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
*J Clin Oncol. 2016;34 (suppl; abstr 6011) | Confidential | 2 | |
PI3K-γ Inhibition Reprograms Macrophages: Turns Tumor
Microenvironment (TME) from Immune Suppressed to Immune Activated
Tumor
Cells
Suppressed
T cells
M2 | PI3Kγ i |
Eganelisib |
1 Eganelisib Inhibition of PI3K-γ Reprograms Pro-tumor (M2) Macrophages/ MDSCs to Anti- Tumor (M1) Function
Anti-tumor (M1)
Macrophages/Activated Myeloid Cells
M1
2 | Relieves Macrophage Suppression, Expands Activated | ||||
T cells and Generates IFN-γ Mediated Immune Response | |||||
3 | Expansion of Activated | 4 | Anti-Tumor Activity of Expanded T | ||
T Cells Up-Regulates PDL1 to | Cells Maintained with Addition of CPI | ||||
Blunt T Cell Response | |||||
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PI3K-γ Inhibition Reprograms Macrophages: Turns Tumor
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 Q2WConfidential 5
*** 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
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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
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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