Tian Zhang: Best practices for second line treatment in Metastatic Urothelial Carcinoma

Tian Zhang, Associate Professor in the Department of Internal Medicine at UT Southwestern Medical Center, shared a post on X:

“Best practices for second line treatment Metastatic Urothelial Carcinoma with Petros Grivas and me.

…Assuming EV+P 1L:

• FGFR3 alts: THOR/erda.
• Trop-2: sacituzumab govitecan.
• HER2 IHC 3+: T-DXd.

Support by edu grants: Astellas, Gilead Sci, Merck, Seagen CME, Bonum CE.

What’s your specialty?

1. Med Onc.
2. Surg Onc.
3. Other MD/DO.
4. APP, RN, PharmD, OtherHCP.

COI & CME info:

Full CME.

1. Answer Pre-survey.
2. Review MedTweetorial
3. claim CME.

mUC SOC changing rapidly.

EV+P in 1L.

What does it mean for subsequent tx?

68yo F w/ mUC s/p EV + P, on pembro monotx x12m (d/ced EV) FGFR3-TACC3 fusion + & cisplatin eligible.

liver mets.

1. Erdafitinib.
2. Gem + carbo.
3. Gem + cisplatin.

Chemo-naive cisplatin eligible pts.

• Post-1L IO monotx.
• 2L gem+cisplatin (or ddMVAC) pref’d.
• Erda for FGFR3 mut/fusion (THOR level 1 evidence for erda post-IO).
• Cisplatin ineligible pts can get gem+carbo or EV (or erda if FGFR3+ alt).

Let’s consider a pt case…

74yo F s/p gem/ + cisplatin.

Avelumab maintenance x12m.

No FGFR3 alterations, HER2 IHC 0.

liver mets.

What would you do next?

1. Enfortumab vedotin.
2. Erdafitinib.
3. Nivolumab.
4. Pembrolizumab.

Preferred 2L tx for cisplatin-ineligible pts after 1L ICI monoTx.

EV or gem + carbo or erdafitinib (if FGFR alt+).

Pembro alone is one of2L tx options for pts who progress after 1L platinum-based chemo and have not received ICI.

Other 2L options(depending on prior tx):

• Erda for FGFR3 alterations.
• EV monotx.

Taxane if no access to.

• Nivo or avelumab if no access to pembro + ICI naïve.
• T-DXd for HER2 3+ IHC (gastric Ca scoring).
• Sacituzumab govitecan (FDA indication withdrawn).

Atezolizumab EMA approved as monotx.

• 1L in cisplatin-ineligible + PD-L1 +ve.

Based on IMvigor 210 & 130 trials.

IMvigor 130:

• mPFS significantly longer in atezo+plat/Gem vs plat/Gem alone.
• mOS not sign. longer in atezo grps vs plat/Gem alone.

IMvigor130 safety results:

• Fewer AEs withdrawal of any agent in atezo only group.
• Most common TRAEs mainly related to chemo.
• Anaemia.
• Neutropenia.
• Thrombocytopenia.

Even w pembro 24 mo PFS rate in KEYNOTE-045 was 12.4%Pts likely to need subsequent line tx.

NCCN guidelines RE: next tx?

Options (if not given prior):

• EV.
• Erda for FGFR3 alt.
• T-DXd for HER2 IHC 3+ (gastric Ca scoring).
• Saci(indication withdrawn, still in NCCN gdlns).

Erdafitinib:

• Jan 19, 2024 FDA regular approval.
• Pts w mUC & FGFR3alt w progression after 1L tx.
• Based on THOR1 trial of pts previously treated w PD-1/PD-L1 ICI.
• Not for pts with no prior PD-1/PD-L1 if ICI eligible.

Erdafitinib cont.

• mOS and mPFS significantly in erdafitinib group vs taxane or vinflunine.

THOR1 trial efficacy results.

Erda. Safety:

Grade ≥3 TRAEs occurred in 45.9% w erdafitinib & 46.4% w chemo .

