Associate Professor Philip Beale Chair ANZGOG Clinical Trials Group Medical Oncologist Sydney Concord Hospital Chris OBrien Lifehouse Royal Prince Alfred Hospital Outline Background to immunotherapy ID: 806620
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Slide1
Immunotherapy – the good news and the bad
Associate Professor Philip Beale
Chair ANZGOG Clinical Trials Group
Medical Oncologist Sydney
Concord Hospital
Chris O’Brien Lifehouse
Royal Prince Alfred Hospital
Slide2Outline
Background to immunotherapy
Immunotherapy in
gynaecological
cancer
Ongoing trials
Future directions
Slide3What is Immune therapy
3 types
1. Immune boosting therapy
2. Immunotherapy – drugs that have been designed to unlock the immune system to allow targeted destruction of cancer cells
3. Vaccine type therapy – preventative and treatment
Slide4Slide51
2
3
5
6
4
tumour cells
dendritic cells
(APCs)
CD8
+
T cell
priming
CD8
+
T cells
proliferate
memory T cells
tumour antigens
‘6 steps’ of the anti-tumour immune response
Chemotherapy
Targeted therapy
Radiotherapy
Slide6Slide7Tumour
vaccines
Presented By Lukas Rob at 2018 ASCO Annual Meeting
Slide8Slide9Overall Survival
Months
Patients at risk:
73%
74%
67%
64%
59%
45%
Percentage of PFS
0
10
20
30
40
50
60
70
80
90
100
0
3
6
9
12
15
18
39
30
24
33
27
21
Overall Survival (%)
36
0
IPI3410412913614916418220522825428531540NIVO5515717518119120121323024426529231630NIVO+IPI491701921982002092212262472652923147*P<0.0001NIVO+IPI (N=314)NIVO (N=316)IPI (N=315)Median OS, mo (95% CI)NRNR (29.1–NR)20.0 (17.1–24.6)HR (98% CI) vs. IPI0.55 (0.42–0.72)*0.63 (0.48–0.81)*--HR (95% CI) vs. NIVO0.88 (0.69–1.12)----NIVO+IPINIVOIPI9Database lock: Sept 13, 2016, minimum f/u of 28 monthsLarkin (2017). Overall Survival Results From a Phase III Trial of Nivolumab Combined With Ipilimumab in Treatment-naïve Patients With Advanced Melanoma (CheckMate 067)
Slide10Immunotherapy 2011-2018 –
FDA
approved indications
2011
2012
2013
2014
2015
2016
2017
2018
Melanoma
(
ipilimumb
)
Melanoma (
nivo
)
NSCLC 2L PDL1+
(
pembro
)
HNSCC 2L
(
pembro
)
Pembro
:
-
cHL
- NSCLC 1L
- Urothelial
-
Any
MSI-H
- Gastric PDL1+
Nivo
:- NSCLC 2L- RCCcHL (Nivo)HNSCC (Nivo)Melanoma (pembro)Nivo:- HCCMerkel cell(avelumab)Urothelial(durvalumab)Atezolizumab:- NSCLCNSCLC - adjuvant(durvalumab)- Melanoma (adjuvant)- MSI-H CRC- Urothelial- UrothelialMelanoma (ipi/nivo)Melanoma (ipilimumb)Melanoma (nivo)Nivo:- NSCLC 2L- RCCMelanoma (pembro)cHL (Nivo)- UrothelialNSCLC 2L PDL1+ (pembro)HNSCC 2L(pembro)Pembro: - cHL- Urothelial HNSCC (Nivo)Atezolizumab:- NSCLCMerkel cell(avelumab)PBS listedTGA approved (non-PBS)- Any MSI-H Gynae FDA approved indication
Slide11Immunotherapy in
Cervical Cancer
Slide12Immunotherapy in recurrent cervical cancer
- reported trials
Trial
Phase
N
Population
Treatment
Results
NCT01585428
1
II
9
Recurrent/metastatic
ACT
ORR 33%
GOG 265
2II
50Recurrent/metastaticAXAL (Lm-LLO)1yr OS 38%
KEYNOTE-0283
1b24
Recurrent/metastaticPembrolizumabORR 17%
KEYNOTE-1584
II47
PD-L1+ recurrent/metastaticPembrolizumabORR 17%
CheckMate
3585I/II24
Recurrent/metastatic cervical, vaginal, vulval
Nivolumab
ORR 20.8%
1: Stevanović et al. (2015) JCO, 33
(14), 1543–1550; 2
: Leath et al., presented at SGO 2017; 3: Frenel
et al. (2017) JCO, 35(36), 4035–4041. 4: Schellens et al., presented at ASCO 2017;
