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Targeting KRAS Mutant Non–Small Cell Lung Cancer with Adagrasib: Current Status and Future Questions

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Intended for use in response to questions about Mirati, including its pipeline, trials, or data.

Outline

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History of Targeting KRAS and Recent Advancements to Directly Target KRAS G12C

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History of Targeting KRAS – Drugging the Undruggable

• KRAS has been the subject of extensive drug development efforts for nearly 40 years³
• Historical attempts to target KRAS (both direct and indirect approaches) have had little success because of the absence of known binding pockets⁵
• The discovery by Ostrem et al of the switch II pocket occurring on the surface of the active and inactive forms of KRAS has led to a better understanding of the complex interactions involved in the RAS family of signaling proteins⁵
• This had led to the development of a number of promising direct KRAS inhibitors being evaluated clinically

mut, mutant; NSCLC, non–small-cell lung cancer; WT, wild type.

1. Zehir A, et al. Nat Med. 2017;23(6)703-713. 2. NIH TCGA: The Cancer Genome Atlas. February 11, 2021; https://www.cbioportal.org. 3. Christensen JG, et al. J Intern Med. 2020;288(2):183-191. 4. Pakkala S, Ramalingam SS. JCI Insight. 2018;3(15):e120858. 5. Ostrem JM, Shokat KM. Nat Rev Drug Discov. 2016;15(11):771-785.

KRAS Prevalence in NSCLC^1,2

NSCLC�Adenocarcinoma

Prevalence of Oncogenic Mutations�in Lung Adenocarcinoma³

KRAS^G12C is mutated in

~14% of patients with NSCLC, comparable to the prevalence

of all EGFR mutations^3,4

Key:

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History of Targeting KRAS – Drugging the Undruggable

Previous Strategies

• Direct inhibitors
• Farnesyl transferase inhibitors
• Downstream effector inhibitors (eg, Raf/MEK and PI3K/AKT/mTOR inhibitors)

PK, pharmacokinetic; WT, wild type.

1. Adapted from Christensen JG, Olson P, Briere T, et al. J Intern Med. 2020; 288:183-191. 2. Hu Q, Shokat KM. Cell. 2018;173(5):1254-1264.

Recent advances allow for the selective and specific targeting of KRAS^G12C while sparing WT KRAS function to improve the therapeutic window^1-2

: January 30, 2020.

: January 30, 2020.

Targeting KRAS�Historically Undruggable¹

1. KRAS^G12C has a cysteine present in its active and inactive forms

3. Inhibitor covalently binds to the cysteine and the induced switch II pocket

2. Binding to the cysteine opens an adjacent switch II pocket

4. KRAS^G12C is irreversibly locked in the inactive state

KRAS Tumor Cell Death

KRAS^G12C Can Be Inhibited Covalently^1,2

With the discovery of the switch II binding pocket…

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Recent Efforts to Directly Target KRAS^G12C in NSCLC

NSCLC, non–small-cell lung cancer.

1. NCT04685135. https://www.clinicaltrials.gov/ct2/show/NCT04685135. Accessed April 15, 2021. 2. NCT04303780. https://www.clinicaltrials.gov/ct2/show/NCT04303780. Accessed April 15, 2021. 3. NCT04449874. https://www.clinicaltrials.gov/ct2/show/NCT04449874. Accessed April 15, 2021. 4. NCT04585035. https://www.clinicaltrials.gov/ct2/show/NCT04585035. Accessed April 15, 2021. 5. NCT04699188. https://www.clinicaltrials.gov/ct2/show/NCT04699188. Accessed April 15, 2021. 6. NCT02740985. https://www.clinicaltrials.gov/ct2/show/NCT02740985. Accessed April 15, 2021. 7. NCT04111458. https://www.clinicaltrials.gov/ct2/show/NCT04111458. Accessed April 15, 2021. 8. NCT04330664. https://www.clinicaltrials.gov/ct2/show/NCT04330664. Accessed April 15, 2021. 9. NCT01859026. https://www.clinicaltrials.gov/ct2/show/NCT01859026. Accessed April 15, 2021. 10. NCT03785249. https://www.clinicaltrials.gov/ct2/show/NCT03785249. Accessed April 15, 2021. 11. NCT04620330. https://www.clinicaltrials.gov/ct2/show/NCT04620330. Accessed April 15, 2021. 12. Hofmann MH, Gmachl M, Ramharter J, et al. Cancer Discov. 2020;10.1158/2159-8290.CD-20-0142. 13. Zehir A, et al. Nat Med. 2017;23(6)703-713.

