Immune oncology vs. targeted therapies in solid tumors

Immune oncology vs. targeted
therapies in solid tumors –
is there a winner?
Dr. Răzvan Curcă
Spitalul Judeţean de Urgenţă Alba-Iulia
Evolution of Cancer Therapy:
Core Treatment Modalities
Surgery
1846
Chemotherapy
1946
Radiation Therapy
1901
Immuno-Oncology
2011
Targeted Therapy
1997
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.
Targeted therapy
Prototype- CML
FDA approved targeted therapies
FDA approved targeted therapies (2)
“FDA approves Zykadia for latestage 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 board
University 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 (1477 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 board
University 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 board
University 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
Baseline

15 weeks of
vemurafenib
23 weeks of
vemurafenib
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
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
General Approaches for
Cancer Immunotherapy
Peptide vaccine
DC vaccine
Genetic vaccine
IL-2
IFN
IL-15
IL-21
Active immunotherapy
Adoptive cell transfer
immunotherapy
T cell cloning
CD40
CD137
OX40
CTLA-4
PD-1
TCR or CAR
genetic engineering
Ipilimumab: Pooled Survival Analysis From
Phase II/III Trials in Advanced Melanoma
1.0
Proportion Alive
0.8
Median OS: 11.4 mos (95% CI: 10.7-12.1)
3-yr OS rate: 22% (95% CI: 20-24)
0.6
0.4
0.2
Ipilimumab
Censored
0
0
Pts at Risk, n
Ipilimumab 1861
12
24
36
48
60
Mos
72
84
96
108
120
839
370
254
192
170
120
26
15
5
0
Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24.
Schadendorf D, et al. J Clin Oncol. 2015
Clinical Development of Anti–PD-1
Checkpoint Inhibitors in Solid Tumors
Antibody
Nivolumab
Molecule
Development Stage
Fully
human
IgG4
Approved (US): advanced melanoma
after previous therapy, advanced NSCLC
after CT
Phase III multiple tumors (NSCLC,
melanoma, RCC, HNSCC, GBM, gastric)
Approved (US): advanced melanoma
Humanized
after previous therapy
Pembrolizumab
IgG4
Phase III multiple tumors (HNSCC, NSCLC,
melanoma, bladder, gastric/GE)
Pidilizumab
Humanized
IgG1
Phase II multiple tumors (pancreatic,
CRC, RCC, prostate, CNS)
AMP-224
Fc-PD-L2
fusion
protein
Phase I
Clinical Development of Anti–PD-1
Checkpoint Inhibitors in Solid Tumors
Antibody
Atezolizumab
(MPDL3280A)
Molecule
Development Stage
Engineered
Phase III multiple tumors
human
(NSCLC, bladder, RCC, TNBC)
IgG1
Avelumab
(MSB0010718C)
Fully
human
IgG1
Phase III (NSCLC)
Durvalumab
(MEDI4736)
Engineered
human
IgG1
Phase III multiple tumors
(NSCLC, HNSCC)
Clinical Development of Other Immune
Checkpoint Inhibitors in Solid Tumors
Target
Antibody
Ipilimumab
CTLA-4
Molecule
Development Stage
Approved: advanced melanoma
Humanized
Phase III multiple tumors
IgG1
(melanoma, NSCLC, SCLC, CRPC,
GBM, RCC)
Tremelimumab
Fully
human
IgG2
Phase III multiple tumors
(HNSCC, NSCLC)
INCB024360
TKI
Phase II multiple tumors
(ovarian, melanoma)
NLG919
TKI
Phase I
B7-H3
MGA271
Humanized
IgG1kappa
Phase I
LAG-3
BMS-986016
---
Phase I
IDO
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
+ Anti–CTLA-4
+ Immune-activating
antibodies or cytokines
Bring T cells
+ TLR agonists or oncolytic
into tumors:
viruses
+ IDO or macrophage
inhibitors
+ Targeted therapies
Vaccines
TCR-engineered ACT
Generate T cells:
CAR-engineered ACT
Proportion Alive and
Progression Free
CheckMate 067: Improved PFS with
Nivo + Ipi or Nivo Alone vs Ipi Alone
Nivo + Ipi
(n = 314)
Nivo
(n = 316)
Ipi
(n = 315)
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)†
_
_
Median PFS, mos (95%
CI)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Nivo + Ipi
Nivo
Ipi
0
3
6
9
Mos
12
15
16
21
*Stratified log-rank P < .00001 vs Ipi.
†Exploratory endpoint. Study not powered to detect a statistical difference between Nivo + Ipi and Nivo.
Larkin J, et al. N Engl J Med. 2015; [epub ahead of print].
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.