immune oncology vs. targeted therapies in solid tumors is ... · tremelimumab fully human igg2...

Immune oncology vs. targeted

therapies in solid tumors –

is there a winner?

Dr. Răzvan CurcăSpitalul Judeţean de Urgenţă Alba-Iulia

Evolution of Cancer Therapy:

Core Treatment Modalities

DeVita VT Jr, et al. Cancer Res. 2008;68:8643–8653; American Cancer Society.

http://www.cancer.org/cancer/cancerbasics/thehistoryofcancer/; Hodi FS, et al. N Engl J Med.

2010;363:711–723; Sznol M, et al. Presented at ASCO 2013: oral presentation; Kantoff PW, et al. N Engl J

Med. 2010;363:411–422; Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9.

Surgery

1846

Radiation Therapy

1901

Chemotherapy

1946

Targeted Therapy

1997

Immuno-Oncology

2011

Targeted therapy

Prototype- CML

FDA approved targeted therapies

FDA approved targeted therapies (2)

“FDA approves Zykadia for late-

stage lung cancer”

April 29, 2014- FDA granted accelerated

approval to Zykadia (ceritinib) for patients

with metastatic ALK-positive NSCLC

previously treated with crizotinib based on

phase I trial data

“Today’s approval illustrates how a

greater understanding of the underlying

molecular pathways of a disease can lead

to the development of specific therapies

aimed at these pathways,” Richard Pazdur

About OnCompass

ONCOMPASS™ Full tests the

following 58 genes: ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R,

CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2,

FGFR3, FLT3, GNA11, GNAS, GNAQ, HNF1A, HRAS, IDH1, IDH2,

JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1,

NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4,

SMARCB1, SMO, SRC, STK11, TP53, VHL,DDR2, CHEK2, PIK3R1,

MAP2K1, JAK1, TGFBR2, PDGFRB, IGFR1, and 3 FISH test from the

followings: HER-2, ALK, c-MET, FGFR1, PIK3CA, EGFR, ROS-1

A list of globally available clinical trials is

also provided.

Molecular tumor boardUniversity of California San Diego

Moores Cancer Center Experience

Includes clinicians, basic scientists,

geneticists and bioinformaticians

34 pretreated pts. included, with a median

of 3 prevous therapies

Median time to test result= 27 days (14-

77 days)

NGS techniques were used (182 or 236

gene panels)

Schwaederle M, Parker BA, Schwab RB, et al. Molecular tumor board: the University of California-San Diego

Moores Cancer Center experience. Oncologist. 2014;19:631-636.

Molecular tumor boardUniversity of California San Diego

Moores Cancer Center Experience

Median number of

molecular

abnormalities by

NGS= 4 (1-14)

No two pts. had the

same abnormalities

107 of them seen only

once

Schwaederle M, Parker BA, Schwab RB, et al. Molecular tumor board: the University of California-San Diego

Moores Cancer Center experience. Oncologist. 2014;19:631-636.

Molecular tumor boardUniversity of California San Diego

Moores Cancer Center Experience

11 evaluable pts. with treatment informed by

molecular diagnosis

3 PRs (PFS 3.4 mo, >6.5 mo and 7.5 mo)

Most common reasons for not receiving

molecular-driven treatment:

◦ Ineligible for clinical trial

◦ Could not travel to trial center

◦ Insurance not cover the cognate agents

Schwaederle M, Parker BA, Schwab RB, et al. Molecular tumor board: the University of California-San Diego

Moores Cancer Center experience. Oncologist. 2014;19:631-636.

Resistance ultimately emerges…

Drug resistance to targeted therapies: déjà vu all over again. Groenendijk FH, Bernards R.

Mol Oncol. 2014 Sep 12;8(6):1067-83.

38-year-old man with BRAF-mutated melanoma

Patient discontinued vemurafenib therapy, but continued to have rapid disease progression and died several weeks later.

Wagle N, et al. J Clin Oncol 2011;29:3085–96

Baseline 15 weeks of

vemurafenib

23 weeks of

vemurafenib

Strategies to overcome resistance

Drug resistance to targeted therapies: déjà vu all over again. Groenendijk FH, Bernards R.

Mol Oncol. 2014 Sep 12;8(6):1067-83.

