KRAS-Mutated CancersClinical Trials Landscape Therapies under investigation for KRAS-Mutated Cancers

June 2020

On your Journey, We are with you!

Executive Summary

• As per clinical phase of development, there are currently ~64 assets in Phase I, ~41 assets in Phase I/II, ~86 assets in Phase II, ~17 assets in Phase III clinical development for KRAS-mutated cancer

• As per indication, colorectal cancer has the highest number of clinical trial trials among KRAS-mutated cancer which are ~93 trials in number, followed by NSCLC (~53 trials), Solid tumors (~32 trials), Pancreatic cancer (~13 trials), Breast cancer (~13 trials), Multiple Myeloma (~8 trials) and others

• As per MoAs, EGFR inhibitors are seeing maximum activity in clinical trials (~95 trials) for KRAS mutated cancer, followed by MAP inhibitors (~45 trials), PD-1 inhibitors (~15 trials), Pi3k inhibitors (~9 trials), KRAS Inhibitors (~ 7 trials)

• As per company/sponsors, the highest number of clinical trials in KRAS mutated cancer are being carried out by Amgen (~32 trials), Novartis (~18 trials), Merck (~17 trials), Roche/Genentech (~16), Pfizer (~16 trials), AstraZeneca (~11 trials), Eli Lilly (~11 trials), BMS (~11 trials), Array Biopharma (~11 trials), GSK (~8 trials), Boehringer Ingelheim (~5 trials), Takeda (~5 trials)

Phase I assets under investigation in KRAS mutated cancers (1/3)

BKM120

NCT01513356/

Novartis

Mesenchymal-marker

based ferrofluid

NCT02080650/Jansse

n Diagnostics

KRAS peptide

vaccine|Nivolumab|Ipi

limumab

NCT04117087/Bristol

-Myers Squibb

JNJ-74699157

NCT04006301/Jansse

n Research &

Development

BI 1701963|

Trametinib

NCT04111458/Boehri

nger Ingelheim

Sotorasib + Other

Anti-cancer

Therapies*

NCT04185883/Amge

n

MEK162 and

mFOLFIRI

NCT02613650/Array

BioPharma

Decitabine +

panitumumab

NCT00879385/Amge

n Inc.

Pembrolizumab +

Trametinib

NCT03299088

Novartis

REOLYSINÂ

+FOLFIRI &

bevacizumab

NCT01274624/

Oncolytics Biotech

AMG 510

NCT04380753/Amge

n

HL-085| Docetaxel

NCT03990077/Shang

hai Kechow Pharma.

AZD4785

NCT03101839/Astra

Zeneca

Panitumumab|

Cabozantinib

NCT02008383

Exelixis

AUY922|Cetuximab

NCT01294826/Novar

tis

Cobimetinib|

MEHD7945A

NCT01986166/Genen

tech.

GSK2110183+

Bortezomib+Dexamet

hasone

NCT01428492/

Novartis

PF-00299804

NCT00728390/Pfizer

HLX55

NCT04169178/

Henlix

BYL719|MEK162

NCT01449058/Array

BioPharma

GSK1120212+

Gemcitabine

NCT01324258/

GlaxoSmithKline

SCB-313

NCT03869697/Clover

Bio AUS

MM-121+Irinotecan+

Cetuximab

NCT01451632/Merri

mack

gedatolisib+Docetaxel

+ Cisplatin

NCT01920061/Pfizer

Erlotinib+PF-

02341066

NCT00965731/Pfizer

TNO155+ EGF816

(nazartinib)

NCT03114319/Novart

is

LXH254+LTT462+Tr

ametinib+ Ribociclib

NCT02974725

Novartis

Trametinib+fluoroura

cil+ radiation therapy

NCT01740648/Terenc

e Williams

Binimetinib+Pemetre

xed+Carboplatin

NCT02185690/Novart

is

RO5126766+VS-6063

NCT03875820/Chuga

i

Pancreatic CancerColorectal/Rectal cancerNon-Small Cell Lung CancerBreast CancerMultiple MyelomaSolid Tumours

