Neoadjuvant Melanoma Trials Data Collection and Endpoint ...

Neoadjuvant Melanoma Trials Data Collection and Endpoint Selection

Christian Blank, MD, PhD, Netherlands Cancer Institute

November 6th, 2019

• Advisory role: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly,GenMab, Pierre Fabre

• Research funding: BMS, Novartis, NanoString

• Stockownership: Uniti Cars, Neon Therapeutics, Forty Seven

Disclosures

The outcome of high risk stage III melanoma patients is poor

After surgery +/- RT the 5 year OS is only 30-60% 1-3

Axilla

1Balch, et al., J Clin Oncol, 2009; 2van Akkooi, et al., Eur J Surg Oncol, 2007; 3van der Ploeg, et al., Ann Surg Oncol, 2011,

• Adjuvant therapy improved the RFS, but EFS remains poor 4,5

1Balch, et al., J Clin Oncol, 2009; 2van Akkooi, et al., Eur J Surg Oncol, 2007; 3van der Ploeg, et al., Ann Surg Oncol, 2011; 4Combi-AD - Long SMR 2017; 5Checkmate-238 - Weber ESMO 2019

Adapted from Menzies et al ASCO 2019

macromets

Dabrafenib + Trametinib Nivolumab

- 3m Months0

0

10

20

30

40

50

60

70

80

90

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50

RFS

(%)

52

3y, 58%2y, 67%

~15-25% screen failures, majority due to

PD

- 3m

RFS

(%)

Months

0102030405060708090

100

0 6 12 18 27 453 9 15 21 3024

3y, 60%2y, 64%

33 36 39 42

~15-25% screen failures, majority due to

PD

Stage IIIB/C

The EFS outcome of high risk stage III melanoma patients is poor

Neoadjuvant versus adjuvant checkpoint inhibition (IPI+NIVO) in macroscopic stage III melanoma – OpACIN

Adjuvant arm

Neo-adjuvant arm

designed by TN Schumacher and CU Blank in 2014

What did we learn from OpACIN?

Neoadjuvant IPI + NIVO:• Did not delay surgery• Was superior compared to

adjuvant therapy in expanding tumor-resident TCR clones

• The pathologic response rate was high (78%)

• None of the patients withpathologic response have relapsed

• highly toxic with 90% grade III/IV adverse events

Blank et al., Nat Med, 2018; Blank et al., ESMO 2019

80%

60%

Multicenter Phase 2 Study to Identify the Optimal neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab – OpACIN-neo

Dosing in Arm A, B, and C based on data from Blank, Rozeman, et al. Nat Med 2018, Long, et al. Lancet Oncol 2017, Meerveld-Eggink, Rozeman, et al. Ann Oncol 2017

-4 0 3 6 12

PBMC

PBMCTumor biopsyPET/CT + CTMRI brain

PBMCCTweek

PBMC

R surgery

2x IPI 3mg/kg q3wkPBMCCT or

PET/CT2x NIVO 3mg/kg q2wk

2x IPI 1mg/kg + NIVO 3mg/kg q3wk

2x IPI 3mg/kg + NIVO 1mg/kg q3wk

Arm A

Arm B

Arm C

40%

20%

50%

Grade 3-4 toxicity

Pathologic Response

80%

77%

65%

18-months Relapse-free survival – OpACIN-neo

According to treatment arm According to pathologic response

| | | | |||| |||| ||| | ||| | |||| |||| || | | || | || || | | |

|

| | | | |

0

25

50

75

100

0 6 12 18Time since surgery (months)

Rel

apse

−fre

e su

rviv

al (%

)

64 64 54 2119 14 6 3No

YesNumber at risk

No pathologic response

Pathologic response (pCR, near-pCR, pPR)

Pathologicresponse

* patient died due to toxicity without signs of melanoma relapse

| | | | | | || | || || | | | || | ||||| | || | | || | | | ||| ||| | | | || | || | | |

0

25

50

75

100

0 6 12 18Time since surgery (months)

Rel

apse

−fre

e su

rviv

al (%

)

30 29 21 829 27 20 924 22 19 7 C

B A

Number at risk

Arm A: 2x IPI3+NIVO1Arm B: 2x IPI1+NIVO3Arm C: 2x IPI3 - 2x NIVO3

Arm pRR

65%77%80%

pRR = pathologic response rate

*

Pathologic response correlates with outcome!

