation of the recommended dose.

The effect of sacituzumab govitecan on corrected QT (QTc) interval prolongation was studied in a substudy of 29 patients from the pivotal Phase III ASCENT study (IMMU-132-05). Sacituzumab govitecan was associated with corrected QT interval by Fredericia (QTcF) prolongation one day post-dose, with a maximum mean change of 9.7 ms (90% Confidence Interval [CI]: 2.7 ms, 16.8 ms). A positive exposure-response relationship between the change from baseline QTcF and the exposure of SN-38 was observed.

No drug-drug interaction studies were conducted with Trodelvy or its components. Inhibitors or inducers of uridine diphospate glucuronosyltransferase family 1 member A1 (UGT1A1) are expected to increase or decrease SN-38 exposure, respectively. Concomitant administration of Trodelvy with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to a potential increase in systemic exposure to SN-38. Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Caution should be exercised when administering UGT1A1 inhibitors or inducers with Trodelvy.

The clinical pharmacology data included reports on the human pharmacodynamic and pharmacokinetic studies, and support the use of Trodelvy for the recommended indication.

For further details, please refer to the Trodelvy Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The Canadian review of the clinical efficacy was based on a critical assessment of the data package submitted to Health Canada. The review completed by the United States FDA was used as an added reference, as per Method 3 of the foreign review approach described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The efficacy of Trodelvy was evaluated in the pivotal, Phase III, randomized, open-label, global, multicenter, active-controlled ASCENT study (IMMU-132-05). A total of 529 patients took part in the study, all of whom had unresectable locally advanced or metastatic triple negative breast cancer (mTNBC) and who had relapsed after at least two prior chemotherapies for breast cancer. One of the prior chemotherapies could have been in the neoadjuvant or adjuvant setting, provided progression occurred within a 12 month period. All patients had received previous taxane treatment in either the adjuvant, neoadjuvant, or advanced stage, unless they had a contraindication or were intolerant to taxanes during or at the end of the first taxane cycle. Poly-adenosinediphosphate-ribose (poly-ADP ribose) polymerase (PARP) inhibitors were allowed as one of the two prior chemotherapies for patients with a documented germ-line breast cancer gene 1 or 2 (BRCA1/BRCA2) mutation.

The median age of patients in the full population (n = 529) was 54 years (range: 27 to 82 years); 99.6% were female; 79% were White, 12% were Black/African American; and 81% of patients were <65 years of age. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (43%) or 1 (57%). An ECOG performance status of 0 indicates a fully active patient able to carry on all pre-disease performance without restriction. An ECOG performance status of 1 represents a patient who is restricted in physically strenuous activity, but is ambulatory and able to carry out work of a light and sedentary nature. Forty-two percent of patients had hepatic metastases, 8% were BRCA1/BRCA2 mutational status positive, and 70% had TNBC at diagnosis.

Magnetic resonance imaging (MRI) was required prior to enrollment for patients with known or suspected brain metastases. Patients with stable brain metastases were allowed to enroll up to a predefined maximum of 15% of patients. In total, 468 patients enrolled who did not have brain metastases and 61 patients enrolled who had brain metastases. Twelve percent had baseline brain metastases that were previously treated and stable.

Overall, 29% of patients had received prior programmed cell death-1(PD-1)/ programmed cell death ligand-1 (PD-1/PD-L1) therapy. Thirteen percent of patients in the Trodelvy group who were part of the intent-to-treat (ITT) population (all patients with and without brain metastases) received only one prior line of systemic therapy in the metastatic setting.

Patients were randomized 1:1 to receive Trodelvy 10 mg/kg (number of patients [n] = 267) as an intravenous infusion on Days 1 and 8 of 21-day treatment cycles, or treatment of physician’s choice (TPC; n = 262) single-agent chemotherapy as per the authorized labelling. Single-agent chemotherapy was determined by the investigator prior to randomization and was selected from one of the following choices: eribulin (n = 139), capecitabine (n = 33), gemcitabine (n = 38), or vinorelbine (except if patient had neuropathy classified as Grade 2 or greater, n = 52). Patients were treated until disease progression or unacceptable toxicity occurred.

The major efficacy outcome was progression-free survival (PFS) as measured by a blinded, independent, centralized group of radiology experts using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria. Progression-free survival was defined as the time from the date of randomization to the date of first radiological disease progression or death due to any cause, whichever came first. The date of progression was the date of the last observation or radiological assessment of target lesions that either showed a predefined increase (+20%) in the sum of the target lesions or the appearance of new non-target lesions.

The major efficacy outcome of the study was met. In the ITT population (all patients with and without brain metastases), an improvement in PFS was observed for patients treated with Trodelvy compared to those treated with TPC. The median PFS was 4.8 months (95% Confidence Interval [CI]: 4.1, 5.8) for the Trodelvy group as compared to 1.7 months (95% CI: 1.5, 2.5) for the TPC group. The hazard ratio was 0.43 (95% CI: 0.35, 0.54, p <0.0001), indicating that Trodelvy significantly improved PFS compared to TPC. For patients with negative brain metastases (BM-ve) status at baseline (n = 468), the median PFS in the Trodelvy group was 5.6 months (95% CI: 4.3, 6.3) with an estimated HR of 0.41 (95% CI: 0.32, 0.52). In the brain metastases positive (BM+ve) population (n = 61), the median PFS in the Trodelvy group was 2.8 months (95% CI: 1.5, 3.9) with an estimated HR of 0.65 (95% CI: 0.35, 1.22).

Major secondary outcomes included objective response rate, duration of response, and overall survival. These outcomes were supportive of the major efficacy outcome.

