Case-Based Discussion on Management of Select Adverse Events | Part 1: Overview of a Treatment Option for HR+/HER2- Metastatic Breast Cancer

Please click to see the full Prescribing Information, including Boxed Warning, and Important Safety Information below.

Click video to watch this presentation by Dr Yuan Yuan, MD, PhD, a breast medical oncologist and physician-scientist who specializes in triple-negative breast cancer and breast cancer immunotherapy. Dr Yuan completed her medical degree in China and a fellowship in hematology and oncology at NYU. Additionally, she holds a PhD in biochemistry and molecular biology from the University of California, Riverside.

Watch this webinar to help understand:

• The key efficacy, safety, and patient-reported outcomes data for a treatment option in patients with pretreated HR+/HER2- metastatic breast cancer.
• The potential management strategies for certain adverse events that may be experienced with this treatment.

This is part 1 of 3:

• Part 1: Overview of a Treatment Option for Pretreated HR+/HER2- Metastatic Breast Cancer
• Part 2: Case Presentation and Questions #1
• Part 3: Case Presentation and Questions #2

Click here to watch the next video.

INDICATIONS

TRODELVY® (sacituzumab govitecan-hziy) is a Trop-2-directed antibody and topoisomerase inhibitor conjugate 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 systemic therapies, at least one of them for metastatic disease.
• Unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.

IMPORTANT SAFETY INFORMATION
BOXED WARNING: NEUTROPENIA AND DIARRHEA

• Severe or life-threatening neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm³ or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
• Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤Grade 1 and reduce subsequent doses. 

CONTRAINDICATIONS

• Severe hypersensitivity reaction to TRODELVY.

WARNINGS AND PRECAUTIONS
Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 64% of patients treated with TRODELVY. Grade 3-4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6%. Neutropenic colitis occurred in 1.4%. Withhold TRODELVY for absolute neutrophil count below 1500/mm³ on Day 1 of any cycle or neutrophil count below 1000/mm³ on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Administer G-CSF as clinically indicated or indicated in Table 1 of USPI.

Diarrhea: Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3-4 diarrhea occurred in 11% of patients. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all patients. Withhold TRODELVY for Grade 3-4 diarrhea and resume when resolved to ≤Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with TRODELVY. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.2%. The incidence of anaphylactic reactions was 0.2%. Pre-infusion medication is recommended. Have medications and emergency equipment to treat such reactions available for immediate use. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Permanently discontinue TRODELVY for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 64% of all patients treated with TRODELVY and Grade 3-4 nausea occurred in 3% of these patients. Vomiting occurred in 35% of patients and Grade 3-4 vomiting occurred in 2% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK₁ receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting. 

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with TRODELVY. The incidence of Grade 3-4 neutropenia was 58% in patients homozygous for the UGT1A1*28, 49% in patients heterozygous for the UGT1A1*28 allele, and 43% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 21% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 9% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function. 

Embryo-Fetal Toxicity: 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 targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose. 

ADVERSE REACTIONS

In the pooled safety population, the most common (≥ 25%) adverse reactions including laboratory abnormalities were decreased leukocyte count (84%), decreased neutrophil count (75%), decreased hemoglobin (69%), diarrhea (64%), nausea (64%), decreased lymphocyte count (63%), fatigue (51%), alopecia (45%), constipation (37%), increased glucose (37%), decreased albumin (35%), vomiting (35%), decreased appetite (30%), decreased creatinine clearance (28%), increased alkaline phosphatase (28%), decreased magnesium (27%), decreased potassium (26%), and decreased sodium (26%). 

In the ASCENT study (locally advanced or metastatic triple-negative breast cancer), the most common adverse reactions (incidence ≥25%) were fatigue, diarrhea, nausea, alopecia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPiCS-02 study (locally advanced or metastatic HR-positive, HER2-negative breast cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, alopecia, and constipation. The most frequent serious adverse reactions (SAR) (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). SAR were reported in 28% of patients, and 6% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPiCS-02 study were reduced neutrophils and leukocytes.

DRUG INTERACTIONS
UGT1A1 Inhibitors: Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY. 

UGT1A1 Inducers: Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY.

Please see full Prescribing Information, including BOXED WARNING.

