Treatment of DLBCL - oncologypro.esmo.org...• Scientific support from the Fondazione Italiana Linfomi ` Vitolo et al ASH 2016 and J Clin Oncol. 2017 Nov 1;35(31):3529-3537 Previously

1

Treatment of DLBCL

Andy Davies

Chair UK National Caner Research Institute High-Grade Lymphoma Sub-Group

ESMO Preceptorship Programme: Lymphoma

Lugano Nov 2018

DISCLOSURE OF INTEREST

Celgene: Research funding; Advisory Board; Honorarium

Roche: Advisory Boards; Honorarium; Research support

Gilead: Advisory Boards; Honorarium; Research support

Takeda: Advisory Boards; Honorarium; Research support, Travel to scientific conferences

CTI: Advisory Boards; Honorarium; Travel to scientific conferences

GSK: Research support

Bayer: Research support

Janssen: Honorarium; Research support

Karyopharma: Advisory Board; Research support

Pfizer: Research support; Honorarium

Acerta Pharma: Research funding and Advisory Board

Kite Pharma: Advisory Board

Haematological Malignancies Research Network 2017

DLBCL

DLBCL is a curable disease

Cunningham, J Clin Oncol (2009) 27:15s,

150 1080Events Totals

PATIENTS at Risk1080 834 621 434 278 134 61 8 0

0.0

0.2

0.4

0.6

0.8

1.0

Months from randomisation

0 6 12 18 24 30 36 42 48

2-year OS: 81% (95% CI: 78%-84%)

Overall survival: UK R-CHOP 14 vs 21

Real World Data

Haematological Malignancies research Network 2017

CHOP PLUS RITUXIMAB VS. CHOP ALONE IN ELDERLY PATIENTS WITH DIFFUSE LARGE-B- CELL LYMPHOMA

CHOP CHEMOTHERAPY PLUS RITUXIMAB COMPARED WITH CHOP ALONE IN ELDERLY PATIENTS WITH DIFFUSE

LARGE-B-CELL LYMPHOMA

BERTRAND COIFFIER, M.D., ERIC LEPAGE, M.D., PH.D., JOSETTE BRIÈRE, M.D., RAOUL HERBRECHT, M.D., HERVÉ TILLY, M.D., REDA BOUABDALLAH, M.D., PIERRE MOREL, M.D., ERIC VAN DEN NESTE, M.D., GILLES SALLES, M.D., PH.D.,

PHILIPPE GAULARD, M.D., FELIX REYES, M.D., AND CHRISTIAN GISSELBRECHT, M.D.

The benefit of rituximab is maintained over time

Coiffier B et al. Blood 2010;116:2040-2045

1.00

0.75

0.50

0.25

0.00

Ove

rall s

urv

iva

l

Time (years)

0 2 4 6 8 10 12

Arm A: CHOP

Arm B: CHOP + Rituximab

GELA LNH-98.5 10-year follow-up

We are going to talk about:

• Risk adapted approach to DLBCL management.

• Tailoring therapy according to genotypes/phenotypes of DLBCL that have been explored to date.

• Is the Cell-of-Origin classification ready for therapeutic stratification?

We are NOT going to talk about:

• Approaches to particular anatomical sites (eg CNS, testis, bone..).

• Management of limited stage disease.

• The difficult problem of elderly patients with DLBCL, where physiology may reduce tolerability of immunochemotherapy.

• Those patients where co-morbidities may require modification of our standard approaches.

Revision to WHO classification 2016

Diffuse large B-cell (NOS)

Germinal Centre B-cell type

Activated B-cell type

T-cell/histiocyte rich large B-cell

Primary DLBCL of central nervous system

Primary cutaneous DLBCL leg type

EBV+ DLBCL, NOS

EBV+ mucocutaneous ulcer

Primary mediastinal lymphoma

Intravascular large B-cell lymphoma

Primary effusion lymphoma

Plasmablastic lymphoma

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement

Swerdlow et al. Blood 2016

There is clear heterogeneity in clinical outcomes

Ziepert at al. J Clin Oncol 28:2373-2380.

