Trial in Progress: Phase 1 Studies of BI 1701963, a SOS1 ...

[Pages:1]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

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: marco.hofmann@boehringer-

#CT210

Introduction

? SOS1i ?

BI 1701963 is the first SOS1::pan-KRAS signaling modifier to enter phase I clinical trials both as a monotherapy as well as in combination.

Here, we present pre-clinical data showing enhanced pathway modulation and synergistic anti-tumor effects following vertical pathway inhibition of BI 1701963 in combination with:

(1) Mitogen-activated protein kinase inhibitors

(trametinib and BI 3011441)

(2) KRAS G12C inhibitors

(MRTX849 and BI 1823911)

(3) Furthermore, the SOS1::pan-KRAS inhibitor treatment sensitizes

tumor cells to increased DNA damage in combination with irinotecan.

Results: SOS1::KRASi BI 1701963

BI-3406 and BI1701963 are SOS1::pan-KRAS inhibitors exhibiting

activity against a broad spectrum of KRAS alleles, including the major

G12D/V/C and G13D oncoproteins, while sparing the interaction of

KRAS with SOS2.

BI-3406

Table 1

Tool Compound

Clinical Candidate F3C

NH2 O

NH

N

O

N

O

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

Figure 1A Biochemical Protein-Protein

B

Interaction Assay

3D Proliferation Assay

Normalized RLU (%DMSO) Percentage proliferation Inhibition

SOS1i BI-3406 (log, M)

SOS1i BI-3406 (log, M)

A, Biochemical protein-protein interaction assay (Alpha Screen) between recombinant SOS1 or SOS2 and recombinant KRAS G12C or KRAS G12D conducted with increasing concentrations of the SOS1i BI-3406 B, In vitro sensitivity panel of NCI-H23 isogenic cell lines treated with BI-3406 in a 3D proliferation assay.

(1) Pre-Clinical Results: SOS1i + MEKi

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

Progressive Tumor Volume (mm3)

A

B PATX110 (G12D) PATX141 (G12D) PATX60 (G12D) PATX219B (G12D)

Tumor Volume (mm3)

Tumor Volume (mm3)

Tumor Volume (mm3)

800 Vehicle BI-406 + Trametinib

600

400

1500 Vehicle BI-406 + Trametinib

1000

1500 Vehicle BI-406 + Trametinib

1000

1000 Vehicle BI-406 + Trametinib

800

600

500 200

400 500

200

0

0

10

20

30

Days on Treatment

0

0

10

20

30

Days on Treatment

0

0

10

20

30

Days on Treatment

0

0

10

20

30

Days on Treatment

PATX118 (Q61H) PATX55 (Q61H) PATX153* (G12V) PATX148 (G12D)

C

1500 Vehicle BI-406 + Trametinib

1000

1000 Vehicle (n=8) BI-406 + Trametinib (n=8) Vehicle (n=5) BI-406 + Trametinib (n=4)

2000 Vehicle BI-1963 + Trametinib

1500

2000 Vehicle (n=5) BI-406 + Trametinib (n=5) Vehicle (N=10) BI-406 + Trametinib (n=10)

1500

500

1000

1000

500

500

500

Tumor Volume (mm3)

Tumor Volume (mm3)

Tumor Volume (mm3)

Intermediate Tumor Volume (mm3)

Gene Signature Score

Stable

Tumor Volume (mm3)

0

0

10 20 30 40

Days on Treatment

0

0

10

20

30

Days on Treatment

PATX147 (Q61R)

800 Vehicle BI-406 + Trametinib

600

400

200

Tumor Volume (mm3)

PATX124 (G12D)

2500 Vehicle BI-406 + Trametinib

2000

1500

1000

500

0

0 5 10 15 20 25 Days on Treatment

0

0

10

20

30

Days on Treatment

Tumor Volume (mm3)

0

0

10

20 30 40

Days on Treatment

0

0

10

20

30

Days on Treatment

PATX53 (G12D)

2000 Vehicle BI-406 + Trametinib

1500

1000

500

0 0 5 10 15 20 25 Days on Treatment

Tumor Volume (mm3)

PATX216 (Q61K)

1000 Vehicle BI-406 + Trametinib

800

600

400

200

0

0

10

20

30

40

Days on Treatment

Vehicle SOS1i + MEKi

A, Rationale of combining SOS1i with MEKi. B, In vivo efficacy of BI-3406 / BI 1701963 (50 mpk, BID) + trametinib (0.1 mpk, BID) in PDAC PDX 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 expression differences between the stable and progressive models.