Video Transcript:

Part 1: Overview of a Treatment Option for HR+/HER2- Metastatic Breast Cancer

Moderator: Welcome and thank you for joining us today for this case-based discussion on management of select adverse events for TRODELVY. I am pleased to introduce Dr. Yuan Yuan who will be presenting and leading today's discussion. Dr. Yuan is a breast medical oncologist and physician scientist who specializes in triple negative breast cancer and breast cancer immunotherapy. Dr. Yuan completed her medical degree in China and a fellowship in hematology and medical oncology at NYU. Additionally, she holds a PhD in biochemistry and molecular biology from the University of California Riverside. Thank you, Dr. Yuan, for being with us here today. Dr. Yuan, please take it away. 

Dr. Yuan: Thank you, Linda, and thank you to the sponsor for the opportunity to share some of the information for you. And this is a promotional program that is provided by Gilead, and the content has been developed in accordance to FDA guidelines. So, I will abide by this information.  

Dr. Yuan: So today we would like to take some time to understand TRODELVY key efficacy, safety and patient-reported outcome data in patients with pretreated hormone receptor positive, HER2- metastatic breast cancer.  

Dr. Yuan: So, as you know, TRODELVY indications have been extended to 2 areas. TRODELVY sacituzumab govitecan is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received 2 or more prior systemic therapies, at least 1 of them for metastatic disease. Unresectable locally advanced or metastatic hormone receptor-positive, HER2-negative, defined by immunohistochemistry or IHC 0 or IHC 1+ or IHC 2+, and ISH negative breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. TRODELVY has a Boxed Warning for neutropenia and diarrhea. Severe or life-threatening neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay. Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to grade 1 or lower and reduce subsequent doses. TRODELVY is contraindicated in those with severe hypersensitivity reaction to TRODELVY. 

Dr. Yuan: So, let's take a deep dive into the landmark TROPiCS-02 trial, which is a phase 3 randomized study specifically focused on patients with hormone receptor positive, HER2 negative locally advanced inoperable or metastatic breast cancer. In this trial, patients were randomized 1-on-1 to sacituzumab govitecan, or TRODELVY, at the dose of 10 mg/kg on days 1 and 8, every 21 days, versus single-agent choice, or physician's choice, which include eribulin, vinorelbine, gemcitabine or capecitabine. These are the patients going back to the far left of the screen. Who are these patients? These are the patients who are hormone receptor positive disease, metastatic, and at least 1 endocrine therapy in the metastatic setting. And taxanes in the (Neo)adjuvant or metastatic setting and at least 2 but not more than 4 lines of chemo for the metastatic disease. So, you notice that this is an important feature of this population. They're rather heavily pretreated. Now, they must have measurable disease by RECIST v1.1. As far as the endpoints, the primary endpoint is progression-free survival, and the secondary endpoint including overall survival and importantly, patient-reported outcomes and safety information. 

Dr. Yuan: Here are the characteristics of TROPiCS-02. If you look at the 2 arms, they're well-balanced, looking at the median age, race, ECOG performance status, they're similar, important features. Again, I want to draw your attention to the visceral metastases. Look at these patients, 95% in both arms had visceral metastasis at baseline. Again, this depicted their very heavily pretreated population and we're talking about visceral metastases. About 84% to 87% of the patients had liver met. About 29% to 22% of the patients had a de novo stage 4 disease. Now, important features also included prior treatment. If you look at some breakdowns on the right-hand side, including prior CDK4/6 inhibitor, there's further characteristics including the time on initial CDK. About 60% of the patients had a relatively short, less than 12 months of CDK4/6 inhibitor treatment. Over 12 months, patients are only around 40%. So, this kind of speaks for, again, those in our practice we mentioned, those so-called fast progressors.  

So, these again speak for the TROPiCS-02 population. Very important for the later slides. Now median lines of therapy, you can see that they're again heavily pretreated. Over 60% of the patients had 3 or more lines of chemotherapy. And the median lines of chemo ranging between 1 to 9 in the sacituzumab arm, and then somewhere around 2 to 7 in the single agent chemotherapy arm. 

Dr. Yuan: So, this is a big primary endpoint, progression-free survival, and the secondary endpoint, overall survival. We can see that in this, again, heavily pretreated population, the central review RECIST criteria showing that sacituzumab govitecan has a significant improved progression-free survival of 5.5 months, in comparison with the chemotherapy arm's 4.0 months. This actually reached the primary endpoint, and fit into the initial statistical design, hazard ratio of 0.66, and log rank P-value less than 0.0003, and look at the progression-free survival. Despite a modest improvement of progression-free survival, you can see a significant improvement of 3 months comparing sacituzumab govitecan versus chemotherapy with a hazard ratio of 0.79. And so, I think this is very important data.  

