Infinity Pharmaceuticals : 2020 SITC Poster

Abstract ID: 434

Background

• Melanoma is one of the deadliest cancers and approximately half of all melanoma patients do not benefit from current immunotherapies*
•	Eganelisib (IPI-549) is a selective PI3K-γ inhibitor that reprograms pro-tumor macrophages to relieve immune suppression and activate anti-tumor T cells
•	The activation of T cells by eganelisib can be maintained, despite IFN-γ mediated upregulation of PDL1, with checkpoint inhibitors (CPIs) providing

Updated clinical data from the melanoma expansion cohort of an ongoing Ph1/1b Study

of eganelisib (IPI-549) in combination with nivolumab

Michael Postow1, Ryan J. Sullivan2, Ezra EW. Cohen3, Martin Gutierrez4, David S. Hong5, Conor Steuer6, Jerry McCarter7, Nora Zizlsperger7, Jeff Kutok7, Brenda O'Connell7, Jennifer Roberts7, Kara Page7, Halle Zhang7, Bartosz Chmielowski8

Memorial Sloan Kettering Cancer Center1, Massachusetts General Hospital2, University of California San Diego3, Hackensack University Medical Center4, MD Andersen Cancer Center5, Emory University Hospital6, Infinity Pharmaceuticals7, University of California Los Angeles8

synergistic anti-tumor effects
• We are currently evaluating safety and anti-tumor activity of eganelisib in combination with CPIs in:
• Patients who progressed on immediate prior CPI therapy in the MARIO-1 Phase1/1b clinical trial
•	CPI naive 2L urothelial cancer patients in MARIO-275
•	CPI naive 1L TNBC and RCC patients in MARIO-3

*Olbryt, M., Rajczykowski et al International Journal of Molecular Sciences 2020

Eganelisib Mechanism of Action

PI3K-γ Inhibition Reprograms Macrophages to Turn Tumor Microenvironment from Immune Suppressed to Immune Activated

Suppressed T cells

Anti-tumor (M1) Macrophages/Activated Myeloid Cells

		PI3K-γ i	M1
	M2	Eganelisib
		2 Relieves Macrophage Suppression, Expands Activated T cells and
1	Eganelisib Inhibition of PI3K-γ	Generates IFN-γ Mediated Immune Response
	Re-programsPro-tumor (M2)	3 Expansion of Activated T Cells Up-	4 Anti-Tumor Activity of Expanded T
	Macrophages/ MDSCs to Anti-Tumor
	(M1) Function	Regulates PDL1 to Blunt T Cell Response	Cells Maintained with Addition of CPI

				IFN-γ -responsive genes	Fold increase	P value
				at C2D1
MARIO-1 monotherapy dose escalation study
demonstrated that treatment with eganelisib is			FCGR1B	1.8	1.5 x 10-3
associated with IFN-γ mediated upregulation of PDL1		GBP2	1.5	5.6 x 10-4
in peripheral blood			GBP5	2.3	1.3 x 10-4
				GBP1	2.0	1.9 x 10-4
				GBP4	1.7	9.4 x 10-4

MARIO-1 Eganelisib Phase 1/1b Trial in Patients with Solid Tumors: Cohort E Design

A key objective of the study is to mount an effective anti-tumor immune response in combination with CPI to generate clinical responses in patients who would not be expected to respond to checkpoint inhibitor therapy alone, including those having progressed on immediate prior CPI therapy

		Treatment Start	Eganelisib Benefit
	NSCLC

Combination Dose Escalation/Expansion		PD

Clinical Response Summary Based on Investigator Assessment per RECIST 1.1 for Melanoma Cohort

More than half (52.6%) of patients who had been refractory to or relapsed following 2 or fewer prior lines of therapy demonstrated a partial response or stable disease
21.1% of patients who had been treated with 2 or fewer prior lines of therapies demonstrated a partial response

	All	Patients ≤ 2	Patients ≥ 3
	Patients	prior lines	prior lines
	N = 40	N = 19	N = 21
Evaluable patients, n	39		20
Best Overall Response
Partial Response (PR), n	4		0
Stable Disease (SD), n	10		4
Progressive Disease (PD), n	24		15
Unknown, n	1		1
Overall Response Rate (ORR) (PR), n (%)	4 (10.3)		0 (0)
Disease Control Rate (DCR) (PR + SD), n (%)	14 (35.9)		4 (20.0)
Progression Free Survival (PFS) in Weeks,	9 (8, 16)		16 (8, 19)
median (95%)

Safety & Tolerability of Melanoma Cohort

Combination treatment with eganelisib and nivolumab is generally well tolerated and associated with a favorable safety profile Most Common TEAEs (All Grade) in >15% of Patients (N=40)

Preferred Term	TEAE	Tx-Related TEAE	Immune-Related
(All)	(All)	Tx-Related TEAE (All)

AST increased	15 (37.5)	13 (32.5)	13 (32.5)
ALT increased	15 (37.5)	13 (32.5)	13 (32.5)
Fatigue	11 (27.5)	8 (20.0)	0
Nausea	11 (27.5)	9 (22.5)	0

Clinical Response: Melanoma Cohort

		Eganelisib + Nivolumab Combination Therapy Demonstrates Clinical Benefit in	Patients on 2 or Fewer Prior Therapies Demonstrated Higher Percent Decrease in Target Lesion
		Patients Not Expected to Respond to CPI Monotherapy Having Progressed on
Size		Immediate Prior CPI Therapy			Duration on Treatment (Weeks)
60	2 or fewer prior therapies
LesionTargetinChange% Baselinefrom	40

