Updated Clinical Data from the SCCHN Expansion Cohort of an Ongoing Ph1/1b Study of Eganelisib (IPI-549) in Combination with Nivolumab
Ezra E. W. Cohen, MD1, Michael Postow, MD2, Ryan Sullivan, MD3, David S. Hong, MD4, Heather Yeckes-Rodin, MD5, Jerry McCarter, RN, BSN 6, Nora Zizlsperger, PhD6, Jeffery Kutok, MD, PhD7, Brenda O'Connell, PhD6, Kara Page6, Jennifer Roberts6, Halle Zhang, PhD6, Bartosz Chmielowski, MD, PhD8
University of California San Diego,2 Memorial Sloan Kettering Cancer Center, 3 Massachusetts General Hospital,
MD Anderson Cancer Center,5 Hematology Oncology Associates of Treasure Coast, 6 Infinity Pharmaceuticals,
Epizyme,8 University of California, Los Angeles
Background
Significant unmet need for head and neck cancer patients (SCCHN)
• Current checkpoint inhibitors are only active in ~16% of patients and there are limited treatment options for those that don't respond*
Eganelisib (IPI 549) is a selective PI3Kγ inhibitor that reprograms pro-tumor macrophages to relieve immune suppression and activate anti-tumor T cells
The activity of T cells by eganelisib can be maintained, despite IFN-γ mediated upregulation of PDL1, with checkpoint inhibitors providing synergistic anti-tumor effects
We are currently evaluating safety and antitumor 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 the MARIO-275 Phase 2 clinical trial
CPI naive 1L TNBC and RCC patients in the MARIO-3 Phase 2 clinical trial
Microenvironment (TME) from Immune Suppressed to Immune Activated
RNA Seq peripheral blood across all dose levels
IFN-γ -responsive
Fold increase
P value
C1D1-monotherapy
C2D1-monotherapy
genes
at C2D1
CD274 (PDL1)
2.4
3.5 x 10-5
CD274 (PDL1)
FCGR1B
1.8
1.5 x 10-3
FCGR1B
GBP2
1.5
5.6 x 10-4
GBP2
GBP5
2.3
1.3 x 10-4
GBP5
GBP1
2.0
1.9 x 10-4
GBP1
GBP4
1.7
9.4 x 10-4
GBP4
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MARIO-1: Eganelisib Phase 1/1b Trial in Patients with Solid Tumors
Cohort E: Combination Therapy in Patients Who Progressed on Immediate Prior CPI therapy
MARIO-1 Study Start***
Combination Dose
NSCLC
Stable Disease
PD
Melanoma
Escalation/Expansion
Eganelisib*+ Nivolumab**
SCCHN
Benefit Eganelisib
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
* 28 day cycles, continuous 40mg QD dosing
** Flat-dose 240 mg Q2WConfidential5
*** Must have de novo or acquired resistance to immediately prior anti-PD-1/anti-PD-L1 therapy
SCCHN Patient Baseline Characteristics, Disposition and Exposure
All Patients had Previously been Refractory to or Relapsed Following Treatment with Anti-PD1/PDL1 Therapies; 85.7% had Progressed on Immediate Prior Anti-PD1/PDL1 Therapies
Characteristics
N = 21
Age median years, (range)
62.0 (29, 80)
Sex, n (%)
Male
16 (76.2)
Female
5 (23.8)
ECOG, n (%)
0
9 (42.9)
1
12 (57.1)
2
0
HPV, n (%)
Y
8 (38.1)
N
4 (19.0)
