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Registrational results of LIBRETTO-001: A phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET-altered thyroid cancersL. Wirth,1 E. Sherman,2 A. Drilon,2 B. Solomon,3 B. Robinson,4 J. Lorch,5 C. McCoach,6 J. Patel,7 S. Leboulleux,8 F. Worden,9 T. Owonikoko,10 M. Brose,11 M. Taylor,12 A. Italiano,13 O. Gautschi,14 M.-E. Garcia,15 S.M. Rothenberg,16 V. Subbiah,17 M. Shah,18 M. Cabanillas17

1Massachusetts General Hospital, Harvard Medical School, Boston, MA; 2Memorial Sloan Kettering Cancer Center, New York, NY; 3Peter MacCallum Cancer Center, Melbourne, VIC, Australia; 4Royal North Shore Hospital, St. Leonards, NSW, Australia; 5Dana-Farber Cancer Institute, Boston, MA; 6University of California, San Francisco, CA; 7University of Chicago, Chicago, IL; 8Gustave Roussy, Villejuif, France; 9University of Michigan, Ann Arbor, MI; 10Emory University School of Medicine, Atlanta, GA; 11University of Pennsylvania, Philadelphia, PA; 12Oregon Health & Science University, Portland, OR; 13Institute Bergonié, Bordeaux, France; 14University of Berne and Cantonal Hospital of Lucerne, Switzerland ; 15Aix Marseille Université, Marseille, France; 16Loxo Oncology, Stamford, CT; 17The Ohio State University, Columbus, OH; 18The University of Texas MD Anderson Cancer Center, Houston, TX

DISCLOSURESCommercial interest Relationship(s)Bayer Consultant

Cue Biopharma Consultant

Eisai Advisory Board, consultant

Exelixis Consultant

Genentech Consultant

Lilly Advisory Board, consultant

Loxo Oncology Advisory Board

Merck Advisory Board

Rakuten Medical Advisory Board

RET is activated by two major mechanisms in thyroid cancer

References: Drilon et al. Nat Rev Clin Oncol. 2018; 15:151‒67; Kato et al. Clin Cancer Res. 2017; 23:1988‒97; Pietrantonio et al. Ann Oncol. 2018; 29:1394‒401; Su et al. PLoS One. 2016; 11:e0165596.

Anti-RET multikinase inhibitors (MKIs): approved for MTC and differentiated thyroid cancers but highly toxic; treatment options after failure of 1st MKI are limited

Selpercatinib* (LOXO-292) is a potent and selective RET inhibitor

*PINN, pending USAN approval. Reference: Subbiah et al. Ann Oncol. 2018; 29:1869‒76.

LIBRETTO-001: selpercatinib in RET-altered cancers

Phase 1 dose escalationSelpercatinib dosed at 20

mg QD‒240 mg BID

Phase 2 dose expansionSelpercatinib dosed at 160

mg BID

• RET alteration

– Determined by local CLIA (or similarly accredited) laboratories

• Primary endpoint– Objective response rate

(RECIST 1.1)• Secondary endpoints

– Duration of response– Progression-free survival– Safety

• Treatment beyond progression permitted with continued benefit

Primary analysis set

n=55

First 55 patients with RET-mutant

MTC who had received prior cabozantinib

and/or vandetanib*

Total enrolledn=531

RET-mutant medullary thyroid

cancern=226

RET fusion-positive thyroid

cancern=27

RET fusion-positive NSCLCn=253

Othern=25

Prior cabozantiniband/or vandetanib

n=124

Cabozantinib/vandetanib-naïve

n=88

Non-measurable disease

n=14

NCT03157128; Data cutoff: June 17, 2019. *Per agreement with FDA, patients with non-measurable disease enrolled during phase 1 dose escalation were eligible for the primary analysis set.

