Antibody drug conjugates in solid tumors

 Solid tumor

1. Enfortumab

2. Sacituzumab

3. TDM-1

Heme malignancies

1. Gemtuzumab

2. Brentuximab

3. Inotuzumab

Enfortumab

ADC targets Nectin-4

Approval 2019

Indication: locally advanced or stage 4 bladder ca, who have progressed on both platinum( or ineligible) and PDl-1 agent

Dose 1.25 mg/kg , max 125 mg, weekly 3 weeks on 1 week off, 28 day cycle

Side effects and issues to watch for:

a. DM: Do not start if CBG > 250.  Closely monitor CBG weekly. Can be seen even in those without DM.

b. Eye issues:  Baseline eye exam, prophylactic eye drops for dry eyes, consider steroid eye drops. Regular eye exam.

c. Peripheral neuropathy- hold, dose reduce

d.  Skin reaction: consider antihistamine prophylactic

 Dose Modifications 

 Hyperglycemia :Blood glucose >250 mg/dL Withhold until elevated blood glucose has improved to ≤ 250 mg/dL, then resume treatment at the same dose level.

 Peripheral Neuropathy  Grade 2 Withhold until Grade ≤1, then resume treatment at the same dose level (if first occurrence). For a recurrence, withhold until Grade ≤1 then, resume treatment reduced by one dose level. Grade ≥3 Permanently discontinue. 

Skin Reactions: Grade 3 (severe) Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level. Grade 4 or recurrent Grade 3 Permanently discontinue.

 Other nonhematologic toxicity Grade 3 Withhold until Grade ≤ 1, then resume treatment at the same dose level or consider dose reduction by one dose level Grade 4 Permanently discontinue. 

 Hematologic toxicity Grade 3, or Grade 2 thrombocytopenia Withhold until Grade ≤ 1, then resume treatment at the same dose level or consider dose reduction by one dose level. Grade 4 Withhold until Grade ≤ 1, then reduce dose by one dose level or discontinue treatment. 

Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. 

 Recommended Dose Reduction Schedule

 Dose Level Starting dose 1.25 mg/kg up to 125 mg 

First dose reduction 1.0 mg/kg up to 100 mg 

Second dose reduction 0.75 mg/kg up to 75 mg 

Third dose reduction 0.5 mg/kg up to 50 mg

Sacituzumab

Target: Trop 2 Ab with a topoisomerase inhibitor SN-38 ( similar to irinotecan, therefore caution with UGT1-A inhibitors)

Approval: 2020 breast cancer, 2021 bladder cancer

2 indications: 

-Metastatic TN breast cancer after 2 lines of treatment for MBC

- metastatic bladder cancer

Dose: 10 mg/kg body weight, IV day 1, day 8, q 21 days

ORR in bladder cancer in single-arm trial 27%

Bladder cancer: TROPHY trial, a single-arm, multicenter trial that enrolled 112 patients with locally advanced or mUC who received prior treatment with platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor. 

AE: neutropenia, nausea, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, decreased appetite, rash, and abdominal pain

TNBC, stage 4: pFS 5.6 months, OS 12 months. ORR 35%NEJM Sacituzumab

DLT- diarrhea, neutropenia ( black box warning for both)

Hold for grade 3 diarrhea and ANC< 1500