Tian Zhang and Petros Grivas discussed best practices for Metastatic Urothelial Carcinoma Therapy

Tian Zhang, Associate Director of Clinical Research at Simmons Comprehensive Cancer Center and Director of Clinical Research at UT Southwestern Medical Center, shared a post on X:

“Best practices for 2L+ 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?

– Medical Oncology
– Surgical Oncology
– Other MD/DO
– APP, RN, PharmD, Other HCP

COI and CME info

Full CME

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

mUC SOC changing rapidly
EV+P in 1L

What does it mean for subsequent therapy?

68 years old Female with mUC s/p EV + P, on pembro monotherapy x12m (d/ced EV)
FGFR3-TACC3 fusion + and cisplatin eligible

New liver mets

Chemo-naive cisplatin eligible patients

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

Let’s consider a patient case…

74 years old Female s/p gem/ + cisplatin

– Avelumab maintenance x12m
– No FGFR3 alterations, HER2 IHC 0
– New liver mets

What would you do next?

– Enfortumab Vedotin
– Erdafitinib
– Nivolumab
– Pembrolizumab

Preferred 2L therapy for cisplatin-ineligible pts after 1L ICI monotherapy

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

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

Other 2L options(depending on prior therapy):

– Erda for FGFR3 alterations
– EV monotherapy

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– Sacituzumab govitecan (FDA indication withdrawn)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 monotherapy

– 1L in cisplatin-ineligible + PD-L1 +ve
– Based on IMvigor 210 and 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 chemotherapy:

1. Anemia
2. Neutropenia
3. Thrombocytopenia

Even with pembro 24 mo PFS rate in KEYNOTE-045 was 12.4%

Patients likely to need subsequent line therapy NCCN guidelines

RE: next treatment?

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 guidlines)

Erdafitinib

– Jan 19, 2024 FDA regular approval
– Patients with mUC and FGFR3alt with progression after 1L therapy
– based on THOR1 trial of pts previously treated with PD-1/PD-L1 ICI
– Not for patients 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% with erdafitinib and 46.4% with chemo
– Most AEs with erdafitinib manageable with dose modification and best supportive care
– Therapy d/c rates 8.1% wit erdafitinib and 13.4% with chemo

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

67 years old Male s/p 1L EV + P
+ FGFR3 alteration
Therapy with 2L erdafitinib
Serum phosphate 8.0 mg/dL

– Continue Current Dose
– Cut Dose in Half
– Withhold dose
– Permanently d/c

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

Erdafitinib=good option for patients with susceptible FGFR3 alt

– What about patients who progress after 1L therapy and no FGFR3alt?
– How does the changing 1L therapy landscape with EV+P affect choice of 2L therapy?

What about T-DXd in mUC?

1st tumor agnostic ADC with FDA approval for Drug-refractory HER2+ IHC3+ Cas

From DESTINY-PanTumor02

– 16 patients with 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 with drawn~Oct 2024

Let’s look original approval and possible reasons for a negative P3 trial

TROPHYU01 Cohorts 1,2,3

1. 113 patients who progrs’d after plat chemo+ICI

– Notable efficacy compared to hist cntls
– Led to accel approval 2021

2. 38 cisplatin-inelig patients s/p ICI therapy

ORR=32%

3.  41 patients who progrs’d after plat chemo with 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
No significant improvement in OS with 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 with neutropenia), chemo 2%

Uromigos thoroughly addressed of sacitizumab govitecan TROPiCS-04 findings presented at ESMO Asia

Worth a listen.

Why TROPiCS4 negative for OS?

Hard to est, consider:

– Late-line,hvly pretherapy pop
– Ltd primary G-CSF prophy in SG arm(~20%)
~5% patients randomized to control never rec’d therapy(~2% in SG arm)
– NO biomarker selection(UGT1A1 gene polym→tox?)
~20% in each arm rec’d salvage EV(confounding)

SUMMARY

• 2L and later line therapies in mUC
• Erdafitinib FDA-approved with FGFR3 alt after prior therapy
• NCCN guidelines updated Jan 2025
• Ongoing trials for SG in different clinical scenarios
• T-DXd for HER2 IHC3+ (based on gastric cancer scoring algorithm)

74 y/o Female s/p gem/ + cisplatin Avelumab maintenance x12m

No FGFR3 alterations, HER2 IHC 0

New liver mets

What would you do next?

– Enfortumab Vedotin
– Erdafitinib
– Nivolumab
– Pembrolizumab

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

67 years old Male s/p 1L EV + P
+ FGFR3 alteration
Therapy with 2L erdafitinib
Serum phosphate 8.0 mg/dL

– Continue Current Dose
– Cut Dose in Half
– Withhold dose
– Permanently d/c.”