5:
Hollebecque et al., presented at ASCO 2017;
Slide13Immunotherapy in cervical cancer
- current trials
Trial
Phase
N
Population
Treatment
AIM2CERV
III
450
1
st
line locally adv. cervical ca
ChemoRT
+/- adjuvant AXAL (Lm-LLO)
NCT02635360
II
881st
line locally adv. cervical caChemoRT
vs. pembro-chemoRT
PRIMMOII
43
Recurrent/persistent cervical ca
Immune ‘cocktail’ (Vit D, aspirin, PPI, cyclophosphamide)+ Curcumin +
3x8Gy RT +
pembrolizumab
NCT02725489II33Advanced women’s cancersDurvalumab + Vigil autologous tumour cell immunotherapy
NCT03340376
II48Recurrent cervical cancer
Atezolizumab +/- doxorubicinNCT02598960I/II30
Recurrent/refractory cervical ca
Nivolumab + BMS-986156 (anti-GITR)
Slide14Immunotherapy in
Uterine Cancer
Slide15Immunotherapy in recurrent endometrial cancer
- reported trials
Trial
Phase
N
Population
Treatment
Results
NCT01876511
1,2
II
86
MMR-deficient cancers
Pembrolizumab
ORR 53%
KEYNOTE-028
3
1b24PD-L1+ endometrial caPembrolizumabORR 13%
NCT01375842
4Ia15
Advanced endometrial caAtezolizumabORR 13%
1. Le et al. (2015) NEJM
, 372(26), 2509–25202. Le et al. (2017) Science,
357(6349), 409–413 3. Ott et al. (2017). JCO, 35(22), 2535–2541
4.
Fleming et a. (2017) Presented at ASCO 2017, abstract #5585
Slide16Immunotherapy in endometrial cancer
- current trials
Trial
Phase
N
Population
Treatment
PHAEDRA
II
70
Advanced endometrial ca
Durvalumab
(anti-PD-1)
AtTEnd
III
450
Advanced endometrial ca
Carbo-paclitaxel +/-
Atezolizumab
NCT03015129
II80Advanced endometrial caDurvalumab +/- tremelimumab
NCT02912572
II70
Advanced endometrial caAvelumab
TOPIC
II
51Advanced endometrial ca
Pembrolizumab
+ doxorubicinNCT03241745
II40Advanced uterine cancerNivolumab
Slide17What about Tumour biology?
Markers on the cancer cells can predict for response to treatment
Mismatch repair deficiency
PD-L1 expression on tumour cells
Tumour mutational burden
Slide18Mismatch repair deficiency predicts response of solid
tumors
to PD-1 blockade
Le et al. (2017)
Science
,
357
(6349), 409–413
Slide19Piulats
, J. M., & Matias-
Guiu
, X. (2016). Immunotherapy in endometrial cancer: In the nick of time.
Clinical Cancer Research
,
22
(23), 5623–5625
May 23, 2017:
FDA grants accelerated approval to
pembrolizumab
for first tissue/site agnostic indication
Slide20Immunotherapy in
Ovarian Cancer
Slide21Zhang, L (2003).
The New England Journal of Medicine
,
348
(3), 203–13
Slide22Immunotherapy in ovarian cancer
- reported trials
Trial
Phase
N
Population
Treatment
Results
Fujita
1
II
24
Post 1st line EOC
ACT
3yr DFS 82 vs. 54.5%
Hamanishi
2II
20Platinum-resistant OCNivolumabORR 15%
Matulonis
3II11Recurrent EOC
IpilimumabORR 9%KEYNOTE-028
4
1b26PD-L1+ recurrent EOCPembrolizumabORR 11.5%
JAVELIN 1b51b
124
Recurrent OCAvelumabORR 9.7%
NCT013758426I12
Recurrent OCAtezolizumab
ORR 22%
1: Fujita et al. (1995) CCR, 1(5), 501–507; 2: Hamanishi
et al. (2015) JCO
, 33(34), 4015–4022; 3: Matulonis et a. (2016)
CCR;22(2 Suppl):Abstract nr B72; 4: Varga et al. (2017)
JCO 35, no. 15_suppl 5513-5513.
5: Disis et al. (2016) JCO.2016.34.15_suppl.5533; 6:
Infante et al. (2016) Annals of Oncology, Volume 27, Issue suppl_6, 1 October 2016, 871P,
Slide23Nivolumab
(anti-PD-1) in Patients with Platinum-Resistant Ovarian Cancer
Hamanishi
, J (2015.
Journal of Clinical Oncology
,
33
(34), 4015–4022.