Adagrasib

Mirati Therapeutics

Monotherapies^1-7

Combination Strategies^8-12

Several new drug candidates take advantage of the increased understanding of mutant KRAS^G12C protein structure and inhibitors that rely on a mutant cysteine for binding¹³

Sotorasib

Amgen

GDC-6036

Genentech

AZD4625

AZD4625

JDQ443

Novartis

D-1553

InvestisBio

Phase 3

Phase 1 or 2

BI 1701963

Boehringer Ingelheim

KRAS + SHP2

KRAS + EGFR

KRAS + Anti–PD-1

KRAS + SOS1

KRAS + MEK

Clinical Development

Preclinical Development

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Clinical Progress of KRAS G12C Inhibitors and Treatment of Patients with NSCLC

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Adagrasib (MRTX849): KRAS^G12C Inhibitor

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Adagrasib: A Differentiated, Highly Selective and Potent KRAS^G12C Inhibitor

�1. NCT03785249. https://www.clinicaltrials.gov/ct2/show/NCT03785249. Accessed April 15, 2021. 2. NCT04330664. https://www.clinicaltrials.gov/ct2/show/NCT04330664. Accessed April 15, 2021. 3. NCT04613596. https://www.clinicaltrials.gov/ct2/show/NCT04613596. Accessed April 15, 2021. 4. NCT04685135. https://www.clinicaltrials.gov/ct2/show/NCT04685135. Accessed April 15, 2021. 5. Cancer Discov. 2020;10(12):OF2.

Currently Enrolling Clinical Trials^1-4

Adagrasib (MRTX849) binds GDP-bound KRAS^G12C, locking KRAS^G12C in off state and abolishing aberrant constitutive signaling

RTKs

(e.g. EGFR family)

SHP2

GTP-

KRAS^G12C

GDP-

KRAS^G12C

RAF

MEK

ERK

Adagrasib

Inhibits KRAS^G12C which suppresses MAP/ERK signaling and tumor growth

Adagrasib (MRTX849) binds GDP-bound KRAS^G12C, locking KRAS^G12C in off state and abolishing aberrant constitutive signaling

Adagrasib is an investigational, oral small molecule therapy showing promising efficacy in patients harboring the KRAS^G12C mutation⁵

KRYSTAL-1 (NCT03785249): Phase 1/2 study of adagrasib in patients with cancer having a KRAS^G12C mutation

KRYSTAL-2 (NCT04330664): Phase 1/2 study of adagrasib in combination with TNO-155 in patients with cancer having a KRAS^G12C mutation

KRYSTAL-7 (NCT04613596): Phase 2 study of adagrasib in combination with pembrolizumab in NSCLC patients having a KRAS^G12C mutation

KRYSTAL-12 (NCT04685135): Phase 3 study of adagrasib vs docetaxel in patients with NSCLC with KRAS^G12C mutation

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KRYSTAL-1: Phase 1/2, Open-Label, Multiple-Expansion-Cohort Trial of Adagrasib in KRAS^G12C Solid Tumors

​

Phase 1

Primary: Safety, MTD, PK, RP2D

Secondary: Objective Response (RECIST 1.1), DOR, PFS, OS

�Phase 2

Primary: ORR (RECIST 1.1)

Secondary: Safety

^aTissue test and/or ctDNA allowed for Phase 1/1b eligibility. ^bApplies to the majority of NSCLC cohorts. ^cMost cohorts allow patients with brain metastases if adequately treated and stable; additional phase 1/1b cohort allows limited brain metastases. ^dPatients subsequently dose escalated up to 600 mg BID. ^ePatients must have declined 1L systemic therapy. ^fSubjects receiving prior treatment with a KRAS^G12C inhibitor not eligible. ^gTrial is registrational. ^hKRAS^G12C mutation detected in tumor tissue and/or blood. �NCT03785249. https://www.clinicaltrials.gov/ct2/show/NCT03785249. Accessed April 15, 2021.

