Canadian Expert Recommendations on Safety Overview and Toxicity Management Strategies for Sacituzumab Govitecan Based on Use in Metastatic Triple-Negative Breast Cancer
Abstract
:1. Introduction
2. Summary of SG Clinical Evidence
3. Safety Overview
4. Management of SG-Related Adverse Events
4.1. Neutropenia
4.2. Diarrhea
4.3. Nausea and Vomiting
4.4. Hypersensitivity and Skin Reactions
4.5. Alopecia
4.6. UGT1A1 and Increased Risk of Adverse Events
4.7. Use in Special Populations
5. Discussion
Future Directions of SG
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
- British Columbia Cancer Agency Sacituzumab Govitecan protocol BRAVSG outlining SG for use as palliative therapy for metastatic triple negative breast cancer: http://www.bccancer.bc.ca/chemotherapy-protocols-site/Documents/Breast/BRAVSG_Protocol.pdf (accessed on 15 May 2024).
- Cancer Care Ontario Drug Formulary link for Sacituzumab Govitecan: https://www.cancercareontario.ca/en/drugformulary/drugs/monograph/74306 (accessed on 20 February 2024).
- Gilead product monograph for Trodelvy (Sacituzumab Govitecan): https://pdf.hres.ca/dpd_pm/00071772.PDF (accessed on 16 May 2024).
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Efficacy Outcomes | IMMU-132-01 (n = 108) * | ASCENT (n = 235) | TROPiCS-02 (n = 272) |
---|---|---|---|
ORR | 33% | 35% | 21% |
Median PFS (95% CI), months | 5.5 (4.1–6.3) | 5.6 (4.3–6.3) | 5.5 (4.2–7.0) |
Median OS (95% CI), months | 13.0 (11.2–13.7) | 12.1 (10.7–14.0) | 14.4 (13.0–15.7) |
Median DOR (95% CI), months | 9.1 (4.6–11.3) | 6.3 (5.5–9) | 8.1 (6.7–9.1) |
CBR † (n) (95% CI) | 45% (49) (35.8–55.2) | 45% (105) | 34% (92) (28.2–39.8) |
Treatment-Related Adverse Event * | Sacituzumab Govitecan Percent of Total Treatment Population (n = 258) | Treatment of Physicians’ Choice Percent of Total Treatment Population (n = 224) | ||||
---|---|---|---|---|---|---|
Any Grade | Grade 3 | Grade 4 | Any Grade | Grade 3 | Grade 4 | |
Any Adverse Event (%) | 98 | 45 | 19 | 86 | 32 | 15 |
Hematologic | ||||||
Neutropenia | 63 | 34 | 17 | 43 | 20 | 13 |
Anemia | 34 | 8 | 0 | 24 | 5 | 0 |
Leukopenia | 16 | 9 | 1 | 11 | 4 | 1 |
Thrombocytopenia | 5 | 1 | 1 | 11 | 1 | 0 |
Febrile Neutropenia | 6 | 5 | 1 | 2 | 2 | <1 |
Gastrointestinal | ||||||
Diarrhea | 59 | 10 | 0 | 12 | <1 | 0 |
Nausea | 57 | 2 | <1 | 26 | <1 | 0 |
Vomiting | 29 | 1 | <1 | 10 | <1 | 0 |
Constipation | 17 | 0 | 0 | 14 | 0 | 0 |
Abdominal Pain | 11 | 1 | 0 | 4 | <1 | 0 |
General | ||||||
Fatigue | 45 | 3 | 0 | 30 | 5 | 0 |
Asthenia | 12 | 1 | 0 | 10 | 1 | 0 |
Other | ||||||
Alopecia | 46 | 0 | 0 | 16 | 0 | 0 |
Decreased appetite | 20 | 2 | 0 | 14 | <1 | 0 |
Nervous system disorders | 25 | <1 | 0 | 24 | 2 | 0 |
Respiratory, thoracic and mediastinal disorders | 16 | 2 | 0 | 8 | <1 | 0 |
Musculoskeletal and connective-tissue disorders | 12 | 0 | 0 | 12 | 1 | 0 |
Infections and infestations | 12 | 2 | <1 | 10 | 2 | 1 |
Pre-Infusion or Concomitant Medications | Sacituzumab Govitecan | Treatment of Physicians’ Choice |
