The effectiveness and value of nadofaragene firadenovec, oportuzumab monatox, and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder ...
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P E R S P E C T I V E S O N V A L U E 797
The effectiveness and value of nadofaragene
firadenovec, oportuzumab monatox, and
pembrolizumab for BCG-unresponsive
non-muscle-invasive bladder cancer
A summary from the Institute for Clinical and Economic Review’s Midwest Comparative
Effectiveness Public Advisory Council
Molly Beinfeld, MPH; Steven J Atlas, MD, MPH; Daniel Touchette, PharmD, MA; Avery McKenna; David Rind, MD;
and Steven D Pearson, MD, MSc
Bladder cancer is the sixth most Calmette-Guerin (BCG), an attenuated
common cancer in the United States. live form of Mycobacterium bovis.5 For Author affiliations
Approximately 80,000 new cases patients with invasive disease or who Molly Beinfeld, MPH; Avery McKenna;
are diagnosed each year, and more are not responding to or tolerating David Rind, MD; and Steven D Pearson,
than 17,000 people die from the dis- intravesical therapy, cystectomy may MD, MSc, Institute for Clinical and
ease annually.1,2 At diagnosis, most be performed to remove the bladder.6,7 Economic Review, Boston, MA. Steven
patients have non-muscle-invasive Although short-term prognosis J Atlas, MD, MPH, Division of General
bladder cancer (NMIBC), meaning for NMIBC is good, patients with Internal Medicine, Massachusetts General
Hospital and Harvard Medical School,
that the cancer involves the inner lin- BCG-unresponsive disease can
Boston, MA. Daniel Touchette, PharmD,
ing of the bladder but has not invaded select cystectomy or further intra-
MA, University of Illinois at Chicago
into the deeper muscle layer. NMIBC vesical chemotherapy with agents College of Pharmacy, Chicago, IL.
includes 3 subgroups that are asso- such as gemcitabine monotherapy
ciated with increasing risk of cancer or combination gemcitabine plus AUTHOR CORRESPONDENCE:
progression: (1) 70% of patients have docetaxel. Response rates to these Molly Beinfeld, mbeinfeld@icer.org
Ta disease, with polyps extend- agents are relatively low, underscor-
ing into the lining of the bladder; ing the need for new bladder-sparing
(2) 20% of patients have T1 disease, treatment options. 8,9 J Manag Care Spec Pharm.
with tumors below the superficial In January 2020, pembrolizumab 2021;27(6):797-804
lining but not involving the muscular (Keytruda), a systemically admin- Copyright © 2021, Academy of Managed
layer of the bladder wall; and (3) 10% istered immunotherapy agent, Care Pharmacy. All rights reserved.
of patients have carcinoma in situ received an additional indication for
(CIS) with flat, superficial growths. 3 BCG-unresponsive CIS disease.10 In
Treatment and related health care addition, 2 new intravesical thera-
costs for patients with bladder can- pies have recently begun the US cancer cells.11,12 It is instilled every
cer is estimated to be $4-$5 billion Food and Drug Administration (FDA) 3 months. Oportuzumab monatox is a
annually in the United States.4 approval process: nadofaragene firad- recombinant fusion protein with a cell
Treatment of NMIBC involves enovec (Adstiladrin) and oportuzumab
adhesion molecule antibody linked to
removal of visible cancer followed monatox (Vicineum). Nadofaragene
a toxin that binds to the cancer cell
by intravesical therapy for those firadenovec uses a recombinant
at increased risk of progression to adenovirus vector that encodes the that releases the toxin into the cell,
invasive disease. The most common human interferon alfa-2b gene with inducing cell death.13 It is instilled
initial intravesical therapy is Bacillus a surfactant to enhance transfer into twice a week for 6 weeks, then weekly
Vol. 27, No. 6 | June 2021 | JMCP.orgThe effectiveness and value of nadofaragene firadenovec, oportuzumab monatox,
798
and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer
FIGURE 1 Phase 3 Results of Nadofaragene Firadenovec: Complete for 6 weeks and then every 2 weeks for
Response and High-Grade Recurrence Free Survival, up to 2 years.