Key Eligibility Criteria

• Solid tumor with KRAS^G12C mutation^a
• Unresectable or metastatic disease
• Prior treatment with a PD-1/L1 inhibitor following or in combination with chemotherapy (NSCLC)^b
• Treated and/or stable brain metastases^c

Phase 1

Dose Escalation

Phase 1b

Dose Expansion and Combination

Phase 2

Monotherapy Treatment

150 mg QD^d

300 mg QD^d

600 mg QD

1200 mg QD

600 mg BID Expansion

Endpoints

Adagrasib + pembro in NSCLC^f

Adagrasib + afatinib in NSCLC

Adagrasib monotherapy

Adagrasib + cetuximab in CRC^f

Cohort A: NSCLC �(tumor G12C)^g

Cohort C: CRC^h

Cohort D: Other solid tumors^h

Cohort B: NSCLC �(ctDNA G12C)^g

Cohort E: NSCLC G12C and STK11 treatment naive^h

Adagrasib NSCLC�treatment-naive^e

Adagrasib NSCLC prior KRAS^G12C inhibitor

Adagrasib limited brain mets

Start Date: January 15, 2019

Estimated Primary Completion Date: December 2021

Estimated Completion Date: September 2022

Status: Enrolling

Sponsor: Mirati Therapeutics

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KRYSTAL-1 Results: Incidence of Treatment-Related Adverse Events

• Grade 5 TRAEs included pneumonitis in a patient with recurrent pneumonitis (n=1) and cardiac failure (n=1)
• 4.5% of TRAEs led to discontinuation of treatment

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; CRC, colorectal cancer; NSCLC, non–small-cell lung cancer.

^aIncludes patients pooled from Phase 1/1b and Phase 2 NSCLC cohorts (n=79), and CRC and Phase 2 other tumor cohorts (n=31). ^bIncludes events reported between first dose and 30 August 2020. �^cThe most common treatment-related SAEs reported (2 patients each) were diarrhea (grade 1, grade 2) and hyponatremia (both grade 3). ^dOccurred in ≥10% of patients.

Data as of 30 August 2020.�Jänne PA et al. Presented at 2020 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 25, 2020; virtual.

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KRYSTAL-1 Results: ORR in Pooled Dataset

BID, twice daily; NSCLC, non–small-cell lung cancer; ORR, objective response rate.

^aBased on investigator assessment of the clinically evaluable patients (measurable disease with ≥1 on-study scan); 14/18 patients (Phase 1/1b) and 51/79 patients (Phase 1/1b and 2 pooled) met these criteria. ^bAt the time of the 30 August 2020 data cut off, 5 patients had unconfirmed PRs. All 5 were confirmed by scans that were performed after the 30 August 2020 data cut-off. ^cOne patient had tumor reimaging too early for response assessment.

Data as of 30 August 2020. The pooled dataset includes data from the NSCLC Phase 1/1b and Phase 2 600 mg BID cohorts.

Jänne PA et al. Presented at 2020 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 25, 2020; virtual.

• Patients in the Phase 1/1b cohort had a median of 3 prior lines of therapy (range 1-9)
• Patients in the pooled cohort had a median of 2 prior lines of therapy (range 1-9)

​

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KRYSTAL-1 Results: Best Tumor Change From Baseline

: January 30, 2020.

• Clinical benefit (DCR) observed in 96.1% (49/51) of patients

​

BID, twice daily; CR, complete response; DCR, durable complete response; NE, not evaluable; NSCLC, non–small-cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease.