INMC pooled analysis• Pooled data from 6 modern NST clinical trials conducted across the INMC.

• Pts with RECIST measurable, surgically resectable, clinical stage III melanoma with nodal metastases who underwent surgery were included.

• Baseline disease characteristics, treatment regimen, pathologic response and RFS were examined.

Adapted from Menzies et al. Presented at ASCO 2019

6

3

12

6

12

8

0

51

26

6

40

44

0 6 12 18 24 30 36 42 48

Blank (OpACIN-neo, IT)

Huang (IT)

Amaria (IT)

Blank (OpACIN, IT)

Long (TT)

Amaria (TT)

Neoadjuvant Adjuvant

weeks

IPI + NIVO(N=107)

N=10

N=11

N= 0

N =86

80% of all patients treated

with IT

EU

AUS/EU

VS

VS

Personalized Response-driven Adjuvant therapy after Combination of neoadjuvant Ipilimumab and Nivolumab in stage IIIB/C melanoma - PRADO

Stage IIIB/C de novo or

recurrent melanomaRECIST 1.1. measurable

(>= 1,5cm short diameter),PA proven

Follow-upCT + ultrasound

q12w

-4 60 12 64

CLND = Complete Lymph node

dissection

CLND

FU*

FU*

no CLND

PET/CT CT neck thorax abdomenMRI brainLab + PBMC Feces collectionTumor biopsyLymph node marker placement

Excision marked lymph nodeCTLab + PBMCFeces collection

CTLab + PBMC

Pathological pCR or near CR

(0-10% vital tumor cells)

CLND

no pathological response (pNR)(> 50% vital tumor cells)

Resection of marked

lymph node

pPR(10-50%

vital tumor cells)

Follow-upCT q12w FU*

* According to institutes standard# BRAF+MEK inhibition in BRAF V600E/K patient is allowed according to patient’s and treating physician’s decision when available † Adjuvant radiotherapy according to patient’s and physician’s decision

NIVO 52wks q4wk#

+ start adjuvant RT†

CT q12w

2 courses Ipilimumab 1mg/kg +

Nivolumab 3mg/kgq3wks

2 courses IPI+NIVO

CLND

Schermers et al., BJS 2019

The pathologic response in the largest lymph node is representing the whole lymph node bed

(MeMaLoc substudy of OpACIN-neo)

What have we learned from PRADO so far?

• IPI1+NIVO3 scheme is again well tolerated

• Pre-treatment application of marker in index LN is feasible

• Fast pathologic evaluation of marked LN is feasible

• Timing of CLND within 3 weeks post marked LN resection and start adjuvanttherapy (if needed) at week 12 is feasible (NKI & MIA experience)

• Parallel RT to NIVO or DAB+TRAM is feasible





Follow-upCT + ultrasound q12w

-4 60 12 64

CLND

FU*

FU*

no CLND



CLND

Resection of marked

lymph node

pPR(10-50%

vital tumor cells)


NIVO 52wks q4wk#

+ start adjuvant RT†

CT q12w

2 courses Ipilimumab 1mg/kg +

Nivolumab 3mg/kgq3wks

|||||

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

0%

25%

50%

75%

100%

74 18 14 14 12 11 10 9 8 8 6 4 2 1 076 32 32 26 24 22 22 21 20 19 16 11 5 2 1 0

Surgery AloneT-VEC + Surgery

Number of Patients at Risk:

Arm 1 (T-VEC + Surgery, N = 76): 29.5%Arm 2 (Surgery Alone, N = 74): 16.5%Median Follow-up = 31.2 monthsOverall P = 0.070Overall HR (80% CI) = 0.75 (0.58, 0.96)

Study Month

Kap

lan-

Mei

er (K

M %

)

ITT Analysis Set: 150 patients enrolled and randomized

RFS is not advisable in neoadjuvant randomized trials: T-VEC neoadjuvant versus upfront surgery

Dummer, et al.