CIS ± Ta/T1, and Ta/T114 The Institute for Clinical and
Economic Review (ICER) conducted
90 a systematic literature review and
80 cost-effectiveness analysis to evaluate
CIS ± Ta/T1
the health and economic outcomes
Proportion with CR or HGRFS
70 Ta/T1
of nadofaragene firadenovec, oportu-
60 zumab monatox, and pembrolizumab
50 for BCG-unresponsive NMIBC.
Complete details of ICER’s system-
40
72.9 atic literature search and protocol, as
30 62.5 58.3 well as the methodology and model
53.4
20 40.8 43.8 structure for the economic evalua-
35
24.3 tion are available on ICER’s website
10
at https://icer.org/assessment/
0 bladder-cancer-2020/.
3 months 6 months 9 months 12 months
In this report, we present the sum-
Time
mary of our findings and highlights of
Note: Error bars represent standard error of proportion with CR or HGRFS. the policy discussion with key stake-
CIS = carcinoma in situ; CR = complete response; HGRFS = high-grade recurrence free survival;
Ta disease = polyps extending into the lining of the bladder; T1 disease = tumors below the superficial holders held at a public meeting of the
lining but not involving the muscular layer of the bladder wall. Midwest Comparative Effectiveness
Public Advisory Council (CEPAC) on
November 20, 2020.
FIGURE 2 Phase 3 Results of Oportuzumab Monatox: Complete
Response and High-Grade Recurrence Free Survival,
Summary of Findings
CIS ± Ta/T1, and Ta/T1a CLINICAL EFFECTIVENESS
The systematic literature review
90
identified only one phase 3 single-
80 CIS ± Ta/T1 arm, open-label prospective study
Proportion with CR or HGRFS
70 Ta/T1 for nadofaragene and oportuzumab
monatox and one phase 2 study of
60
pembrolizumab, making indirect
50 comparisons of relative effectiveness
40 difficult. At the time of the review,
71 only the pivotal trial of nadofaragene
30 58 firadenovec had been published,14 and
20 45 42
40 our review also evaluated information
28 from conference abstracts, regulatory
10
21 18 documents, and data submitted by the
0
3 months 6 months 9 months 12 months manufacturers.
Time The pivotal trials of nadofaragene
Note: Error bars represent standard error of proportion with CR or HGRFS.
firadenovec and oportuzumab mona-
a
Unpublished data, Sesen Bio, 2020. tox included similar distributions of
CIS = carcinoma in situ; CR = complete response; HGRFS = high-grade recurrence free survival; patients with CIS ± Ta/T1 and non-CIS
Ta disease = polyps extending into the lining of the bladder; T1 disease = tumors below the superficial
with high-grade Ta/T1 disease and
lining but not involving the muscular layer of the bladder wall.
used the same definitions of BCG-
unresponsive disease. However, the
nadofaragene firadenovec pivotal trial
JMCP.org | June 2021 | Vol. 27, No. 6The effectiveness and value of nadofaragene firadenovec, oportuzumab monatox,
799
and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer
FIGURE 3 Phase 2 Results of Pembrolizumab: Complete Response events (TEAEs) and discontinuation.
