trial in progress: phase 1 studies of bi 1701963, a sos1

Trial in Progress: Phase 1 Studies of BI 1701963, a SOS1::KRAS Inhibitor, in Combination with MEK inhibitors, Irreversible KRASG12C Inhibitors or Irinotecan Marco H. Hofmann1*, Hengyu Lu3, Ulrich Duenzinger2, Daniel Gerlach1, Francesca Trapani1, Annette A. Machado3, Joseph R. Daniele3, Justin K. Huang3, Christopher A. Bristow3, Irene C. Waizenegger1,

Michael Gmachl1, Dorothea Rudolph1, Christopher P. Vellano3, Marcelo Marotti3, Vitomir Vucenovic2, Timothy P. Heffernan3, Joseph R. Marszalek3, Mark P. Petronczki1 and Norbert Kraut1

0 10 20 30 40

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200

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1500

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Days on treatment

Tum

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Vehicle MRTX-849 100 mpk QDx5/wkMRTX + BI-3406 50mpk BIDx5/wkBI-3406 50 mpk BIDx5/wk

VehicleBI 1701963MRTX-849 (100mg/kg)MRTX-849 + BI 1701963

• Trials exploring the combination of BI 1701963 with irreversibleKRAS G12C inhibitors (MRTX849 and BI 1823911) will includecohorts of patients with previously treated KRAS G12C mutantNSCLC and CRC and are anticipated to begin in 2021.

• NCT04627142 is a phase I dose escalation trial of BI 1701963 incombination with irinotecan patients aged ≥18 years with previouslytreated unresectable locally advanced or metastatic colorectal cancer(CRC) harbouring KRAS mutations. 95 patients will be enrolled in thetrial which runs in China only.

• Primary endpoints include dose-limiting toxicities and objectiveresponse rate. Secondary endpoints include pharmacokinetic andpharmacodynamic properties of monotherapy and combinationregimens, treatment-related adverse events and preliminary efficacy.

• Key inclusion criteria include activating KRAS mutation, age ≥18years, ≥1 evaluable lesion (RECIST v1.1), ECOG PS ≤1 andadequate organ function. Key exclusion criteria include previoustherapy with RAS-, MAPK- or SOS1-targeting treatments, history ofretinal vein occlusion or retinopathy and decreased cardiac function.

• As of March 10, 2021, 28 patients have been treated in theBI 1701963 monotherapy arm, 16 patients have been treated in theBI 1701963 + trametinib combination arm in dose escalation (Part A).

1Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria, 2Boehringer Ingelheim International GmbH, Ingelheim, Germany, 3TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

*Corresponding author: [email protected]

Presented at the Virtual AACR Annual Meeting 2021This study was funded by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of poster development and have approved the final version.

• Our preclinical results support the positioning of SOS1::pan-KRAS inhibitors as a backbone combination partner fortargeting KRAS-dependent tumors.

• SOS1::pan-KRASi + MEKi combinations leads to tumor stasisor regressions in KRAS mutant models.

• SOS1::pan-KRAS inhibitors sensitize KRAS G12C mutanttumors to covalent KRAS G12C inhibitors that bind toKRAS(OFF).

• SOS1::pan-KRAS inhibitors sensitizes KRAS mutant cancercells to the effects of irinotecan.

• Phase I clinical trial with BI 1701963 in monotherapy andcombination with MEK inhibitors (NCT04111458),KRAS G12C inhibitors or irinotecan (NCT04627142) areeither ongoing or will be started in 2021.

Key Findings and Conclusions

Introduction (1) Phase I Clinical Trials: SOS1i + MEKi (3) Phase I Clinical Trials: SOS1i + Irinotecan

• BI 1701963 is the first SOS1::pan-KRASsignaling modifier to enter phase I clinicaltrials both as a monotherapy as well as incombination.

• Here, we present pre-clinical data showingenhanced pathway modulation andsynergistic anti-tumor effects followingvertical pathway inhibition of BI 1701963 incombination with:

(1) Mitogen-activated protein kinase inhibitors (trametinib and BI 3011441)

(2) KRAS G12C inhibitors (MRTX849 and BI 1823911)

Results: SOS1::KRASi BI 1701963

(1) Pre-Clinical Results: SOS1i + MEKi

#CT210

• Pre-clinical combination data supported the start of multiple phase Itrials investigating the safety, tolerability, recommended dose andpreliminary efficacy of BI 1701963 alone and in combination with otheranti-cancer agents.

