Presented at the Immuno-Oncology Summit August 31, 2016. Studies from ASCO16 on immune checkpoint combinations, immune checkpoints with other therapies, immune checkpoints and CAR T, and other studies that enrich our understanding of immuno-oncology as a broad-based discipline for cancer therapy.
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RATIONAL COMBINATION IMMUNOTHERAPY: The best of ASCO16 clinical data
1. Summary of Key Clinical Combination
Trials Presented at ASCO
Paul Rennert, President & CSO, Aleta Biotherapeutics Inc.
Founder & Principal, SugarCone Biotech LLC
.
1
31 August 2016
2. IO combos at ASCO
2
I feel a little bit like this
3. The Drive for IO Combinations
• Increase response rates, durability of response
! Find the next ipilimumab/nivolumab combination
• Impact cancers currently resistant to immune
checkpoint (ICI) therapy
• An ideal profile ...
! Potent combination
! Modest toxicity or does not add toxicity
! May be broadly active or indication selective or tumor
phenotype selective
3
4. The ICI Combination Landscape
4
Produced by Beacon: IO Combination Database
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5. So three examples
• ICI combinations
• ICI & targeted therapy
• ICI & cellular therapeutics
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6. www.sugarconebiotech.com
ICI Combinations
• Where to begin?
• Diverse targets and cell types
• Inhibitory and activating
pathways
• Known and unknown biology
How do you approach this
complexity?
Mahoney, Rennert, Freeman. 2015. Nat Rev DD 6
7. Deconstructing ICI combinations
• Members of the Ig superfamily (home of CTLA4, PD-1, PD-L1)
• Interesting targets but no clinical data yet
Rennert, 2016. in: Novel Immunotherapeutic Approaches to the Treatment of Cancer 7
8. Deconstructing ICI combinations
• Multiple antibodies in clinical development, none very far advanced
• All appear relatively tolerable once dose is established
• Although diverse MOA are postulated within this group of receptors, it is
unclear how much the biology will overlap or be affected by FcR-engagement
Mahoney, Rennert, Freeman. 2015. Nat Rev DD 8
• Activating pathways of the TNFRSF
9. Agonist mAbs to 4-1BB and OX40
• There are many clinical and preclinical programs targeting
these receptors with agonist mAbs
• At ASCO we heard updates on two of these programs
• Phase Ib: PF-05082566 plus pembrolizumab in patients
with advanced solid tumors (4-1BB, Pfizer)
• Phase Ib: MOXR0916 plus atezolizumab in patients with
advanced solid tumors (OX40, Genentech)
• Both are dose escalation studies, on top of fixed anti-PD-1
(pembro) or anti-PD-L1 (atezo) therapy
9
11. Phase Ib study of PF-05082566 (utomilumab) in
combination with pembrolizumab
• Established MTD (>5mpk) = selected Phase 2 dose
• Safety/tolerability good: AEs were similar to those seen
with pembro alone
• Efficacy:
! n = 23
! 6 confirmed responses (4 PR, 2 CR, ORR = 26%)
! Responses were in indications known to be ICI responsive
(RCC, NSCLC, H&N, SCLC) plus 1 thyroid carcinoma.
