1. Wolfram C. M. Dempke SaWo Oncology Ltd June 7, 2017
ASCO 2017: An Update
Wolfram C. M. Dempke
SaWo Oncology Ltd
June 7, 2017

2. Outline of My Talk IOs or TKIs for NSCLC – what’s new?
Trastuzumab/Pertuzumab: The APHINITY Trial
IOs or TKIs for NSCLC – what’s new?
IOs – Pick the Winner
Step it Up a Notch: New IO Molecules
ALK Inhibitors – Is there Light at the Horizon?

3. Outline of My Talk IOs or TKIs for NSCLC – what’s new?
Trastuzumab/Pertuzumab: The APHINITY Trial
IOs or TKIs for NSCLC – what’s new?
IOs – Pick the Winner
Step it Up a Notch: New IO Molecules
ALK Inhibitors – Is there Light at the Horizon?

4. APHINITY Trial: Design
The APHINITY Trial (N = 4805) is a randomised phase III trial evaluating the efficacy and safety of pertuzumab (P) plus trastuzumab (T) and chemotherapy compared to trastuzumab and chemotherapy as an adjuvant therapy.
HER-2/neu-positive breast cancer patients underwent operation und were then randomised to either:
- chemotherapy plus P+T followed by P+T (for one year)
- chemotherapy plus T+Placebo followed by T+Placebo (one year)
Primary endpoint: DFS, secondary endpoint: OS, QoL, cardiac toxicity

5. APHINITY Trial: Results
The trial met its primary endpoint (DFS after 3 years).
DFS for the node-positive cohort: 92% versus 90.2% (HR = 0.77, p = 0.019).
No differences were seen for DFS in the node-negative cohort.
No differences for cardiac toxicity were observed.
Conclusion: Pertuzumab significantly improved DFS in patients with node-positive HER-2/neu-positive EBC when added to chemotherapy and trastuzumab.

6. APHINITY Trial Total revenues of Herceptin®: 7 Billion USD/year.
Running out of patent (EU: 2014; US 2018).
Production of biosimilars remains a challenge.
Interesting business strategy: boost the revenues of Herceptin® by combining it with Perjeta® (pertuzumab).
Proof-of-concept studies: CLEOPATRA, NEOSPHERE, and APHINITY

7. Outline of My Talk IOs or TKIs for NSCLC – what’s new?
Trastuzumab/Pertuzumab: The APHINITY Trial
IOs or TKIs for NSCLC – what’s new?
IOs – Pick the Winner
Step it Up a Notch: New IO Molecules
ALK Inhibitors – Is there Light at the Horizon?

8. First-line TKIs for NSCLC
Three TKIs targeting EGFR mutated NSCLC have been approved for first-line treatment:
- Gefitinib (IRESSA®)
- Erlotinib (TARCEVA®)
- Afatinib (GILOTRIF®
Treatment with these drugs resulted in a significant PFS prolongation (8-12 months) compared with chemotherapy.
However, to date no OS benefit has been shown with any of these drugs.

9. First-line TKIs for NSCLC
Two head-to-head comparison studies have been conducted to further evaluate the most active drug:
- LUX-LUNG-7 Trial (phase IIb)
- ARCHER 1050 Trial (phase III)
Lux-Lung-7 Trial: Afatinib versus Gefitinib as first-line treatment in EGFRmut advanced or metastatic NSCLC patients (N = 319).
Primary endpoints: PFS and OS
Results: PFS 11.0 versus 10.9 months (p = 0.017); OS versus 24.5 months (p = NS)

10. First-line TKIs for NSCLC
ARCHER 1050: Dacomitinib (45 mg) versus Gefitinib (250 mg) as first-line treatment in EGFRmut advanced or metastatic NSCLC patients (N = 452).
Primary endpoint: PFS, secondary endpoint: OS
Results: PFS 14.7 versus 9.2 months (HR = 0.59), OS data not yet mature. Toxicity: Dermatitis, Diarrhea.
Overall conclusion: Dacomitinib might be the new first- line option for EGFRmut NSCLC patients.