Age adjusted IPI

StageLDHPerformance status

IPI

Age greater than 60 yearsStage III or IV diseaseElevated serum LDHECOG > 2More than 1 extranodal site

ESMO Guidelines

aaIPI=0 no bulk aaIPI=1/aaIPI=0 +bulk aaIPI>2

R-CHOP 21 x6 R-ACVBP + consolid. R-CHOP 21 x8

R-CHOP 21 x6 + IFRT (to bulk)

R-CHOP 14 x6 +Rx2

R-CHEOP14 x6

R-ACVBP + HDT

R-CHOP14 +HDT

Clinical trial

Young (age <61)

No clear standard in this groupTilly et al. 2015 Annals of Oncol, 26,116–125

Is there much yet to be achieved withconventional chemotherapy

?Probably not…..

Intensified regimens…might they hold the answer?

Fisher RI, et al . N Engl J Med1993; 328:1002– 006.

Dose Density: UK R-CHOP14 vs. 21

Cunningham, D, et al. Lancet 2013; 381:1817–1826.

Newly diagnosedCD20+ve DLBCL

R-CHOP21CHOP21 × 8 cycles

Rituximab × 8 cycles

R-CHOP14CHOP14 × 6 cyclesRituximab × 8 cycles

Lenograstim Day 4-12

n=540

n=540

Stratified by• IPI (0-1, 2, 3, 4-5)• Age ≤60 vs. >60• Treatment centre

1080 patients; 119 sitesRecruitment March 2005 - Nov 2008

R

Progression-free

survival

Overall survival

R-CHOP14 vs 21: no difference in outcome


R-CHOP14 vs 21: no subgroup could be identified


Young (age 18-59) aa IPI 1n=380Median age 47

55% stage III/IV, 44% bulk

Other ways of improving dose intensity: GELA LNH03-2B

Recher C, et al Lancet 2011: 378:1858-18676.

Improved outcome in R-ACVBP arm


► Improvement in EFS, PFS and OS

► Outcome of R-CHOP x 8 arm inferior to those observed in MInT with R-CHOP x 6

► Excess utilisation of healthcare resource

► Excess of toxicity


R-ACVBP R-CHOP

Toxicity (grade >3)

Neutropenia 78% 64%

Anemia 35% 5%

Thrombocytopenia 30% 3%

Febrile neutropenia 38% 9%

Toxic deaths (n) 3 2

Phase III Randomized Study of R-CHOP vs. DA-EPOCH-R and Molecular Analysis

of Untreated Large B-Cell Lymphoma: CALGB/Alliance 50303

Wyndham H. Wilson, Sin-Ho Jung, Brandelyn N. Pitcher, Eric D.Hsi, Jonathan Friedberg, Bruce Cheson, Nancy L. Bartlett, Scott Smith,

Nina Wagner-Johnston, Brad S. Kahl, Louis M. Staudt, Kristie A. Blum, Jeremy Abramson, Oliver W. Press, Richard I. Fisher, Kristy L. Richards,

Heiko Schoder, Julie E. Chang, Andrew D. Zelenetz, John P. Leonard

Abstract 469, American Society of Hematology, Dec 4, 2016

50303 Event Free Survival

Years from Study Entry

Pro

babi

lity

even

t fre

e

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

R-CHOPDA-EPOCH-R

Arm N Events 3 Y (95% CI) 5 Y (95% CI)

R-CHOP 233 64 0.81 (0.75-0.85) 0.69 (0.62-0.75)

DA-EPOCH-R 232 70 0.79 (0.73-0.84) 0.66 (0.59-0.72)

Median follow-up 5.0 y

HR=1.14 (0.82-1.61)p = 0.4386

Increasing dose intensity…High dose therapy

Greb A, et al. Cancer Treat Rev 2007; 33: 338–346

Survival Rates among All Eligible Patients Who Underwent Randomization.