^aTwo timepoint assessments of CR were separated by recurrent disease associated with treatment interruption due to hypoxia; this patient remains on treatment and in 2 consecutive scans (1 after August 30 data cut-off) demonstrated 100% tumor regression in target and nontarget lesions after resuming treatment.

Data as of 30 August 2020. The pooled dataset includes data from the NSCLC Phase 1/1b and Phase 2 600 mg BID cohorts.

Jänne PA et al. Presented at 2020 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 25, 2020; virtual.

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KRYSTAL-1 Results: Duration of Treatment in Pooled Dataset

Study Phase

Phase 1/1b

Phase 2

Evaluable Patients

Duration of Treatment, months

PR

PR

PR

PR

SD

PR

SD

SD

PR

PR

SD

PR

PR

PR

SD

PR

SD

PR

SD

PR

PR

SD

PR

SD

PR

PR

SD

SD

PR

PR

SD

SD

SD

SD

NE

SD

PD

SD

SD

SD

PR

SD

PR

SD

SD

SD

PR

SD

SD

SD

• Median follow-up: 3.6 months
• Median time to response: 1.5 months
• 78% (18/23) of responders have not progressed and remain on study
• 65% (33/51) of patients remain on treatment

​

NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

Data as of 30 August 2020. Pooled dataset includes NSCLC Phase 1/1b and Phase 2 600 mg BID cohorts.

Jänne PA et al. Presented at 2020 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 25, 2020; virtual.

​

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Sotorasib (AMG 510): KRAS^G12C Inhibitor

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Sotorasib: A First-In-Class KRAS^G12C Inhibitor

�1. NCT04303780. https://www.clinicaltrials.gov/ct2/show/NCT04303780. Accessed April 15, 2021. 2. NCT03600883. https://www.clinicaltrials.gov/ct2/show/NCT03600883. Accessed April 15, 2021. 3. NCT04185883. https://www.clinicaltrials.gov/ct2/show/NCT04185883. Accessed April 15, 2021. 4. NCT04380753. https://www.clinicaltrials.gov/ct2/show/NCT04380753. Accessed April 15, 2021.

Selected Clinical Trials^1-4

CodeBreaK 200 (NCT04303780): Phase 2 study of sotorasib in KRAS p.G12C mutated NSCLC

CodeBreaK 100 (NCT03600883): Phase 1/2 study of sotorasib in patients with solid tumors with a specific KRAS mutation

CodeBreaK 101 (NCT04185883): Phase 1 study of sotorasib in patients with advanced solid tumors with a KRAS p.G12C mutation

CodeBreaK 105 (NCT04380753): Phase 1 study of sotorasib in patients of Chinese descent with KRAS p.G12C mutated advanced/metastatic solid tumors

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CodeBreaK 100: Phase 1/2 study of Sotorasib in Patients With Solid Tumors With a Specific KRAS Mutation

DCR, disease control rate; DOR, duration of response; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TTR, time to recurrence.

^aNo more than 3 prior lines of therapies were allowed; ^bTreatment beyond disease progression was allowed if certain criteria were met; ^cSafety follow-up occurs 30 (+7) days after the last dose of sotorasib; long-term follow-up occurs every 12 (±2) weeks for up to 3 years.

NCT03600883. https://www.clinicaltrials.gov/ct2/show/NCT03600883. Accessed April 15, 2021.

Safety and Long-term Follow-up^c

Radiographic scan every 6 weeks up to week 48 and once every 12 weeks thereafter

Screening / Enrollment

Sotorasib was orally administered at 960 mg once daily until disease progression^b

​

Primary: ORR (RECIST 1.1) by blinded independent central review

Secondary: DOR, DCR, TTR, PFS, OS, safety

Endpoints

Start Date: August 27, 2018

Estimated Primary Completion Date: November 2021

Estimated Completion Date: February 2024

Status: Enrolling

Sponsor: Amgen

Key Eligibility Criteria

• Locally advanced or metastatic NSCLC
• KRAS p.G12C mutation as assessed by central testing of tumor biopsies
• Progressed on prior standard therapies^a
• No active brain metastases

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CodeBreaK 100 Results: Tumor Response

ORR, objective response rate.