and CIS ± Ta/T116 For the 2 intravesical therapies, TEAEs
generally included bladder-related
90 symptoms such as irritative voiding,
80 hematuria, and urinary tract infec-
tion. For pembrolizumab, TEAEs
70
included immune-mediated adverse
Proportion with CR
60 CIS ± Ta/T1 events (AEs) and infusion reactions.
50 In the pivotal trial of nadofaragene
firadenovec, 146 (93%) of 157 patients
40
evaluated for safety reported at least
30 1 TEAE, of which 14 (9%) were serious,
20 40.6
but only 3 (2%) patients discontinued
38
28 due to TEAEs.14 In the pivotal trial of
10
19 19 oportuzumab monatox, 117 (88%) of
0 133 patients in the safety population
3 months 6 months 9 months 12 months 15 months
reported any TEAE, of which 19 (14%)
Time
were serious, with 4 (3%) patients
Note: Error bars represent standard error of proportion with CR. discontinuing treatment due to TEAEs
CI = carcinoma in situ; CR = complete response; Ta disease = polyps extending into the lining of the bladder; (unpublished data, Sesen Bio, 2020).
T1 disease = tumors below the superficial lining but not involving the muscular layer of the bladder wall.
In the pivotal trial of pembrolizumab,
99 (97%) of 102 patients in the safety
population reported any AE, of which
26 (26%) were serious, with 10 (10%)
required a biopsy at the 12-month In the pivotal trial of nadofaragene patients discontinuing due to AEs
evaluation, whereas the oportuzumab firadenovec, 55 (53%) of 103 patients (unpublished data, Merck, 2020).16
monatox pivotal trial did not. This with CIS ± Ta/T1 disease achieved a
biopsy could have resulted in addi- CR at 3 months, declining to 24% at LIMITATIONS OF THE
tional patients being identified as 12 months. For patients with high- CLINICAL EVIDENCE
having recurrent disease who would grade Ta/T1 disease alone, HGRFS The primary limitation in the clini-
not have been found without a biopsy. was 35 (73%) of 48 patients at 3 months cal evidence for these 3 agents is the
Efficacy outcomes were reported for and 44% at 12 months (Figure 1).14,15 lack of data from randomized con-
all eligible patients in the nadofara- In the pivotal trial of oportuzumab trolled trials. The FDA permitted
gene firadenovec trial who received monatox, 36 (40%) of 89 patients single arm trials for this population
the study drug, whereas patients who with CIS ± Ta/T1 disease achieved a because randomizing patients to pla-
did not complete induction therapy CR at 3 months, declining to 17% at cebo or minimally effective therapies
were excluded in the oportuzumab 12 months. For patients with high- was deemed unethical. The lack of
monatox trial. At the time of this pub- grade Ta/T1 disease alone, HGRFS head-to-head comparative data near
lication, only data from the CIS ± Ta/ was 27 (71%) of 38 patients at 3 months the time of launch is not unexpected,
T1 cohort of the pivotal trial of pem- and 42% at 12 months (Figure 2; but the lack of randomization in the
brolizumab were available. This trial unpublished data, Sesen Bio, 2020). pivotal trials makes even indirect
included the additional inclusion cri- In the pivotal trial of pembroli- comparisons needed to guide judg-
teria that patients either be ineligible zumab among patients with CIS ± Ta/ ments of relative effectiveness highly
for or decline cystectomy. The most T1 disease, 39 (41%) of 96 patients uncertain.
common outcomes reported in the achieved a CR at 3 months, which Differences in study populations
pivotal trials were complete response declined to 19% at 12 months (Figure 3). between the single arm trials and
(CR) and high-grade recurrence free Outcomes for the Ta/T1 cohort were in assessing and reporting outcomes
survival (HGRFS) at prespecified time not available at the time of the report further complicate the comparability
points after initial evaluation (unpub- (unpublished data, Merck, 2020).16 of the trial results. Although out-
lished data, Sesen Bio, 2020; Merck, Harms recorded in these trials comes of nadofaragene firadenovec
2020).14 included treatment-emergent adverse and oportuzumab monatox show
Vol. 27, No. 6 | June 2021 | JMCP.orgThe effectiveness and value of nadofaragene firadenovec, oportuzumab monatox,
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and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer
TABLE 1 Incremental Cost-Effectiveness Ratios Compared With oportuzumab monatox were not avail-
Hypothetical Treatment Comparator in Patients With able at the time of the report, the
CIS ± Ta/T1 price for nadofaragene firadenovec
was set to equal the annual price of
Cost per year in
Cost per QALY progression-free pembrolizumab ($164,337), whereas
Intervention gained Cost per evLYG state oportuzumab was set at $150,000
Nadofaragene firadenovec $151,000 $135,000 $100,000 per year net of all rebates based on
Oportuzumab monatox $382,000 $343,000 $281,000 analyst estimates. Full details on
Pembrolizumab $114,000 $103,000 $76,000
ICER’s cost-effectiveness analysis and
model are available on ICER’s web-
CIS = carcinoma in situ; evLYG = equal value life-year gained; QALY = quality-adjusted life-year;
Ta disease = polyps extending into the lining of the bladder; T1 disease = tumors below the superficial site at https://icer.org/assessment/
lining but not involving the muscular layer of the bladder wall. bladder-cancer-2020.