11. Biomarkers Current biomarkers can be divided into two classes:
- Phenotype biomarkers (e.g., PD-L1 etc.)
- Genomic markers (e.g., MSI)
Two biomarkers have been approved by FDA to date:
- PD-L1
- MSI
Rimm et al. 2017

12. Biomarkers: Issues
PD-L1 can be up- or downregulated during treatment (“not just there”).
Tests for PD-L1 are not inter- changeable.
Tumour heterogenicity is large.
Fresh versus archieved tissue?

13. PD-L1: Tumour Heterogeneity

14. PD-L1: Assays
SP142 not comparable with the others since it is raised against intracellular domains (underscores PD-L1).

15. Variability: IgG Isoforms and ADCC
Drug
Target
Ig Subtype
ADCC
Assay
Cut-off
Nivolumab
PD-1
Fully human IgG4 No
DAKO 28-8
>1-10%
Pembrolizumab
Humanized IgG4κ
No*
DAKO 22C3
> 50%
Atezolizumab
PD-L1
Fully human IgG1
No**
Ventana SP142
Durvalumab
Humanized IgG1
No***
Ventana SP263
≥ 25%
Avelumab
Yes
DAKO/Agilent
73-10
*Mutation at C228P to prevent ADCC
**Fc region modified to prevent ADCC
***FC point mutation to decrease ADCC

16. IO Treatment: TMB
Tumour mutation burden (TMB) correlates with response to IO treatment.
Several mutations (e.g., EFGR, MET, K-ras, STK11) have been correlated ORRs following IO treatment.
However, no data for ALK and ROS mutations is available so far.
Chalmers et al. 2017

17. IO Treatment: TMB EGFR mutations:
- PD-L1 expression and EGFRmut very rare
- PFS and OS is worse following IO treatment
- CheckMate 370 study ongoing in EGFRmut patients
MET mutations:
- higher TILs and highter PD-L1 expression
- higher ORRs following IO treatment

18. IO Treatment: TMB K-ras mutations:
- better outcome of patients following IO treatment
- however, STK11 is often co-mutated
STK11 mutations:
- poor outcome of patients following IO treatment
- clinical significance still unclear

19. Outline of My Talk IOs or TKIs for NSCLC – what’s new?
Trastuzumab/Pertuzumab: The APHINITY Trial
IOs or TKIs for NSCLC – what’s new?
IOs – Pick the Winner
Step it Up a Notch: New IO Molecules
ALK Inhibitors – Is there Light at the Horizon?

20. Checkpoint Inhibitors
“Are all checkpoint inhibitors for NSCLC equal – or are some more equal than the others?“

21. Second-line NSCLC: Efficacy
Drug
Trial
ORR
PFS OS
Nivolumab
CheckMate 017
CheckMate 057
20%
19.2%
3.5 mo
2.3 mo
9.2 mo
12.2 mo
Pembrolizumab
Keynote 010*
18%
4.0 mo
12.7 mo
Atezolizumab
OAK
14%
2.8 mo
13.8 mo
Avelumab
JAVELIN
12%
11.6 weeks
8.4 mo
Durvalumab
ATLANTIC** (3L)
16.4%
3.3 mo
20.9 mo
*10 mg/kg with PD-L1 ≥ 1%
**PD-L1 ≥ 25%

22. Toxicity: Meta-Analysis
Parameter
PD-1 Inhibitors
(N = 3284)
PD-L1 Inhibitor
(N = 2615)
P-value
Overall AEs (%) 72 65
0.3
Grade 3-5 AEs (%) 22 21
0.5
Fatigue, any grade (%) 19
0.4
Diarrhea, any grade (%) 9 12
Rush, any grade (%) 7
0.8
AE Rates:
Nivolumab: 76%; Pembrolizumab 67.5%; Atezolizumab 65%; Durvalumab 60.9; Avelumab 67%

23. Checkpoint Inhibitors: Costs
Drug
Target
Dose
Cumulative costs
(6 weeks, 80 kg patient)
Nivolumab
PD-1
3 mg/kg
q2weeks
$ 21,990
Pembrolizumab
2 mg/kg
q3weeks
$ 21,662
Atezolizumab
PD-L1
1200 mg
$ 20,688
Durvalumab
10 mg/kg
$ 21,800
Avelumab
$ 21,658

24. Checkpoint Inhibitors for NSCLC
To date no head-to-head comparisons are available for checkpoint inhibitors.
All checkpoint inhibitors have comparable ORRs in the second-line setting.
Small differences are seen in the first-line setting.
Toxicity is slightly worse for anti-PD-1 drugs compared with anti-PD-L1 antibodies.