^aAccording to central review, 2 patients did not have measurable lesions at baseline per RECIST 1.1 and were excluded from response assessment; ^b2 patients stopped treatment without post-baseline scans and were deemed as “missing scan”; 2 patients had 1 post-baseline scan and were assessed as “not evaluable” by central review.

Li BT, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.

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CodeBreaK 100 Results: Treatment-Related Adverse Events

TRAE, treatment-related adverse events.

^a1 patient (0.8%) reported grade 4 TRAEs (pneumonitis and dyspnea)

Li BT, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.

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CodeBreaK 100 Results: Depth of Tumor Response

CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

^aGraph excluded 3 patients without post-baseline measurement in target lesions.

Li BT, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.

• Tumor shrinkage of any magnitude was observed in 81% of patients (101/124)
• Median percentage of best tumor shrinkage among all responders was 60%

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CodeBreaK 100 Results: Durability of Tumor Response

OS, overall survival; PFS, progression-free survival.

Li BT, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.

• Median duration of response: 10.0 months (95% Cl: 6.9, 11.1)
• Median time to objective response: 1.4 months
• 43% (20/46) of responders remained on treatment without progression as of the data cutoff

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Future Questions and Directions for Targeting KRAS G12C

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Co-mutations of Special Interest

• Growing evidence suggests that KRAS-mutant NSCLC may have genetic heterogeneity rather than a single KRAS mutation¹
• The pattern of genetic co-mutations varies with different KRAS subtypes, including TP53, STK11, KEAP1, ATM, MET, and ERBB2 mutations^1-2
• KRAS mutations are usually considered mutually exclusive with other known activating driver mutations in NSCLC³
• It has been hypothesized that these co-mutations may hold prognostic and therapeutic significance in KRAS-mutant NSCLC⁴

NSCLC, non–small-cell lung cancer; ORR, objective response rate; WT, wild type.

1. Arbour KC, et al. Clin Cancer Res. 2018;24(2):334-340. 2. Scheffler M, et al. J Thorac Oncol. 2019;14(4):606-616. 3. Gainor JF, et al. Clin Cancer Res. 2013;19(15):4273-4281. 4. Aredo JV, et al. Lung Cancer. 2019;133:144-150. 5. Jänne PA, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. Presented at: 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics; October 24-25, 2020; Virtual. Abstract LBA-03.

: January 30, 2020.

Response Rate, %

64%

9/14

33%

10/30

36%

5/14

48%

14/29

48%

11/23

38%

9/24

45%

23/51

ORR in Patients Harboring �KRAS^G12C Co-mutations

STK11 KEAP1 TP53 KRAS^G12C

(all patients)

• Initial results from KRYSTAL-1 demonstrated that adagrasib had better efficacy in patients with KRASG12C and STK11 co-mutations than in those with a KRASG12C mutation alone
• ORR was 64% in patients with KRASG12C and STK11 co-mutations vs 33% in patients with the KRASG12C mutation and WT STK11⁵

Emerging Role of Co-mutations

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Promising Combination Strategies for KRAS-Mutant NSCLC

KRAS + SHP2 Inhibition

KRAS + EGFR Inhibition

KRAS + Checkpoint Inhibitor

KRAS + SOS1 Inhibition

• Early attempts to develop monotherapies that inhibit SHP2 were not successful in KRAS-mutant cell lines¹
• Emerging data suggests that KRAS^G12C- and KRAS-mutant NSCLC have been found to be dependent on SHP2 activity in vivo¹
• Ongoing clinical studies are evaluating the combination of a KRAS^G12C inhibitor and a SHP2 inhibitor^2-3

NSCLC, non–small-cell lung cancer.

