T h e ne w e ngl a nd jou r na l o f m e dicine
`
`E d i t o r i a l s
`
`Renal-Cell Cancer — Targeting an Immune Checkpoint
`or Multiple Kinases
`David I. Quinn, M.B., B.S., Ph.D., and Primo N. Lara, Jr., M.D.
`
`Therapy for advanced renal-cell cancer has
`evolved considerably in the past decade, with
`new agents greeted like “buried treasure,” al-
`though these agents come with substantial costs
`to both patients and the health system. Before
`2005, the widely used systemic agents were cyto-
`kines — interferon alfa and interleukin-2, which
`yielded modest efficacy and substantial toxicity.
`Nevertheless, underlining the immunogenic
`nature of renal-cell cancer, durable complete
`responses occur in some patients who receive
`interleukin-2; these patients are mostly cured.1
`After 2005, angiogenesis and mammalian target
`of rapamycin (mTOR) pathway inhibitors dis-
`placed cytokine therapy.2,3 Although the most
`effective sequence of therapies is not known,
`most patients with advanced renal-cell cancer
`receive a vascular endothelial growth factor
`(VEGF)–receptor (VEGFR) kinase inhibitor up
`front; at disease progression, options include
`another type of angiogenesis-targeted therapy or
`“switching the mechanism of action” to an mTOR
`inhibitor (e.g., everolimus). For everolimus, the
`benchmark median progression-free survival is
`4.9 months and the median overall survival is
`14.8 months; these values are based on a place-
`bo-controlled trial involving patients whose dis-
`ease progressed during angiogenesis-targeted
`therapy.4 In previously treated patients, therapy
`with sorafenib (a VEGFR inhibitor) resulted in
`better overall survival than did therapy with
`temsirolimus (an mTOR inhibitor),5 whereas
`axitinib proved superior to sorafenib with regard
`to progression-free survival6 (Table 1).
`Two newer agents — nivolumab, an immuno-
`therapeutic agent that inhibits the T-cell check-
`point regulator programmed death 1 (PD-1),10,11
`and cabozantinib, a multikinase inhibitor tar-
`
`geting VEGFR, MET, RET, and AXL9,12 — now
`join the list of active therapies. In two trials now
`published in the Journal, patients whose disease
`progressed during VEGFR-targeted therapy were
`randomly assigned to receive the new agent or
`everolimus. In the nivolumab trial (CheckMate
`025),10 the primary end point was overall sur-
`vival; in the cabozantinib trial (METEOR),9 it
`was progression-free survival.
`The benefit from these agents, as compared
`with everolimus, is unequivocal. With nivolum-
`ab, there was a clinically relevant reduction in
`the risk of death (27%), a higher tumor response
`rate (25% vs. 5%), and a lower incidence of high-
`grade treatment-related adverse events (19% vs.
`37%). With cabozantinib, there was a 42% re-
`duction in the risk of progression or death, a
`higher response rate (21% vs. 5%), and a similar
`incidence of high-grade adverse events (68% vs.
`58%). These results — in particular, the data on
`overall survival from the nivolumab trial — es-
`tablish new efficacy benchmarks for this patient
`context (Table 1).
`Yet for all the success reported here, many
`questions remain. Complete remissions, the first
`step to a cure with “old-fashioned” immuno-
`therapy with interleukin-2, remained disappoint-
`ingly elusive in these studies. For cabozantinib,
`the rate was 0%; for patients with a partial tu-
`mor response, long-term durability of the re-
`sponse was rare. In the case of nivolumab, the
`complete remission rate was 1%. Although it is
`possible that complete remission with nivolum-
`ab may be unnecessary to achieve a long-term
`benefit, the lack of profound responses begs for
`selection or combination approaches that expand
`the benefit spectrum. The activity of nivolumab
`is somewhat analogous to that of interleukin-2,
`
`1872
`
`n engl j med 373;19 nejm.org November 5, 2015
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at UNIVERSITY OF CHICAGO LIBRARIES on February 25, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1108-0001
`
`

`
`Editorials
`
`0.002
`
`(0.57–0.93)
`
`0.73
`
`0.005‡
`
`(0.51–0.89)
`
`0.67
`
`0.37
`
`(0.8–1.17)
`
`0.97
`
`0.01
`
`(1.05–1.63)
`
`1.31
`
`0.162
`
`(0.65–1.15)
`
`0.87
`
`25.0
`
`19.6
`
`NC
`
`NC
`
`20.1
`
`19.2
`
`12.3
`
`16.6
`
`14.8
`
`14.4
`
`mo
`
`0.11
`
`(0.75–1.03)
`
`0.88
`
`<0.001
`
`(0.45–0.75)
`
`0.58
`
`<0.0001
`
`(0.544–0.812)
`
`0.665
`
`0.19
`
`(0.71–1.07)
`
`0.87
`
`0.001
`
`(0.25–0.43)
`
`0.33
`
`4.6
`
`4.4
`
`7.4
`
`3.8
`
`6.7
`
`4.7
`
`4.3
`
`3.9
`
`4.9
`
`1.9
`
`mo
`
`25
`
`5
`
`21
`
`5
`
`19
`
`9
`
`8
`
`8
`
`1.8
`
`0
`
`%
`
`0
`
`0
`
`0
`
`0
`
`1
`
`P Value
`
`Hazard Ratio
`
`(95% CI)
`
`Survival
`Median
`
`P Value
`
`Hazard Ratio
`
`(95% CI)
`
`Survival
`Median
`
`Overall Survival
`
`Progression-free Survival
`
`¶ Dose reduction was not permitted.