Dr. Yuan: So, an important, I would say, landmark time point. So, if you look at the left side of the table here, at 6 months of time, the sacituzumab govitecan-treated patients, 46% of them have remained progression-free and the chemotherapy is 30%. 

But if you move on to 12 months, you can see that the differences further widen. The chemotherapy arm only has 7% of patients still on treatment not progressing, but for sacituzumab govitecan, that is increased to 21%. I think that's really important data to share with patients in clinic, how to we explain the efficacy. And again, you look at the 12 months overall survival rate, in SG treated patients, overall survival, 61%, in chemotherapy, 47%. This analysis was prespecified but was not powered for statistical significance and should be considered descriptive only. Therefore, the results require cautious interpretation and could represent chance findings. 

Dr. Yuan: Time to deterioration of global health status/QoL, fatigue and pain were prespecified secondary endpoints. SG statistically significantly extended time to deterioration of global health status or QoL and fatigue. The EORTC QLQ-C30 is not all-inclusive and does not include adequate assessment of additional expected treatment-related symptoms or overall side effects bother from the patient's perspective. The results should be interpreted with caution due to the open-label design of the study and because time to deterioration may be confounded by events not related to disease or treatment.    

Dr. Yuan: So, important adverse events which are reported in the TROPiCS-02 study. So there are some, you can find information in the package insert, but in total, severe adverse events occurred in 28% of the patients, which includes severe diarrhea happened in 5%, febrile neutropenia 4%, neutropenia 3%. Also including other, 2% each of abdominal pain, colitis, neutropenic colitis, et cetera. Fatal activity of adverse reaction occurred in 2% of the patient who received sacituzumab, including arrhythmia, nervous disorder and pulmonary embolism. Permanent discontinuation rate is relatively low, in 6% of the patients, and again was similar to the other causes we discussed earlier. The causes of the discontinuation were highlighted here in the fourth bullet point. And notice that in TROPiCS-02 there was no ILD (interstitial lung disease). And note that in this study, 54% of the patient received supportive G-CSF. 

Dr. Yuan: The most common, which is defined by 25% or more adverse events, including lab abnormalities with SG were decreased leukocytes, decreased neutrophils, decreased hemoglobin, decreased lymphocytes, diarrhea, fatigue, nausea, alopecia, increased glucose, constipation, and decreased albumin. 

Dr. Yuan: Now let's take a deeper dive into these individual toxicities we mentioned earlier. Neutropenia: severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 64% of patients treated with TRODELVY.  Grade 3 to 4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6%. Neutropenic colitis occurred in 1.4%. Withhold TRODELVY for absolute neutrophil count below 1500 on day 1 of any cycle or neutrophil counts below 1000 on day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Administer G-CSF as clinically indicated or indicated in Table 1 of USPI. Diarrhea: Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3 to 4 diarrhea occurred in 11% of patients. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all patients. Withhold TRODELVY for grade 3 to 4 diarrhea and resume them when resolved to grade 1 or lower. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, which is dosed at 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures, including fluids and electrolyte substitution, may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication such as atropine for subsequent treatments. 

Dr. Yuan: Hypersensitivity and infusion-related reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with TRODELVY. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients. Grade 3 to 4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.2%.  The incidence of anaphylactic reactions was 0.2%. Pre-infusion medication is recommended. Have medications and emergency equipment to treat such reactions available for immediate use.   Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Permanently discontinue TRODELVY for Grade 4 infusion-related reactions. 

Nausea and vomiting: Nausea occurred in 64% of all patients treated with TRODELVY, and grade 3 to 4 nausea occurred in 3% of all these patients. Vomiting occurred in 35% of patients, and grade 3 to 4 vomiting occurred in 2% of these patients.  Premedicate with a 2 or 3-drug combination regimen such as dexamethasone, with either a 5-HT3 receptor antagonist or an NK₁ receptor antagonist, as well as other drugs as indicated for prevention of chemotherapy-induced nausea and vomiting. Withhold TRODELVY doses for grade 3 nausea or grade 3 to 4 vomiting, and resume with additional supportive measures when resolved to grade 1 or lower. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting. 