3 populations to be discussed: (1) MTC PAS; (2) MTC, cabozantinib/vandetanib naïve; (3) RET fusion-positive thyroid cancer

Patient characteristics: RET-mutant MTCCharacteristic PAS (n=55) Cabo/Vande-Naïve

(n=88)

Female / Male, n (%) 19 (35) / 36 (65) 30 (34) / 58 (66)

Median age (range), years 57 (17–84) 58 (15–82)ECOG performance status, n (%)

012

11 (20)41 (75)

3 (5)

43 (49)42 (48)

3 (3)Median prior systemic regimens (range) 2 (1–8) 0 (0–2)Prior cabozantinib and/or vandetanib, n (%)

Cabozantinib onlyVandetanib onlyCabozantinib and vandetanib

55 (100)13 (24)18 (33)24 (44)

----

Prior multikinase inhibitor (MKI), n (%)1≥2

55 (100)26 (47)29 (53)

7 (8)6 (7)1 (1)

Prior non-MKI systemic therapy, n (%) 17 (31) 9 (10)

Brain metastases, n (%)‡ 4 (7) 2 (2)Measurable disease, n (%) 53 (96) 86 (98)

RET mutations (n=143)

Data cutoff: June 17, 2019. Total % may be different than the sum of the individual components due to rounding. *Extracellular cysteine mutation defined as mutation including at least 1 of the following cysteine residues: 609, 611, 618, 620, 630, and 634. **Other includes: D631-L633delinsE (5), E632-L633del (4), A883F (4), D631-L633delinsV (2), L790F (2), D898-E901del (2), D898_E901del + D903_S904delinsEP, K666N, T636-V637insCRT, D378-G385delinsE (all 1 each). ‡Includes patients with non-target CNS metastases.

M918T 57%V804M/L 8%

Extracellular Cys* 19%Other** 16%

Activity of selpercatinib: RET-mutant MTC PAS (n=55)

Investigator response assessments as of June 17, 2019. Total % may be different than the sum of the individual due to rounding. 4 patients not shown in waterfall plot: 2 discontinued prior to any post-baseline imaging assessments, and 2 did not have measurable disease at baseline. *Includes 2 unconfirmed PRs awaiting confirmatory response assessments. Cabo–cabozantinib; NE—not evaluable, n=2 patients who discontinued prior to any post-baseline imaging assessments. Vande–vandetanib.

n=55

ORR (95% CI) 56%(42%‒70%)*

CR 6%PR 51%SD 35%PD 5%NE 4%

-100

-80

-60

-40

-20

0

20

40

Best

Tum

or R

espo

nse (

%)

CaboVandeOther MKI

Prior therapy

Activity of selpercatinib: cabozantinib/vandetanib-naïve RET-mutant MTC (n=76)

Investigator response assessments as of June 17, 2019. Total % may be different than the sum of the individual due to rounding. Data include patients with at least one evaluable post-baseline imaging assessment and those who discontinued therapy prior to any post-baseline imaging assessment. 4 patients not shown in waterfall plot: 2 patients discontinued prior to any post-baseline imaging assessments and 2 did not have measurable disease at baseline. *Includes 9 unconfirmed PRs awaiting confirmatory response assessments. NE—not evaluable, n=2 patients who discontinued prior to any post-baseline imaging assessments.

n=76

ORR (95% CI) 59%(47%‒70%)*

CR 1%PR 58%SD 38%PD 0%NE 3%

Best

Tum

or R

espo

nse (

%)

-80

-60

-40

-20

20

40

0

-100

Durability of selpercatinib benefit: primary analysis set

• ORR, DOR, PFS similar regardless of prior therapy (e.g. cabozantinib only, vandetanib only, or cabozantinib and vandetanib) or RET mutation status (M918T vs other)

• Of 15 patients in the PAS that progressed, 13 continued treatment post-progression, for 1.0–19.9 months

Data cutoff: June 17, 2019. Shading in PAS Kaplan-Meier curves indicates the 95% confidence band.

Duration of response

100

80

60

40

20

0

0 5Months since start of response

Patie

nts w

ith re

spon

se (%

)

10 15

29 24 12 228 17 6 0No. at risk:

Median DOR: not reached (95% CI: 11.1 months‒NE)Number of events: 6/29Median follow-up: 10.6 months

Progression-free survival

Median PFS: not reached (95% CI: 11.3 months‒NE)Number of events: 18/55Median follow-up: 11.1 months

100

80

60

40

20

0

0 5Months since start of treatment

Patie

ntsf

ree f

rom

pro

gres

sion (

%)

10 15 20 25

30 11 4 039 15 6 1No. at risk: 55 4649

Durability of selpercatinib benefit: cabozantinib/vandetanib-naïve

Data cutoff: June 17, 2019. No shading to show 95% confidence band due to a very low number of events.