RAS pathway super-inhibition

C. Robert et. al. ESMO 2014

Romanian-derived perspective on

future of targeted therapy

SHIVA- proof of concept trial

SHIVA- proof of concept trial

SHIVA- proof of concept trial

SHIVA- proof of concept

randomized trial

Immuno-Oncology

Active immunotherapy

Adoptive cell transfer

immunotherapy

IL-2

IFN

IL-15

IL-21

Peptide vaccine

DC vaccine

Genetic vaccine

OX40

CD137

CD40

PD-1

CTLA-4

T cell cloningTCR or CAR

genetic engineering

General Approaches for

Cancer Immunotherapy

Pts at Risk, n

Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0

Pro

po

rti

on

Alive

0

0.2

0.4

0.6

0.8

1.0

Mos

0 12 24 36 48 60 72 84 96 108 120

Median OS: 11.4 mos (95% CI: 10.7-12.1)

Ipilimumab

Censored

Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24. Schadendorf D, et al. J Clin Oncol. 2015

Ipilimumab: Pooled Survival Analysis From

Phase II/III Trials in Advanced Melanoma

3-yr OS rate: 22% (95% CI: 20-24)

Clinical Development of Anti–PD-1

Checkpoint Inhibitors in Solid Tumors

Antibody Molecule Development Stage

NivolumabFully

human IgG4

Approved (US): advanced melanoma after previous therapy, advanced NSCLC

after CTPhase III multiple tumors (NSCLC,

melanoma, RCC, HNSCC, GBM, gastric)

PembrolizumabHumanized

IgG4

Approved (US): advanced melanoma after previous therapy

Phase III multiple tumors (HNSCC, NSCLC, melanoma, bladder, gastric/GE)

PidilizumabHumanized

IgG1 Phase II multiple tumors (pancreatic,

CRC, RCC, prostate, CNS)

AMP-224Fc-PD-L2

fusion protein

Phase I

Clinical Development of Anti–PD-1

Checkpoint Inhibitors in Solid Tumors

Antibody Molecule Development Stage

Atezolizumab(MPDL3280A)

Engineered human

IgG1

Phase III multiple tumors (NSCLC, bladder, RCC, TNBC)

Avelumab(MSB0010718C)

Fully human

IgG1Phase III (NSCLC)

Durvalumab(MEDI4736)

Engineeredhuman

IgG1

Phase III multiple tumors (NSCLC, HNSCC)

Clinical Development of Other Immune

Checkpoint Inhibitors in Solid Tumors

Target Antibody Molecule Development Stage

CTLA-4

IpilimumabHumanized

IgG1

Approved: advanced melanomaPhase III multiple tumors

(melanoma, NSCLC, SCLC, CRPC, GBM, RCC)

TremelimumabFully

human IgG2

Phase III multiple tumors (HNSCC, NSCLC)

IDO

INCB024360 TKIPhase II multiple tumors

(ovarian, melanoma)

NLG919 TKI Phase I

B7-H3 MGA271Humanized IgG1kappa

Phase I

LAG-3 BMS-986016 --- Phase I

Mutational load in different tumors

Alexandrov et al. Nature 500, 415–42: 22 August 2013

Management of Cancer in the

Post Anti–PD-1/PD-L1 Era

Anti–PD-1/anti–PD-L1

Generate T cells:

+ Anti–CTLA-4

+ Immune-activating

antibodies or cytokines

+ TLR agonists or oncolytic

viruses

+ IDO or macrophage

inhibitors

+ Targeted therapies

Bring T cells

into tumors:

Vaccines

TCR-engineered ACT

CAR-engineered ACT

CheckMate 067: Improved PFS with

Nivo + Ipi or Nivo Alone vs Ipi Alone

Larkin J, et al. N Engl J Med. 2015; [epub ahead of print].

1.00.9

0.8

0.7

0.6

0.5

0.4

0.3

0.1

0

0.2Pro

po

rtio

n A

live a

nd

Pro

gre

ss

ion

Fre

e

Nivo + Ipi

Nivo

Ipi

*Stratified log-rank P < .00001 vs Ipi.†Exploratory endpoint. Study not powered to detect a statistical difference between Nivo + Ipi and Nivo.

Mos0 3 6 9 12 15 16 21

Nivo + Ipi(n = 314)

Nivo(n = 316)

Ipi(n = 315)

Median PFS, mos (95% CI)

11.5(8.9-16.7)

6.9(4.3-9.5)

2.9(2.8-3.4)

HR (99.5% CI) vs Ipi 0.42(0.31-0.57)*

0.57(0.43-0.76)*

_

HR (95% CI) vs Nivo 0.74(0.60-0.92)†

_ _

Conclusion

Targeted therapy has now much more data

and clinical applications than immunotherapy

Targeted therapy drugs have great success in

some cases, but many times resistence will

emerge and the treatment ultimately will fail

Rational combinations of targeted therapy

could improve outcome, but the expected

benefit is still limited

Conclusion

Targeted immunotherapy comes with high

hopes for curing cancer

Experience with immuno-oncology is till

now very promising, but not offering

certainties for most cancer patients

A minority of patients could achieve long

term complete remissions, which are more

or less equivalent with cure

Biomarkers for identifying responding

patients are currently under investigation

Conclusion

Combinations of targeted immune-therapy

with other weapons from therapeutic

armametarium (like chemotherapy,

radiotherapy and even classical targeted

therapy) are eagerly awaited and currently

under broad investigation

Final conclusion

There is not clear winner till now, only high

hopes.