unknown
9 (42.9)
Best Response to Prior anti-
n (%)
PD1/PDL1, N = 21
PR
5 (23.8)
SD
4 (19.0)
PD
9 (42.9)
Unknown
3 (14.3)
Prior Therapies, N = 21
n (%)
Prior therapies, n (%)
1
2
(9.5)
2
3 (14.3)
3
6 (28.6)
4 or more
10
(47.6)
Anti-PD1/PDL1
21 (100)
Chemotherapy
14
(66.7)
Anti-EGFR
12
(57.1)
Anti-CTLA4
3 (14.3)
Anti-CD20
2
(9.5)
Immune stimulatory
2
(9.5)
Last Line of Therapy Prior to Study
n (%)
Anti-PD1/PDL1
18
(85.7)
Anti-CD20
2
(9.5)
Anti-EGFR
1
(4.8)
Immune stimulatory
1
(4.8)
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Eganelisib + Nivolumab was Generally Well-Tolerated and Associated with a Favorable Safety Profile
Most Common TEAEs (All Grade) in ≥15% of Patients (N=21)
Tx-Related
Immune-
Preferred Term
TEAE (All)
related Tx-
TEAE (All)
Related TEAE
(All)
Fatigue
13 (61.9)
8 (38.1)
0
Pyrexia
9 (42.9)
3 (14.3)
0
Decreased Appetite
9 (42.9)
3 (14.3)
0
Pruritus
6 (28.6)
3 (14.3)
3 (14.3)
Weight Decreased
6 (28.6)
0
0
Nausea
6 (28.6)
4 (19.0)
0
Diarrhea
6 (28.6)
0
0
Dyspnea
5 (23.8)
1 (4.8)
0
Abdominal Pain
5 (23.8)
2 (9.5)
0
Vomiting
4 (19.0)
2 (9.5)
0
Myalgia
4 (19.0)
2 (9.5)
0
Dizziness
4 (19.0)
1 (4.8)
0
Headache
4 (19.0)
0
0
Grade 3 and above TEAEs in ≥ 5% of Patients (N=21)
Preferred Term
TEAE
Tx-Related
Immune-related
TEAE
Tx-Related TEAE
(≥ Grade 3)
(≥ Grade 3)
(≥ Grade 3)
Anemia
3 (14.3)
1 (4.8)
0
Disease Progression
3 (14.3)
0
0
Sepsis
2 (9.5)
0
0
Nausea
2 (9.5)
1 (4.8)
0
Abdominal Pain
2 (9.5)
1 (4.8)
0
Data Snapshot
1 June 2020
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Eganelisib + Nivolumab Demonstrates Evidence of Clinical Activity in Patients Not Expected to Respond to CPI Monotherapy having Progressed on Immediate Prior CPI Therapy
Total
≤ 2 Prior
≥ 3 Prior
Lines
Lines
N = 21
N = 11
N = 10
Evaluable Patients*, n
20
10
10
Best Overall Response**
Partial Response (PR), n
Stable Disease (SD), n
Progressive Disease (PD), n
11
6
5
Unknown, n
0
0
0
Overall Response Rate (ORR) (PR), n
(%)
Disease Control Rate (DCR) (PR + SD), n (%)
Progression Free Survival (PFS in
Weeks), Median (95%)
Disposition and Exposure
N = 21
Patient Disposition
Continuing on Treatment, n (%)
0
Discontinued from Treatment, n (%)
21 (100)
Discontinued for Disease Progression, n (%)
15
(71.4)
Adverse Event, n (%)
2
(9.5)
Other, n (%)
2
(9.5)
Death, n (%)
1
(4.8)
Investigator Decision, n (%)
1
(4.8)
Summary of Exposure
Duration of Exposure, Median wks (min, max)
11.3 (2.6, 48.7)
# Cycles Completed, Median (min, max)
3 (1, 14)
IPI-549 dose compliance, Median
91.5%
Data Snapshot 5 October 2020
Response-EvaluableIs defined as having at least 1 post-baseline response assessment or discontinued the treatment phase due to disease progression (including death caused by disease progression) within 16 weeks (+ 2-week window) of the first dose of study treatment.
