What does the evidence say about the efficacy of Trodelvy as compared with single-agent chemotherapy in patients with relapsed or refractory metastatic triple-negative breast cancer?

Comment by InpharmD Researcher

Sacituzumab govitecan is an effective and well-tolerated treatment for refractory, metastatic triple-negative breast cancer as compared to single agent chemotherapy, and was granted accelerated approval by the FDA.
Background

The National Comprehensive Cancer Network (NCCN) Guidelines for breast cancer state that sacituzumab govitecan is recommended for recurrent or stage IV triple-negative breast cancer for adults who have received at least two prior therapies for metastatic disease. (1)

References:

1. Gradishar WJ, Anderson BO, Abraham J, Aft R, Agnese D, Allison KH, Blair SL, Burstein HJ, Dang C, Elias AD, Giordano SH, Goetz MP, Goldstein LJ, Isakoff SJ, Krishnamurthy J, Lyons J, Marcom PK, Matro J, Mayer IA, Moran MS, Mortimer J, O'Regan RM, Patel SA, Pierce LJ, Rugo HS, Sitapati A, Smith KL, Smith ML, Soliman H, Stringer-Reasor EM, Telli ML, Ward JH, Young JS, Burns JL, Kumar R. Breast Cancer, Version 5.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020 Apr;18(4):452-478. doi: 10.6004/jnccn.2020.0016. PMID: 32259783.
Relevant Prescribing Information

TRODELVY(TM) (sacituzumab govitecan-hziy) is a Trop-2-directed antibody and topoisomerase inhibitor conjugate that received accelerated approval for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease.

Trodelvy is indicated for intravenous infusion only, with the recommended dose being 10 mg/kg once weekly on Days 1 and 8 of continuous 21-day treatment cycles until disease progression or unacceptable toxicity.

Warnings for Trodelvy include severe neutropenia and diarrhea. Trodelvy should be withheld when the absolute neutrophil count falls below 1500/mm3 or
neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for
secondary prophylaxis. Initiate anti-infective treatment in patient with febrile neutropenia without delay

Other precautions include hypersensitivity reactions, nausea vomiting (anitemetic prevention recommended), and embryo-fetal toxicity. Additionally, patients with who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia following initiation of treatment.

Most common adverse reactions (incidence >25%) include; nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What does the evidence say about the efficacy of Trodelvy as compared with single-agent chemotherapy in patients with relapsed or refractory metastatic triple-negative breast cancer?

Please see Table 1 for your response.

 

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer

The ASCENT Trial

Design

Global, phase 3, open-label, randomized trial

N= 529 (468 included in results)

Objective

To evaluate the efficacy and safety of sacituzumab govitecan (Trodelvy) as compared with single-agent chemotherapy of the physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer.

Study Groups

Sacituzumab govitecan (n= 267) (n= 235 without brain metastases)

 

Single-agent chemotherapy (n= 262) (n= 233 without brain metastases):

Eribulin (n= 126)

Vinorelbine (n= 47)

Capecitabine (n= 31)

Gemcitabine (n= 29)

Inclusion Criteria

Patients with metastatic, triple-negative breast cancer that was relapsed or refractory to two or more previous standard chemotherapy regimens for unresectable, locally advanced or metastatic disease. Patients were required to have had previous therapy including a taxane (for any indication).

Exclusion Criteria

Pregnant and lactating women were excluded. Patients were also excluded due to the following: Gilbert syndrome; positive for HIV, hepatitis B or C infection; unstable angina, myocardial infarction, or congestive heart failure within 6 months; active chronic obstructive pulmonary disorder or moderate-to-severe chronic respiratory illness within 6 months; history of significant bleeding, intestinal obstruction or gastrointestinal perforation within 6 months; infection requiring antibiotics within 1 week; active chronic or history of inflammatory bowel disease; prior use of irinotecan; rapid deterioration during screening (eg, significant change in performance status, ≥20% decrease in serum albumin, or unstable pain symptoms requiring analgesic management); or other 8 concurrent medical or psychiatric conditions that may confound the study interpretation or completion/follow-ups

Methods

Patients were randomly assigned in a 1:1 ratio to receive either intravenous (IV) sacituzumab govitecan at a dose of 10 mg per kilogram of body weight, on days 1 and 8 of a 21-day cycle, or a single-agent chemotherapy regimen in patients with relapsed or refractory metastatic triple-negative breast cancer.

Single-agent chemotherapy regimens were decided by the physician prior to randomization and included:

  • 1.4 mg of eribulin per square meter of body-surface area, IV on days 1 and 8 of a 21-day cycle (North America)
  • 1.2 mg of eribulin per square meter, IV on days 1 and 8 of a 21-day cycle (North America)
  • 25 mg of vinorelbine per square meter, IV on day 1 weekly
  • 1000 to 1250 mg of capecitabine per square meter, orally, twice daily on days 1 to 14 of a 21-day cycle
  • 800 to 1200 mg of gemcitabine per square meter, IV on days 1, 8, and 15 of a 28-day cycle

 

The trial took place globally at 88 sites in seven different countries.