11J Clin Oncol 34, 2016 (suppl; abstr 3002)
12. Efficacy similar to pembro monotherapy
• 5 were durable:
12J Clin Oncol 34, 2016 (suppl; abstr 3002)
14. A phase Ib dose escalation study of the OX40 agonist
MOXR0916 and the PD-L1 inhibitor atezolizumab in
patients with advanced solid tumors
• Established MTD (none) and selected Phase 2 dose
(300mg)
• Safety/tolerability – well tolerated, AEs similar to
atezolizumab alone
• Trial moving to expansion cohorts in melanoma, RCC,
NSCLC, urothelial Ca and TNBC
! these are ICI responsive indications
14J Clin Oncol 34, 2016 (suppl; abstr 101)
15. Efficacy similar to atezolizumab monotherapy
15J Clin Oncol 34, 2016 (suppl; abstr 101)
• Durable responses: 10/51 (20%)
16. What can we say about these early studies
16
• Results generally viewed as underwhelming – at a minimum we were
looking for better response rates than a-PD-1/PD-L1 monotherapy
• These therapeutics appear to have had the desired phamacologic
effect
! CD8 numbers and IFNγ levels were increased in some patients in the
anti-4-1BB study
! PD-L1 was induced in some patients in the anti-OX40 study (this is IFNγ-
dependent and therefore likely to be CD8-dependent)
• Results are preliminary but do not suggest that these therapeutics will
reach new indications (i.e. patients with ICI-refractory tumors)
• The big biopharmas have the bandwidth to continue to prosecute
these targets – small companies with such assets will have to endure a
longer timeframe to clinical validation
17. ICI & targeted therapy:
attacking a "non-responsive" tumor
• Colorectal Cancer (CRC) has not responded to ICI
therapy
• Three abstracts at ASCO16 were therefore of
immediate importance
! Correlation of Immunoscore with outcome
! Response of MSI-hi CRC to ICI
! Encouraging data from the combination of a MEK inhibitor
with atezolizumab in CRC
17
19. Immunoscore
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• standardized measurement of T cell density within a tumor tissue
(CD3+ T cells and CD3+/CD8+ T cells)
• CRC samples were classified as Immunoscore (IM) high, intermidiate
or low
• Patients were followed to assess time to disease recurrence
J Clin Oncol 34, 2016 (suppl; abstr 3500)
20. This suggests that some CRC patients could be
ICI responsive
20
• but clearly there are other constraints, as the response in
CRC across CTLA4 and PD-pathway inhibitor trials was at
or near zero
J Clin Oncol 34, 2016 (suppl; abstr 3500)
21. Response of MSI-hi CRC to ICI
21
Abstract #3501, presented by Dr Overman
J Clin Oncol 34, 2016 (suppl; abstr 3501)
22. Subset of CRC
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• MSI-high: high mutational burden: 15% of early CRC, 4% of metastatic
CRC
• Patients received nivolumab first, then either stayed on nivo or moved
to nivo plus ipilimumab (2 dose regimens)
J Clin Oncol 34, 2016 (suppl; abstr 3501)
23. Efficacy was surprisingly good
23
• ORR: 33% in the nivo/ipi combo arm
J Clin Oncol 34, 2016 (suppl; abstr 3501)
ORR CR PR SD
MSS, nivo 10 (n=1) nr nr nr
MSS,
combo
0 nr nr nr
MSI-hi,
nivo
26 0 26 30
MSI-hi,
combo
33 0 33 52
26. ICI and targeted therapeutics
• ~15% early CRC and 4% of metastatic CRC
• what else can we do?
26
27. MEK signaling implicated in CRC tumor cell
survival/proliferation
27
• Combining targeted therapeutics with ICI has yielded
mixed results – toxicity and lack of additive efficacy
• Targeting MEK has no impact on CRC
• MEK has been a controversial target for IO combos
• Nevertheless, preclinical data suggested that synergy
might be achieved in CRC
29. The Landscape
29J Clin Oncol 34, 2016 (suppl; abstr 3502)
• Cobimetinib is a highly selective MEK1/2 inhibitor
• The combination of cobi & atezo was tested in a dose escalation plus
expansion cohort trial – both drugs are from Genentech
36. Cellular Therapeutics and ICI
• There are many preclinical studies investigating the
use of ICI to enhance CAR T cell therapies
• Leave you with a case study from Dr Schuster's clinical
trial of CTL019 CAR T cells in NHL, running at UPenn
• These unpublished data were presented by Dr David
Porter (Genentech) in a session devoted to the future of
cellular therapies
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38. Cellular Therapeutics and ICI
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• A remarkable response in a patient who was certainly
out of options
Dr Porter
39. Cellular Therapeutics and ICI
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• Next steps: PD-1 KO CAR T cells
• Combination therapy with ICI
• Sequential therapy with ICI
• and so on
40. Issues with cellular therapies – solid tumors
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• Immuno-suppressive TME
• Sub-optimal expansion esp in MRD or in cases where
solid tumors are heavily consolidated prior to therapy
! Persistence is linked to expansion
! Antigen acccessibility may be limiting
• Antigen specificity is often an issue (Her2, EGFR,
mesothelin, CAIX)
• Lots of problems to solve...
41. ICI Combos – summary
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• ICI combos: Progress will be made – perhaps with fits and
starts – but the sheer breadth of available therapeutics
suggests that best-in-class combos are coming
• ICI and targeted therapeutics: despite many failures,
examples such as cobi/atezo will encourage the field to
continue looking for combos with acceptible profiles
• ICI and cell therapeutics – certainly an interesting start –
but likely solves only one of several critical issues that limit
cell therapy for solid tumors