SAVOIR: a Phase III study of savolitinib vs sunitinib in patients with MET-driven papillary renal cell carcinoma (PRCC)Toni K. Choueiri1, Daniel Y.C. Heng2, Jae Lyun Lee3, Mathilde Cancel4, Remy B. Verheijen5, Anders Mellemgaard5, Lone H. Ottesen5, Melanie M. Frigault6, Anne L’Hernault5, Zsolt Szijgyarto5, Sabina Signoretti7, Laurence Albiges8,9

1Dana-Farber Cancer Institute and Harvard Medical School; 2Department of Medical Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, Canada; 3Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; 4CHU Bretonneau Centre, Tours University, France; 5Oncology R&D, AstraZeneca, Cambridge, UK; 6Oncology R&D, AstraZeneca, Boston, MA, USA; 7Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; 8Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 9Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France

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Introduction• PRCC is the most common type of non-clear cell RCC, accounting for approximately 15% of all RCC1–3

• As a subset of PRCC cases are MET-driven, MET inhibition may be an appropriate targeted treatment approach1,2

• MET has been found to be associated with major chromosome-level alterations in PRCC4

• Savolitinib (AZD6094, HMPL-504, volitinib) is a potent and selective MET-TKI under investigation in several malignancies5–7

• Preclinical data and Phase I studies have shown that savolitinib has promising activity in animal models of PRCC, and leads to partial responses in patients with MET-driven PRCC8,9

• In a single-arm Phase II study, savolitinib demonstrated antitumor activity in patients with MET-driven PRCC10

• Partial responses were confirmed in 18% of patients with MET-driven PRCC vs none with MET-independent disease10

• This Phase II trial justified the investigation of savolitinib in a randomized controlled trial of MET-driven, locally advanced or metastatic PRCC10

• Here we report the results from the Phase III SAVOIR study (NCT03091192), which assessed savolitinib vs standard of care sunitinib in patients with MET-driven, locally advanced or metastatic PRCC

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1. Linehan et al. N Engl J Med 2016;374:135–145; 2. Akhtar et al. Adv Anat Pathol 2019;26:124–132; 3. Graham et al. Eur Urol Oncol 2019;2:643–648; 4. Albiges et al. Clin Cancer Res 2014;20:3411–3421; 5. Hua et al. Cancer Res. 2015;75(15 Suppl):CT305; 6. Jia et al. J Med Chem 2014;25:57:7577–7589; 7. Gavine et al. Mol Oncol 2015;9:323–333; 8. Schuller et al. Clin Cancer Res 2015;21:2811–2819; 9. Gan et al. Clin Cancer Res 2019;25:4924–4932; 10. Choueiri et al. J Clin Oncol2017;35:2993–3001. PRCC, papillary renal cell carcinoma; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor

SAVOIR study designOpen-label, randomized, Phase III trial (NCT03091192)

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RECIST 1.1 assessment every 6 weeks‡ until objective

progressive diseaseRandomized 1:1

Approximately 360–450 patients were planned to be screened, in order to randomize ~180 patients

After external data on predicted PFS with sunitinib in patients with MET-driven disease became available, study enrollment was closed early1

• Primary endpoints: PFS by BICR

• Secondary endpoints: OS and ORR by BICR, safety and HRQoL

1. Albiges et al. ASCO; May 29–31, 2020; presented here: abstract e19321; 2. Frigault et al. AACR 2018;78:4541–4541.*In the absence of co-occurring FH or VHL mutations.2 #Patients were excluded if they had previously received sunitinib or a MET inhibitor. ‡Follow-up every 12 weeks after first year. BICR, blinded independent central review; HRQoL, health-related quality of life; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PRCC, papillary renal cell carcinoma; QD, once daily; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors

Key inclusion criteria • ≥18 years

• Central confirmation of a MET-driven tumor (chromosome 7 gain / MET or HGF amplification / MET kinase domain mutations)*

•Measurable disease

• Karnofsky Performance Status ≥80%

• Patients could have received prior systemic treatment in the advanced setting or be treatment-naïve#

Patients with locally advanced or metastatic PRCC Savolitinib

600 mg QD (or 400 mg if <50 kg)

Sunitinib50 mg QD in 6-week

cycles of 4 weeks on / 2 weeks off

SAVOIR patient disposition

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Data cut-off August 19, 2019.*Enrollment was stopped before reaching target 180 patients due to external data on predicted PFS with sunitinib in patients with MET-driven disease becoming available. #Patients who had MET-driven alteration in Part 1 screening but did not fulfil eligibility criteria for the main study in Part 2 screening, and therefore were not randomized. ‡Patients in the savolitinib group were to receive 600 mg of savolitinib, or 400 mg of savolitinib if they weighed <50 kg; all patients in this group received 600 mg savolitinib. PFS, progression-free survival

Sunitinib 50 mg (n=27)

Screened patients (N=254)

Ongoing treatment at data cut-off (n=14, 42%)