• NCT04111458 is a first-in-human dose escalation and expansion trialof BI 1701963 alone and in combination with trametinib in patientsaged ≥18 years with previously treated solid tumours harbouringKRAS mutations. Approximately 140 patients will be included in thetrial. Parts B and C will only include patients with advanced non-smallcell lung cancer (NSCLC).

BI-3406 and BI1701963 are SOS1::pan-KRAS inhibitors exhibitingactivity against a broad spectrum of KRAS alleles, including the majorG12D/V/C and G13D oncoproteins, while sparing the interaction ofKRAS with SOS2.

Tool Compound

BFigure 1A

Nor

mal

ized

RLU

(%D

MSO

)

Perc

enta

ge p

rolif

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Inhi

bitio

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SOS1i BI-3406 (log, M)SOS1i BI-3406 (log, M)

Figure 2: SOS1i + MEKi combination exhibits differential response in pancreaticcancer PDX models.

Figure 5: SOS1i + Irinotecan Combination

A, Biochemical protein-protein interaction assay (Alpha Screen)between recombinant SOS1 or SOS2 and recombinant KRAS G12C orKRAS G12D conducted with increasing concentrations of the SOS1iBI-3406 B, In vitro sensitivity panel of NCI-H23 isogenic cell linestreated with BI-3406 in a 3D proliferation assay.

Figure 1: SOS1i blocks the interaction of SOS1 and KRAS and thereby inhibitsthe proliferation of NCI-H23 isogenic cell lines carrying a KRAS G12D, G12V,G12C or G13D allele.

N

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F3C NH2

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BI-3406

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VehicleBI-406 + Trametinib

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PATX147 (Q61R)

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PATX216 (Q61K)

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PATX53 (G12D)

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PATX124 (G12D)

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PATX153* (G12V)

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PATX219B (G12D)

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PATX141 (G12D)

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PATX60 (G12D)

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PATX110 (G12D)

PATX118 (Q61H)

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Days on Treatment

Vehicle (n=5)BI-406 + Trametinib (n=5)Vehicle (N=10)BI-406 + Trametinib (n=10)

0 10 20 300

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Days on Treatment

Vehicle (n=8)BI-406 + Trametinib (n=8)Vehicle (n=5)BI-406 + Trametinib (n=4)

PATX148 (G12D)PATX55 (Q61H)

Inte

rmed

iate

Vehicle SOS1i + MEKi

Stab

lePr

ogre

ssiv

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Gene Signature Score

Figure 3: SOS1i + MEKi combination exhibits anti-tumor response in KRASmut

colorectal cancer PDX models.

A, Rationale of combining SOS1i with MEKi. B, In vivo efficacy ofBI-3406 / BI 1701963 (50 mpk, BID) + trametinib (0.1 mpk, BID) in PDACPDX models. Responses are categorized as progressive, intermediate,and stable. C, Models are sorted by first the Principal Component (PC1)of a gene signature developed by using the sum replicates, nested model,and cross-class pairwise methods based on baseline gene expressiondifferences between the stable and progressive models.

C

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F3008 (CRC)

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BI-1963, 50 mg/kg, bid

lip. Irinotecan 5 mg/kg, q7d

Combination Natroso

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Irinotec

an

BI-196

3

Irinotec

an +

BI-196

3 0.00

0.25

0.50

0.75

1.00

1.25

1.50

% p

ositi

ve a

rea

✱p= 0.01

CleavedCaspase 3 (cC3)

Irinotec

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Irinotec

an +

BI-196

30

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H-S

core

✱✱ p=0.079

yH2AX(DNA Damage)

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Rel

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LoVo CDXKRAS G13D

0.1

1

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SW620 CDXKRAS G12V

MIA PaCa-2 CDXKRAS G12C A, Rationale of combining

SOS1i with irinotecan B, invivo efficacy in CDX modelsC, Modulation of yH2AX andcleaved caspase measuredby IHC in LoVo tumorfollowing 8 days of treatment.

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VehicleAMG-510 30 mpk QDx5/wkAMG-510 + BI-1963 50 mpk BIDx5/wk

Tumor0

20

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60

DUSP6 mRNA copies

Avg

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ies/

posi

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cell

-6

-4

-2

0

2MPAS score

MPA

S

A, In vivo efficacy of BI-3406 / BI 1701963 (50 mpk, BID) + trametinib(0.1 mpk, BID) in KRASmut CRC PDX models. B, RNAScope wasevaluated on tumor samples collected from B8182 endpoint samples(4 hours post-1st dose).

