RATIONAL COMBINATION IMMUNOTHERAPY: The best of ASCO16 clinical data

Summary of Key Clinical Combination Trials Presented at ASCO

Paul Rennert, President & CSO, Aleta Biotherapeutics Inc.

Founder & Principal, SugarCone Biotech LLC .

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31 August 2016

IO combos at ASCO

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I feel a little bit like this

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

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The ICI Combination Landscape

4Produced by Beacon: IO Combination Database

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So three examples

•  ICI combinations

•  ICI & targeted therapy

•  ICI & cellular therapeutics

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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

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

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

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

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Abstract #3002. Dr Tolcher presenting...

J Clin Oncol 34, 2016 (suppl; abstr 3002)

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.

11 J Clin Oncol 34, 2016 (suppl; abstr 3002)

Efficacy similar to pembro monotherapy

•  5 were durable:

12 JClinOncol34,2016(suppl;abstr3002)

Abstract #101, presented by Dr Infante


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


Efficacy similar to atezolizumab monotherapy


•  Durable responses: 10/51 (20%)

What can we say about these early studies

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•  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

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

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Abstract #3500, presented by Dr Galon


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


This suggests that some CRC patients could be ICI responsive

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•  but clearly there are other constraints, as the response in CRC across CTLA4 and PD-pathway inhibitor trials was at or near zero


Response of MSI-hi CRC to ICI

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Abstract #3501, presented by Dr Overman J Clin Oncol 34, 2016 (suppl; abstr 3501)

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)


Efficacy was surprisingly good

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•  ORR: 33% in the nivo/ipi combo arm


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

Progression-free survival

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•  responses


median for MSS patients

Overall survival

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•  responses


median for MSS patients

ICI and targeted therapeutics

•  ~15% early CRC and 4% of metastatic CRC •  what else can we do?

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MEK signaling implicated in CRC tumor cell survival/proliferation

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•  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

Cobimetinib plus atezo

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Abstract #3502, presented by Dr Bendell J Clin Oncol 34, 2016 (suppl; abstr 3502)

The Landscape


•  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

The patients


•  relapsed/refractory, many late stage

Tolerability


•  No additive toxicity, generally similar to MEK inhibitor monotherapy

Efficacy


•  ORR 17-20%, all PR. SD in another 20-22% of patients

Durable responses seen


•  Durability see with both PR and SD responses

Clinically meaningful impact


•  Durable responses are reflected in PFS and OS results

Clinically meaningful impact


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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Dr Porter 37


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•  A remarkable response in a patient who was certainly out of options

Dr Porter


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•  Next steps: PD-1 KO CAR T cells

•  Combination therapy with ICI

•  Sequential therapy with ICI

•  and so on

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...

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

@PDRennert

[email protected]

www.aletabio.com

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Aleta Biotherapeutics is focused on transforming cellular therapeutics to allow a broad spectrum of cancer

indications to be targeted, including currently intractable solid tumors

RATIONAL COMBINATION IMMUNOTHERAPY: The best of ASCO16 clinical data

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