Immunotherapeutic Combination of
IL-15 Super-Agonist (ALT-803) + Nivolumab
in Non-small Cell Lung Cancer
John Wrangle, MD, MPH
Medical University of South Carolina
Investigator Sponsored Trial
ClinicalTrials.gov Identifier: NCT02523469
Disclosures
 Altor Bioscience, support for this IIT and preclinical studies
The Problem
• NSCLC is the #1 cancer killer in SC, the US, and the world
• PD1 blockade ORR only ~20%, and CBR is ~40%
• PDL1 staining is a poor predictor of response to
immunotherapy
The Solution?
• Tobacco control/cessation
• Combination strategies
• Improved predictors of response
Immunotherapy in NSCLC
Nivo in second-line Squamous NSCLC
Nivo in second-line Squamous NSCLC
Tumor/Immune-microenvironment Interaction
1.
2.
3.
4.
Immuno/immuno combo
Immuno/targeted combo
Immuno/chemo combo
Immuno/XRT combo
Nature Reviews, 2012
Can combo I/O be effective?
1. Much higher response rates in melanoma (and likely NSCLC) to therapy with
combo ipi/nivo. But at the expense of much higher toxicity.
2.
Responses to
addition of ipi after
relapse on nivo
Our Strategy for I/O Combination
1. Anti-PD1 mAb, known activity in NSCLC. This will likely be the
backbone of I/O combinations for the foreseeable future.
2. Cytokines (specifically IL-2R gamma-chain agonists like IL-2)
•
•
•
•
Responses in solid tumors, including durable complete
responses and possibly cures
These are lymphocyte growth factors
IL-15 stimulates NK proliferation in addition to CD8+ T-cells
ALT-803 is an alternative to IL-2, is an IL-15 super-agonist
Preclinical Treatment Schema: PD1 blockade + IL-15 super-agonist
unpublished
unpublished
Combined ALT-803 + Nivolumab in NSCLC: QUILT-2.002
Phase II
Arm A
Anti-PD1 mAb Naïve
(n= max of 40)
Phase Ib
ALT-803 escalation
+ nivolumab
(n = up to 21)
RP2D
Phase II
Arm B
Anti-PD1 mAb Relapsed
& Refractory
(n= max of 30)
Study Endpoints
Primary Endpoints
 Phase Ib: Safety, tolerability, and the RP2D.
 Phase II: ORR of ALT-803 + Nivo in 2nd line NSCLC
Secondary Endpoints
 PK, immunogenicity, and immune correlates
 PFS, OS, and duration of response
Dose Escalation
Cohort
ALT-803
1
6 mcg/kg SC
2
10 mcg/kg SC
3
15 mcg/kg SC
4
20 mcg/kg SC
Nivolumab
240mg IV
Treatment Schema: Induction combination therapy followed by single agent maintenance
Week
1
2
Nivo
3
4
5
6
d
ALT-803
…
4 cycles = 6 months combo therapy
ClinicalTrials.gov Identifier: NCT02523469
nivo monotherapy until progression
Treatment Schema: Re-induction (pending amendment)
!
…
…
ClinicalTrials.gov Identifier: NCT02523469
Study Endpoints
Primary Endpoints
 Phase Ib: Safety, tolerability, and the recommended phase II
dose of the combination.