Dr. Yuan: Increased risk of adverse reactions in patients with reduced UGT1A1 activity: Patients with homozygous for the UGT1A1*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia, and may be at increased risk for other adverse reactions with TRODELVY. The incidence of grade 3 to 4 neutropenia was 58% in patients homozygous for the UGT1A1*28 allele, 49% in patients heterozygous for the UGT1A1*28 allele, and 43% in patients homozygous for the wild-type allele. The incidence of grade 3 to 4 anemia was 21% in patients homozygous for the allele, 10% in patients heterozygous for the allele, and 9% in patients homozygous for the wild-type. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions.  Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration, and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function. 

Embryo-fetal toxicity: 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 targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose. 

Dr. Yuan: Adverse reactions: In the pooled safety population, the most common, which is defined by 25% or more adverse reactions including lab abnormalities, were decreased leukocyte count 84%, decreased neutrophil count 75%, decreased hemoglobin 69%, diarrhea 64%, nausea 64%, decreased lymphocyte count 63%, fatigue 51%, alopecia 45%, constipation 37%, increased glucose 37%, decreased albumin 35%, vomiting 35%, decreased appetite 30%, decreased creatinine clearance 28%, increased alkaline phosphatase 28%, decreased magnesium 27%, decreased potassium 26%, and decreased sodium 26%. 

In the ASCENT study, locally advanced or metastatic triple-negative breast cancer, the most common adverse reactions incidence 25% or more were fatigue, diarrhea, nausea, alopecia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions, which is defined by over 1%, were neutropenia 7%, diarrhea 4%, and pneumonia 3%.  Serious adverse reactions were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common grade 3 to 4 lab abnormalities including incidence of 25% or more in the ASCENT study, were reduced neutrophils, leukocytes, and lymphocytes.  

In the Tropics-02 study, for locally advanced or metastatic HR-positive, HER2-negative breast cancer, the most common adverse reactions, which is defined by incidence of 25% or more, were diarrhea, fatigue, nausea, alopecia, and constipation. The most frequent serious adverse reactions, which is defined by over 1%, were diarrhea 5%, febrile neutropenia 4%, neutropenia 3%, abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting, 2% each. Serious adverse reactions were reported in 28% of patients, and 6% discontinued therapy due to adverse reactions. The most common grade 3 to 4 lab abnormalities, which is defined by incidence of 25% or more in the TROPiCS-02 study, were reduced neutrophils and leukocytes.  

Dr. Yuan: Drug interactions include UGT1A1 inhibitors. Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY.  

UGT1A1 Inducers: Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY. 

Dr. Yuan: So, this is an important table that we'll probably use in the cases to practice, in the next part of the talk. So, we want you to pay attention to this. So, if the patient develops adverse reactions, such as grade 4 neutropenia over 7 days, if the first occurrence, we need the dose reduced by 25%, and administer G-CSF. If grade 3 to 4 neutropenia, then the same thing. Or at time of scheduled treatment, grade 3 to 4 neutropenia delays the dose by 2 or 3 weeks for recovery to less than grade 1. All 3 criteria would lead to further dose reduction. So, then you have some guidance here. If a patient had a first or second occurrence, then you dose reduce accordingly. But if the patient, despite all the management, dose reduction, and a third recurrence happens, then that's going to drive us to permanently discontinue the treatment. 

Slow or interrupt the infusion rate if the patient develops an infusion-related reaction. Permanently discontinue SG for life-threatening infusion-related reactions.  

Dr. Yuan: Similarly, in the management table for GI toxicities, there's 3 or 4 different scenarios here. Any grade 4 diarrhea, of any duration, or grade 3 to 4 diarrhea that is not controlled with antidiarrheal agents, or other grade 3 to 4 diarrhea persisting over 48 hours, despite optimal medical management, will drive us to have dose reduction for the following treatment, including first time occurrence, 25% dose reduction, second time, which is going to lead to dose going down to 5 milligram per kg. And then there's no third tier, so the patient will have to discontinue the treatment permanently. Now, so again, this, there's detailed information you can find in the package insert regarding how to manage this therapy.  

Dr. Yuan: For severe non-neutropenic toxicity, this is a sort of a lump sum table providing similar guidance, any grade 4 event or grade 3 to 4 event that is not controlled, or other grades 3 to 4 non-hematological events persisting over 48 hours. And then there's somewhat of a repetition comparing to the first 2 tables, but literally we only have 2 chances of dose reduced, but no third dose reduction.  

Do not re-escalate the SG dose after a dose reduction for adverse reactions has been made. Slow or interrupt the infusion rate if the patient develops an infusion-related reaction. Permanently discontinue SG for life-threatening infusion-related reactions.