Figure 3: SOS1i + MEKi combination exhibits anti-tumor response in KRASmut colorectal cancer PDX models.

A

2000

1500

B8182 KRAS G12C

B8182 KRASG12C

Vehicle BI-1963 (50 mpk) + Tram (0.1 mpk)

C0999 KRAS G12D

2000

C0999 KRASG12D

Vehicle

BI-406 50mpk + Tram. 0.1mpk

1500

Tumor Volume (mm3)

Tumor Volume (mm3)

1000

1000

500

500

0

0

5

10

15

Days on study

B

DUSP6

EGR1

20

DUSP4

0

0

5

10 15 20 25

Days on study

SPRY4

JUNB POL2RA

Tumor Volume (mm3)

C1047 KRAS G12C

600

C1047 KRASG12C

Vehicle

BI-406 50mpk + Tram. 0.1mpk

400

200

0

0

10

20

30

Days on study

PDX: B8182

150

VeVhiechleicle

Tumor Volume (mm3)

C1035 KRAS G12V

1000 C1035 KRASG12V

Vehicle BI-406 50mpk + Tram. 0.1mpk 800

600

400

200

0

0

5

10 15 20 25

Days on study

BI-B19I6137+0T1ra9m63+Trametinib

100

Relative Average Copy/cell

Vehicle

MEKi

SOS1i +

50

0 DUDUSSPP66 EEGGRR11 DDUUSSPP46 JJUUNNBB SSPPRYR4Y4AveArvageerage POPLO2LRR2AA

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

(2) Pre-Clinical Results: SOS1i + KRASG12Ci

Tumor Volume (mm3)

Avg copies/positive cell MPAS

Figure 4: SOS1i + KRAS G12Ci Combination in KRAS G12Cmut CRC PDX models

A

B

3000

B8182 (CRC)

Vehicle AMG-510 (30 Vehicle

AMG-510 30 mpk QDx5/wk

DUDSUPS6Pm6RNmARcNopAies MMPPAASSSsccoorree

60

2

2500

mg/kg) AMG-510 + BI-1963 50 mpk BIDx5/wk

AMG-510 +

0

2000 BI 1701963

40

1500

-2

1000

20

-4

500

0 0

5

10

15

20

25

0

-6

Days on Treatment

Tumor

A, Rationale combining SOS1i with KRAS

G12Ci. In vivo efficacy and biomarker

analysis of B, AMG 510 (30 mpk, QDx5/wk)

alone or combined with BI 1701963

C

2000 1500 1000

500 400

300

200

F3008 (CRC)

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

(50 mpk, BIDx5/wk) in B8182 model and C,

MRTX849 (100 mpk, QD), BI-3406 (50

mpk, BID), and the combination in F3008

model. DDUUSSPP66

ppHHHH33

40

1.5

30 1.0

20 0.5

10

Avg. copies/cell % positive cells

Tumor Volume (mm3)

100 0

10

20

30

40

Days on treatment

0 Tumor DUSP6+

0.0 Tumor pHH3+

Vehicle BI-3406 50 mpk BIDx5/wk

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

Vehicle

MRTX-849 100mpk QDx5/wk

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

MRTX-849+BI-3406 50mpk BIDx5/wk

(3) Pre-Clinical Results: SOS1i + Irinotecan

Figure 5: SOS1i + Irinotecan Combination

A

B LoVo CDX

KRAS G13D

10

C yH2AX

(DNA Damage)

p=0.079

250

Cleaved

Caspase 3 (cC3)

1.50

p= 0.01

1.25

H-Score % positive area

Rel. Tumor Volume

200

1.00

150

0.75

1

100

0 10 20 30 40

0.50

Vehicle Control

50

0.25

BI-1963, 50 mg/kg, bid 0

0.00

IrinotecanIr+inBoIt-e1c9a63n IrinotecanIr+iNnBBaoIItt--re11oc99sa66o3nl3

lip. Irinotecan 5 mg/kg, q7d

Combination

B

Rel. Tumor Volume

MIA PaCa-2 CDX KRAS G12C

SW620 CDX KRAS G12V

10

10

Rel. Tumor Volume

1

1

0.1 0

10 20 30 40 Day

0.1 0 10 20 30 40 50 60 Day

A, Rationale of combining SOS1i with irinotecan B, in vivo efficacy in CDX models C, Modulation of yH2AX and cleaved caspase measured by IHC in LoVo tumor following 8 days of treatment.

