Medivir : Presentation

176P Liver pharmacodynamics in an open-label phase Ib/IIa study of fostroxacitabine bralpamide (fostrox, MIV-818) in combination with lenvatinib in 2L/3L hepatocellular carcinoma

Hong Jae Chon1, Jeong Heo2, Maria Reig3, Teresa Macarulla4, Victor Moreno5, Beate Haugk6, Tom Ness7, Pia Baumann8, Sujata Bhoi8, Malene Jensen8, Karin Tunblad8, Hans Wallberg8, Fredrik Öberg8

1CHA Bundang Medical Center, South Korea, 2Pusan National University Hospital, South Korea, 3Hospital Clinic de Barcelona, 4Hospital Vall d'Hebron, Barcelona, 5START Madrid-FJD,6Royal Victoria Infirmary, Newcastle upon Tyne, 7Newcastle University and Newcastle Hospitals NHS Foundation Trust, 8Medivir AB, Sweden

Background / Introduction

Fostrox is an orally administered prodrug with liver targeted inhibition of DNA replication, achieving a

Liver pharmacodynamics

Tumor selective effect in the liver

Fostrox + lenvatinib clinical data

Impact on liver function during treatment

100-fold higher liver exposure of the active metabolite versus IV troxacitabine (rat study), minimizing systemic exposure. With a slow

turnover in normal hepatocytes, selective cytotoxicity in tumor cells is expected, reducing the risk of negative impact on liver function.

Most patients with advanced HCC progress within half a year on a first line standard of care immunotherapy (IO) combination and there is currently limited treatment options in the second line setting.

Fostrox is in clinical development in combination with lenvatinib (LEN) in second line advanced HCC, providing synergistic and complementary mechanism of actions for improved efficacy and to overcome treatment resistance on a prior IO. (NCT03781934).

Study Design

		Fostrox + LEN	Fostrox + LEN	Treatment until PD
•	Adv/inop HCC	RP2D - 30 mg
30 mg (n=3)	Primary Endpoint:
•	2L/3L		(n=15)
		Safety
•	≥ 18 y
•	ECOG ≤ 1	Fostrox + LEN		Key Secondary
•	Child-Pugh A
	Endpoints: ORR, DCR,
		20 mg (n=3)		TTP/PFS

Imaging assessment with CT and MRI every 6 weeks

Objectives:

Table 2: Liver biopsy characteristics

Patient		Prior		Viral/		Tumor		Tumor
	Treatment		non-viral	Cellularity	Necrosis
	5			Atezo/Bev	Viral (HepC)		5		>95
	7			Atezo/Bev		Non-viral		15		0
	9			Atezo/Bev	Viral (HepB)		70		20
		Regorafenib
	10			Sorafenib		Non-viral		30		0
	11			Sorafenib		Non-viral		60		0
	12			Atezo/Bev	Viral (HepB)		60		0
	15			Atezo/Bev	Viral (HepB)		2		0
	18			Atezo/Bev	Viral (HepC)		40		0
	450
cells	400
350
tumour	300
250
/500
200
CCD8+	150
100
	50
	0
		5	7	9	10	11	12	15	18

Biopsy number

Figure 2. T-cell infiltration in liver biopsies

H&E

pH2AX

GLUT1/pH2AX

Ki67

P=0.014 (n=8)

Figure 3. DNA-damage in non-malignant liver vs tumor in cycle 2 biopsies

P=0.0011(n=8)

Figure 4. Proliferation in non-malignant liver vs tumor in cycle 2 biopsies

Patients at risk 21

21

16

15

14

14

11

10

Figure 6. ALT level from baseline to treatment cycle 8

	-1,50
	-1,75
	-2,00
Score	-2,25
-2,50
ALBI
-2,75
	-3,00
	-3,25
	-3,50	C1D1	C2D1	C3D1	C4D1	C5D1	C6D1	C7D1	C8D1
At risk	21					21					16		15		14		14		11	10

Figure 8. ALBI score from baseline to treatment cycle 8

Patients at risk 21

21

16

15

14

14

11

10

Figure 7. AST level from baseline to treatment cycle 8

Biopsy data on tumor cell selectivity of fostrox in the liver is supported by:

• No increase in ALT and AST levels over treatment time
• Only 5% increase in mean ALBI score from baseline to cycle 8
• Deterioration in ALBI score* was seen in only 3 out of 21 patients, at cycles 3, 5 and 6 respectively

*Deterioration defined as > 0.5 increase in ALBI score over 2 visits

• Primary: safety and tolerability
• Key secondary: ORR, DCR, PFS
• Exploratory: PK/PD effects of fostrox in combination with lenvatinib Dosing:
• Fostrox: oral, QD for 5 days/21 days cycle
• LEN: oral, 8 or 12 mg QD according to weight