…may improve PFS for poorer prognosis patients (not OS)

PFS OS

All patients high or high-intermediate IPI

Stiff PJ et al. N Engl J Med 2013;369:1681-1690

Similar findings in Italian DLCL04 Study Chiappella Lancet Oncol 2017

Intensification of therapy based in interim PET…

Duehrsen et al. Blood 128:1857

PETAL Trial

Aggressive lymphoma(DLBCL n=606)

R-CHOP-14 x2

Interim PET

negative positive

A1 R-CHOP14 x4

A2 R-CHOP14 x4

+ Rx2B1

R-CHOP14 x6B2

B-ALL

Integrative Genetic and

Clinical Analysis

through Whole Exome

Sequencing in 1001

Diffuse Large B Cell

Lymphoma (DLBCL)

Patients Reveals Novel

Disease Drivers and

Risk Groups

We should be capitalising on biological insights

Zhang et al ASH 2016 and Reddy Cell 2017

Overall survival of R-CHOP-treated patients in Lunenburg analysis

Salles G et al. Blood 2011;117:7070-7078

Application of complex models of biological heterogeneity

Wright, George et al. (2003) Proc. Natl. Acad. Sci. USA 100, 9991-9996

But how to distinguish phenotype?

Hans, C. P. et al. Blood 2004;103:275-282

► Getting it right is important when looking prospectively at therapy, not prognosis

► The immunophenotype is not that good:

► CD10+ (about 1/3), Mum-1-: Almost all GCB

► CD10- (2/3) hard to distinguish ABC from GCB on immuno’s

► Bcl-6 is a difficult stain

► Discordance with mRNA (~20%)

► Conflicting IHC datasets

► Lunenberg project demonstrates poor correlation between centres (technical and interpretative)

Lots of different IHC Algorithms…

Rita Coutinho et al. Clin Cancer Res 2013;19:6686-6695

Other emerging platforms

Deeper biological insights

A Reddy et al., 2017; Cell, 171:481-494

R Schmitz et al., 2018 N Engl J Med;378:1396-1407.

B Chapuy et al., 2018Nat Med; 24:679–690

A new taxonomy

DLBLDLBL

ABCABC

MCD/Cluster 5MCD/Cluster 5

BN2/Cluster 1BN2/Cluster 1

N1N1

Cluster 2Cluster 2

UNC

GCBGCB Cluster 4Cluster 4

Cluster 3/EZBCluster 3/EZB

• Header

• First level bold bullet: text…

• First level bold old bullet

- Second level bullet

- Third level bullet



-

• Header

• First level bullet: text…

EXAMPLE HEADER UPPERCASE TEXT…

References… …Footnote

Anti CD40 moAbDacetuzumab

Surface markers

Anti CD20 moAbOfatumumab

GA-101

Anti CD22Epratuzumab

Inotuzumab Ozogamicin

polatuzumab

Microenvironment

Lenalidomide

Proteosome inhibitorsBortezomib

Bcl-2 family

inhibitorsABT-263

Survivin inhibitorsYM155

Syk inhibitorsFostamatinib

entosplentib

PKC inhibitorsEnzastaurin

HDAC inhibitorsVorinostat

Panobinostat

Nedd8-activating

enzyme inhibitorsMLN4924

Aurora kinase

inhibitors

mTOR inhibitorsEverolimus

Temsirolimus

Hsp 90 inhibitorsKW 2478

Btk inhibitorsIbrutinib

ONO/GS-4059

ACP-196

PI3K inhibitorsIdelalisib

Copanlisib

Duvelisib

TGR-1202

Actionable mutations

EZH2E7438

CD79a/bAEB071

CD22

CD20

CD80

Pathways

T-cell exhaustion

• Header







-

• Header





Surface markers


GA-101



polatuzumab

Microenvironment

Lenalidomide


Bcl-2 family

inhibitorsABT-263



entosplentib



Panobinostat

Nedd8-activating


Aurora kinase

inhibitors


Temsirolimus



ONO/GS-4059

ACP-196


Copanlisib

Duvelisib

TGR-1202


EZH2E7438

CD79a/bAEB071

CD22

CD20

CD80

Pathways

T-cell exhaustion

36

Study design

International, open-label, randomized Phase III study in 1L DLBCL pts

• Scientific support from the Fondazione Italiana Linfomi

`

Vitolo et al ASH 2016 and J Clin Oncol. 2017 Nov 1;35(31):3529-3537

Previously untreated DLBCL

• Age ≥18 years• IPI ≥2 or IPI 1 not due to age alone or IPI

0 with bulky disease (one lesion ≥7.5cm)• Adequate hematologic function• ≥1 bi-dimensionally measurable lesion• ECOG PS ≤2• Target enrolment: 1400

