An open-label, randomized, controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab, versus chemotherapy alone in previously untreated locally advanced or metastatic urothelial cancer

Urothelial Cancer
Urothelial cancer is estimated to kill nearly 200,000 patients globally on an
annual basis, including more than 65,000 in Europe and 33,000 in the United
States (US) (Bray 2018; Ferlay 2018; Siegel 2019). Annual diagnoses of new
cases of urothelial cancer (UC) are estimated to be more than 549,000
worldwide, including more than 197,000 in Europe and 158,000 in the US (Bray
2018; Ferlay 2018; Siegel 2019).Those patients with metastatic UC represent a
population with significant unmet medical need, as the 5-year mortality rate
for this disease exceeds 85% (von der Maase 2005).

Metastatic Urothelial Cancer
First-line therapy for locally advanced and metastatic UC in patients with
sufficient renal function consists of cisplatin-based combinations, like
methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or gemcitabine
plus cisplatin, which demonstrate an objective response rate (ORR) of up to
55%, including approximately 12% complete responses (CRs) (von der Maase 2000).
Despite initial chemosensitivity, most patients are not cured and the outcome
of metastatic UC after these regimens is poor: median time to progression is 7
months and median overall survival (mOS) is 14 months. Long-term survival is
poor (approximately 15%) and the prognosis is particularly grim for patients
with visceral metastases, for whom the 5 year survival rate is 7% (Bellmunt
2011; von der Maase 2000; von der Maase 2005).
Unfortunately, more than 50% of patients with UC are cisplatin-ineligible due
to poor renal function, poor performance status, or co-morbidities (De Santis
2012). An even higher unmet need exists in this population. For these
cisplatin-ineligible patients, carboplatin is the platinum-containing therapy
of choice. Carboplatin is also an alkylating agent, similar to cisplatin, but
with less nephrotoxicity, neurotoxicity, and ototoxicity (Dogliotti 2007). In
first line therapy for cisplatin-ineligible metastatic UC in patients, response
rates to treatment with carboplatin monotherapy range from 8%-18% (Bamias
2006). In the European Organisation for Research and Treatment of Cancer
(EORTC) 30986 trial, carboplatin combined with gemcitabine in a
cisplatin-ineligible patient population resulted in a confirmed ORR of 36.1%.
Median progression-free survival (mPFS) was 5.8 months and median OS was 9.3
months (De Santis 2012). The modest efficacy reported for available
platinum-containing therapies highlights the need for additional treatment
options for patients with metastatic UC.
Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1)
inhibitors have demonstrated a survival benefit compared to chemotherapy in the
management of late line metastatic UC. Randomized phase 3 trials have been
reported for both atezolizumab (Tecentriq®) and pembrolizumab (Keytruda®) in
the second-line (2L+) metastatic UC setting. In the IMvigor211 trial, median OS
was not significantly different between the 2 arms (11.1 months vs. 10.6
months, respectively) (Powles 2018). KEYNOTE 045 studied pembrolizumab vs.
investigator's choice of chemotherapy in metastatic UC patients who had
recurred or progressed following platinum-containing chemotherapy. This study
demonstrated a statistically significant improvement in OS (10.3 months vs. 7.4
months) when comparing the pembrolizumab arm to the chemotherapy arm (Bellmunt
2017).
In the US, both atezolizumab(Tecentriq®) and pembrolizumab (Keytruda®) have
also received accelerated approvals for first-line use in cisplatin-ineligible
UC patients based on open label, single-arm studies that showed ORRs of 24% and
29%, respectively (Tecentriq® Prescribing Information, Genentech, Apr 2017)
(Keytruda® Prescribing Information, Merck, May 2017). This was followed by
European Union approval in September 2017. In May 2018, the Food and Drug
Administration (FDA) issued an alert regarding decreased survival in patients
with low expression of PD-L1 being treated in the first-line setting with
pembrolizumab or atezolizumab monotherapy, compared with platinum-containing
chemotherapy. Subsequent prescribing information for pembrolizumab and
atezolizumab were revised to require high PD-L1 expression in first-line
metastatic UC patients who are not eligible for cisplatin containing
chemotherapy. This development has further limited the options for metastatic
UC patients with low expression of PD-L1.