Petros Grivas, Clinical Director of the Genitourinary Cancers Program at the University of Washington, also shared a post on X:

“Best practices for 2L+ therapy Metastatic Urothelial Carcinoma with Tian Zhang 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?

– Medical Oncology
– Surgical Oncology
– Other MD/DO
– APP, RN, PharmD, Other HCP

COI and CME info

Full CME

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

mUC SOC changing rapidly
EV+P in 1L

What does it mean for subsequent therapy?

68 years old Female with mUC s/p EV + P, on pembro monotherapy x12m (d/ced EV) FGFR3-TACC3 fusion + and cisplatin eligible

New liver mets

In your practice, what would you use next?

– Erdafinitinib
– Gem+carbo
– Gem+cisplastin

Chemo-naive cisplatin eligible patients

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

Let’s consider a patient case…

74 years old Female s/p gem/ + cisplatin

– Avelumab maintenance x12m
– No FGFR3 alterations, HER2 IHC 0
– New liver mets

What would you do next?

– Enfortumab Vedotin
– Erdafitinib
– Nivolumab
– Pembrolizumab

Preferred 2L therapy for cisplatin-ineligible pts after 1L ICI monotherapy

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

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

Other 2L options(depending on prior therapy):

– Erda for FGFR3 alterations
– EV monotherapy

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 monotherapy

– 1L in cisplatin-ineligible + PD-L1 +ve
– Based on IMvigor 210 and 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

1. Anemia
2. Neutropenia
3. Thrombocytopenia

Even with pembro 24 mo PFS rate in KEYNOTE-045 was 12.4%

Patients likely to need subsequent line therapy NCCN guidelines

RE: next treatment?

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 guidlines)

Erdafitinib

– Jan 19, 2024 FDA regular approval
– Patients with mUC and FGFR3alt with progression after 1L therapy
– based on THOR1 trial of pts previously treated with PD-1/PD-L1 ICI
– Not for patients 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% with erdafitinib and 46.4% with chemo
– Most AEs with erdafitinib manageable with dose modification and best supportive care
– Therapy d/c rates 8.1% wit erdafitinib and 13.4% with chemo

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

67 years old Male s/p 1L EV + P
+ FGFR3 alteration
Therapy with 2L erdafitinib
Serum phosphate 8.0 mg/dL

– Continue Current Dose
– Cut Dose in Half
– Withhold dose
– Permanently d/c

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

Erdafitinib=good option for patients with susceptible FGFR3 alt

– What about patients who progress after 1L therapy and no FGFR3alt?
– How does the changing 1L therapy landscape with EV+P affect choice of 2L therapy?

What about T-DXd in mUC?

1st tumor agnostic ADC with FDA approval for Drug-refractory HER2+ IHC3+ Cas

From DESTINY-PanTumor02

– 16 patients with 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 with drawn~Oct 2024

Let’s look original approval and possible reasons for a negative P3 trial

TROPHYU01 Cohorts 1,2,3

1. 113 patients who progrs’d after plat chemo+ICI

– Notable efficacy compared to hist cntls
– Led to accel approval 2021

2. 38 cisplatin-inelig patients s/p ICI therapy

ORR=32%

3.  41 patients who progrs’d after plat chemo with 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 pretherapy mUC
No significant improvement in OS with 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 with neutropenia), chemo 2%

Uromigos thoroughly addressed of sacitizumab govitecan TROPiCS-04 findings presented at ESMO Asia

Worth a listen.

Why TROPiCS4 negative for OS?

Hard to est, consider:

– Late-line,hvly pretherapy pop
– Ltd primary G-CSF prophy in SG arm (~20%)
~5% patients randomized to control never rec’d therapy (~2% in SG arm)
– No biomarker selection (UGT1A1 gene polym→tox?)
~20% in each arm rec’d salvage EV (confounding)

SUMMARY

• 2L and later line therapies in mUC
• Erdafitinib FDA-approved with FGFR3 alt after prior therapy
• NCCN guidelines updated Jan 2025
• Ongoing trials for SG in different clinical scenarios
• T-DXd for HER2 IHC3+ (based on gastric cancer scoring algorithm)

74 y/o Female s/p gem/ + cisplatin Avelumab maintenance x12m
No FGFR3 alterations, HER2 IHC 0
New liver mets

What would you do next?

– Enfortumab Vedotin
– Erdafitinib
– Nivolumab
– Pembrolizumab

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

67 years old Male s/p 1L EV + P
+ FGFR3 alteration
Therapy with 2L erdafitinib
Serum phosphate 8.0 mg/dL

– Continue Current Dose
– Cut Dose in Half
– Withhold dose
– Permanently d/c.”

Further Reading:

Enfortumab Vedotin (Padcev): Uses in Cancer, Side Effects, Dosage, Expectations, and More