For each population, we esti-
mated time in progression-free state,
total costs, total quality-adjusted
life-years (QALYs), total equal value
TABLE 2 Incremental Cost-Effectiveness Ratios Compared
With Hypothetical Treatment Comparator in Patients life-years gained (evLYGs), and
With High-Grade Ta/T1 Disease Alone total life-years (LYs) for each treat-
ment over a lifetime time horizon.
Cost per year Base-case analyses were assessed
Cost per QALY in progression-free
Intervention gained Cost per evLYG state from the health care perspective. A
Nadofaragene firadenovec $93,000 $87,000 $65,000 discount rate of 3% was applied to all
costs, QALYs, evLYGs, and LYs.
Oportuzumab monatox $123,000 $117,000 $88,000
The base-case cost-effectiveness,
evLYG = equal value life-year gained; QALY = quality-adjusted life-year; Ta disease = polyps extending into
the lining of the bladder; T1 disease = tumors below the superficial lining but not involving the muscular with each drug compared with the
layer of the bladder wall hypothetical comparator with a 0%
CR at 3 months, were $151,000 per
QALY gained for nadofaragene firad-
enovec, $382,000 per QALY gained for
response rates that are similar to or 3-month CR rate could be varied in oportuzumab monatox, and $114,000
better than currently available treat- a sensitivity analysis. For the base per QALY gained for pembrolizumab.
ments, such as gemcitabine with or case, this hypothetical treatment Tables 1 and 2 summarize the full
without docetaxel, there continues was completely ineffective, with a CR results for all incremental cost-
to be considerable uncertainty about of 0% at 3 months. We evaluated the effectiveness outcomes evaluated.
their long-term efficacy. Because cost-effectiveness of all treatments In scenario analyses, when the CR
they are administered in the bladder, in 2 populations: CIS ± Ta/T1 (popula- of the hypothetical comparator was
they appear to have few serious side tion 1) and high-grade Ta/T1 disease increased to 20% in the CIS ± Ta/T1
effects. For pembrolizumab, the trial alone (population 2). We developed a population, the incremental cost-
data suggest similar response rates, de novo semi-Markov decision ana- effectiveness ratio for nadofaragene
but because it is given systemically, lytic model with model structure and firadenovec and oportuzumab
more patients report side effects, and inputs informed by key clinical trials, monatox increased to $155,000 and
its use is associated with infrequent previous economic models, system- $407,000, respectively. We did not
but potentially serious AEs. atic literature reviews, and input conduct scenario analyses for pem-
from stakeholders (patients, advocacy brolizumab. In the high-grade Ta/T1
LONG-TERM COST-EFFECTIVENESS groups, clinicians, payers, research- population, altering the hypothetical
Lacking comparative data on which ers, and manufacturers). comparator’s CR to 30% resulted in
to base our incremental cost-effec- Costs and utilities for model incremental cost-effectiveness ratios
tiveness analysis, we evaluated all health states were derived from 3 of $107,000 for nadofaragene firad-
agents compared with a hypotheti- key studies.17-19 Since the prices for enovec and $147,000 for oportuzumab
cal comparator treatment whose nadofaragene firadenovec and monatox.
