Advancing the Management of Urothelial Cancer With Immuno-Oncology and Targeted Approaches: Key Concepts for Urology Professionals on the Front Lines of Care
Neal D. Shore, MD, FACS, Arjun Balar, MD, and Noah M. Hahn, MD, prepared useful Practice Aids pertaining to bladder cancer for this CME activity titled "Advancing the Management of Urothelial Cancer With Immuno-Oncology and Targeted Approaches: Key Concepts for Urology Professionals on the Front Lines of Care." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2Q6c1U4. CME credit will be available until June 5, 2020.
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Advancing the Management of Urothelial Cancer With Immuno-Oncology and Targeted Approaches: Key Concepts for Urology Professionals on the Front Lines of Care
1. Treatment of Urothelial Carcinoma
Access the activity, “Advancing the Management of Urothelial Cancer With Immuno-Oncology and Targeted
Approaches: Key Concepts for Urology Professionals on the Front Lines of Care,” at PeerView.com/XNW40.
PRACTICE AID
Checkpoint Inhibitors (CPIs)
Recent Approvals
Newly Diagnosed (Cisplatin-Ineligible
and PD-L1+ or Any Platinum Ineligible)
Pretreated (Prior Platinum-Based
or Relapsed Within 1 Year of
Perioperative Cisplatin)
Ongoing Phase 3
Investigations1
Atezolizumab
April 2017 (Phase 2 IMvigor210)
Companion diagnostic: Ventana PD-L1 (SP142)
Assay (August 2018); PD-L1–stained tumor-infiltrating
immune cells covering ≥5% of the tumor area
Pembrolizumab
May 2017 (Phase 2 KEYNOTE-052)
Companion diagnostic: Dako 22C3 PD-L1 IHC 22C3
PharmDX (August 2018); uses CPS ≥10 based on
PD-L1 staining in tumor and immune cells
Atezolizumab
May 2016 (Phase 2 IMvigor210)
Durvalumab
May 2017 (Phase 1/2 Study 1108)
Pembrolizumab
May 2017 (KEYNOTE-045)
Nivolumab
February 2017 (Phase 2 CheckMate -275)
Avelumab
May 2017 (Phase 1b JAVELIN)
IMvigor130 (NCT02807636) Active/not recruiting
Atezolizumab vs atezolizumab + chemotherapy
vs chemotherapy
KEYNOTE-361 (NCT02853305) Active/not recruiting
Pembrolizumab vs pembrolizumab + chemotherapy
vs chemotherapy
DANUBE (NCT02516241)
Durvalumab ± tremelimumab vs chemotherapy
CheckMate -901 (NCT03036098)
Nivolumab + ipilimumab vs nivolumab + chemotherapy
vs chemotherapy
NILE (NCT03682068)
Durvalumab + chemotherapy vs durvalumab + tremelimumab
+ chemotherapy vs chemotherapy
JAVELIN Bladder 100 (NCT02603432)
Avelumab + BSC vs BSC
First-Line&Maintenance
CheckMate -274 (NCT02632409)
Nivolumab vs placebo
IMvigor010 (NCT02450331) Active/not recruiting
Atezolizumab vs observation
AMBASSADOR (NCT03244384)
Pembrolizumab vs observation
Adjuvant
NIAGARA (NCT03732677)
Durvalumab + chemotherapy → adjuvant durvalumab
vs chemotherapy alone
NCT03661320
Nivolumab + chemotherapy → adjuvant nivolumab vs
nivolumab + chemotherapy + BMS-986205 (an IDO inhibitor)
→ adjuvant nivolumab + BMS-986205
vs chemotherapy
Neoadjuvant
POTOMAC (NCT03528694)
Durvalumab + BCG (induction and maintenance) vs
durvalumab + BCG (induction only) vs BCG
KEYNOTE-676 (NCT03711032)
Pembrolizumab + BCG vs BCG
ALBAN (NCT03799835)
Atezolizumab + BCG vs BCG
NMIBC
S1806 (NCT03775265) Not yet recruiting
CRT ± atezolizumab in localized disease
Bladder
Anti–PD-1/PD-L1
agents approved
since 2016!5
2. Treatment of Urothelial Carcinoma
Access the activity, “Advancing the Management of Urothelial Cancer With Immuno-Oncology and Targeted
Approaches: Key Concepts for Urology Professionals on the Front Lines of Care,” at PeerView.com/XNW40.