---|---|---|
Antiemetics/antinauseants | 86% | 63% |
Analgesics/antipyretics | 77% | 64% |
Antidiarrheals | 55% | 10% |
Anti-inflammatory/anti-rheumatic agents | 35% | 33% |
G-CSF | 49% | 23% |
Adverse Event | Authors’ Recommendations | |
---|---|---|
Severe Neutropenia | Occurrence | |
Grade 4 neutropenia lasting ≥ 7 days OR Grade 3–4 febrile neutropenia OR At time of scheduled SG dose, grade 3–4 neutropenia that delays dosing by 2–3 weeks for recovery to grade ≤ 1 | First | Reduce SG dose by 25% and administer G-CSF (consider filgrastim if available) |
Second | Reduce SG dose by 50% and administer G-CSF (consider filgrastim if available) | |
Third | Discontinue SG and administer G-CSF (consider filgrastim if available) | |
At the time of scheduled SG dose, grade 3–4 neutropenia that delays SG dosing beyond 3 weeks for recovery to grade ≤ 1 | First | Discontinue SG and administer G-CSF (consider filgrastim if available) |
Non-Hematological Toxicities | ||
Diarrhea (grade 3 or 4) at the time of scheduled SG dose | Evaluate for infectious causes. If negative, initiate treatment. Treatment: At the onset of diarrhea, promptly initiate loperamide:
Patient education: All patients should be given take-home medications with clear instructions for the treatment of diarrhea. Withhold SG until diarrhea is resolved to grade ≤ 1. | |
Excessive cholinergic response (including abdominal cramping, diarrhea, rhinorrhea, increased salivation, lacrimation, diaphoresis, and flushing) | Provide atropine 0.3–0 6 mg IV or SC. Prophylactic atropine 0.3 mg SC prior to SG may be required for subsequent treatments. | |
Nausea (grade 3) or vomiting (grade 3 or 4) at the time of scheduled SG dose | Premedication: A 2–3 drug combination regimen 30 to 60 min prior to SG infusion (e.g., dexamethasone with either a 5-HT3 RA or an NK-1 RA, as well as other drugs, as indicated) for the prevention of CINV. Consider dexamethasone 8 mg or 12 mg po, and the following:
Patient education: All patients should be given take-home medications with clear instructions for prevention and treatment of nausea/vomiting. | |
Grade 4 diarrhea, nausea, or vomiting of any duration OR Grade 3 diarrhea, nausea, or vomiting not controlled by medication or persisting for >48 h despite optimal medical management OR At time of scheduled treatment, grade 3–4 non-neutropenic hematologic or non-hematologic toxicity which delays dose by 2–3 weeks for recovery to grade ≤ 1 | First | Reduce SG dose by 25% |
Second | Reduce SG dose by 50% | |
Third | Discontinue SG | |
Grade 3–4 non-neutropenic hematologic or non-hematologic toxicity which does not recover to grade ≤ 1 within 3 weeks | First | Discontinue SG |
Hypersensitivity reaction | Premedication: Antipyretics and H1/H2 blockers prior to infusion. Corticosteroids may be used for patients who had prior infusion reactions prior to SG infusion. Infusion: The initial infusion should be slow (50 mg/h or less) and given over 3 h. If no IRR, subsequent infusions can be given over 1 h. Monitoring: monitor patients throughout and for ≥30 min post-infusion. Adjustment:
| |
The dose of SG should not be re-escalated after a dose reduction for adverse reactions has been carried out |
NCCN Preferred Options for Highly Emetogenic IV Agents | ||
---|---|---|
Category | Day 1 | Day 2, 3, 4 |
Corticosteroids | Dexamethasone 12 mg po/IV once | Dexamethasone 8 mg po/IV daily |
5HT3 RA Choose 1 | Granisetron 10 mg sc once, or 2 mg po once, or 0.01 mg/kg (max 1 mg) once, or 3.1 mg/24 h transdermal patch applied 24–48 h prior to first dose Ondansetron 16–24 mg po once or 8–16 mg IV once Palonosetron 0.24 mg IV once | |
NK1 RA Choose 1 | Aprepitant 125 mg po once Aprepitant injectable emulsion 130 mg IV once Fosaprepitant 150 mg IV once Netupitant 300 mg/palonosetron 0.5 mg po once | Aprepitant 80 mg po daily only if aprepitant po is used on day 1 |
Atypical Antipsychotic | Olanzapine 5–10 mg po once | Olanzapine 5–10 mg po daily |
(A) | |||
UGT1A1 Allele Status in SG Arm | ASCENT (%) (n = 258) | TROPiCS-02 (%) (n = 268) | Combined (%) (n = 526) |
UGT1A1 status known | 250 (96.9) | 250 (93.3) | 500 (95.1) |
Wildtype (*1/*1) | 113 (43.8) | 103 (38.4) | 216 (41.1) |
Heterozygous (*1/28) | 96 (37.2) | 119 (44.4) | 215 (40.9) |
Homozygous (*28/*28) | 34 (13.1) | 25 (9.3) | 59 (11.2) |
Other UGT1A1 genotype | 7 (2.7) | 3 (1.1) | 10 (1.9) |
(B) | |||
Treatment-Related Adverse Event | Homozygous Wild Type (*1/*1) (n = 216) | Heterozygous (*1/*28) (n = 215) | Homozygous (*28/*28) (n = 59) |
All grade neutropenia | 149 (69.0) | 141 (65.6) | 43 (72.9) |
Grade 3 or 4 neutropenia | 106 (49.1) | 113 (52.6) | 36 (61.0) |
All grade anemia | 71 (32.9) | 72 (33.5) | 28 (47.5) |
Grade 3 or 4 anemia | 11 (5.1) | 16 (7.4) | 7 (11.9) |
All grade diarrhea | 125 (57.9) | 134 (62.3) | 38 (64.4) |
Grade 3 or 4 diarrhea | 17 (7.9) | 24 (11.2) | 11 (18.6) |
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Manna, M.; Brabant, M.; Greene, R.; Chamberlain, M.D.; Kumar, A.; Alimohamed, N.; Brezden-Masley, C. Canadian Expert Recommendations on Safety Overview and Toxicity Management Strategies for Sacituzumab Govitecan Based on Use in Metastatic Triple-Negative Breast Cancer. Curr. Oncol. 2024, 31, 5694-5708. https://doi.org/10.3390/curroncol31090422
Manna M, Brabant M, Greene R, Chamberlain MD, Kumar A, Alimohamed N, Brezden-Masley C. Canadian Expert Recommendations on Safety Overview and Toxicity Management Strategies for Sacituzumab Govitecan Based on Use in Metastatic Triple-Negative Breast Cancer. Current Oncology. 2024; 31(9):5694-5708. https://doi.org/10.3390/curroncol31090422
Chicago/Turabian StyleManna, Mita, Michelle Brabant, Rowen Greene, Michael Dean Chamberlain, Aalok Kumar, Nimira Alimohamed, and Christine Brezden-Masley. 2024. "Canadian Expert Recommendations on Safety Overview and Toxicity Management Strategies for Sacituzumab Govitecan Based on Use in Metastatic Triple-Negative Breast Cancer" Current Oncology 31, no. 9: 5694-5708. https://doi.org/10.3390/curroncol31090422