1. Hallin J, et al. Cancer Discov. 2020;10(1):54-71. 2. NCT04330664. https://www.clinicaltrials.gov/ct2/show/NCT04330664. Accessed April 15, 2021. 3. NCT04185883. https://www.clinicaltrials.gov/ct2/show/NCT04185883. Accessed April 15, 2021. 4. Amodio V, et al. Cancer Discov. 2020;10(8):1129-1139. 5. NCT01859026. https://www.clinicaltrials.gov/ct2/show/NCT01859026. Accessed April 15, 2021. 6. Herbst RS, et al. Presented at: 2019 ESMO Immuno-Oncology Congress; December 11-14, 2019; Geneva, Switzerland. Abstract LBA4. 7. NCT03785249. https://www.clinicaltrials.gov/ct2/show/NCT03785249. Accessed April 15, 2021. 8. Hofmann MH, et al. Cancer Discov. 2020;10.1158/2159-8290.CD-20-0142.

• The EGFR signaling pathway is often activated in tumor cells to bypass KRAS inhibition⁴
• This dual inhibition may thwart the tumor’s ability to bypass KRAS inhibition and enhance outcomes observed with inhibiting either target alone⁴
• Several studies are currently evaluating this approach^3,5

​

• There is also interest in combining KRAS inhibition with a checkpoint inhibitor, the standard of care in advanced NSCLC⁶
• Research on the combination of adagrasib and the PD-1 inhibitor pembrolizumab in patients with NSCLC is being conducted⁷

​

• BI-3406 is a selective SOS1:KRAS interaction inhibitor that has shown efficacy in KRAS-driven cancers in preclinical studies⁸
• As BI-3406 increases the extent and duration of MAPK pathway inhibition when used in combination with a KRAS^G12C or MEK inhibitor, it may more effectively deter adaptive resistance⁸

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Combining KRAS Inhibition With Immunotherapy and Other Targeted Therapies

Adagrasib + PD-1 Checkpoint Inhibitor

• Emerging data implicate SHP2 and RTK dependency of KRAS-mutant cancers, particularly KRAS^G12C, and KRAS-mutant NSCLC has been found to be dependent on SHP2 activity in vivo^4,5
• Preclinical studies of adagrasib combined with SHP2 inhibition in several xenograft models of KRAS^G12C -mutant tumors have demonstrated greater activity for the combination compared with each agent alone^5-7
• The addition of a SHP2 inhibitor to adagrasib may augment antitumor activity through inhibition of feedback activation and consequently prevent resistance^4,7,8

CR, complete response; NSCLC, non–small-cell lung cancer; TMB, tumor mutational burden.�1. Campbell JD, Alexandrov A, Kim J, et al. Nat Genet. 2019;48(6):607–616. 2. Goodman AM, Kato S, Bazhenova L, et al. Mol Cancer Ther. 2017;16(11):2598–2608. 3. Briere D, Calinisan A, Aranda R, et al. Poster presented at: 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26–30, 2019; Boston, MA. 4. Hallin J, Engstrom LD, Hargis L, et al. Cancer Discov. 2020;10(1):54–71. 5. Mainardi S, Mulero-Sánchez A, Prahallad A, et al. Nat Med. 2018;24:961-967 6. Hao HX, Liu C, LU H, et al. Clin Cancer Res. 2020;7(1):342-354. 7. Hallin J, et al. Poster presented at: AACR; June 22, 2020; virtual. 8. LaMarche MJ, Acker M, Arginturu A, et al. J Med Chem. 2020;63(22):13578-13594.