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cle

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DUSP6 EGR1 DUSP4 SPRY4 JUNB POL2RAB

A A B

C

B8182 (CRC)

A, Rationale combining SOS1i with KRASG12Ci. In vivo efficacy and biomarkeranalysis of B, AMG 510 (30 mpk, QDx5/wk)alone or combined with BI 1701963(50 mpk, BIDx5/wk) in B8182 model and C,MRTX849 (100 mpk, QD), BI-3406 (50mpk, BID), and the combination in F3008model.

A B

B

C

• Primary endpoints include dose-limiting toxicities and objectiveresponse rate. Secondary endpoints include pharmacokineticparameters of monotherapy and combination regimens, treatment-related adverse events and preliminary efficacy.

• Key inclusion criteria include previous treatment with standardfluoropyrimidine-based chemotherapy, activating KRAS mutation, age≥18 years, ≥1 evaluable lesion (RECIST v1.1), ECOG PS ≤1 andadequate organ function. Key exclusion criteria include previoustherapy with RAS-, MAPK- or SOS1-targeting treatments or irinotecan(Part B and C only), history of retinal vein occlusion or retinopathyand decreased cardiac function.

• As of March 10, 2021, 4 patients have been treated in the trial.

(2) Phase I Clinical Trials: SOS1i + KRASG12Ci

(2) Pre-Clinical Results: SOS1i + KRASG12Ci

(3) Pre-Clinical Results: SOS1i + Irinotecan

Tumor DUSP6+0

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Avg.

copie

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Vehicle MRTX-849100mpk QDx5/wk

MRTX-849+BI-340650mpk BIDx5/wk

Tumor pHH3+0.0

0.5

1.0

1.5

pHH3

% po

sitive

cells

(3) Furthermore, the SOS1::pan-KRAS inhibitor treatment sensitizestumor cells to increased DNA damage in combination with irinotecan.

SOS1i

Additional data will be presented in poster #1271, Savarese et al. Part

C:

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Monotherapy

BI 1701963Dose will be escalated until MTD / RP2D is

reached or 2000 mg QDn≥3 per dosage

BI 1701963 TRD 1n=12

BI 1701963 TRD 2n=12

Combination therapy

BI 1701963 + trametinibDose will be escalated until the MTD / RP2D

or highest tested monotherapy dose (BI 1701963) or a max. of 2 mg QD

(trametinib) is reached n≥3 per dosage

BI 1701963 + trametinib

TRD 1 n= 10

BI 1701963 + trametinib

TRD 2 n= 10

If ≥1 OR observed, add n=15 patients

If ≥1 OR observed, add n=15 patients

was initiated after first

three dose levels

BI 1701963 confirmed as

safe

Figure 6: NCT04111458 Study Design

TRD: therapeutically relevant dose; MTD: maximum tolerated dose; RP2D: recommended phase 2 dose

Part C: Combination Therapy

Expansion

Part B: Combination Therapy Dose

EscalationPart A:

Monotherapy Safety Run-In

BI 1701963At least two dose levels that have been confirmed safe in the first-in-human trial monotherapy arm will

be investigated

n≥6 per dosage

Figure 7: NCT04627142 Study Design

BI 1701963+ irinotecan

BI 1701963 dose will be escalated until the MTD / RP2D of the

combination is reached

n≥3-6 per dosage

BI 1701963 + irinotecan

TRD 2 n= 25

BI 1701963 + irinotecan

TRD 1n= 25

R

TRD: therapeutically relevant dose; MTD: maximum tolerated dose; RP2D: recommended phase 2 dose

Table 1

DUSP6 pHH3

DUSP6 mRNA MPAS ScoreFigure 4: SOS1i + KRAS G12Ci Combination in KRAS G12Cmut CRC PDX models

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C1047 KRASG12C

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C1035 KRASG12V

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B8182 KRASG12C

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C0999 KRASG12D

3D Proliferation Assay

B8182 KRAS G12C C0999 KRAS G12D C1047 KRAS G12C C1035 KRAS G12V

DUSP6 EGR1 DUSP4 JUNB SPRY4 Average POLR2A0

50

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Copy

/cel

l Vehicle BI-1963+TramPDX: B8182

DUSP6 EGR1 DUSP6 JUNB SPRY4 Average POL2RA

Vehicle BI 1701963+Trametinib

VehicleAMG-510 (30 mg/kg)AMG-510 + BI 1701963

Clinical Candidate

Biochemical Protein-ProteinInteraction Assay

trial in progress: phase 1 studies of bi 1701963, a sos1

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