1. as backboone for combiantion of chemo and immunotherapy
Cesare Gridelli
Division of Medical Oncology
“S.G. Moscati” Hospital – Avellino (Italy)
NAB-PACLITAXEL:
as backboone for combiantion
of chemo and immunotherapy

2. Experimental approaches to build on active immunotherapies to maximise clinical benefit
1. Drake CG. Ann Oncol. 2012;23(suppl 8):viii41–viii46; 2. Hannani D, et al. Cancer J 2011;17:351–358; 3. Ménard C, et al. Cancer Immunol Immunother 2008;57:1579–1587; 4. Ribas A, et al. Curr Opin Immunol 2013:25:291–296

4. Mechanisms of immunogenic tumor cell death induced by chemotherapy
Emens LA et al, Cancer Immunol Res 2015

5. Increased antigen loads by chemotherapy
Discovery Medicine, 2017

6. Chemotherapy modulates tumor immunity by mechanisms
distinct from immunogenic cell death
Emens LA et al, Cancer Immunol Res 2015

8. PFS & OS
Papadmitrakopoulou Va et al. ASCO meeting 2017, abstract N° 9094

10. CBDCA/nab-paclitaxel + CBDCA/nab-paclitaxel +
Phase I-II trials including Nab-paclitaxel and Pembrolizumab in advanced NSCLC
NCT
Phase I
CBDCA/nab-paclitaxel +
Pembrolizumab
Stage IV
NSCLC
NCT
Phase II
CBDCA/nab-paclitaxel +
Pembrolizumab
Stage IV
NSCLC
Pembrolizumab X4
Nab-PTX X4
NCT
Phase II
Nab-PTX X4
Pembrolizumab X4
Stage IV NSCLC
No PD after DDP CT R
Randomize 1:1:1
Pembrolizumab +
Nab-PTX X4

11. ABI-007-ST-001 Phase I Study of Nivolumab + nab®-Paclitaxel Regimens in Solid Tumors: Results From the Pancreatic Cancer and Non-Small Cell Lung Cancer Cohorts
George B, Kelly K, Ko A, Soliman HH, Trunova N, Wainberg ZA, Waterhouse DM, O’Dwyer PJ, Hochster HS
nab® is a registered trademark of Celgene Corporation.
George B, et al. Poster at ESMO 2016 [abstract 2027].

12. Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Background and Objectives1
Chemotherapy leads to tumor lysis and release of tumor antigens, which may prime the immune system for checkpoint inhibitors2
Combining chemotherapeutic agents, including nab-paclitaxel (nab-P), with an immune checkpoint inhibitor has demonstrated antitumor activity in patients with mTNBC3 and NSCLC4
Here we present interim results from 2 of the 3 cohorts (PC and NSCLC) of a phase I safety trial of nivo + nab-P in advanced PC (± Gem), advanced NSCLC (+ Carbo), and MBC
Safety, including DLTs, and preliminary efficacy for patients from the PC (Arms A and B) and NSCLC (Arm C) cohorts in Part 1 were assessed in this analysis
1. George B, et al. Poster at ESMO 2016 [abstract 2027]. 2. Chen DS, Mellman I. Immunity. 2013;39: Adams S, et al. J Clin Oncol. 2016;34(suppl) [abstract 1009]. 4. Camidge DR, et al. J Thorac Oncol. 2015;10(9 suppl 2):S176 [Oral presentation 02.07].

13. Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Study Designa
This interim analysis examines only Part 1 of Arms A, B, and C.
Part 1
Part 2
Patients with LAPC or MPC with 1 prior CT regimen
Arm Ab
nab-P 125 mg/m2 d1, 8, 15 of 28-day cycle
+ nivo 3 mg/kg d1 and 15 of 28-day cycle (n ≈ 6)
Arm A
Safety expansion with RP2D (n ≈ 20)
If Arm A deemed safe
If dose level safe
CT-naive patients with LAPC or MPC R
Arm Bb
nab-P 125 mg/m2 d1, 8, 15 of 28-day cycle
+ Gem 1000 mg/m2 d1, 8, 15 of 28-day cycle
+ nivo 3 mg/kg d1 and 15 of 28-day cycle (n ≈ 6)
If dose level safe
Arm B
Safety expansion with RP2D (n ≈ 14)
Arm Cb,d
nab-P 100 mg/m2 d1, 8, 15 of 21-day cycle × 4 cycles
+ Carbo AUC 6 d1 of 21-day cycle × 4 cycles
+ nivo 5 mg/kg d15 of 21-day cyclee (n ≈ 6)
Stage IIIB/IV NSCLC
No prior therapyc
If Arm C deemed safe
If dose level safe
Arm C
Safety expansion with RP2D (n ≈ 14)
Stage IIIB/IV NSCLC
No prior therapyc R
If dose level safe
Arm Dd,f
nab-P 100 mg/m2 d1, 8, 15 of 21-day cycle × 4 cycles
+ Carbo AUC 6 d1 of 21-day cycle × 4 cycles
+ nivo 5 mg/kg d15 of 21-day cycleg (n ≈ 6)
Arm D
Safety expansion with RP2D (n ≈ 14)
Footnotes
George B, et al. Poster at ESMO 2016 [abstract 2027].

14. Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Methods
Endpoints
Primary
To identify DLTs (Part 1)
To determine percentage of patients with grade 3/4 TEAEs or treatment discontinuation due to a TEAE (Parts 1 and 2)
Secondary
TEAEs leading to dose reduction, dose delay, or treatment discontinuation
PFS (investigator assessed)a; OS; DCRa; ORRa; and DORa
DLT Evaluationb Criteria
Received ≥ 2 cycles of nivo + standard nab-P therapy and remained on study for 14 additional calendar days after the last dose of nivo in the second cycle
Received ≥ 1 nivo dose and discontinued treatment due to DLT prior to completing 2 cycles of nivo
Statistical Analysis
Endpoints and 95% CIs were calculated using descriptive statistics
Safety data are summarized for all treated patients and nivo-treated patients separately
a Based on RECIST v1.1. b Up to 6 DLT-evaluable patients will be enrolled initially in each treatment arm at the given dose level for DLT assessment.
George B, et al. Poster at ESMO 2016 [abstract 2027].

15. Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Selected Patient Characteristics
NSCLC (Arm C)
Arm A
(n = 11)
Arm B
(n = 6)
All Treated
(n = 21)
Nivo Treated
(n = 18)a
Age, median (range), y
< 65, n (%)
≥ 65, n (%)
62.0 ( )
6 (54.5)
5 (45.5)
71.0 ( )
1 (16.7)
5 (83.3)
65.0 ( )
9 (42.9)
12 (57.1)
66.5 ( )
7 (38.9)
11 (61.1)
Sex, female, n (%)
4 (66.7)
15 (71.4)
13 (72.2)
Histology, n (%)
Adenocarcinoma
Squamous
11 (100) NA
6 (100)
7 (33.3)
6 (33.3)
Data cutoff dates: 25 May 2016 (NSCLC), and 28 June 2016 (PC)
a Two patients, who did not receive nivo, discontinued treatment due to AEs; data for 1 patient who did not receive nivo are pending.
George B, et al. Poster at ESMO 2016 [abstract 2027].

16. Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Safety
Most Common Grade 3/4 Adverse Eventsa, n (%) PC
Arm A (n = 11)
Arm B (n = 6)
Anemia
2 (18.2)
2 (33.3)
Neutropenia
Pulmonary embolism NR
NSCLC (Arm C)
All Patients (n = 21)
Nivo-Treated Patients (n = 18)
6 (28.6)
6 (33.3)
4 (19.0)
4 (22.2)
Hypokalemia
3 (14.3)
3 (16.7)
No DLTs observed among the 7 DLT-evaluable patients in Arm A
1 DLT observed among the 6 DLT-evaluable patients in Arm B
No DLTs observed among the 5 DLT-evaluable patients in Arm C
No grade 3/4 pneumonitis was reported
Grade 2 pneumonitis occurred in 1 patient (Arm C), but it resolved after 7 days
a All patients will be followed for AEs for up to 100 days or until patient withdraws consent from the entire study.
George B, et al. Poster at ESMO 2016 [abstract 2027].

17. Median nivo treatment durations for patients were as follows:
Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Treatment Discontinuation and Duration
PC: 9 patients in Arm A discontinued treatment (8 due to PD, 1 patient withdrew); 1 patient in Arm B discontinued treatment (due to “other” reasons)
NSCLC: In Arm C, 7 patients discontinued treatment: 4 due to PD, 2 due to AEs, and 1 due to “other” reasons
4 of the 5 nivo-treated patients who discontinued treatment did so due to PD
Median nivo treatment durations for patients were as follows:
Arm A: 12.6 weeks (range, )
Arm B: 15.5 weeks (range, )
Arm C: 21.1 weeks (range, )
George B, et al. Poster at ESMO 2016 [abstract 2027].