Duration

Enrollment: November 2017 to September 2019

Outcome Measures

Primary end-point: progression-free survival among patients without known baseline brain metastases

Progression-free survival was defined as the time from randomization until objective tumor progression or death or was censored at the last radiographic assessment for patients without progression or death.

Secondary end points: overall survival, safety

Baseline characteristics

Characteristic – no. (%)

Sacituzumab govitecan (n= 235)

Chemo

Sex:

Female

233 (99)

233 (100)

Male

2 (1)

0

Median age (range)–yr

54 (29-82)

53 (27-81)

Race:

White

188 (80)

191 (78)

Black

28 (12)

28 (12)

Asian

9 (4)

9 (4)

Other or not specified

10 (4)

15 (6)

ECOG ( Eastern Cooperative Oncology Group) performance-status score at screening:

0

108 (46)

98 (42)

1

127 (54)

135 (58)

Germline BRCA1 or BRCA2 mutation status:

Negative

133 (57)

125 (54)

Positive

16 (7)

18 (8)

Major tumor locations:

Lung

108 (46)

97 (42)

Liver

98 (42)

101 (43)

Axillary lymph nodes

57 (24)

73 (31)

bones

48 (20)

55 (24)

Median no. of previous anticancer regimens (range)

3 (1-16)

3 (1-12)

Previous chemotherapy regimens:

2 or 3

166 (71)

164 (70)

>3

69 (29)

69 (30)

Previous chemotherapy drugs:

Taxanes

235 (100)

233 (100)

Anthracyclines

191 (81)

193 (83)

Cyclophosphamide

192 (82)

192 (82)

Carboplatin

147 (63)

160 (69)

Capecitabine

147 (63)

159 (68(

Previous use of PARP (poly adenosine diphosphate–ribose polymerase) inhibitors

17 (7)

18 (8)

Previous use of PD-1 or PD-L1 (programmed death/ligand) inhibitors

67 (29)

60 (26)

Results

 

Outcome

Patients without brain metastases

p-value

Full population

 

Sacituzumab govitecan (n= 235)

Chemotherapy

(n= 233)

Hazard ratio for disease progression or death (95% CI)

Sacituzumab govitecan (n= 267)

Chemotherapy

Hazard ratio for disease progression or death (95% CI)

Median progression-free survival (95% CI)–mo

5.6 (4.3-6.3)

1.7 (1.5-2.6)

0.41 (0.32-0.52)

p < 0.001

4.8 (4.1-5.8)

1.7 (1.5-2.5)

0.43 (0.35-0.54)

Median overall survival (9% CI)

12.1 (10.7-14.0)

6.7 (5.8-7.7)

0.48 (0.38-0.59)

11.8 (10.5-13.8)

6.9 (5.9-7.7)

0.51 (0.41-0.62)

 

 

Safety

 

Event

Sacituzumab govitecan (n= 258)

No. (%)

Chemotherapy (n= 224)

No. (%)

 

Grade 3

Grade 4

Grade 3

Grade 4

Any adverse event

117 (45)

48 (19)

71 (32)

33 (15)

Neutropenia

88 (34)

44 (17)

45 (20)

29 (13)

Anemia

20 (8)

0

11 (5)

0

Leukopenia

23 (9)

3 (1)

10 (4)

2 (1)

Thrombocytopenia

2 (1)

2 (1)

3 (1)

0

Febrile neutropenia

12 (5)

3 (1)

4 (2)

1 (<1)

Diarrhea

27 (10)

0

1 (<1)

0

Nausea

6 (2)

1 (<1)

1 (<1)

0

Vomiting

2 (1)

1 (<1)

1 (<1)

0

Constipation

0

0

0

0

Abdominal pain

3 (1)

0

1 (<1)

0

Fatigue

8 (3)

0

12 (5)

0

Asthenia

2 (1)

0

3 (1)

0

Alopecia

0

0

0

0

Decreased appetite

4 (2)

0

1 (<1)

0

Nervous system disorders

1 (<1)

0

5 (2)

0

Respiratory, thoracic, and mediastinal disorders

5 (2)

0

1 (<1)

0

Musculoskeletal and connective-tissue disorders

0

0

3 (1)

0

Infections and infestations

6 (2)

1 (<1)

4 (2)

3 (1)

Study Author Conclusions

Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan.

InpharmDTM Researcher

Critique

Sacituzumab govitecan is an effective and well-tolerated treatment for refractory, metastatic triple-negative breast cancer as compared to single agent chemotherapy, and was granted accelerated approval by the FDA.

While sacituzumab govitecan was shown to be effective, there is a limitation with the multiple chemotherapies used, as there is heterogeneity of safety risks and efficacy associated with each agent. Additionally, the trial was not powered to examine differences between the individual chemotherapy agents.

 

 

References:

Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O'Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. doi: 10.1056/NEJMoa2028485. PMID: 33882206.