G-CHOP arm

G 1000mg C1 D1/8/15 and C2–8 D1CHOP 6 or 8 cycles every 21 days

R-CHOP arm

R 375mg/m2 C1–8 D1CHOP 6 or 8 cycles every 21 days

Randomized 1:1

• Number of CHOP cycles pre-planned in advance for all pts at each site

• Randomization stratification factors: planned number of CHOP cycles, IPI, geographic region

Using a novel anti CD20….no

37

Investigator-assessed PFS (primary endpoint)

*Stratified analysis; stratification factors: IPI score, number of planned chemotherapy cycles

R-CHOP,

n=712

G-CHOP,

n=706

Pts with event,n (%)

215 (30.2)

201 (28.5)

1-yr PFS, % 79.8 81.6

2-yr PFS, % 71.3 73.4

3-yr PFS, % 66.9 69.6

HR (95% CI),p-value*

0.92 (0.76, 1.11),p=0.3868

Median follow-up: 29 months

Kaplan-Meier plot of investigator-assessed PFS by treatment arm

No. of patients at riskR-CHOPG-CHOP

712706

616622

527540

488502

413425

227240

142158

96102

4139

62

R-CHOP (n=712)G-CHOP (n=706)

6 12 18 24 30 36 42 48 54Time (months)

60

Pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0

0

Vitolo et al ASH 2016 and J Clin Oncol. 2017 Nov 1;35(31):3529-3537

• Header







-

• Header





Surface markers


GA-101



polatuzumab

Microenvironment

Lenalidomide


Bcl-2 family

inhibitorsABT-263



entosplentib



Panobinostat

Nedd8-activating


Aurora kinase

inhibitors


Temsirolimus



ONO/GS-4059

ACP-196


Copanlisib

Duvelisib

TGR-1202


EZH2E7438

CD79a/bAEB071

CD22

CD20

CD80

Pathways

T-cell exhaustion

Lenalidomide

Chanan-Khan, A. A. et al. J Clin Oncol; 26:1544-1552 2008

• Immunomodulatory properties

• Modulation of both cellular and cytokine tumour cell microenvironment

• Activates T cell and NK response to tumour cell

• Down regulates pro-survival cytokines

• Enhanced ADCC activity with rituximab

Differential response according to cell oforigin in DLBCL (n=40). Retrospective review.

Hernandez-Ilizaliturri et al. Cancer 2011

Response rates Progression-free survival

Can over come the adverse outcome of ABC phenotype….

Grzegorz S. Nowakowski et al. JCO 2015;33:251-257

R-CHOP R2-CHOP

ROBUSTClinical Study Design: Phase III double blind

DLBCL Select by GEP

ABC

6 x R-CHOP21 + Lenalidomide 15 mg x 14*n=280

6 x R-CHOP21 + Placebo x 14*n=280

GCB, unclassified Ineligible

R

*Option for 2 additional rituximab doses after completing

treatment regimen (if considered standard of care per local practice)

� Newly diagnosed DLBCL of ABC type

� IPI ≥ 2; ECOG PS ≤ 2; Age 18–80

� Primary Endpoint = PFS

� N = 560ClinicalTrials.gov.NCT02285062

REMARC: Lenalidomide maintenance (aaIPI>1; 60-80 yrs)

Thieblemont et al. JCO 2017

Thieblemont et al. JCO 2017

PFS OS

36% patients discontinued therapy as a result of toxicity (vs 16% placebo)

72% required a dose reduction

55% aged <70..? Fit for an alternative approach

PET positive at end of induction had greatest benefit (HR=0.59 vs 0.78)

• Header







-

• Header





Surface markers


GA-101



polatuzumab

Microenvironment

Lenalidomide


Bcl-2 family

inhibitorsABT-263



entosplentib



Panobinostat

Nedd8-activating


Aurora kinase

inhibitors


Temsirolimus



ONO/GS-4059

ACP-196


Copanlisib

Duvelisib

TGR-1202


EZH2E7438

CD79a/bAEB071

CD22

CD20

CD80

Pathways

T-cell exhaustion

Is it possible to reverse the adverse outcomes of ABC DLBCL with bortezomib?...no

• The nuclear factor-kB (NF-kB) pathway is constitutively activated in ABC DLBCL1

• The proteasome inhibitor bortezomib is a potent inhibitor of NF-ĸB2; may therefore have specific utility in non-GCB DLBCL and overcoming the negative prognosis associated with non-GCB phenotype3,4

46

1Davis RE et al. J Exp Med. 2001;194(12):1861-1874.2Bu R et al. Leuk Lymphoma. 2014; 55(2):415-424.3Ruan J et al. J Clin Oncol. 2011;29(6):690-697.4Dunleavy et al. Blood. 2009; 113(24):6069-6076.