18. % Change From Baseline in Total Length
Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Efficacy: Change from Baseline in Total Lengtha of Target Lesions
Arm A: Pancreatic Cancerb
Active on study
Discontinued treatment Never received nivo
Best Overall Response CR PR SD PD
Treatment Discontinuation
Progression AE
Other reason
160
120 80
% Change From Baseline in Total Length 40
−40
−80 1 2 3 4 5 6 7 8
Months on Treatment
2 patients had a PR and 4 had SD
a Total length = sum of the longest diameters of the non-nodal target lesions and the shortest axis of lymph nodes. All tumor response evaluations were unconfirmed. b All treated patients.
George B, et al. Poster at ESMO 2016 [abstract 2027].

19. % Change From Baseline in Total Length
Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Efficacy: Change from Baseline in Total Lengtha of Target Lesions
Arm B: Pancreatic Cancerb
Active on study
Discontinued treatment Never received nivo
Best Overall Response CR PR SD PD
Treatment Discontinuation
Progression AE
Other reason
160
120 80
% Change From Baseline in Total Length 40
−40
−80 1 2 3 4 5
Months on Treatment
3 patients had a PR and 3 had SD
a Total length = sum of the longest diameters of the non-nodal target lesions and the shortest axis of lymph nodes. All tumor response evaluations were unconfirmed. b All treated patients.
George B, et al. Poster at ESMO 2016 [abstract 2027].

20. % Change From Baseline in Total Length
Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Efficacy: Change from Baseline in Total Lengtha of Target Lesions
Arm C: Non-Small Cell Lung Cancerb
Active on study
Discontinued treatment Never received nivo
Best Overall Response CR PR SD PD
Treatment Discontinuation
Progression AE
Other reason 50
% Change From Baseline in Total Length
−50
−100 1 2 3 4 5 6 7 8 9 10
Months on Treatment
9/21 patients had a PR and 10 had SD; data pending for 2 patients
9/18 nivo-treated patients in Arm C had a PR, 8 had SD; 1 patient data pending
a Total length = sum of the longest diameters of the non-nodal target lesions and the shortest axis of lymph nodes. All tumor response evaluations were unconfirmed. b All treated patients.
George B, et al. Poster at ESMO 2016 [abstract 2027].

21. Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Authors’ Conclusions
These interim results indicate that the addition of nivo to standard nab-P regimens may be feasible in patients with PC and advanced NSCLC
Addition of nivo to nab-P or nab-P/Carbo was tolerable, with no DLTs or unexpected AEs in Arm A or Arm C, and 1 DLT in Arm B
Grade 3/4 pneumonitis, an AE occasionally seen in studies of other checkpoint inhibitors, was not observed
Based on the promising safety findings and the antitumor activity in Part 1 of Arms A and C:
Patients with advanced PC are currently enrolling in Arm B for first-line treatment with nivo + nab-P + Gem
Patients with advanced NSCLC are currently enrolling in Part 2 of Arm C for first-line treatment with nivo + nab-P + Carbo
George B, et al. Poster at ESMO 2016 [abstract 2027].

22. Liu et al, ASCO 2017

23. Liu et al, ASCO 2017

24. CBDCA/nab-paclitaxel + CBDCA+nab-paclitaxel
Atezolizumab in 1-line: phase III trials combined to chemo in Non squamous NSCLC
CLOSED
Impower 130
CBDCA/nab-paclitaxel +
Atezolizumab 1200 mg q21
Stage IV
Non squamous NSCLC
ECOG PS 0–1 R
Randomize 1:2
CBDCA+nab-paclitaxel
Primary endpoint N. pts Stratified by PD-L1 status
PFS TC3-any IC vs TC0/1/2-IC2/3 vs TC0/1/2-IC01

25. CBDCA/nab-paclitaxel + CBDCA+nab-paclitaxel
Atezolizumab in 1-line: phase III trials combined to chemo in Squamous NSCLC
CLOSED
IMpower 131
CBDCA/paclitaxel +
Atezolizumab 1200 mg q21
Stage IV
Squamous NSCLC
ECOG PS 0–1 R
Randomize 1:1:1
CBDCA/nab-paclitaxel +
Atezolizumab 1200 mg q21
CBDCA+nab-paclitaxel
Primary endpoint N. pts Stratified by PD-L1 status
PFS TC3-any IC vs TC0/1/2-IC2/3 vs TC0/1/2-IC01