Per investigator assessment (RECIST 1.1)
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Eganelisib + Nivolumab Combination Therapy Demonstrates Clinical Benefit in Patients Not Expected to Respond to CPI Monotherapy having Progressed on Immediate Prior CPI Therapy
Size from Baseline
Best Change From Baseline in Target Lesions
140
120
100
80
60 2 or fewer prior therapies
Duration on Treatment
(2 or Fewer Lines of Therapies)
Duration on Treatment (Months)
Best % Change in Target Lesion
40
20
0 -20-40-60-80
3 or more prior therapies
PR SD PD
Based on Investigator Assessment per RECIST v1.1
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Eganelisib + Nivolumab Combination Therapy Elicits Partial Response in Patients Not Expected to Respond to CPI Monotherapy having Progressed on Immediate Prior CPI Therapy
Patient Case Studies:
Start of MARIO-1 Therapy
After Progression on Immediately Prior CPI
Patient A: stage IV disease at study entry
Refractory to pembrolizumab after 15 months (best response PR)
63% tumor reduction
PFS: 11 months
Start of MARIO-1 therapy
After Progression on Immediately Prior CPI
Patient B: stage IV disease at study entry
Refractory to pembrolizumab after 5 months (best response SD)
36% tumor reduction
PFS: 7 months
Confidential 10
Targeted Inhibition of PI3Kγ Pathway with Eganelisib has Potential to Benefit HPV+ Patients with T Cell Inflamed SCCHN Tumors
Previous Studies*
MARIO-1
Clinical Activity Associated with T Cell Inflamed SCCHN Tumors
In pre-clinical models, targeted inhibition of the PI3Kγ pathway in combination with anti-PD1 suppresses growth and improves survival of HPV+ SCCHN tumors
In HPV+ SCCHN patients, low PI3Kγ expression profile associated with survival benefit
Cancer Genome Atlas (n=97) Human HPV+ SCCHN Tumors
Log rank test p<0.001
1200
1000
(cells/mmsq)
PR
800
SD
PD
CD8+
600
Tumoral
400
200
0
Observed Benefit in HPV+ Patients
50% of HPV positive patients (n=8) achieved stable disease, as compared to 0% of HPV negative patients (n=3)
*Kaneda et al, Nature (2016) 539:437
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Combination Therapy Shows Evidence of Clinical Activity in Patients Who Would Not be Expected to Respond to Checkpoint Inhibitors Therapy Alone
Key Findings:
Treatment with
Results in Clinical Activity in
Combination Eganelisib +
SCCHN Patients with 2 or
Nivolumab is Generally
Fewer Prior Lines of Therapy,
Well-Tolerated
Including Those having
Progressed on Immediate Prior
CPI Therapy
Eganelisib has Potential to
Benefit HPV+ Patients with T cell
Inflamed SCCHN Tumors
Further Exploration in This Combination is Warranted:
Phase 2 Window of Opportunity
Study Underway
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Next Step: Phase 2 Window of Opportunity Study of IPI-549 in Patients with Locally Advanced HPV+ and HPV- Head and Neck Squamous Cell Carcinoma
Protocol 172058: UCSD Moores Cancer Center Investigator Initiated Trial
Objectives:
1
To detect a change in the PI3Kgamma regulated
Patients with Locally
Advanced, Previously
Untreated HNSCC
Amenable to Surgical
Resection
Baseline tumor measurement
Tumor biopsy (non-surgical)
gene expression signature of immune suppression
To detect change in myeloid, T cell composition
• RNA profiling
Therapy:
eganelisib 40 mg QD PO days 1-21
2
and immune activation markers by IHC as well as
TCR sequencing
3
To determine safety and tolerability of eganelisib
and change in tumor size in patients with locally
advanced HNSCC
• Multiplex IHC
• DNA isolation/TCR sequencing
3 weeks
Surgical Tissue
Specimen
Standard Therapy, Survival, Toxicity Follow-Up
Confidential 13
Acknowledgments
We thank the patients for
The investigators and
Study Sponsor - Infinity
participating in this clinical
their staff at the
Pharmaceuticals in collaboration
trial and their families
clinical trial sites
with Bristol Myers Squibb
For additional information please contact info@infi.com
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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 22:50:00 UTC
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