Slide24<br />KEYNOTE-100 (NCT02674061): Phase 2, Two-Cohort Study of Pembrolizumab for Recurrent Advanced Ovarian Cancer<br />
Presented By Ursula Matulonis at 2018 ASCO Annual Meeting
Slide25<br />
Presented By Ursula Matulonis at 2018 ASCO Annual Meeting
Slide26Best Change From Baseline in Tumor Size in Cohorts A + B: Based on RECIST v1.1 per BICR
Presented By Ursula Matulonis at 2018 ASCO Annual Meeting
Slide27Immunotherapy in
recurrent
ovarian cancer
- current/planned trials
Trial
Phase
N
Population
Treatment
NCT02498600
II
96
Recurrent EOC
Nivolumab +/- Ipilimumab
ATLANTE
III
405
Platinum sensitive EOC
Carbo-combo + Bevacizumab +/-
Atezolizumab
JAVELIN 200III
550
Platinum resistant EOC
Lip Dox vs. Avelumab vs. both
NRG GY009
III
488Platinum resistant EOC
Lip Dox +
Atezolizumab and/or Bev
ANITAIII414Platinum sensitive EOC
Platinum-combo
niraparib +/- Atezolizumab
AVANOVA-Immune1II338Platinum sensitive EOC
Niraparib/Bev +/- anti-PD-1 (part 1)
Slide28Immunotherapy in
newly diagnosed
ovarian cancer
- current/planned trials
Trial
Phase
N
Population
Treatment
iPRIME
II
75
Fronline
EOC
NACT +/-
Durvalumab
+ Tremelimumab
JAVELIN 100III951Frontline EOC
CP +/- Avelumab
IMaGYN050
III1300Frontline EOCCP + Bev +/- Atezolizumab
ATHENA
III1000Frontline EOC
CP Rucaparib and/or NivolumabFIRSTIII
700
Frontline EOCCP +/- TSR-042 TSR-042 +
niraparibENGOT ov43III1500
Frontline EOC
CP +/- pembrolizumab + olaparib
Slide29Dendritic Cell Vaccine <br />With Chemotherapy In Patients With Epithelial Ovarian Carcinoma After Primary Debulking Surgery
Presented By Lukas Rob at 2018 ASCO Annual Meeting
Slide30DCVAC/OvCa
Presented By Lukas Rob at 2018 ASCO Annual Meeting
Slide31DCVAC/OvCa
Presented By Lukas Rob at 2018 ASCO Annual Meeting
Slide32Study Design in First-Line Setting
Presented By Lukas Rob at 2018 ASCO Annual Meeting
Slide33PFS<br />~ 6-month Benefit in mPFS and 57% Decrease<br />in The Hazard of Progression in Arm B
Presented By Lukas Rob at 2018 ASCO Annual Meeting
Slide34OS<br />A Trend Towards Improved OS in Arm B
Presented By Lukas Rob at 2018 ASCO Annual Meeting
Slide35Future directions:
‘closing’ the immune cycle
Slide36Sullivan, R. J., & Flaherty, K. T. (2015). New Strategies in Melanoma: Entering the Era of Combinatorial Therapy.
Clinical Cancer Research
,
21
(11), 2424–2435.
Novel immunotherapy combinations
Slide37New ideas
Combination therapy
1. Adding to chemotherapy (already being trialled successfully in lung cancer
2. Combination immunotherapy – successful in melanoma treatment
3. Adding immunotherapy to other targeted agents (
PARPi
in ovarian cancer)
4. Better understanding of which treatment works for which patient
Slide38Willis, J. C. D (2015).
Nature Reviews Immunology
,
15
(March), 1–7
Slide39April 2016 cover (reproduced without permission)
Can we afford to wait for all these trials of promising drugs?
Can we
afford not to?
Slide40Immunotherapy in
gynaeoclogical
cancers….both good and bad news
Slide41Good news :
we have identified a group of patients with endometrial cancer who definitely respond to immunotherapy
Many new trials are underway or reporting
New ideas are being generated every month
Not so good news:
Response rates - so far - are generally modest, 10-20%, but can last for some time
Need to be smarter in picking the right patients and the right time in treatment to get the best results
Bad news
Immunotherapy doesn’t work for many patient with ovarian cancer
Costs are high
Approval is difficult
Conclusion
Slide42Pembro
:
Melanoma (
nivo
)
NSCLC 2L PDL1+
(
pembro
)
HNSCC 2L
(
pembro
)
Pembro
:
-
cHL
- NSCLC 1L
- Urothelial
-
Any
MSI-H
Nivo
:
- NSCLC 2L
- RCC
cHL
(
Nivo
)
HNSCC (
Nivo
)
Melanoma
(
pembro
)Nivo:- HCCMerkel cell(avelumab)Urothelial(durvalumab)Atezolizumab:- NSCLC- Melanoma (adjuvant)- MSI-H CRC- Urothelial- UrothelialMelanoma (ipi/nivo)- Any MSI-H ‘Future’ approved indications?20142015201620172018201920202021?Cervical cancer(pembro)?ovarian?endometrial(e.g. MMR+POLE)