Ruan J et al. J Clin Oncol. 2011;29(6):690-697

Progression-free survival: Treatment arm and phenotype

ABC: N=244 GCB: N=475 Unc. N=199

HR=0.792, p=0.309

71.6%

64.7%

75.8%

72.9%

HR=0.873, p=0.458

68.2%

67.8%

HR=1.096, p=0.729

Davies et al ICML 2017

• Schaffer A L, et al. 2012. Ann. Rev. Immunol30:565-610

How about targeting BTK?...no

Ibrutinib: Activity in ABC

Wilson et al 2015

PHEONIXClinical Study Design: Double blind randomised phase III

DLBCLSelect by

IHC

Non-GC

6 x R-CHOP21 + ibrutinib

6 x R-CHOP21 + Placebo

GC Ineligible

R

*Option for 2 additional rituximab doses after completing

treatment regimen (if considered standard of care per local practice)

� Newly diagnosed DLBCL of non-GC

� ECOG PS ≤ 2; Age 18–80

� Primary Endpoint = EFS

� N = 800ClinicalTrials.gov.NCT02285062

EFS OS<65

>65 EFS OS

Younes et al. ASH 2018

Top line…

• 67.7% had ABC subtype.

• Ibr + RCHOP did not improve EFS in pts with non-GCB (by IHC) or ABC

(by GEP) DLBCL: (HR) for EFS was 0.934 (95%CI: 0.726-1.200) for non-GC

and 0.949 (95% CI, 0.704-1.279) for ABC

• SAEs were greater in the ibr + RCHOP vs pbo + RCHOP arm (53.1% vs

34.0%), particularly febrile neutropenia and pneumonia,

• In pts ≥ 65 yrs, there were more SAEs (67.4% vs 40.6%). In pts < 65 yrs,

grade ≥ 3 AEs were similar.

Age Ibr + R-CHOP R-CHOP

<65 90.4% 91.1%

>65 69.0% 90.0%

In receipt of >6

cycles

The paradigm for study design….don’t change practice yet

R-CHOP

R-CHOP+X

DLBCL RBiological and

clinical stratification

Ongoing X=Lenalidomide

IbrutinibBortezomibBrentuximabEverolimus

TazemetostatMore to come…

Can we practically deliver this design in

phase III with so many agents?

Overall survival from diagnosis

Overall survival from 2 years event free

Events occur early…

Maurer M J et al. JCO 2014;32:1066-1073

Primary Refractory Early relapse Late relapse

Eligible for HDT

consolidation

Not eligible for HDT

• Age

• Co-morbidity

• No response to reinduction

• No stem cells at harvest

Reinduction regimen

(I hate ‘salvage’)

Followed by HDT+PBSCT

Reinduction regimen


Eligible for HDT

consolidation


• Age

• Co-morbidity



Reinduction regimen



Reinduction regimen

PARMA Trail (Phillip NEJM 1995)

• PARMA study (n=215 aggressive relapsed disease)

• 109 demonstrated chemosenstivity after DHAP x2: randomised DHAP x4 more or BEAC + ABMT

• OS 53 vs 32% at 5 years (P=0.038)

• Time to relapse (< or > 12 months most important prognostic factor, along with second line aaIPI and response to salvage PR vs CR

Evolving Standards of Care in Non-Hodgkin’s Lymphomaclinicaloptions.com/oncology

Guideline Recommendations for Treatment of Relapsed DLBCL

� Second-line therapy in candidates for high-dose therapy + ASCT

– DHAP ± rituximab

– ESHAP ± rituximab

– GDP ± rituximab

– GemOx ± rituximab

– ICE ± rituximab

– MINE ± rituximab

� Second-line therapy for patients who are not candidates for high-dose therapy

– Clinical trial

– Rituximab

– CEPP ± rituximab

– Lenalidomide

– EPOCH ± rituximab

NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas V.1.2010. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.