JMCP.org | June 2021 | Vol. 27, No. 6The effectiveness and value of nadofaragene firadenovec, oportuzumab monatox,
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and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer
TABLE 3 Votes on Other Benefits and Contextual Considerations for Nadofaragene Firadenovec and
Oportuzumab Monatox
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
This intervention will not differentially benefit a This intervention will differentially benefit a historically
historically disadvantaged or underserved community disadvantaged or underserved community
5 votes 6 votes 0 votes
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Small health loss without this treatment as measured by Substantial health loss without this treatment as
absolute QALY shortfall measured by absolute QALY shortfall
4 votes 4 votes 3 votes
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Small health loss without this treatment as measured by Substantial health loss without this treatment as
proportional QALY shortfall measured by proportional QALY shortfall
1 vote 7 votes 3 votes
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Will not have a significant impact on improving return to Will have a significant impact on improving return to work
work and/or overall productivity vs the comparator and/or overall productivity vs the comparator
3 votes 7 votes 1 vote
QALY = quality-adjusted life-year.
TABLE 4 Votes on Other Benefits and Contextual Considerations for Nadofaragene Firadenovec
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Uncertainty or overly favorable model assumptions Uncertainty or overly unfavorable model assumptions
creates significant risk that base-case cost-effectiveness creates significant risk that base-case cost-effectiveness
estimates are too optimistic estimates are too pessimistic
2 votes 7 votes 2 votes
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Very similar mechanism of action to that of other active New mechanism of action compared with that of other
treatments active treatments
0 votes 3 votes 7 votes
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Delivery mechanism or relative complexity of regimen Delivery mechanism or relative complexity of regimen
likely to lead to much lower real-world adherence and likely to lead to much higher real-world adherence and
worse outcomes relative to an active comparator than better outcomes relative to an active comparator than
estimated from clinical trials estimated from clinical trials
0 votes 3 votes 7 votes
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Will not significantly reduce the negative impact of the Will significantly reduce the negative impact of the
condition on the family and caregiver vs the comparator condition on the family and caregiver vs the comparator
1 vote 9 votes 0 votes
Vol. 27, No. 6 | June 2021 | JMCP.orgThe effectiveness and value of nadofaragene firadenovec, oportuzumab monatox,
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and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer
TABLE 5 Votes on Other Benefits and Contextual Considerations for Oportuzumab Monataox
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Uncertainty or overly favorable model assumptions Uncertainty or overly unfavorable model assumptions
creates significant risk that base-case cost-effectiveness creates significant risk that base-case cost-effectiveness
estimates are too optimistic estimates are too pessimistic
2 votes 7 votes 1 vote
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Very similar mechanism of action to that of other active New mechanism of action compared to that of other
treatments active treatments
0 votes 3 votes 7 votes
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Delivery mechanism or relative complexity of regimen Delivery mechanism or relative complexity of regimen
likely to lead to much lower real-world adherence and likely to lead to much higher real-world adherence and
worse outcomes relative to an active comparator than better outcomes relative to an active comparator than
estimated from clinical trials estimated from clinical trials
0 votes 8 votes 2 votes
1 (suggests lower value) 2 (intermediate) 3 (suggests higher value)
Will not significantly reduce the negative impact of the Will significantly reduce the negative impact of the
condition on family and caregivers vs the comparator condition on family and caregivers vs the comparator
2 votes 8 votes 0 votes
The ICER health benefit price benchmark (HBPB) is a deliberation of the evidence on clinical and cost-effective-
suggested price range based on cost-effectiveness thresh- ness of health care interventions. The Midwest CEPAC is
olds at the $100,000 and $150,000 per QALY or evLYG. The composed of medical evidence experts, including practicing
HBPB for nadofaragene firadenovec ranged from $158,600 clinicians, methodologists, and leaders in patient engage-
to $262,000 per year. The HBPB for oportuzumab mona- ment and advocacy. Their deliberation includes input from
tox ranged from $92,800 to $162,100 per year. We did clinical experts and patient representatives specific to the
not calculate a HBPB for pembrolizumab given that its condition under review, as well as formal comment from
original indication was not for NMIBC. Full results are manufacturers and the public. A policy roundtable con-
available on ICER’s website at https://icer.org/assessment/ cludes each meeting during which representatives from
bladder-cancer-2020. insurers and manufacturers join clinical experts and patient
representatives to discuss how best to apply the findings of
LIMITATIONS OF THE COST-EFFECTIVENESS MODEL the evidence to clinical practice, insurance coverage, and
As noted earlier, there was considerable uncertainty in the pricing negotiations.
