Thread by @laura_huppert

@TumorBoardTues @hoperugo 1/20 #TumorBoardTuesday #BCSM #OncTwitter

CASE: 54yo post-menopausal 👩 with HR+/HER2- (IHC 1+, 🐠FISH neg) MBC who had disease progression on 3 lines of endocrine/targeted rx, then capecitabine.

Scans show progression in liver.

🤔 What therapy would you use next?

@TumorBoardTues @hoperugo 2/20 #TumorBoardTuesday

What is HER2-low #BreastCancer?
🔹 HER2 IHC 1+ or 2+/ISH neg
🔹 Large % of HR+ BC (~67%), less in TNBC
🔹 Prognosis/biology indistinct from HER2-0
🔹 Unreliable IHC scoring; need better tests!
🔹 NOT a BC subtype; but targetable

tinyurl.com/2p89vteh

@TumorBoardTues @hoperugo 3/20 #TumorBoardTuesday

Antibody-drug conjugates (ADCs)

Novel chemo delivery system with 3 parts:
1️⃣Targeted ab (selectivity)
2️⃣Linker
3️⃣Cytotoxic payload (potent chemo)

T-DXd:
1️⃣Anti-HER2 IgG1 mAb
2️⃣Tetrapeptide-based linker
3️⃣Topo-1 inhibitor

tinyurl.com/yc8639j4

@TumorBoardTues @hoperugo 4/20 #TumorBoardTuesday

✨Destiny-Breast04 trial✨

📍Phase 3 study: 557 pts w/ HER2-low BC were randomized 2:1 to T-DXd vs. physician’s choice chemo (cape, eribulin, gemcitabine, paclitaxel, nab-paclitaxel)
Primary endpt PFS in HR+ (88.7% of study pop)

tinyurl.com/3fhpmwwv

@TumorBoardTues @hoperugo 5/20 #TumorBoardTuesday

✨Destiny-Breast04✨

T-DXd outperformed chemo for both median PFS & OS:
🔸 mPFS 10.1 mo vs. 5.4 mo in HR+ cohort
🔸 mPFS 9.9 mo vs. 5.1 mo among all pts
🔸 mOS 23.9 mo vs. 17.5 mo in HR+ cohort (HR 0.64)
🔸 mOS 23.4 mo vs. 16.8 mo among all pts (HR 0.64)

@TumorBoardTues @hoperugo 6/20 #TumorBoardTuesday

🔥 Based on the data from DB04, the 🇺🇸 @FDA recently approved T-DXd for pts with unresectable or metastatic HER2-low #breastcancer after one line of chemo and refractory to ET if HR+! 🥳 🥳 🥳

bit.ly/3d4X2JQ

@TumorBoardTues @hoperugo @FDA 7/20 #TumorBoardTuesday

Back to our case 🔎

👩 Our pt was started on T-DXd.

👩🏼‍🏫 In general, we recommend the use of T-DXd in pts with HR+/HER2- HER2-low BC after endocrine/targeted therapies and after at least one line of chemo.

@TumorBoardTues @hoperugo @FDA 8/20 #TumorBoardTuesday

First, what are the side effects of T-DXd & how should they be managed?
🔹 Nausea/vomiting
🔹 Neutropenia
🔹 Infusion-related reactions
🔹 Alopecia
🔹 Fatigue
🔹 ILD/pneumonitis
🔹 ⬇️ LVEF

📍 See recommended management here 👇🏽
tinyurl.com/5cx4sn7v

@TumorBoardTues @hoperugo @FDA 9/20 #TumorBoardTuesday

Let’s talk a bit more about the risk of ILD/pneumonitis 🫁

🤔 In pts on T-DXd, how often do you get a chest CT to screen for pneumonitis/ILD in year 1?

@TumorBoardTues @hoperugo @FDA 10/20 #TumorBoardTuesday

🫁 ILD/pneumonitis

👩🏼‍🏫 Recommend CT chest every 9-12 weeks & w/ any respiratory symptoms during year 1.