For the ITT population, there were 83 responders (31%) in the Trodelvy group and 11 responders (4%) in the TPC group. The median duration of response was 6.3 months in the Trodelvy group and 3.6 months in the TPC group. The median overall survival for the ITT population was 11.8 months (95% CI: 10.5, 13.8) for the Trodelvy group as compared to 6.9 months (95% CI: 5.9, 7.7) for the TPC group, with a hazard ratio of 0.51 (95% CI: 0.41, 0.62, p <0.0001). In the BM-ve population, the median OS in the Trodelvy group was 12.1 months (95% CI: 10.7, 14.0) with an estimated HR of 0.48 (95% CI: 0.38, 0.59). In the BM+ve population, the median OS in the Trodelvy group was 6.8 months (95% CI: 4.7, 14.1) with an estimated HR of 0.87 (95% CI: 0.47, 1.63).

In the context of the recommended indication and the available treatment options, these efficacy results are considered substantial evidence of clinical effectiveness.

Indication

The New Drug Submission for Trodelvy was filed by the sponsor with the following indication:

Trodelvy (sacituzumab govitecan) is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who received at least two prior therapies.

Health Canada approved the following indication:

Trodelvy (sacituzumab govitecan) is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior therapies, at least one of them for metastatic disease.

For more information, refer to the Trodelvy Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The Canadian review of the clinical safety was based on a critical assessment of the data package submitted to Health Canada. The multidisciplinary review completed by the United States FDA was used as an added reference, as per Method 3 of the foreign review approach described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The clinical safety of Trodelvy was evaluated based on data from the pivotal ASCENT study (IMMU-132-05) described in the Clinical Efficacy section and the Phase I/II basket study IMMU–132-01. The dataset included 660 patients who received at least one dose of 10 mg/kg Trodelvy, 366 of whom had TNBC, and 224 who received TPC therapy. Both studies excluded patients with a known history of Gilbert’s disease or bone only disease, human immunodeficiency virus (HIV), hepatitis B/C, cardiovascular disease, active chronic inflammatory bowel disease, clinically significant bleeding, and clinically significant active chronic obstructive pulmonary disease.

The data described below reflect exposure to Trodelvy as a single agent in 258 patients with mTNBC who had received prior systemic chemotherapy for advanced disease from the pivotal ASCENT study (IMMU-132-05). The median duration of treatment was 4.4 months (range: 0 to 23 months).

The most common adverse reactions with an incidence greater than 25% reported in patients receiving Trodelvy were: neutropenia (64.0%), diarrhea (65.1%), nausea (62.4%), fatigue (51.6%), alopecia (46.9%), anemia (39.5%), constipation (37.2%), vomiting (33.3%), and decreased appetite (27.5%).

Serious adverse reactions occurred in 26.9% of patients receiving Trodelvy. Serious adverse reactions that occurred in greater than 1% of patients receiving Trodelvy were febrile neutropenia (5.0%), diarrhea (3.5%), neutropenia (2.7%), pneumonia (2.7%), anemia (1.2%), and abdominal pain (1.2%). Fatal adverse reactions occurred in 0.8% of patients who received Trodelvy, including respiratory failure (0.4%).

Adverse reactions leading to permanent discontinuation of Trodelvy occurred in 4.7% of patients, with the most common being pneumonia (0.8%) and fatigue (0.8%).

Adverse reactions leading to a dose reduction of Trodelvy occurred in 21.7% of patients. The most frequent adverse reactions occurring in 1% or more patients that lead to a dose reduction were neutropenia (8.9%), diarrhea (4.7%), febrile neutropenia (2.7%), nausea (1.9%), fatigue (1.9%), and anemia (1.2%). Adverse reactions led to a treatment interruption of Trodelvy in 63% of patients. The most frequent adverse reactions that led to a treatment interruption in 4% of patients or more were neutropenia (46.1%), leukopenia (5.0%), and diarrhea (5.4%). Granulocyte-colony stimulating factor (G-CSF) was used in 47% (122/258) of patients who received Trodelvy.

The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Trodelvy: severe or life-threatening neutropenia and severe diarrhea. Other major safety issues identified in the safety analysis associated with the use of Trodelvy in mTNBC patients were hypersensitivity reactions and nausea and vomiting. In patients treated with Trodelvy, 62% experienced neutropenia, with Grade 3 to 4 neutropenia occurring in 47% of patients. Febrile neutropenia also occurred in 6% of patients. Diarrhea occurred in 63% of patients treated with Trodelvy, with Grade 3 diarrhea occurring in 10% of patients. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients treated with Trodelvy. Nausea occurred in 67% of patients treated with Trodelvy, with Grade 3-4 nausea occurring in 4% of patients.

Based on its mechanism of action, Trodelvy can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. Trodelvy contains a genotoxic component, SN-38, and is toxic to rapidly dividing cells. Pregnant women and females of reproductive potential must be advised of the potential risk to a fetus. The pregnancy status of females of reproductive potential should be verified prior to the initiation of treatment with Trodelvy and effective contraception should be used during treatment with

Trodelvy until 6 months after the last dose. Due to the potential for genotoxicity, male patients with female partners of reproductive potential should be advised to use effective contraception during treatment with Trodelvy until 3 months after the last dose.

It is unknown if Trodelvy is excreted in human milk. Because of the potential for serious adverse reactions in a breastfed child, women are advised not to breastfeed during treatment and for one month after the last dose of Trodelvy.

There are no data on the use of Trodelvy in patients with moderate or severe renal impairment or end-stage renal disease (creatinine clearance ≤15 mL/min). No dose adjustment is necessary in patients with mild hepatic impairment. The safety of Trodelvy in patients with moderate or severe hepatic impairment has not been established.

Appropriate warnings and precautions are in place in the approved Trodelvy Product Monograph to address the identified safety concerns. For more information, refer to the Trodelvy Product Monograph, approved by Health Canada and available through the Drug Product Database.