	20
	0
	-20				PR
	-40				SD
Best	-60	3 or more prior therapies			PD

			On Study
-80


	-100
Objective Responses Observed in Melanoma Patients that Progressed on Immediate Prior Treatment with Anti-PD1/PDL1 Therapy
		Time (weeks)	Time (weeks)	Time (weeks)

fromChangebaseline	lesionstarget	‐30	0	20	70	120	lesionstarget	‐20	0	20	40	60	80	fromChangebaseline	lesionstarget	‐40	‐20	0	20	40
‐60				fromChangebaseline	‐100						‐100
		0						0								0
		‐20						‐50
															‐50
		‐40
%						%								%

	Start of MARIO-1 Therapy After	Start of MARIO-1 Therapy After		Start of MARIO-1 Therapy After
	Progression on Immediate Prior CPI	Progression on Immediate Prior CPI		Progression on Immediate Prior CPI
• Patient A with Stage III melanoma at entry to study	• Patient B with Stage IV melanoma at entry to study	• Patient C with Stage IV melanoma at entry to study
•	Refractory to pembrolizumab after 3 months of	• Refractory to nivolumab after 5 months of treatment (best	•	Refractory to pembrolizumab (CR for 1 year; PD after 6
	treatment (best response PD)	response PD)		months of therapy)
• 57% tumor reduction in response to treatment with	• 79% tumor reduction in response to treatment with	• 76% tumor reduction in response to treatment with
	eganelisib + nivolumab	eganelisib + nivolumab		eganelisib + nivolumab
•	PFS: > 25 months	• PFS: 14 months	•	PFS: 6 months
				Baseline
Treatment with Eganelisib + Nivolumab is Associated with Decreased Immune Suppression and

Eganelisib*+ Nivolumab**

SCCHN

Melanoma

Pyrexia	9 (22.5)	5 (12.5)	0
Decreased appetite	9 (22.5)	6 (15.0)	0

Increased Immune Activation in Melanoma

Decreased MDSCs, T Cell Reinvigoration and Upregulation of Interferon-γ Responsive Factors in Peripheral Blood

*28 day cycles, continuous 40mg QD dosing; **Flat-dose 240 mg Q2W

Baseline Characteristics, Disposition and Exposure of Melanoma Cohort

100% of patients were refractory to or relapsed following anti-PD1/PDL1 therapy, and 87.5% had immediate prior anti-PD1/PDL1 therapy

Anemia	8 (20.0)	2 (5.0)	0
Pruritus	8 (20.0)	7 (17.5)	7 (17.5)
ALP increased	7 (17.5)	6 (15.0)	6 (15.0)

-(cells/mL)	MDSC	change	T Cell Reinvigoration			Interferon-γ Responsive Factors
				CXCL9			CXCL10


	N=33	N=32	change	N=34	change		N=34
		fold						Cycle 7
		2
		Log

Characteristics	N=40
Age median years, (range)	65.5	(46, 86)
Sex, n (%)
Male	20	(50.0)
Female	20	(50.0)
ECOG, n (%)

Prior therapies, N = 40	n (%)
Prior therapies
1	5 (12.5)
2	6 (15.0)
3	9 (22.5)
4 or more	20 (50.0)
Anti-PD1/PDL1	40 (100)

Vomiting	7 (17.5)	4 (10.0)	0
Rash	7 (17.5)	7 (17.5)	7 (17.5)

Grade 3 and above TEAEs in > 5% of Patients (N=40)

	TEAE	Tx-Related TEAE	Immune-Related
Preferred Term	Tx-Related TEAE
(≥ Grade 3)	(≥ Grade 3)

CD14+CD11b+CD33+HLADR	Log2 foldchange		Ki67+of PD1+ mCD8+ (%)		fold	fold
				2
		2			CXCL10 (pg/mL) Log
C2D1	C1D1	CXCL9 (pg/mL) Log	C1D1	C2D1	C2D1
	C1D1		C2D1	C1D1

0	21	(52.5)
1	17	(42.5)
2	1	(2.5)
Best response to prior anti-PD1/PDL1,n (%)
CR	4 (10.0)
PR	3	(7.5)
SD	18	(45.0)
PD	10	(25.0)
Unknown	5 (12.5)

Immediate Prior	35 (87.5)

Anti-CTLA4	28 (70.0)
Investigational immunotherapy	17 (42.5)
MEK/ERK inhibitor	9 (22.5)
BRAF inhibitor	5 (12.5)
Chemotherapy	4 (10.0)

			(≥ Grade 3)
AST increased	9 (22.5)	9 (22.5)	9 (22.5)
ALT increased	5 (12.5)	5 (12.5)	5 (12.5)
Disease progression	4 (10.0)	0	0
Rash maculo-papular	3 (7.5)	3 (7.5)	3 (7.5)
Rash	3 (7.5)	3 (7.5)	3 (7.5)

Conclusions

Treatment with a combination of eganelisib + nivolumab:

Demonstrates an acceptable safety profile
Validates the on-mechanism eganelisib effect of decreased immune suppression (MDSC) and increased immune activation (T Cell reinvigoration, upregulation of IFN-γ responsive factors including CXCL9, CXCL10 and PDL1)
Results in clinical activity (ORR of 21.1%, DCR of 52.6%) in melanoma patients with 2 or fewer prior lines of therapy, including those having progressed on immediate prior CPI therapy

Acknowledgements

We thank the patients for participating in this clinical trial and their families as well as the investigators and staff at the clinical trial sites.
This study is sponsored by Infinity Pharmaceuticals in collaboration with Bristol Myers Squibb.

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Infinity Pharmaceuticals Inc. published this content on 09 November 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 27 November 2020 22:50:01 UTC

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