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