Pharmaceutical and Therapeutic Background
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to
suppress immune control. The normal function of PD-1, expressed on the cell
surface of activated T cells under healthy conditions, is to down-modulate
unwanted or excessive immune responses, including autoimmune reactions. PD-1
(encoded by the gene Pdcd1) is an Ig superfamily member related to cluster of
differentiation 28 (CD28) and cytotoxic T lymphocyte-associated protein 4
(CTLA-4) that has been shown to negatively regulate antigen receptor signaling
upon engagement of its ligands (PD-L1 and/or PD-L2) (Greenwald 2005; Okazaki
2001).
The structure of murine PD-1 has been resolved (Zhang 2004). PD-1 and its
family members are type I transmembrane glycoproteins containing an Ig-variable-
type domain responsible for ligand binding and a cytoplasmic tail responsible
for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition
motif, and an immunoreceptor tyrosine-based switch motif. Following T-cell
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading
to the dephosphorylation of effector molecules such as CD3 zeta (CD3*), protein
kinase C-theta (PKC*), and zeta-chain-associated protein kinase (ZAP70), which
are involved in the CD3 T-cell signaling cascade (Chemnitz 2004; Okazaki 2001;
Riley 2009; Sheppard 2004). The mechanism by which PD-1 down-modulates T cell
responses is similar to, but distinct from, that of CTLA-4, because both
molecules regulate an overlapping set of signaling proteins (Francisco 2010;
Parry 2005). As a consequence, the PD-1/PD-L1 pathway is an attractive target
for therapeutic intervention in locally advanced or metastatic UC.

Enfortumab Vedotin and Pembrolizumab in Combination
PD-1/PD-L1 inhibitors unleash the antitumor activity of T-lymphocytes by
targeting the T cell inhibition pathway (Sonpavde 2017), and have shown
effective antitumor activity as a single agent in locally advanced or
metastatic UC. Although these agents are able to induce durable responses, most
patients do not respond to PD-1/PD-L1 monotherapy. Combining PD-1/PD L1
inhibitors with a novel therapy, such as enfortumab vedotin, may be beneficial.
Data from preclinical studies of brentuximab vedotin (a CD30-directed ADC
comprising the same linker and MMAE payload as enfortumab vedotin), shows
potential to induce immunogenic cell death (ICD), antigen presentation, and
tumor immune infiltration (Gardai 2015). These results suggest that the effects
are due to MMAE. Treatment with brentuximab vedotin in vitro and in preclinical
models has been shown to induce hallmarks of ICD. ICD is characterized by
induction of the endoplasmic reticulum stress response and subsequent surface
presentation of danger-associated molecular patterns immune stimulatory
molecules. These danger-associated molecular patterns induce innate immune
migration and activation into the tumor cell activation (Cao 2018; Cao 2017).
Based on the potential enhancement of immune response, it is hypothesized that
combining enfortumab vedotin with a PD-(L)-1 inhibitor will result in improved
response leading to prolonged progression-free survival (PFS) and OS in
patients with locally advanced or metastatic UC.
Common AEs associated with enfortumab vedotin are reviewe

This study has been transitioned to CTIS with ID 2023-503421-19-00 check the CTIS register for the current data.

This study will evaluate the efficacy, safety, and PK of enfortumab vedotin in
combination with pembrolizumab, with or without platinum-containing
chemotherapy, versus standard of care gemcitabine plus platinum-containing
chemotherapy in subjects with previously untreated locally advanced or
metastatic UC. Specific objectives and corresponding endpoints for the study
are summarized below.

Objectives

Primary Objectives
* To compare PFS between experimental arm (enfortumab vedotin + pembrolizumab
[Arm A] and the control arm (gemcitabine + cisplatin or carboplatin [Arm B]) by
blinded independent central review (BICR)
* To compare overall survival (OS) between experimental arm (Arm A) and the
control arm (Arm B)

Secondary Objectives
* To compare the objective response rate (ORR) between the experimental arm
(Arm A) and the control arm (Arm B) by BICR
* To compare time to pain progression (TTPP) from the subject perspective
between the experimental arm (Arm A) and the control arm (Arm B)
* To compare average change in pain from the subject perspective between the
experimental arm (Arm A) and the control arm (Arm B)
* To evaluate PFS between the experimental arm (Arm A) and the control arm (Arm
B) by investigator assessment
* To evaluate the ORR between the experimental arm (Arm A) and the control arm
(Arm B) by investigator assessment
* To evaluate the DOR between the experimental arm (Arm A) and the control arm
(Arm B)
* To evaluate the disease control rate (DCR) between the experimental arm (Arm
A) and the control arm (Arm B)
* To evaluate the impact of study treatment on quality of life (QOL),
functioning, and symptoms from the subject perspective
* To evaluate the safety profile of each treatment regimen

Exploratory Objectives
* To assess PFS, ORR, and DOR per the modified RECIST v1.1 for immune based
therapeutics (iRECIST) in Arm A
* To assess subject reported health resource utilization (HRU)
* To assess the pharmacokinetics of enfortumab vedotin, and MMAE
* To assess the development of ATA to enfortumab vedotin
* To assess biomarkers of biological activity, resistance and predictive
biomarkers of response

This is a phase 3 open-label, 2-arm randomized, controlled multicenter study to
evaluate the combination of enfortumab vedotin + pembrolizumab, versus standard
of care gemcitabine + platinum-containing chemotherapy, in subjects with
previously untreated locally advanced or metastatic urothelial cancer. The
study is designed to assess the dual primary endpoints of progression-free
survival (PFS) and overall survival (OS) of experimental Arm A (enfortumab
vedotin + pembrolizumab) compared to control Arm B (gemcitabine + cisplatin or
carboplatin), and experimental Arm C (enfortumab vedotin + pembrolizumab +
cisplatin or carboplatin) compared to control Arm B. Subjects will be
randomized in a 1:1 manner to one of the study arms with the following
stratification factors: cisplatin eligibility (eligible or ineligible), PD-L1
expression (high or low), and liver metastases (present or absent).

