Pan-ErbB/HER inhibition enhances activity of KRASG12C inhibitors in preclinical models of KRASG12C mutant cancersJacqulyne Robichaux, PhDUniversity of Texas MD Anderson Cancer Center, Houston, Texas

Jacqulyne Robichaux

I have the following financial relationships to disclose:Grant/Research support from: Spectrum Pharmaceuticals, TakedaPatent/Royalties: Spectrum Pharmaceuticals

-and-I will discuss the following off label use and/or investigational use in my presentation:Erlotinib, poziotinib, afatinib, adagrasib, sotorasib

KRASG12C mutations are a substantial and targetable subgroup of NSCLC

Adapted from Skoulidis and Heymach 2019 Nat Rev Can1 Robichaux et al 2021 Nature2 Mack et al 2020 Cancer 3 Jonna et al 2019 Clin Can Res4 Russo et al 2020 Precis Cancer Med5 Robichaux et al 2019 Cancer Cell

KRASG12C mutations comprise ~25,000 patients per year in the US

Sotorasib is a first in class and clinicallyactive KRASG12C inhibitor

Skoulidis et al. N Engl J Med 2021

Objective Response Rate: 37.1%Disease Control Rate: 80.6%

Sotorasib(AMG 510)

KRASG12C inhibitor adaptation occurs through targetable pathways

Created In BioRender

Sotorasib and adagrasib preventnucleotide cycling of KRASG12C

KRASG12C inhibitor adaptation correlates with upregulation of EGFR signaling

AcD = actinomycin

HB-EGF activates EGFR and HER4

Xue et al Nature 2020

KRASG12C inhibitor treatment increased phosphorylation of entire EGFR/HER family

Hypothesis: pan-HER/ERBB inhibitors may enhance G12Ci activity to a greater extent compared to EGFR-specific inhibitors

Sotorasib

HCC44 H2122 H3580.75

1.00

1.25

1.50

1.75

2.00

Sotorasib1µM 72hrs

Fold

cha

nge

from

DM

SO

DMSOpEGFR

pHER2pHER3

pHER4

0.006

<0.0010.007<0.001

<0.0010.029

<0.001<0.001 <0.001

<0.0010.007

<0.001

HCC44 H2122 H3580.75

1.00

1.25

1.50

1.75

2.00

Adagrasib1µM 72hrs

Fold

cha

nge

from

DM

SO

DMSOpEGFR

pHER2pHER3

pHER4

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

ns<0.001

<0.001

0.002

<0.001

<0.001

Second-generation EGFR TKIs have variable HER selectivity compared to EGFR

Poziotinib is a pan-HER inhibitor with greater selectivity for HER2-4 than EGFR

Afatinib has greater selectivity for EGFR than other HER family members

1 10 1000

25

50

75

100

Ba/F3 Cells

[Poziotinib, nM]

% V

iabi

lity

HER4 + NRG1

EGFR + EGFHER2/HER3 + NRG1HER2/HER4 + NRG1HER3/HER4 +NRG1

1 10 100 10000

25

50

75

100

Ba/F3 Cells

[Afatinib, nM]

% V

iabi

lity

HER4 + NRG1

EGFR + EGFHER2/HER3 + NRG1HER2/HER4 + NRG1HER3/HER4 +NRG1

Does pan-HER inhibition synergize with G12Ci more than EGFR-specific inhibitors?

Dose response matrix for each drug pair Calculate Synergy (BLISS)

Compare BLISS scores and phosphorylation of

EGFR/HER family members across cell lines

BLISS >10: SynergisticBLISS -10 – 10: AdditiveBLISS <-10: Antagonistic

Combination of G12Ci with poziotinib is more synergistic than EGFR specific inhibitors

Erlotinib(EGFR)

Afatinib(EGFR/HER2)

Poziotinib(pan-HER)

-10

0

10

20

Adagrasib

BLIS

S In

dex

0.0001<0.0001

ns

BLISS >10: SynergisticBLISS -10 – 10: AdditiveBLISS <-10: Antagonistic

Erlotinib(EGFR)

Afatinib(EGFR/HER2)

Poziotinib(pan-HER)

-10

0

10

20

30

Sotorasib

BLIS

S In

dex

0.00070.0004

ns

Pan-HERi prevents G12Ci induced phospho-HER upregulation more than EGFR selective inhibitors

pEGFR pHER2 pHER3 pHER40.50

0.75

1.00

1.25

1.50

1.75

Adagrasib

Fold

cha

nge

from

DM

SO

DMSOG12Ci (1µM)

Pozi (5nM) + G12Ci (1µM)Afat (50nM) + G12Ci (1µM)

<0.001 <0.001

0.006

ns

<0.001<0.001

<0.001

0.017

0.002 <0.001

ns

0.007

<0.001

ns<0.001

0.006

pEGFR pHER2 pHER3 pHER40.50

0.75

1.00

1.25

1.50

1.75

Sotorasib

Fold

cha

nge

from

DM

SO

DMSOG12Ci (1µM)

Pozi (5nM) + G12Ci (1µM)Afat (50nM) + G12Ci (1µM)

ns

<0.001<0.001

<0.001

ns

0.001<0.001

0.0010.004<0.001

ns

0.007

0.020<0.001

0.001

ns

Conclusions and Future Directions

Poziotinib is a potent pan-HER inhibitor with greater HER2-4 inhibition than EGFR

Pan-HER inhibition prevented G12Ci induced phospho-HER upregulation more than EGFR selective inhibitor

Pan-HER inhibition resulted in greater synergy with KRASG12C inhibitors than EGFR or EGFR/HER2 inhibitors

Ongoing work: Determine if addition of pan-ErbB inhibitor (vs EGFR or EGFR/HER2) to

G12C inhibitor treatment prolongs survival/PFS of G12C PDX models at tolerable doses

Acknowledgements

Ana Galan CoboAllyson PfeilSimon HeekeMonique NilssonFahao ZhangHibiki UdagawaAlissa PoteeteXiaoyang RenJayanthi Gudikote

Junqin HeKelly GaleThiru ArumugamSonia PatelYu QianYan YangXiaoxing YuXiang Zhang

Heymach Lab Gulf Coast ConsortiumDrug ScreeningRied PowellMary SobieskiNghi NguyenStephan Clifford

PDX Models (ongoing)Bingliang FangXiaoshan ZhangChenghui Ren

FundingRexanna’s Foundation for Fighting Lung CancerMD Anderson Lung Cancer Moon Shots ProgramLung SPORE CA070907R01CA247975CPRIT RP200150R01CA234183-01A1Spectrum Pharmaceuticals Stading and Hallman Funds