Most AEs w erdafitinib manageable w dose modification & best supportive care.

Tx d/c rates 8.1% w erdafitinib & 13.4% w chemo.

When managing possible AEs with erda, what would you do next for this patient…

• 67yo M s/p 1L EV + P.
• + FGFR3 alteration.
• Tx w 2L erdafitinib.
• Serum phosphate 8.0 mg/dL.

1. Continue current dose.
2. Cut dose in half.
3. Withhold dose.
4. Permanently d/c.

For phosphate of 8.0 mg/dL, withhold erdafitinib & restart once phosphate <5.5 mg/dL.

Erdafitinib=good option for pts w susceptible FGFR3 alt.

What about pts who progress after 1L tx & no FGFR3alt?

How does the changing 1L tx landscape w EV+P affect choice of 2L tx?

What about T-DXd in mUC?

1st tumor agnostic ADC w FDA approval for Tx-refractory HER2+ IHC3+ Cas.

• From DESTINY-PanTumor02.
• 16 pts w/ HER2 IHC3+ mUC.
• 56.3% ORR, mPFS 7.4mo, mOS 13.4mo.
• No significant neuropathy.

AEs: pneumonitis, neutropenia, N/V, left ventricular dysfunction.

Sacituzumab govitecan(SG) an ADC Trop-2.

An active agent in mUC but failed to show stat. significant longer OS over taxane or vinflunine (VIN) in TROPiCS-04.

FDA approval w/drawn~Oct 2024.

Let’s look at original approval & possible reasons for a negative P3 trial.

TROPHYU01 Cohorts 1,2,3

• =113 pts who progrs’d after plat chemo+ICI.
• Notable efficacy compared to hist cntls.

Led to accel approval 2021.

• =38 cisplatin-inelig pts s/p ICI tx.
• ORR=32%.

• = 41 pts who progrs’d after plat chemo w 2L SG+pembro.
• ORR=41%.
• mPFS=5.3m.
• mOS=12.7m.

TROPHY-U-01 Cohort 3 trial safety of sacituzumab govitecan.

TRAEs led to:

• SG interruptions in 46%.
• SG dose reduction in 39%.
• SG d/c in 15%.

TROPiCS-04

Ph3 RCT SG vs chemo in pretx mUC.

sig. improvmt in OS w/ SG compared to taxane or VIN.

mOS:

SG 10.3 vs chemo 9.0mo.

(HR:0.86; 95% CI:0.73–1.02; p=0.087).

Grade ≥3 TRAEs (SG): Neutropenia(35%; FN 12%), diarrhea (15%).

G5 AEs: SG 7% (16 inf w neutropenia), chemo 2%.

• Late-line,hvly pretx pop.
• Ltd primary G-CSF prophy in SG arm(~20%).
• ~5% pts randomized to control never rec’d tx(~2% in SG arm).
• Biomarker selection(UGT1A1 gene polym→tox?).
• ~20% in each arm rec’d salvage EV(confounding).

SUMMARY:

2L & later line tx in mUC.

• Erdafitinib FDA-approved w/ FGFR3 alt after prior tx.
• NCCN guidelines updated Jan 2025.
• Ongoing trials for SG in different clinical scenarios.
• T-DXd for HER2 IHC3+ (based on gastric cancer scoring algorithm).

mUCPostPoll ​​

CME.

74yo F s/p gem/ + cisplatin.

Avelumab maintenance x12m.

No FGFR3 alterations, HER2 IHC 0.

liver mets.

What would you do next?

1. Enfortumab vedotin.
2. Nivolumab.
3. Pembrolizumab.
4. Erdafitinib.

mUCPostPoll

CME.

When managing possible AEs with erda,

OncTwitter what would you do next for this patient…

• 67yo M s/p 1L EV + P.
• + FGFR3 alteration.
• Tx w 2L erdafitinib.
• Serum phosphate 8.0 mg/dL.

1. Continue current dose.
2. Cut dose in half.
3. Withhold dose.
4. Permanently d/c.”