High Dose Chemotherapy plus ASCT:

CORAL trial experience

Gisselbrecht C et al, JCO 2010

Gisselbrecht C et al. JCO 2010;28:4184-4190

©2010 by American Society of Clinical Oncology

The limited value of HDT+PBCT in relapsed DLBCL

Friedberg 2011

ORCHARRD

Van Imhoff et al JCO 2016

Value of pre-auto PET

Van Imhoff et al JCO 2016

Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation.. Fenske et al. BJH 2016

n=503Median age 51


Eligible for HDT

consolidation


• Age

• Co-morbidity



Reinduction regimen



Reinduction regimen

R-GemOX in R/R DLBCL

Mournier er al.

Pixantrone..real world experience (Eyre et al 2016)

92 R/R DLBCL

85% refractory disease

72% had an international

prognostic index (IPI) 3–5

Median PFS 2·0 months (95%

confidence interval (CI) 1·5–2·4

Median OS was 3·4 months (95%

CI 2·7–4·5).

ORR 24% (complete response

10%; partial response 14%).

• Header







-

• Header





Surface markers


GA-101



polatuzumab

Microenvironment

Lenalidomide


Bcl-2 family

inhibitorsABT-263



entosplentib



Panobinostat

Nedd8-activating


Aurora kinase

inhibitors


Temsirolimus



ONO/GS-4059

ACP-196


Copanlisib

Duvelisib

TGR-1202


EZH2E7438

CD79a/bAEB071

CD22

CD20

CD80

Pathways

T-cell exhaustion

Targeted chemotherapy in clinical development

Goy A, et al. Blood. 2010;116(21): Abstract 430.

PolatuzumabVedotin

Target CD79b

DLBCL: PFS and OS significantly longer with Pola-BR

Progression Free Survival

% P

atie

nts

Months

Overall Survival

% P

atie

nts

Months

71Sehn et al. EHA 2018

1Combined DLBCL and FL cohorts 2Peripheral neuropathy reported by MedRA SMQ (Standardized MedRa Query)

Adverse Events at Rate ≥20% by Treatment Group1

� SAEs occurred more frequently in pola-BR (33% BR vs 55% pola-BR) – Most common were infections (18% vs 23%) and febrile neutropenia (3% vs 12%)

0 10 20 30 40 50 60

Grade1Grade2Grade3Grade4

010203040

BR Pola-BR

NeutropeniaNausea

Diarrhea

FatigueThrombocytopenia

AnemiaPyrexia

Decreased appetite

Peripheral neuropathy2

0

72Sehn et al. EHA 2018

CAR-T

CAR-T cell manufacturing process

Apheresis to product release <21 days

ASH 2017 update: Strange and difficult names…

Name Company Abstract Trial Specifiction

Axibcabtagene

Ciloleucel

Gilead/KITE No. 577

Schuster et al

ZUMA-1 CD28 signal

Tisagenlecleuc

el

Novartis No. 578

Neelapu et al

JULIET Lentiviral

transduction

41BB signal

Lisocabtagene

Maraleucel

Juno / Celgene No. 581

Abramson et

al

TRANSCEND

NHL-001

41BB signal

Zuma-1 DOR

Neelapu et al (2017) NEJM

3/7 (43% ) phase 1 patients have ongoing

CR at 24 months

ZUMA-1: Safety

30% patient remain in response without detectable T-cells

A molecular precision approach to DLBCL?...almost

• Don’t think of DLBCL as one disease

• There are challenges in defining molecular sub-groups in a timely fashion and the appropriate diagnostic platform.

• Targeted therapies may potentially change the landscape of therapy for DLBCL...not yet. Next year it may be different.

• Much still needs to be proved and phase III studies are needed (no matter how difficult)…

• We need to better refine the molecular heterogeneity and to continue to better exploit our new knowledge of the biology.

Documents

Treatment of DLBCL - oncologypro.esmo.org...• Scientific support from the Fondazione Italiana Linfomi ` Vitolo et al ASH 2016 and J Clin Oncol. 2017 Nov 1;35(31):3529-3537 Previously