`§ Value reflects cases of treatment-related grade 3 or 4 toxic effects.
`‡ The result was nonsignificant at the time of analysis.
`† Value reflects all cases of grade 3 or 4 toxic effects.
`* CI denotes confidence interval, NC not calculated (end point not reached), and NR not reported.
`
`<1
`
`0
`
`0
`
`<1
`
`0
`
`0
`
`0.5
`
`8
`
`7
`
`0
`
`0.6
`
`8
`
`8
`
`1.4
`
`0
`
`19§
`
`37§
`
`68†
`
`58†
`
`NR
`
`NR
`
`62†
`
`61†
`
`NR
`
`NR
`
`%
`
`or DeathCompleteOverall
`Grade 5
`
`3 or 4
`Grade
`
`Response Rate
`
`Toxic Effects
`
`0¶
`
`26
`
`60
`
`25
`
`31
`
`52
`
`16
`
`33
`
`%
`
`1
`
`7
`
`Reduction
`
`Dose
`
`8
`
`13
`
`9
`
`10
`
`8
`
`4
`
`0
`
`2.8
`
`13
`
`1.4
`
`%
`
`Discontinuation
`
`for Adverse
`
`Events
`
`Nivolumab
`
`Everolimus
`
`CheckMate 02510
`
`Cabozantinib
`
`Everolimus
`
`METEOR9
`
`Axitinib
`
`Sorafenib
`
`AXIS6,8
`
`Temsirolimus
`
`Sorafenib
`
`INTORSECT5
`
`Everolimus
`
`Best supportive
`
`care
`
`RECORD-17
`
`Group
`Trial and Treatment
`
`n engl j med 373;19 nejm.org November 5, 2015
`
`1873
`
`Table 1. Comparison of End Points from Recent Phase 3 Trials Involving Previously Treated Advanced Renal-Cell Cancer.*
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at UNIVERSITY OF CHICAGO LIBRARIES on February 25, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1108-0002
`
`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`to which a fixed proportion of patients (20 to 25%)
`have a response. Patients who have a response
`may represent a prevalent “immune-responsive”
`subset of patients who benefit from either cyto-
`kines or checkpoint inhibitors. Actionable im-
`munologic drivers of renal-cell cancer response
`are not clear. In other tumors, PD-1 ligand 1
`(PD-L1) expression, in tumor cells or infiltrating
`immune cells, is associated with benefit from
`PD-1 or PD-L1 inhibitors. Unfortunately, PD-L1
`expression in renal-cell cancer tissue did not
`delineate the patients who were more likely to
`benefit. Alternative immunologic signatures, such
`as the number of immunogenic mutations, may
`be associated with efficacy and survival, but they
`require prospective validation.13 In addition, the
`most effective duration of therapy with nivolum-
`ab and whether the therapy should continue
`beyond progression remains unknown. For cabo-
`zantinib, it is uncertain whether the inhibition
`of MET, RET, or AXL drives clinical activity or
`whether the benefit is simply due to a VEGFR-
`inhibitory effect.12
`What does the addition of nivolumab and
`cabozantinib to the therapeutic armamentarium
`for previously treated advanced renal-cell cancer
`mean for the practicing clinician? Given the
`overall survival advantage it confers and its rela-
`tively good side-effect profile, nivolumab is the
`choice for patients who have disease progression
`while they are receiving VEGF-targeted therapy
`(Table 1). Cabozantinib is a salvage treatment
`for patients whose tumors progress during VEGF
`therapy; however, without a significant overall
`survival benefit and with significant side effects
`necessitating dose reduction in 60% or more of
`patients, it will not precede nivolumab in the
`therapeutic sequence. Cabozantinib will compete
`with other VEGFR inhibitors as third-line or
`later therapy.5,6,8 Trials comparing cabozantinib
`with other VEGF-targeted therapies are much
`needed; a randomized phase 2 trial of sunitinib
`versus cabozantinib will provide this, albeit in the
`context of first-line therapy (ClinicalTrials.gov
`number, NCT01835158).
`Finally, there is the practical question of
`whether these new therapies provide sufficient
`value in resource-constrained health care envi-
`ronments. New cancer treatments are typically
`marketed at a price that most patients cannot
`afford without insurance. In the United States,
`federally funded programs cover approximately
`
`50% of patients with advanced renal-cell cancer.
`We are obligated to ensure that medicines pro-
`vide maximal therapeutic benefit with the fewest
`side effects and smallest fiscal burden. Currently,
`Medicare is unable to negotiate for the best
`terms across its entire patient base; this repre-
`sents a contrivance of free-market economics
`that is in no one’s best interest. Effective treat-
`ments will work only if they are accessible to the
`patients they are designed to help. Buried trea-
`sure and value must coexist.
`Disclosure forms provided by the authors are available with
`the full text of this article at NEJM.org.
`
`From the University of Southern California Norris Comprehen-
`sive Cancer Center, Los Angeles (D.I.Q.), and the University of
`California Davis Comprehensive Cancer Center, Sacramento
`(P.N.L.).
`
`This article was published on September 25, 2015, at NEJM.org.
`
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`phase III trial of high-dose interleukin-2 versus subcutaneous
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`12. Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL over-
`comes resistance to sunitinib therapy in renal cell carcinoma.
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`DOI: 10.1056/NEJMe1511252
`Copyright © 2015 Massachusetts Medical Society.
`
`1874
`
`n engl j med 373;19 nejm.org November 5, 2015
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at UNIVERSITY OF CHICAGO LIBRARIES on February 25, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1108-0003