PRACTICE AID
Antibody–Drug Conjugates (ADCs)
Mechanism of Action
Selected Clinical Trials1
Target: Nectin-4, a type 1
transmembrane cell adhesion
molecule overexpressed in
epithelial cancers
Linker: Protease cleavable
Payload: MMAE
Target: Trop-2, an epithelial
cell-surface glycoprotein
highly expressed in
muscle-invasive disease
Linker: Hydrolysable
Payload: SN-38, the active
metabolite of irinotecan
Enfortumab Vedotin2
Sacituzumab Govitecan (IMMU-132)3
EV-103 (NCT02091999)
Phase 1
Enfortumab vedotin dose escalation in
patients with resistant/recurrent tumors
expressing nectin-4, including in patients
previously treated with CPIs
EV-201 (NCT03219333)
Pivotal Phase 2
Enfortumab vedotin in patients with locally
advanced or metastatic UC who previously
received CPIs
EV-301 (NCT03474107)
Phase 3
Enfortumab vedotin vs chemotherapy in
patients with previously treated locally
advanced or metastatic UC that shows
radiographic progression or has relapsed
during or after CPI therapy
TROPHY-U-01 (NCT03547973)
Phase 2
Sacituzumab govitecan in patients
with unresectable locally advanced or
metastatic UC who progress after platinum-
based chemotherapy and CPI therapy or
who are ineligible for platinum-based
chemotherapy and progress after CPI
1Binds to
antigen
5 Cell cycle arrest
and apoptosis
2Complex is internalized
4Microtubule
disruption
3Payload is
released
3. Treatment of Urothelial Carcinoma
Access the activity, “Advancing the Management of Urothelial Cancer With Immuno-Oncology and Targeted
Approaches: Key Concepts for Urology Professionals on the Front Lines of Care,” at PeerView.com/XNW40.
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
BCG: Bacillus Calmette-Guerin; CPI: checkpoint inhibitor; CPS: combined positive score; CRT: chemoradiotherapy; ECM: extracellular matrix; FGF: fibroblast growth factor; FGFR: fibroblast growth factor
receptor; IDO: indoleamine 2,3-dioxygenase 1; IHC: immunohistochemistry; MMAE: monomethyl auristatin E; NMIBC: non–muscle-invasive bladder cancer; PD-1: programmed cell death protein 1;
PD-L1: programmed death ligand 1; UC: urothelial carcinoma.
1. www.clinicaltrials.gov. Accessed April 19, 2018. 2. Challita-Eid PM et al. Cancer Res. 2016;76:1-11. 3. Bardia A et al. 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO 2018). Abstract
1004. 4. Touat M et al. Clin Cancer Res. 2015;21:2684-2694. 5. https://www.targetedonc.com/news/fda-grants-fast-track-designation-to-vofatamab-for-fgfr3-bladder-cancer. Accessed April 22, 2019.
FGF FGF
FGF
FGF
FGFR
HSPG
FGF FGF
FGFRL1
SEF
SPRY
FRS2
PLC-y
DAG STAT
GAB1
SOSGRB2
RAS RAF
MEK
ERK MKP3
MKP1
AKT
PKC
PI3K
Nucleus
Transcription of
target genes
Cytoplasm
Extracellular
PIP2
P
P
P
P
P
P
P
P
P
P
P
P
IP3
Plasma membrane
Proliferation
and survival
Resistance to
anticancer agents
Neoangiogenesis
FGFR alterations:
Amplification (receptor
overexpression) or
mutation/translocation
(ligand-independent
signaling)
FGF ligand:
Amplification
(autocrine) or
ECM/stromal-
cell release
(paracrine)
FGFR Inhibitors
FGFRs are a family of receptor tyrosine
kinases that are upregulated in multiple
different cancers and are involved in tumor
cell differentiation and proliferation, tumor
angiogenesis, and tumor cell survival;
alterations in the FGFR gene, such as
mutations and translocations, have been
implicated in the pathogenesis of UC
Erdafitinib
Approved April 12, 2019
(Phase 2 BLC2001)
Patients with locally advanced or metastatic UC, with susceptible
FGFR3 or FGFR2 genetic alterations (therascreen FGFR RGQ RT-
PCR Assay), that has progressed during or following platinum-
containing chemotherapy, including within 12 months of
neoadjuvant or adjuvant platinum-containing chemotherapy
First Approval of a Targeted
Therapy in UC
Erdafitinib
THOR (NCT03390504)
Phase 3
Erdafitinib vs chemotherapy or pembrolizumab in previously
treated patients with advanced UC harboring selected
FGFR aberrations
Cohort 1: 1-2 prior therapies, including ≥1 prior anti–PD-L1–
containing regimen
Cohort 2: 1 prior therapy that does not include an anti–PD-L1 agent
Pemigatinib
FIGHT-201 (NCT02872714)
Phase 2
Pemigatinib in patients with metastatic or unresectable UC
harboring FGF/FGFR alterations who have failed ≥1 therapy or are
platinum ineligible
NCT03914794
Phase 2
Pemigatinib in NMIBC patients with recurrent low- or
intermediate-risk tumors
Vofatamab
FIERCE-21 (NCT02401542)
Phase 1/2
Vofatamab alone or in combination with docetaxel versus
docetaxel alone in FGFR3-mutant/fusion patients with stage IV,
locally advanced, or metastatic UC who have relapsed after, or are
refractory to, ≥1 prior line of chemotherapy
FIERCE-22 (NCT03123055)
Phase 1/2
Vofatamab + pembrolizumab in patients with locally advanced
or metastatic UC who have progressed following platinum-based
chemotherapy and are CPI naïve
FIERCE-23
Vofatamab as a single agent in patients with NMIBC
Selected Clinical Trials1,5
Not yet recruiting
Planned
Active/not recruiting
FGFR Signaling Pathway4
4. Urologists' Guide to Managing Adverse
Events Associated With Immune
Checkpoint Inhibitors1,2
Access the activity, “Advancing the Management of Urothelial Cancer With Immuno-Oncology and Targeted
Approaches: Key Concepts for Urology Professionals on the Front Lines of Care,” at PeerView.com/XNW40.