📌 Treat even grade 1 ILD, hold for grade 1 until resolution of GGO.

📍See recommended ILD management here 👇🏽
tinyurl.com/5cx4sn7v

@TumorBoardTues @hoperugo @FDA 11/20 #TumorBoardTuesday

Who is at risk for ILD?

In 1150 pts on T-DXd, ILD rate 15.4% (2.2% G5), mostly in yr 1 (87.0%)

Risk factors:
✅ age <65yr
✅ enrollment in Japan
✅ spO2 <95%
✅ renal dsfxn
✅ 🫁 comorbidities
✅ ⬆️ dose
✅ ⬆️ time since dx

tinyurl.com/4zne2mtr

@TumorBoardTues @hoperugo @FDA 12/20 #TumorBoardTuesday

Does T-DXd work in pts with active brain mets?

👉🏼 Based on data from the phase 2 TUXEDO1 study in HER2+ MBC, yes!
🧠 Intracranial-ORR 73%, mPFS 14 mo.
No new safety signals & global QOL & cognitive fxn maintained w/ tx

tinyurl.com/27r8wskh

@TumorBoardTues @hoperugo @FDA 13/20 #TumorBoardTuesday

What is the threshold level of HER2 expression for activity with T-DXd?

✨ Phase 2 DAISY 🌼trial: T-DXd activity seen in HER2 IHC 0 cohort with short PFS (Dieras SABCS 21); more studies needed– ex Destiny Breast06 including HER2 ultralow (NCT04494425)

@TumorBoardTues @hoperugo @FDA 14/20 #TumorBoardTuesday

Back to case🔎

11mo later our pt’s disease progressed on T-DXd

Can we use another ADC?

🏝 TROPiCS-02: Sacituzumab govitecan was effective in pts with heavily pre-treated HR+/HER2- MBC. SG is an ADC w/ a Trop-2 ab linked to SN-38 topo-I inhib payload

@TumorBoardTues @hoperugo @FDA ✨TROPiCS-02✨

📍543 patients with HR+/HER2- MBC w. progression on ET and 2-4 prior lines chemo were randomized to SG vs chemo.
📍mPFS was 5.5mo with SG vs 4.0mo with chemo (HR 0.66).

👉🏼OS benefit also announced today! 🥳

tinyurl.com/3c9ekp25

@TumorBoardTues @hoperugo @FDA 16/20 #TumorBoardTuesday

What other ADCs are in development for pts w/ #breastcancer?

🤩 Lots of exciting ADC studies underway for pts w/ BC!

@TumorBoardTues @hoperugo @FDA 17/20 #TumorBoardTuesday

In summary…

👩🏼‍🏫 Here is a roadmap for how to generally approach tx for pts with HR+/HER2- MBC based on current available data!

@TumorBoardTues @hoperugo @FDA 18/20 #TumorBoardTuesday

⚡️Bonus Hypothetical⚡️

🤨 What if this pt instead had TNBC? What would you use for 2nd line tx?

📌 Remember, DB04 only had 58 pts w/ TNBC; 18 in control arm.
📌 Sacituzumab govitecan has data in this setting in the phase 3 ASCENT trial.

@TumorBoardTues @hoperugo @FDA 19/20 #TumorBoardTuesday

✨ASCENT trial✨

📍468 pts with mTNBC were randomized to SG vs chemo.
📍mPFS 5.6 mo with SG vs 1.7mo with chemo; mOS was 12.1 mo with SG vs 6.7mo with chemo.
📍Treatment related AE: neutropenia, leukopenia, diarrhea

tinyurl.com/bdhmzzk4

@TumorBoardTues @hoperugo @FDA 20/20 #TumorBoardTuesday #BCSM #Onctwitter

In summary…

👩🏼‍🏫 Here is a roadmap for how to generally approach tx for pts with metastatic TNBC based on current available data!