Remaining questions for a phase 3 trial

• Response-driven scheme? Adjuvant versus only FU in MPR patients?

• Primary endpoint EFS ?

• Event also non-melanoma death? Elderly populations!

• Index LN approach versus TLND?

• Stratify for BRAF status? How fast BRAF status available

• Stratify continents?



CLND

FU*

FU*

no CLND



CLND

Resection of marked

lymph node

pPR(10-50%

vital tumor cells)


Adjuvant PD-1 blockade or

BRAF + MEK inhibtion




6 weeksneo-

adjuvant PD-1 + CTLA-4

blockade

TLND§,# Standard adjuvant therapy start no later than w12

-4 60 12 64

FU*

Remaining questions for a phase 3 trial

• Timing of CLND within 3 weeks post marked LN resection feasible?

• Start adjuvant therapy (if needed) at week 12 broadly feasible?

• Pathology fast enough? pRR or MPR as surrogate markers?

• Adjuvant RT parallel NIVO or DAB+TRAM in NR patients?

• How to deal with change to other adjuvant therapy in non-MPR which will be reality



CLND

FU*

FU*

no CLND



CLND

Resection of marked

lymph node

pPR(10-50%

vital tumor cells)


Adjuvant PD-1 blockade or

BRAF + MEK inhibtion




6 weeksneo-

adjuvant PD-1 + CTLA-4

blockade

TLND§,# Standard adjuvant therapy start no later than w12

-4 60 12 64

FU*

Department of Medical OncologyLisette RozemanJudith VersluisIrene ReijersMaartje RohaanMarnix Geukes FoppenSandra AdriaanszHenk MalloWilma UyterlindeJudith LijnsveltSofie WilgenhofHans van ThienenJohn Haanen

Department of Molecular Oncologyand Immunology Oscar KrijgsmanEsmée HoefsmitPetros DimitriadosTrieu My VanMesele ValentiPia KvistborgLorenzo FanchiMembers of the Blank groupDaniel Peeper

Ton Schumacher

Department of PathologyBart van de WielCarolien BiermanLinda Bosch

Department of Surgical OncologyAlexander van AkkooiMichel WoutersWinan van HoudtMartin KlopAnne Miek Koenen

Department of BiometricsKarolina Sikorska Alex TorresLindsay GrijpinkSteven VanhoutvinHarm van Tinteren

Department of RadiologyAnnemarie BruiningStijn Heijmink

CFMPBDennis PetersSten CornelissenLinde BraafAnnegien Broeks

Department of Psychosocial Research and EpidemiologyAnnelies BoekhoutLonneke van de Poll

Patients and their families Collaborators OpACIN-Neo trialGeorgina LongAlexander MenziesRichard ScolyerMIA surgical and trial teamJohan HanssonKarolinska Institute surgical and trial team

International Melanoma NeoadjuvantConsortiumMDA Cancer Center– Jennifer Wargo, Roda Amaria, Hussein Tawbi, Liz Burton, Michael TetzlaffMIA – Georgina Long, Alexander Menzies, Maria Gonzales, Richard ScolyerAll other members of the INMC https://melanoma-inc.org

BMSBauke StegengaAndrew EvansVikki GoodmanConstance PfeiferBrian Lamon

NanoStringSarah Warren

[email protected]

Acknowledgements

Neoadjuvant Melanoma Trials Data Collection and Endpoint ...

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