Phase II: Define the response rate of ALT-803 added to
nivolumab in patients with advanced and unresectable non-small
cell lung cancer.
Secondary Endpoints
 Pharmacokinetics, immunogenicity, and immune correlates of
ALT-803 in combination with nivolumab in patients with nonsmall cell lung cancer.
 Progression-free survival, overall survival, and duration of
response of all treated patients.
ALT-803 + Nivolumab in advanced NSCLC: Experience to Date
Phase IB
›
6 μg/kg SubQ
3 patients enrolled, no DLTs
› 10 μg/kg SubQ
3 patients enrolled, no DLTs
› 15 μg/kg SubQ
6 patients enrolled, 3 no DLTs, 3 completing DLT period
ClinicalTrials.gov Identifier: NCT02523469
ALT-803 + Nivolumab in advanced NSCLC: Experience to Date
Patient
Dose
Cohort
Time on Therapy
PD-L1 Status
Best Response
MUSC 01-01
(46 yo M)
6 μg/kg
10 weeks
PDL1 Pending (VA)
Stable Disease (+11%)
MUSC 02-02
(57 yo F)
6
10 months
0%
Stable Disease (+0%)
MUSC 03-03
(45 yo M)
6
10 months
90%
Partial Response (-65%)
MUSC 04-04
(47 yo M)
10 μg/kg
8 months (ongoing)
90%
Partial Response (-57%)
MUSC 05-05
(57 yo F)
10
7 months (ongoing)
10%+, EGFR mutant
Stable Disease (-8%)
MUSC 06-06
(70 yo M)
10
5 months (ongoing)
0%
Stable Disease (-33%)
MUSC 07-07
(67 yo F)
15 μg/kg
4 months (ongoing)
PDL1 pending, BRAF V600E
Stable Disease (+33%)
UMN 01-01
15
3 months
0%
Progressive Disease
CCF 01-01
15
2 month (ongoing)
PDL1 pending
Stable Disease (-15%)
ClinicalTrials.gov Identifier: NCT02523469
ALT-803 + Nivolumab in advanced NSCLC: Experience to Date
Event Name
Gr 1
Gr 2
Gr 3
Fatigue
4
2
1
Anorexia
4
1
5
Fever
2
3
5
Flu like symptoms
5
Injection site reaction
2
3
5
Dyspnea
1
3
4
Nausea
3
1
4
Chills
3
Cough
2
Headache
3
Hypotension
1
Night sweats
3
3
Anxiety
2
2
Back pain
2
2
Diarrhea
2
2
Dizziness
2
Hot flashes
2
Non-cardiac chest pain
1
Pain
Gr 4
7
5
3
1
3
3
2
3
2
2
1
1
Abdominal pain
2
1
2
1
1
Aches
1
1
Anemia
1
1
Bright red mucus
1
1
Chest flutter
1
1
Concentration impairment
1
1
Constipation
Dehydration
1
1
1
1
Dysgeusia
1
1
Edema limbs
1
1
Elbow pain
1
Fall
1
1
1
Generalized muscle
weakness
1
Hearing loss
1
Hemoptysis
1
Hives
1
1
1
1
Hypernatremia
1
1
Hyperglycemia
1
1
1
Hypertension
1
1
Hypokalemia
1
1
Hyponatremia
1
1
Hypophosphatemia
1
1
Hypoxia
1
1
Infusion related reaction
1
1
Ingrown toenail
1
1
Lymphocyte count decreased
1
1
Muscle aches
1
1
Otitis media
1
1
Pain in extremity
1
Pleural effusion
Pruritus
1
1
1
1
1
Renal failure
1
1
Sinus tachycardia
1
1
Sore throat
1
1
Swollen arm
1
1
Temporal pain
1
1
Toe infection
1
1
Tremor right hand
1
1
Tumor pain
1
Vomiting
1
Weight loss
Wheezing
1
Event Name
Fatigue
Anorexia
Fever
Flu like
symptoms
Injection site
reaction
Dyspnea
Nausea
Chills
Cough
Headache
Hypotension
Night sweats
Anxiety
Back pain
Diarrhea
Dizziness
Hot flashes
Non-cardiac
chest pain
Pain
1
1
1
l
Total
1
1
ClinicalTrials.gov Identifier: NCT02523469
Gr 1
Gr 2
Gr 3
4
4
2
2
1
3
1
5
Gr 4
Total
7
5
5
5
2
3
5
1
3
3
2
3
1
3
2
2
2
2
2
3
1
4
4
3
3
3
3
3
2
2
2
2
2
1
1
1
2
1
2
1
2
ALT-803 + Nivolumab in advanced NSCLC: Experience to Date
Event Name
Gr 1
Gr 2
Gr 3
Fatigue
4
2
1
Anorexia
4
1
5
Fever
2
3
5
Flu like symptoms
5
Injection site reaction
2
3
5
Dyspnea
1
3
4
Nausea
3
1
4
Chills
3
Cough
2
Headache
3
Hypotension
1
Night sweats
3
3
Anxiety
2
2
Back pain
2
2
Diarrhea
2
2
Dizziness
2
Hot flashes
2
Non-cardiac chest pain
1
Pain
Gr 4
Total
7
5
3
1
3
3
2
3
2
2
1
1
Abdominal pain
2
1
2
1
1
Aches
1
1
Anemia
1
1
Bright red mucus
1
1
Chest flutter
1
1
Concentration impairment
1
Constipation
Dehydration
1
1
1
1
1
Dysgeusia
1
1
Edema limbs
1
1
Elbow pain
1
1
Fall
1
1
Generalized muscle
weakness
1
Hearing loss
1
Hemoptysis
1
Hives
1
1
1
1
Hyperglycemia
1
Hypernatremia
1
1
1
1
Hypertension
1
1
Hypokalemia
1
1
Hyponatremia
1
1
Hypophosphatemia
1
Hypoxia
Infusion related reaction
Ingrown toenail
1
1
1
1
1
1
1
Lymphocyte count decreased
1
1
Muscle aches
1
1
Otitis media
1
1
Pain in extremity
1
Pleural effusion
Pruritus
1
1
1
1
1
1
Sinus tachycardia
1
1
Sore throat
1
1
Swollen arm
1
1
Temporal pain
1
1
Toe infection
1
1
Tremor right hand
1
1
Tumor pain
1
Vomiting
1
Wheezing
1
1
1
1
Fatigue
Pain
Abdominal
pain
Generalized
muscle
weakness
Hyperglycemia
Hypophosphat
emia
Lymphocyte
count
decreased
Weight loss
1
Renal failure
Weight loss
Event
1
1
ClinicalTrials.gov Identifier: NCT02523469
Gr 1
Gr 2
Gr 3
Gr 4
Total
4
2
1
1
1
7
2
1
1
1
1
1
1
1
1
1
1
1
1
ALT-803 + Nivolumab in advanced NSCLC: Experience to Date
ClinicalTrials.gov Identifier: NCT02523469
Pseudo-progression
Patient #4 (-57% by RECIST)
June 20th, 2016
July 19th, 2016
2.6 cm
10.5 cm
1.9 cm
2.3 cm
December 13th, 2016
0.9 cm
1.0 cm
Patient #7
ALT-803 + ICB: Future Directions
A Phase II Study Pembrolizumab in Combination with ALT-803 in
Untreated Patients With Advanced Or Metastatic PDL1+ NSCLC
Safety
Lead-In
(n = 10)
Phase II
(n = total 41)
What’s coming….
• Chemo/Pembro 1st line?
• Ipi/Nivo… 2nd line? 1st line?
• Immuno/immuno combo I/O
Acknowledgements
Clinical Trial Participants


Mark Rubinstein, Ph. D
Altor Biosciences
Laboratory Research Team
Marzena Swiderska-syn, DVM
Samantha Suriano, BS
Clinical Research Team
Kate Anderton, Cameron Coggins,
Tricia Bentz
Joni Harris & Stacey Coggins




Funding
NIH, K12 CA157688
ACS IRG
email: [email protected]
Cell: 504-251-4160