Enrollment:

• 15 sites in the UK, Spain and South Korea

Figure 1: Summary of study design for phase 1b/2a fostrox + LEN in advanced HCC

A

F+L

Figure 5. Paired cycle 2 biopsy

(A=archival) and F+L=fostrox+lenvatinib) showing increased DNA- damage (pH2AX) in proliferative (Ki67) regions, and increased hypoxia (GLUT1) after treatment

• Tumor selective DNA-damage (pH2AX) is observed in liver biopsies from patients on fostrox+lenvatinib
• Low or absent DNA-damage in non-malignant liver tissue
• Infiltration of CD8+ T-cells is seen in most tumors

Clinical Efficacy

Fostrox + LEN (n = 21)			Prior IO	Non-refractory
Median TTP, mo	10.8
		(n = 19)	(n = 16)
95% CI	(4.1 - NE)
			ORR	26%	36%
ORR	24%
			DCR	79%	88%
DCR	81%

Patient Characteristics

Table 1: Patient demographics and disease characteristics at study start

	N = 21
Mean age (range)	62 yrs (42 - 82)
Gender, Female / Male (%)	24 / 76
ECOG Performance status 0/1 (%)	71 / 29
Child-Pugh A (%)	100

Methods

Needle biopsies containing both tumor and normal liver tissue were collected in Cycle 2, 2 to 4 hours after fostrox dosing, fixed in 10% neutral buffered formaldehyde and embedded in paraffin. Slides from the on-treatment biopsy and, if present, an archival/predose sample, were stained with hematoxylin/eosin (H&E), and immunohistochemistry analysis of DNA damage (pH2AX-Ser139), proliferation (Ki-67),T-cells (CD8), and hypoxia (GLUT1) were performed. Double staining for pH2AX/GLUT1 was performed to detect co-localization of DNA damage and hypoxia

Patients at risk 21	16	14	10	9	4	2	2	1	1	1	All patients	21	16	14	10	9	4	2	2	1	1	1
											Prior IO combo	19	15	13	10	9	4	2	2	1	1	1
											Non-primary	16	13	11	8	8	3	2	2	1	1	1
											refractory prior Tx
Figure 9. Time to progression, ORR & DCR in all patients		Figure 10. Time to progression, ORR & DCR in key subgroups*

*All patients received fostrox + LEN. Subgroups: Prior IO combo = patients previously treated with IO combination; Non-refractory prior Tx = patients stable or better > 12 weeks on prior treatment

Viral/Non-viral (%)	76* / 24
Extra hepatic lesion(s) Y/N (%)	67 / 33
AFP ≥400 ng/mL at baseline Y/N (%)**	45/55
Region, Asia / Europ (%)	67 / 33
Prior treatment lines; 2nd line/3rd line (%)	81 /19
Prior atezolizumab/bevacizumab in 1L (%)	86
Prior local therapy (TACE, RFA etc)	70
PD on prior treatment (%)	100
Primary refractory on prior therapy (%)***	22
Starting dose fostrox, 20mg / 30mg (%)	14 / 86

*HepB-81% and HepC-19%; **AFP- NA for 1 pt; ***Active treatment ≤ 12 weeks. Data NA for 3 patients

Conclusions

• Liver pharmacodynamics and clinical lab data confirms fostrox tumor cell selectivity without signals of deterioration of liver function
• Fostrox + lenvatinib data in phase 1b/2a indicates longer term clinical benefit with an estimated median time to progression of 10.8 months
• A randomized phase IIb study is planned to confirm the potential benefit of the combination of fostrox and lenvatinib in second-line HCC, post first-line IO combination

Acknowledgements: all investigators and participating patients with families in South Korea, Spain and UK

Disclosure: Hong Jae Chon is an investigator in the fostrox+lenvatinib combination study, and has received travel support from Medivir AB

Abbreviations: Heptatocellular carcinoma (HCC), recommended phase II dose (RP2D), progressive disease (PD), overall response rate (ORR), disease control rate (DCR), time to progression (TTP), progression free survival (PFS), Eastern Cooperative Oncology Group Performance Status (ECOG PS), Response evaluation criteria in solid tumors (RECIST 1.1) , Modified RECIST (mRECIST), Pharmacokinetics/Pharmacodynamics (PKPD), Computerized tomography (CT), Magnetic Resonance Imaging (MRI), Complete Response (CR), Partial Response (PR), Stable disease (SD), Trans arterial chemoembolisation (TACE), radio frequency ablation (RFA), treatment emergent adverse events (TEAE), maximum tolerated dose (MTD), Common Terminology Criteria for Adverse Events (CTCAE), Immunotherapy (IO), non-target lesion (NTL), target lesion (TL)