Discontinued treatment (n=19, 58%)

Ongoing treatment at data cut-off (n=9, 33%)

Discontinued treatment (n=18, 67%)

Randomized (n=60)*

Analyzed (n=33, 100%) Analyzed (n=27, 100%)

Excluded (n=194)Screen failure (Part 1): no detected MET-driven alteration (n=181)Screen failure (Part 2): Failure to meet randomization criteria# (n=10)Death (n=2)Withdrawal by patient (n=1)

Savolitinib 600 mg‡ (n=33)

SAVOIR patient baseline characteristics

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Data cut-off August 19, 2019. *Calculated from IVRS. #Patients can be counted in more than one subtype group for MET-driven by SAVOIR clinical trial assay. ‡Amplification of ≥6 copies (in diploid genome). †MET kinase domain mutations (allele frequency >5%). §Gain of 1 copy above ploidy of the genome. BICR, blinded independent central review; IMDC, Independent Data Monitoring Committee; IVRS, interactive voice response system; VEGF-TKI, vascular endothelial growth factor receptor tyrosine kinase inhibitor

Demographic characteristics Savolitinib 600 mg (N=33) Sunitinib 50 mg (N=27)

Age, median (range), years 60 (23, 78) 65 (31, 77)

Sex: male / female, n (%) 29 (88) / 4 (12) 17 (63) / 10 (37)

Race: white / black / Asian / other, n (%) 29 (88) / 1 (3) / 2 (6) / 1 (3) 23 (85) / 1 (4) / 3 (11) / 0

IMDC risk group*: poor / intermediate / favorable, n (%) 4 (12) / 22 (67) / 7 (21) 3 (11) / 17 (63) / 7 (26)

Line of therapy, n (%)1st line≥ 2nd line with prior VEGF-TKI≥ 2nd line without prior VEGF-TKI

28 (85)3 (9)2 (6)

25 (93)0

2 (7)

Karnofsky Performance Status: 100% / 90% / 80%, n (%) 11 (33) / 15 (45) / 7 (21) 4 (15) / 16 (59) / 7 (26)

SAVOIR clinical trial assay-specific MET-driven (BICR)#, n (%)MET amplification‡

HGF amplification‡

MET mutation†

Chromosome 7 gain§

1 (3)1 (3)2 (6)

30 (91)

1 (4)0

3 (11)26 (96)

SAVOIR progression-free survival

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Data cut-off August 19, 2019.1. Albiges et al. J Clin Oncol 2018;36:3624–3631; 2. Ravaud et al. Ann Oncol 2015;26:1123–1128. BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; NC, not calculated; PFS, progression-free survival

1.0

0.8

0.6

0.4

0.2

0.0

Pro

bab

ility

of

PFS

Savolitinib (n=33)Sunitinib (n=27)

0 3 6 9 12 15 18 21 24

Time From Randomization (Months)

33 21 15 8 4 3 3 1 0

27 19 11 7 4 1 0 0 0

Savolitinib

Sunitinib

Number of Patients at RiskNumber Randomized/

Number of Events

33/17

27/20

Median PFS by BICR in months (95% CI)Savolitinib 7.0 (2.8, NC)Sunitinib 5.6 (4.1, 6.9)

HR (95% CI): 0.71 (0.37, 1.36)Log-rank two-sided P-value: 0.313

PFS reported for sunitinib was in range with previous studies1,2

Censored observations+

SAVOIR overall survival

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Data cut-off August 19, 2019.BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; NC, not calculated; OS, overall survival

Median OS by BICR in months (95% CI)Savolitinib NC (11.9, NC)Sunitinib 13.2 (7.6, NC)

HR (95% CI): 0.51 (0.21, 1.17)Log-rank two-sided P-value: 0.110

1.0

0.8

0.6

0.4

0.2

0.0

Pro

bab

ility

of

OS

Savolitinib (n=33)Sunitinib (n=27)

0 3 6 9 12 15 18 21 24

Time From Randomization (Months)

33 31 30 22 13 7 6 2 0

27 25 22 14 10 5 3 1 0

Savolitinib

Sunitinib

Number of Patients at RiskNumber Randomized/

Number of Events

33/9

27/13

Censored observations+

SAVOIR antitumor activity

Endpoint, n (%) [95% CI] Savolitinib (N=33) Sunitinib (N=27)

ORR by BICR,*All partial responses

9 (27) [13.3, 45.5] 2 (7) [0.9, 24.3]

Disease control rate by BICR,#

At 6 monthsAt 12 months

16 (48) [30.8, 66.5]10 (30) [15.6, 48.7]

10 (37) [19.4, 57.6]6 (22) [8.6, 42.3]

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Data cut-off August 19, 2019.1. Albiges et al. J Clin Oncol 2018;36:3624–3631; 2. Ravaud et al. Ann Oncol 2015;26:1123–1128. *Response did not need confirmation. #Disease control rate = complete response + partial responses + stable disease at time point. BICR, blinded independent central review; CI, confidence interval; DoR, duration of response; NC, not calculated; ORR, objective response rate