Duration of response

36 20 7 224 13 3 0No. at risk:

Patie

nts w

ith re

spon

se (%

)

100

80

60

40

20

0

0 5Months since start of response

10 15

Median DOR: not reached (95% CI: NE‒NE)Number of events: 0/36Median follow-up: 5.5 months

0 5 10 15 20

76 44 16 462 25 5 2 0No. at risk:

Progression-free survival

100

80

60

40

20

0

Patie

ntsf

ree f

rom

pro

gres

sion (

%)

Median PFS: not reached (95% CI: NE‒NE)Number of events: 1/76Median follow-up: 5.7 months

Months since start of treatment

Activity of selpercatinib: biochemical response in MTC PASCalcitonin BRR

n=54CEA BRR

n=53

ORR (95% CI) 91%(80%‒97%)

64%(50%‒77%)

CR 22% 15%PR 69% 49%SD 0% 19%PD 2% 13%NE 7% 4%

-100

-80

-60

-40

-20

0

40

80

Best

Calc

itoni

n Re

spon

se (%

)

-100

-80

-60

-40

-20

0

40

80

Best

CEA

Res

pons

e (%

)Calcitonin and CEA biochemical response rate (BRR) defined as: normalization (CR); ≥ -50% reduction (PR); between -50% to +50% (SD); ≥ 50% increase (PD); of serum tumor markers for ≥ 4 weeks from baseline. Patients with normal serum tumor markers at baseline are excluded from BRR analysis. NE: patient discontinued treatment prior to determination of CR/PR/SD/PD or biochemical response could not be confirmed at a later time point. Adapted from: Wells, et al. J Clin Oncol. 2012; 30:134‒41.

Patient characteristics: RET fusion-positive thyroid cancer Characteristic RET fusion-positive

thyroid cancer (n=27)

Female / Male, n (%) 13 (48) / 14 (52)

Median age (range), years 54 (20–88)

ECOG performance status, n (%)012

8 (30)16 (59)3 (11)

Histology, n (%)PapillaryHürthle cellPoorly differentiatedAnaplastic

21 (78)1 (4)

3 (11)2 (7)

Median prior systemic regimens (range) 3 (1–7)

Prior radioactive iodine (RAI), n (%) 24 (89)

Prior systemic therapy other than RAI, n (%) 19 (70)

Prior lenvatinib and/or sorafenib, n (%) 13 (48)

Brain metastases, n (%)** 7 (26)

Measurable disease, n (%) 26 (96)

CCDC6 52%

NCOA4 33%

Other* 15%

RET fusion partners (n=27)

Data cutoff: June 17, 2019. Total % may be different than the sum of the individual components due to rounding. *Includes CCDC186, ERC1, KTN1 and RUFY3 (all 1 each). **Includes patients with non-target CNS metastases.

Activity of selpercatinib: RET fusion-positive thyroid cancer (n=26)

Investigator response assessments as of June 17, 2019. Total % may be different than the sum of the individual due to rounding. Data include patients with at least one evaluable post-baseline assessment and those who discontinued therapy prior to any post-baseline imaging assessment. 2 patients not shown in waterfall plot: 1 did not have measurable disease at baseline, and 1 deemed not evaluable on study by the investigator. *Includes 2 unconfirmed PRs awaiting confirmatory response assessments. NE—not evaluable, n=1 patient deemed not evaluable on study by the investigator; RAI‒radioactive iodine.

PapillaryHürthle cell

AnaplasticPoorly differentiated

RAILenvatinibSorafenibTaxane chemo

Prior therapy

-100

-80

-60

-40

-20

0

20

40Be

st Tu

mor

Res

pons

e (%

)

Durability of selpercatinib benefit: RET fusion-positive thyroid cancer

• Of 5 patients that progressed, 5 continued treatment post-progression, for 0.4–8.5+ months

Data cutoff: June 17, 2019. No shading to show 95% confidence band due to a very low number of events.