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
ASCO: American Society of Clinical Oncology; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; irAE: immune-related adverse event.
1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768.
• In general, checkpoint inhibitor therapy should be continued with close monitoring, with the
exception of some neurologic, hematologic, and cardiac toxicities
Minimalornosymptoms;diagnosticchangesonly
Grade 1
What is the spectrum of potential irAEs?Why do irAEs occur?
Immune checkpoint inhibitors are associated
with important clinical benefits, but general
immunologic enhancement can also lead to
a unique spectrum of irAEs
A team-based approach to identification and
management of irAEs is important, particularly
as immune checkpoint inhibitors move into
management paradigms for earlier disease states
General recommendations and management principles include the following:
irAEs are often diagnosed by
exclusion; other causes should be ruled
out (including AEs of other therapies
used), but immunotherapy-related
toxicity should always be included
in the differential
There should be a high level of
suspicion that new symptoms are
treatment-related; early recognition,
evaluation, and treatment of irAEs
plus patient education are essential
for best outcome
Depending on severity of irAEs,
management may require corticosteroid
or other immunosuppressive treatment
and interruption or discontinuation
of therapy
If appropriate immunosuppressive
treatment is used, patients generally
recover from irAEs
Use of immunosuppressive therapy
to manage irAEs does not affect
response to immunotherapy
How should irAEs be diagnosed and managed?
• Hold checkpoint inhibitor therapy for most grade 2 toxicities
• Consider resuming immunotherapy when symptoms and/or laboratory values revert to
grade 1 or lower
• Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone or equivalent) may be administered
Grade 3 toxicities:
• Hold checkpoint inhibitor therapy
• Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d or methylprednisolone IV 1-2 mg/kg/d)
• If symptoms do not improve with 48-72 hours of high-dose corticosteroids, infliximab may be
offered for some toxicities
• Taper corticosteroids over the course of at least 4-6 weeks
• When symptoms and/or laboratory values revert to grade 1 or lower, rechallenging with
immunotherapy may be offered; however, caution is advised, especially in those patients with
early-onset irAEs. Dose adjustments are not recommended
Grade 4 toxicities:
• In general, permanent discontinuation of checkpoint inhibitor therapy is warranted, with the
exception of endocrinopathies that have been controlled by hormone replacement
Brahmer JR et al. Management of Immune-Related Adverse Events in PatientsTreated
With Immune Checkpoint InhibitorTherapy: American Society of Clinical Oncology
Clinical Practice Guideline. J Clin Oncol. 2018;36:1714-1768.
For organ-specific assessment and management of irAEs, please see the ASCO guidelines:
Additional resources available on the ASCO website:
https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/
supportive-care-and-treatment-related-issues#/29866
Grade 2
Mild to moderate symptoms
Severe or life-threatening symptoms
Grades 3/4
Any organ system can be affected; commonly occurring are pulmonary
(pneumonitis), dermatologic (rash, pruritus, blisters, ulcers, vitiligo),
gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis, pancreatitis),
and endocrine (thyroiditis, hypophysitis, adrenal insufficiency) irAEs
The precise pathophysiology is unknown, but translational studies have
shown that T-cell, antibody, and cytokine responses may be involved
Q
Q
Q
A
A
A
Increasing T-cell
activity against
antigens that
are present in
tumors and
healthy tissue
Activated T cell
Antithyroid
antibodies
Increasing
levels of
inflammatory
cytokines
Increasing levels
of pre-existing
autoantibodies
Enhancing
complement-mediated
inflammation due to
direct binding of an
anti–CTLA-4antibody
with CTLA-4
expressed on
normal tissue
Activated T cell
Anti–CTLA-4 antibody
CTLA-4 on pituitary
Complement-
mediated
inflammation
Cytokines
Tumor with antigen
and activated T cells
Pancreatitis,
autoimmune diabetes
Colitis
Enteritis
Encephalitis, aseptic meningitis
Thyroiditis, hypothyroidism,
hyperthyroidism Dry mouth, mucositis
Hypophysitis
Uveitis
Pneumonitis
Thrombocytopenia,
anemia
Hepatitis
Adrenal insufficiency
Nephritis
Vasculitis
Arthralgia
Neuropathy
Rash, vitiligo
Myocarditis