• As of the data cut-off, no responding patients in the savolitinib group had disease progression, compared with 1 of 2 responding patients in the sunitinib group; response rate reported for sunitinib was in range with previous studies1,2

• It was not possible to calculate median DoR from the data as there were too few events

• Three responders on savolitinib were followed for >6 months after onset of response

Best percentage change from baseline in target lesion size

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Data cut-off August 19, 2019. *Savolitinib n=27; sunitinib n=24. Target lesion size, best percentage change waterfall plot by BICR. Nine patients (savolitinib n=6; sunitinib n=3) were not included in the target lesion size plot: no target lesions present at baseline that were selected as target lesions for the purpose of BICR assessment n=7 (savolitinib n=5; sunitinib n=2); no post-baseline target lesion assessment captured n=2 (savolitinib n=1; sunitinib n=1). BICR, blinded independent central review

Bes

t C

han

ge f

rom

Bas

elin

e in

Tar

get

Lesi

on

Siz

e (%

)

100

50

0

-50

-100

100

50

0

-50

-100

Savolitinib*

Sunitinib*

Best Objective Response: Progressive Disease Stable Disease Partial Response

Patients who experienced any tumor shrinkage Savolitinib: n=18, 67%Sunitinib: n=17, 71%

SAVOIR safety summary

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Data cut-off August 19, 2019.*Possible treatment related SAEs that led to discontinuation were: ascites, increased alanine aminotransferase and increased aspartate aminotransferase for savolitinib; and thrombocytopenia and aggravated condition for sunitinib. #These values reflect the number of patients who received ≥1 post-discontinuation disease-related anticancer therapy; subjects could receive more than one type of anticancer therapy. AE, adverse event; SAE, serious adverse event

Patients with an event, n (%) Savolitinib 600 mg (N=33) Sunitinib 50 mg (N=27)

Any AEPossibly causally related to treatment

30 (91)22 (67)

27 (100)25 (93)

Any AE grade ≥3Possibly causally related to treatment

14 (42)8 (24)

22 (81)17 (63)

Any AE leading to deathPossibly causally related to treatment

00

3 (11)1 (4)

Any AE leading to dose interruption of treatment 9 (27) 15 (56)

Any SAEPossibly causally related to treatment

8 (24)4 (12)

8 (30)4 (15)

Any SAE leading to treatment discontinuationPossibly causally related to treatment*

3 (9)2 (6)

2 (7)2 (7)

Received post-discontinuation disease-related therapy 12 (36)# 5 (19)#

Most common adverse events independent of causality

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AEs*, n (%) Savolitinib 600 mg (N=33) Sunitinib 50 mg (N=27)

All Grade ≥3 All Grade ≥3

Any AE 30 (91) 14 (42) 27 (100) 22 (81)

Anemia 2 (6) 0 12 (44) 4 (15)

Nausea 2 (6) 0 9 (33) 0

Decreased appetite 1 (3) 0 8 (30) 1 (4)

Palmar-plantar erythrodysesthesia syndrome 0 0 7 (26) 0

Thrombocytopenia 0 0 7 (26) 2 (7)

Diarrhea 0 0 6 (22) 1 (4)

Hypertension 1 (3) 0 6 (22) 4 (15)

Edema peripheral 11 (33) 0 3 (11) 0

Alanine aminotransferase increased 8 (24) 5 (15) 3 (11) 2 (7)

Aspartate aminotransferase increased 8 (24) 4 (12) 5 (19) 2 (7)

Dyspnea 7 (21) 1 (3) 4 (15) 0

Data cut-off August 19, 2019.*≥20% in either treatment group.AE, adverse event

Conclusions• Although patient numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an

improved safety profile vs sunitinib

• Patients receiving savolitinib experienced fewer grade ≥3 AEs and required fewer dose modifications than those receiving sunitinib, and there were fewer treatment-related AEs of any grade in the savolitinib group

• More patients from the savolitinib arm received a subsequent therapy

• Overall, in SAVOIR, early termination of recruitment precludes definitive conclusions from being drawn due to the small dataset. However, based on the emerging data, further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted

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AE, adverse event; PRCC, papillary renal cell carcinoma

AcknowledgmentsThanks to all the patients and their families

The study (NCT03091192) was funded by AstraZeneca, Cambridge, UK, the manufacturer of savolitinib. Savolitinib is being developed in partnership with Hutchison Medi Pharma

The authors would like to acknowledge Preeyah Purang, BSc, of Ashfield Healthcare Communications, Macclesfield, UK, for medical writing support that was funded by AstraZeneca, Cambridge, UK, in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3)

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In press at JAMA Oncology

• SAVOIR: A Phase 3 Study of Savolitinib Vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma

• Publication planned for end of May 2020

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