Subjects in Arm A will receive enfortumab vedotin at 1.25 mg/kg, administered
as an IV infusion on Days 1 and 8 of every 3-week cycle, and pembrolizumab 200
mg as an IV infusion on Day 1 of every 3-week cycle, after completion of the
enfortumab vedotin infusion.

Subjects in Arm B will receive gemcitabine at 1000 mg/m2 as an IV infusion on
Days 1 and 8 of every 3 week cycle. Cisplatin (70 mg/m2) or carboplatin (area
under the curve [AUC] 4.5, or AUC of 5 according to local guidelines) will be
administered on Day 1 of every 3-week cycle, with adequate pre- and
post-hydration, by IV infusion per institutional standards.

Pembrolizumab 200 mg will be administered as an IV infusion on Day 1 of every
3-week cycle after completion of the platinum containing chemotherapy infusion.
Response will be assessed by computed tomography (CT) scans with contrast
(unless contraindicated) every 9 weeks (±1-week) timed from the randomization
date. For subjects who cannot receive CT scans with contrast, other
protocol-specified imaging methods may be used Appendix C). Brain scans should
be repeated at this time point in subjects with a history of CNS metastasis or
signs/symptoms of CNS metastasis. Bone imaging should also be repeated at this
time point in subjects with a history of skeletal metastasis or suspicion of
skeletal metastases based on imaging or symptoms. Objective responses will be
confirmed per RECIST v1.1 with repeat scans done at the next scheduled response
assessment per protocol after first documentation of response. Subsequent
response assessments should be performed every 9 weeks (±1-week) until 18
months after randomization, then every 12 weeks (±1-week). Tumor imaging should
also be performed, and blinded independent central review (BICR) evaluation
triggered, whenever disease progression is suspected.

Subjects may continue on study treatment until progressive disease
(BICR-confirmed or clinical progression [see Section 7.3]), an adverse event
(AE), pregnancy, investigator decision, start of a subsequent anticancer
therapy, subject decision (non-AE), study termination by the sponsor,
completion of the maximum number of drug cycles allowed, or other reason
unrelated to an AE (see Section 4.3). Treatment beyond disease progression per
RECIST v1.1 may be considered in subjects in study Arm A (enfortumab vedotin
[EV] + pembrolizumab) who are deriving clinical benefit as defined in Section
5.7. Subjects treated beyond disease progression per RECIST v1.1 may continue
until confirmed disease progression per iRECIST as assessed by the investigator
(Seymour 2017) (Appendix K). Confirmatory scans must be performed 4 to 9 weeks
after disease progression per RECIST v1.1 by BICR. Treatment with gemcitabine
and treatment with platinum-containing chemotherapy may be given up to 6
cycles. Treatment with pembrolizumab will be discontinued once the subject has
received a maximum of 35 administrations (approximately 2 years). There is no
upper limit to the number of cycles of enfortumab vedotin permitted. Palliative
radiotherapy on a nontarget bone lesion that is not progressing is permitted
and will not be considered a subsequent anticancer therapy; however,
radiotherapy on any new or progressing (per BICR-assessed RECIST v1.1) lesion
will be considered a subsequent anticancer therapy and subjects will not be
permitted to resume study treatment. Surgical resection for curative intent
during study treatment may be permitted in subjects with favorable tumor
response after discussion with the medical monitor.

Subjects who discontinue treatment for reasons other than disease progression
or consent withdrawal will continue to receive response assessments every 9
weeks (±1-week) for the first 18 months timed from the randomization date, and
every 12 weeks (±1-week) thereafter, until the subject has
radiologically-confirmed disease progression per RECIST v1.1 guidelines as
determined by BICR, initiates a subsequent anticancer therapy, dies, withdraws
consent, or the study closes, whichever occurs first. After progression and
discontinuation of study treatment, subjects will be followed every 12 weeks
(±1-week) to obtain information on subsequent anticancer therapy, and to assess
survival status until death, study closure, or subject withdraws consent,
whichever occurs first.
Safety will be monitored over the course of the study by an Independent Data
Monitoring Committee (IDMC).

Protocol amendment 7 includes all this information