(1) Phase I Clinical Trials: SOS1i + MEKi

? Pre-clinical combination data supported the start of multiple phase I

trials investigating the safety, tolerability, recommended dose and preliminary efficacy of BI 1701963 alone and in combination with other anti-cancer agents.

? NCT04111458 is a first-in-human dose escalation and expansion trial

of BI 1701963 alone and in combination with trametinib in patients aged 18 years with previously treated solid tumours harbouring KRAS mutations. Approximately 140 patients will be included in the trial. Parts B and C will only include patients with advanced non-small cell lung cancer (NSCLC).

Figure 6: NCT04111458 Study Design

Part A: Dose escalation

Monotherapy

BI 1701963

Dose will be escalated until MTD / RP2D is reached or 2000 mg QD n3 per dosage

was initiated after first three dose levels

BI 1701963 confirmed as

safe

Combination therapy

BI 1701963 + trametinib

Dose will be escalated until the MTD / RP2D or highest tested monotherapy dose (BI 1701963) or a max. of 2 mg QD (trametinib) is reached n3 per dosage

BI 1701963

TRD 1 n=12

BI 1701963

TRD 2 n=12

BI 1701963 +

trametinib

TRD 1 n= 10

BI 1701963 +

trametinib

TRD 2 n= 10

Part B: Dose confirmation

Part C: Dose expansion

If 1 OR observed, add n=15 patients

If 1 OR observed, add n=15 patients

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

? Primary endpoints include dose-limiting toxicities and objective

response rate. Secondary endpoints include pharmacokinetic and pharmacodynamic properties of monotherapy and combination regimens, treatment-related adverse events and preliminary efficacy.

? Key inclusion criteria include activating KRAS mutation, age 18

years, 1 evaluable lesion (RECIST v1.1), ECOG PS 1 and adequate organ function. Key exclusion criteria include previous therapy with RAS-, MAPK- or SOS1-targeting treatments, history of retinal vein occlusion or retinopathy and decreased cardiac function.

? As of March 10, 2021, 28 patients have been treated in the

BI 1701963 monotherapy arm, 16 patients have been treated in the BI 1701963 + trametinib combination arm in dose escalation (Part A).

(2) Phase I Clinical Trials: SOS1i + KRASG12Ci

? Trials exploring the combination of BI 1701963 with irreversible

KRAS G12C inhibitors (MRTX849 and BI 1823911) will include cohorts of patients with previously treated KRAS G12C mutant NSCLC and CRC and are anticipated to begin in 2021.

Presented at the Virtual AACR Annual Meeting 2021

This 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.

(3) Phase I Clinical Trials: SOS1i + Irinotecan

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

Figure 7: NCT04627142 Study Design

BI 1701963

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

be investigated

n6 per dosage

BI 1701963 + irinotecan

BI 1701963 dose will be escalated R until the MTD / RP2D of the combination is reached

n3-6 per dosage

BI 1701963 + irinotecan

TRD 1 n= 25

BI 1701963 + irinotecan

TRD 2 n= 25

Part A: Monotherapy Safety Run-In

Part B: Combination Therapy Dose

Escalation

Part C: Combination Therapy

Expansion

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

? Primary endpoints include dose-limiting toxicities and objective

response rate. Secondary endpoints include pharmacokinetic parameters of monotherapy and combination regimens, treatmentrelated adverse events and preliminary efficacy.

? Key inclusion criteria include previous treatment with standard

fluoropyrimidine-based chemotherapy, activating KRAS mutation, age 18 years, 1 evaluable lesion (RECIST v1.1), ECOG PS 1 and adequate organ function. Key exclusion criteria include previous therapy with RAS-, MAPK- or SOS1-targeting treatments or irinotecan (Part B and C only), history of retinal vein occlusion or retinopathy and decreased cardiac function.

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

Key Findings and Conclusions

? Our preclinical results support the positioning of SOS1::panKRAS inhibitors as a backbone combination partner for targeting KRAS-dependent tumors.

? SOS1::pan-KRASi + MEKi combinations leads to tumor stasis or regressions in KRAS mutant models.

? SOS1::pan-KRAS inhibitors sensitize KRAS G12C mutant tumors to covalent KRAS G12C inhibitors that bind to KRAS(OFF).

? SOS1::pan-KRAS inhibitors sensitizes KRAS mutant cancer cells to the effects of irinotecan.

? Phase I clinical trial with BI 1701963 in monotherapy and combination with MEK inhibitors (NCT04111458), KRAS G12C inhibitors or irinotecan (NCT04627142) are either ongoing or will be started in 2021.

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