Phase I assets

Active, Not recruiting

Not yet recruiting

Recruiting

*Other Cancer Therapies: Drug: PD1 inhibitorDrug: MEK inhibitorDrug: SHP2 allosteric inhibitorDrug: Pan-ErbB tyrosine kinase inhibitorDrug: PD-L1 inhibitorDrug: EGFR inhibitorDrug: Chemotherapeutic regimen

ASCO 2020 Readouts

Not shown…Phase I/II, Phase II, Phase III

ASCO Results 2020KRAS Mutated Cancers

ASCO20 Alert: AMG 510 monotherapy was well tolerated in KRASG12C mutated CRC

Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation is associated with poor prognosis in colorectal cancer (CRC). AMG 510 is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C by locking it in the inactive guanosine diphosphate-bound state. In a previous interim analysis of the phase 1, first-in-human trial of AMG 510, we observed a favorable safety profile and preliminary antitumor activity in patients (pts) with advanced solid tumors harboring KRAS p.G12C. Here, we present updated data in pts with CRC.

Methods:Key inclusion criteria were KRAS p.G12C mutation identified through molecular testing, measurable disease, and progression on standard therapy. Primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), as assessed per RECIST 1.1, and overall survival (OS). Oral daily doses of 180, 360, 720, and 960mg were tested in the dose escalation phase, and 960mg dose was selected for the expansion phase.

Results:As of Jan 8, 2020, 42 pts with CRC (21 female [50%], median age: 57.5 years [range: 33–82]) were enrolled and dosed (25 on 960mg). All pts received prior systemic therapies; 19 pts (45.2%) received > 3 prior lines. Median follow-up was 7.9 months (mos) (range: 4.2–15.9). 13 pts (31.0%) died, and 8 pts (19.0%) remained on treatment (tx). 22 (52.4%) and 8 (19.0%) pts had remained on tx for more than 3 and 6 months, respectively. Progressive disease was the most common reason for tx discontinuation. 20 pts (47.6%) had tx-related adverse events (TRAEs): 18 (42.9%) had grade 2 or lower TRAEs; 2 (4.8%) had grade 3 TRAEs, which were diarrhea (2.4%) and anemia (2.4%). There were no dose-limiting toxicities, fatal TRAEs, or TRAEs leading to tx discontinuation. Overall, ORR and DCR were 7.1% (3/42) and 76.2% (32/42), respectively. At 960mg, ORR and DCR were 12.0% (3/25) and 80.0% (20/25). 3 pts with PR had duration of response of 1.5, 4.2, and 4.3 months, respectively, and their responses were still ongoing at data cutoff. In all pts treated with all doses, median duration of stable disease was 4.2 mos(range: 2.5[+]–11.0). PFS/OS will be reported.

Abstract Number: 4018 Indication: Colorectal cancer Source Reliability: High

Background

Methods & Results

Drug Name(s): AMG-510 Dev. Stage: Phase 1/2 (NCT03600883) MOA: K-Ras inhibitor (Small Molecule)

In pts with heavily pretreated KRAS p.G12C mutant CRC, AMG 510 monotherapy was well tolerated, with the majority of pts achieving disease control. Study is ongoing

1. https://meetinglibrary.asco.org/record/185490/abstract

Conclusion Sources: Secondary

CodeBreak 100: Activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer.

Abstract Title

Not shown…ASCO results for other Trials

Methodology & Disclaimer• All the trials captured are either industry

sponsored/associated or run in collaboration with other hospitals or academic groups or institutes

• The trials/assets captured are global in nature with no filters applied on trial location or company headquarters

• All the trials with status other than withdrawn/ terminated/ suspended have been included

• There are no filters applied on study start date or primary completion date, giving the exercise a wider scope

• The trials/assets with direct/undirect action on KRAS-mutated cancer have been captured

• Information covered in each cell are as follows: Asset in monotherapy/combination; NCTId, sponsor company, Trial status and the indication the trial is active in

• Source: Trial Trove, a paid subscription database, Clinical Trials.gov, company press release, ASCO posts, Pubmed/research articles and general secondary

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