Median DOR: not reached (95% CI: 9.5 months‒NE)Number of events: 2/14Median follow-up: 9.3 months

0 5Months since start of response

10 15 20

14 10 5 313 9 4 1 0No. at risk:

Duration of response

100

80

60

40

20

0

Patie

nts w

ith re

spon

se (%

)

Progression-free survival

Median PFS: not reached (95% CI: 10.0 months‒NE)Number of events: 5/26Median follow-up: 9.9 months

100

80

60

40

20

0

0 5

Months since start of treatment

10 15 20

26 19 10 422 14 6 2 0No. at risk:

Patie

ntsf

ree f

rom

pro

gres

sion (

%)

Selpercatinib safety profileLIBRETTO-001 safety database, n=531

Treatment-emergent AEs (≥15% overall) Treatment-related AEs

Adverse event Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 3 Grade 4 TotalDry mouth 29% 4% – – 32% – – 27%Diarrhea 21% 8% 2% – 31% 1% – 16%Hypertension 4% 11% 14% <1% 29% 8% <1% 18%Increased AST 17% 5% 6% 1% 28% 4% 1% 22%Increased ALT 13% 4% 7% 1% 26% 6% 1% 21%Fatigue 15% 9% 1% – 24% <1% – 14%Constipation 19% 3% <1% – 22% <1% – 11%Headache 15% 4% 1% – 20% <1% – 7%Nausea 15% 4% <1% – 19% <1% – 8%Peripheral edema 16% 4% <1% – 19% – – 10%Increased creatinine 14% 4% – <1% 18% – – 10%

• 9 patients (1.7%) discontinued due to treatment-related toxicity

Data cutoff: June 17, 2019. AE‒adverse event. Total % for any given AE may be different than the sum of the individual grades, due to rounding.

Selpercatinib overcomes germline RET V804M gatekeeper mutation

Baseline Cycle 2

• 56-year-old man with hereditary RET V804M-mutant MTC

• Massive metastatic infiltration of the liver

• 3 prior anti-RET MKIs: cabozantinib, vandetanib, lenvatinib

• Initiated selpercatinib at 80 mg BID with escalation to 160 mg BID

• Rapid reduction in serum CEA and calcitonin, resolution of diarrhea, abdominal distension, and abdominal pain

• Confirmed CR by RECIST 1.1 after 8 weeks of treatment

• Remains on treatment at 20 months

Data cutoff: June 17, 2019. Red arrows indicate target lesions. Wirth et al, DOI: 10.1200/PO.19.00189 JCO Precision Oncology - published online September 11, 2019. Images courtesy of L. Wirth.

• 73-year-old man with CCDC6-RET fusion-positive anaplastic thyroid cancer

• Metastatic disease to lungs and brain*

• Previous surgery, SRS, and docetaxel/doxorubicin

• Initiated selpercatinib at 160 mg BID

• Confirmed PR by RECIST 1.1 after 8 weeks of treatment

• Remains on treatment at 14 months

Data cutoff: June 17, 2019. *All CNS lesions considered non-target due to prior radiation. Red arrow indicates target lesions, D – diaphragm.Dias-Santagata et al, Thyroid, manuscript in review. Images courtesy of L. Wirth.

Selpercatinib activity in CCDC6-RET fusion-positive anaplastic thyroid cancer

D

D

D

Conclusions• Selpercatinib demonstrated robust and durable anti-tumor activity in RET-mutant MTC and RET fusion-positive thyroid cancer

– Prior cabozantinib and/or vandetanib MTC (n=55): – Heavily pre-treated population (53% with ≥2 MKIs)– ORR 56% (95% CI: 42‒70) – Median DOR not reached (95% CI: 11.1‒NE), median PFS not reached (95% CI: 11.3‒NE)– Significant and stable reductions in calcitonin and CEA in most patients

– Cabozantinib/vandetanib-naïve MTC (n=76): ORR 59% (95% CI 47‒70), median DOR, PFS not reached– RET fusion-positive thyroid cancer (n=26): ORR 62% (95% CI 41‒80), median DOR, PFS not reached

• Favorable safety profile– Safety database (n= 531):

– Most AEs low grade and unrelated to selpercatinib– Only 1.7% discontinued therapy for treatment-related AEs

• Outcomes with selpercatinib after treatment with approved MKIs comparable to outcomes with MKIs when they are used in first line, and less toxic

• New Drug Application (NDA) submission to US FDA planned by the end of 2019

Randomized, global phase 3 trial: selpercatinib vs. cabozantinib or vandetanib (investigator’s choice) in kinase inhibitor-naïve RET-mutant MTC (in the coming months)

LIBRETTO-001 patients, their families and caregivers

LIBRETTO-001 investigators and study staff

Array Biopharma, Alturas Analytics

International Thyroid Oncology Group

Acknowledgements