Adagrasib + SHP2 Inhibitor RMC-4550

​

Tumor Volume, mm³

Study Day

• KRAS^G12C mutations are smoking-related transversion mutations associated with relatively high TMB and PD-L1 expression^1,2
• Adagrasib plus anti–PD-1 therapy led to durable CR (cure) in the majority of mice and a survival advantage relative to either agent as monotherapy³
• In mouse models showing CR, reintroduction of tumor cell inoculum failed to result in re-formation of tumor, demonstrating durable antitumor immunity for the combination^1-3

​

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Patient Case: Response to the Combination of Adagrasib + TNO155 (SHP2 Inhibitor)^a

• Adagrasib 600 mg BID + TNO155 (initial dose)
• 53-year-old male, smoker, diagnosed �with NSCLC
• Treatment history
• Neoadjuvant carbo/pem x 4 cycles, 2017
• Carbo/pem/bev >pem/bev maintenance, �2017-2018
• Atezo x 6 cycles, 2018-2019
• Pem + pembro x 6 cycles, March-October 2019
• KRAS^G12Ci (AMG 510) x 4 cycles, November 2019-February 2020 (-40% →PD)
• SHP2 (RMC4630) + cobimetinib x 1 cycle �(stopped due to an AE)
• FCN-437c (CDK4/6 inhibitor), March-June 2020
• TRAEs
• Grade 1 diarrhea
• Disease assessments
• Off oxygen and out of a wheelchair within days: neck mass flattened within 1 week
• Currently in cycle 7

​

​

​

​

Post–Cycle 3 PR, (-60%)

Baseline

AE, adverse event; atezo, atezolizumab; bev, bevacizumab; BID, twice daily; carbo, carboplatin; CD, cluster of differentiation; NSCLC, non–small-cell lung cancer; pem, pemetrexed; pembro, pembrolizumab; PD, progressive disease; PR, partial response.

^aStudy of combination of adagrasib + TNO155 conducted in collaboration with Novartis. ClinicalTrials.gov. NCT04330664.

Data as of 24 August 2020.

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Mechanisms of Acquired Resistance to KRAS^G12C Inhibition

• Clinical mechanisms of acquired resistance to KRAS^G12C inhibitors are unknown
• A recent study characterized histologic and genomic mechanisms of resistance among patients treated with adagrasib for KRAS^G12C mutant cancers
• Researchers compared repeat biopsies and ctDNA to baseline samples prior to adagrasib administration
• Mutagenesis screens were used to to identify secondary KRAS mutations that confer resistance to KRAS^G12C inhibitors

Awad M, et al. Mechanisms of acquired resistance to KRAS G12C inhibition in cancer. Presented at: the American Association for Cancer Research Annual Meeting 2021. April 9-14, 2021. Virtual. Abstract LB002.

64%

9/14

33%

10/30

36%

5/14

48%

14/29

48%

11/23

38%

9/24

45%

23/51

Study Population (N=30)

Resistance Mechanisms to KRAS Inhibitors

Sample for Sequencing

Participants

• Treated with adagrasib monotherapy
• Experienced tumor reduction or clinical benefit followed by disease progression

27

Intended for use in response to questions about Mirati, including its pipeline, trials, or data.

Acquired Amplifications in KRAS (G12C allele) and MET

Awad M, et al. Mechanisms of acquired resistance to KRAS G12C inhibition in cancer. Presented at: the American Association for Cancer Research Annual Meeting 2021. April 9-14, 2021. Virtual. Abstract LB002.

28

Intended for use in response to questions about Mirati, including its pipeline, trials, or data.

Summary of Resistance Mechanisms

NSCLC, non–small-cell lung cancer; CRC, colorectal cancer.

Awad M, et al. Mechanisms of acquired resistance to KRAS G12C inhibition in cancer. Presented at: the American Association for Cancer Research Annual Meeting 2021. April 9-14, 2021. Virtual. Abstract LB002.

• Diverse mechanisms confer resistance to KRAS^G12C inhibitors, including secondary KRAS mutations, MAPK pathway alterations, acquired genomic rearrangements, and histologic transformation
• Several cases displayed multiple concurrent resistance mechanisms
• Novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS^G12C-mutant cancers

Key Results

29

Intended for use in response to questions about Mirati, including its pipeline, trials, or data.

The Path Forward

.

Improve understanding of resistance mechanisms to help refine our ability to evaluate novel targeted agents and combination approaches

KRAS inhibition may play a key role in reversing the immunosuppressive tumor microenvironment, enabling tumors to respond to CPI regimens

The potential role for KRAS inhibition in the adjuvant or neoadjuvant setting, including resectable disease

Combining KRAS inhibitors with other targeted therapies used in the 1L metastatic setting

CPI, checkpoint inhibitor; 1L, first-line.