long-term estimates for the effectiveness of nadofaragene The ICER report on treatments for BCG-unresponsive
firadenovec, oportuzumab monatox, and pembrolizumab, NMIBC was the subject of a Midwest CEPAC meeting on
and this uncertainty affects any cost-effectiveness analy- November 20, 2020. Following the discussion, the Midwest
sis of these agents. The model’s base-case assumption of an CEPAC panel members deliberated on key questions raised
ineffective (0% CR) hypothetical comparator is likely overly by ICER’s report. The results of their votes on the clinical
conservative, so the base-case results can be viewed as the evidence were as follows: (1) the panel voted 7-4 that the
most optimistic scenario and should therefore be inter- clinical evidence was adequate to demonstrate greater
preted with caution. net health benefit for nadofaragene firadenovec compared
with best supportive care; (2) the panel voted 8-3 that the
Policy Discussion evidence was adequate to demonstrate greater net health
benefit for oportuzumab monatox compared with best
The Midwest CEPAC is one of the independent appraisal supportive care; (3) the panel voted 11-0 that the clinical
committees convened by ICER to engage in the public evidence was inadequate to distinguish the net health
JMCP.org | June 2021 | Vol. 27, No. 6The effectiveness and value of nadofaragene firadenovec, oportuzumab monatox,
803
and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer
benefit of nadofaragene firadenovec lower-cost regimens and set- Beinfeld, McKenna, Rind, and Pearson
from oportuzumab monatox; (4) the ting prices relative to higher-cost are employed by ICER. Touchette received
funding from ICER for work on this report
panel voted 11-0 that the evidence was options adds to the growing finan-
and has also received fees from Monument
inadequate to demonstrate a greater cial toxicity of oncology care. Analytics and AstraZeneca, unrelated to
net health benefit of nadofaragene • It seems likely that the FDA label this work. The University of Illinois at
firadenovec compared with pembro- for the emerging treatments will Chicago (UIC) and Touchette hold a pat-
lizumab; (5) the panel voted 10-1 that be limited to BCG-unresponsive ent for the model described in this report.
The model is included in ICER’s Interactive
the evidence was inadequate to dem- patients, and payers may therefore
Modeler, for which a fee is paid to UIC
onstrate a greater net health benefit wish to consider requiring docu- and Touchette. Atlas also received funding
of oportuzumab monatox compared mentation of a trial of BCG as a from ICER for work on this report.
with pembrolizumab. criterion for coverage.
The CEPAC panel also voted on • Patient groups should continue ACKNOWLEDGMENTS
“other potential benefits” and “con- their efforts to encourage inno-
The authors thank Maggie O’Grady,
textual considerations” as part of a vation while pushing life science
Mrinmayee Joshi, Kanya Shah, Rick
process intended to signal to policy- companies to generate better evi- Chapman, and Monica Fredrick for their
makers whether there are important dence to guide patient and clinician contributions to this report.
considerations when making judg- decision making. Patient groups
ments about long-term value for should embrace their power to REFERENCES
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