Awad M, et al. Mechanisms of acquired resistance to KRAS G12C inhibition in cancer. Presented at: the American Association for Cancer Research Annual Meeting 2021. April 9-14, 2021. Virtual. Abstract LB002.

30

Intended for use in response to questions about Mirati, including its pipeline, trials, or data.

Conclusions

.

• Several new drug candidates take advantage of the increased understanding of mutant KRAS^G12C protein structure and inhibitors that rely on the mutant cysteine for binding

​

• Adagrasib (Mirati Therapeutics) and sotorasib (Amgen) are currently being tested in phase 3 clinical trials

​

• Growing evidence suggests that KRAS-mutant NSCLC frequently may have genetic heterogeneity rather than a single KRAS mutation

​

• Current efforts to target KRAS in NSCLC include studies aimed at understanding resistance mechanisms in patients treated with KRAS^G12C inhibitors to help refine novel targeted agents and combination approaches

31

Intended for use in response to questions about Mirati, including its pipeline, trials, or data.

KRYSTAL-2: Phase 1/2, Open-Label, Multiple-Expansion-Cohort Trial of Adagrasib + TNO155^a (SHP2 Inhibitor) in KRAS^G12C Solid Tumors

CRC, colorectal cancer; MTD, maximum tolerated dose; NSCLC, non–small-cell lung cancer; ORR, objective response rate; PK, pharmacokinetics; TRAEs, treatment-related adverse events. �^aTNO155 is in development by Novartis; ^†tissue test and/or ctDNA allowed for Phase 1/1b eligibility.

ClinicalTrials.gov. NCT04330664. Accessed February 24, 2021.

Key Eligibility Criteria�

• Solid tumor with KRAS^G12C mutation based on sponsor-approved local or central tissue positive test^†
• Unresectable or metastatic disease
• No available treatment with curative intent

Start Date: April 22, 2020

Estimated Primary Completion Date: September 2022

Estimated Completion Date: October 2022

Status: Enrolling

Sponsor: Mirati Therapeutics

Outcome Measures

Primary: Safety, PK, MTD, RP2D

Secondary: Clinical activity (ORR by RECIST 1.1)

Phase 1

Phase 1b

Phase 2

Dose�Escalation

Expansion

Cohorts

32

Intended for use in response to questions about Mirati, including its pipeline, trials, or data.

KRYSTAL-7: A Phase 2 Trial of Adagrasib in Combination With Pembrolizumab in Patients With Advanced NSCLC With KRAS^G12C Mutation

Key Eligibility Criteria�

• NSCLC with KRAS^G12C based on sponsor-approved test
• Unresectable or metastatic disease
• No prior CPI or KRAS inhibitor

BID, twice daily; CPI, checkpoint inhibitor; NSCLC, non–small-cell lung cancer; Q3W, every 3 weeks; TPS, tumor proportion score.�Dosing: pembrolizumab, 200 mg Q3W.�Spira AI, Lawler WE, Shum M, et al. Poster presented at 2020 IASLC World Conference on Lung Cancer; January 28, 2021; virtual.�ClinicalTrials.gov. NCT04613596. Accessed February 24, 2021.

COHORT A: TPS <1%�Adagrasib 600 mg BID + pembrolizumab�(n=60)

COHORT B: TPS ≥1%

Adagrasib 600 mg BID + pembrolizumab�(n=60)

​

Outcome Measures

Primary: ORR (RECIST 1.1)

Secondary: PFS, OS, safety, DOR, molecular analyses

Start Date: December 2, 2020

Estimated Primary Completion Date: October 30, 2022

Estimated Completion Date: November 30, 2022

Status: Enrolling

Sponsor: Mirati Therapeutics

33

Intended for use in response to questions about Mirati, including its pipeline, trials, or data.