25. Outline of My Talk IOs or TKIs for NSCLC – what’s new?
Trastuzumab/Pertuzumab: The APHINITY Trial
IOs or TKIs for NSCLC – what’s new?
IOs – Pick the Winner
Step it Up a Notch: New IO Molecules
ALK Inhibitors – Is there Light at the Horizon?

26. GITR-Agonist: BMS
GITR (CD357) is expressed on Treg and NK cells. The ligand GITR-L is secreted by APC cells and inhibits Treg cells whilst NK cells are activated (“co-stimulatory molecule”).
BMS is a fully human IgG1 GITR agonist that has ADCC activity.
Phase I/IIa study (N = 66, advanced solid tumours): either BMS (240 mg) alone or in combination with nivolumab (240 mg) (NCT )
Objectives: Safety, efficacy, PD, PK, immunogenicity

28. GITR-Agonist: BMS
No dose-limiting toxicities were seen for the combination.
Most common AEs were fatigue (14%), chills (16%), pyrexia (30%), and immunogenicity was low.
Antitumour activity of the combination was observed in several patients treated (4 PRs)
Further investigation of this combination is ongoing.

29. Arginase-Inhibitor: CB-1158
Arginine is required for T cell activation and proliferation.
Arginase is secreted by macrophages in the tumour microenvironment leading to arginine depletion.
This results in depletion of CD8+ TILs.
CB-1158 is on oral arginase inhibitor that can restore T cell activation (increase of CD8+ TILs) and was found to act synergistically with checkpoint inhibitors.

30. Arginase Expression in Solid Tumours

31. CB-1158: Combination Data in vivo

33. Arginase-Inhibitor: CB-1158
A phase I study is ongoing (NCT ) (9 patients have been enrolled to date).
A >90% inhibition of plasma arginase was found.
Arginine levels increase 4-fold following treatment with 100 mg CB-1158.
Drug is well tolerated (no DLT, no grade 3 AEs so far)
CB-1158 is the first-in-class arginase inhibitor.

34. M7824: PD-L1/TGF-β-Inhibitor
M7824 is a novel bifunctional fusion protein comprised of a fully human IgG1 monoclonal antibody against PD-L1 fused to the soluble extracellular domain of TGF-β receptor II, which acts as a TGF-β trap.
The molecule is currently undergoing phase I testing in heavily pre-treated solid tumours (N = 16; NCT ).

37. M7824: PD-L1/TGF-β-Inhibitor
Several patients experienced grade 3 AEs (e.g., bullous pemphigoid, colitis, anaemia, pancreatitis) (→ manageable).
No grade 4-5 AEs occurred, however, colitis and anaemia might be dose-limiting (at 20 mg/kg).
There was evidence of efficacy across all dose levels:
- 1 CR (cancer of the cervix)
- 1 PR (pancreatic carcinoma)
- 3 SD (pancreatic cancer, cervical carcinoma, carcinoid)

38. M7824: Cervical Carcinoma

39. M7824: Pancreatic Carcinoma

40. Outline of My Talk IOs or TKIs for NSCLC – what’s new?
Trastuzumab/Pertuzumab: The APHINITY Trial
IOs or TKIs for NSCLC – what’s new?
IOs – Pick the Winner
Step it Up a Notch: New IO Molecules
ALK Inhibitors – Is there Light at the Horizon?

41. ALK as a Target for NSCLC
Approximately 3-5% of NSCLCs harbour the ALK rearrangement (anaplastic lymphoma kinase).
ALK-positive NSCLC patients have distinct clinical features (e.g., brain metastasis in up to 40% of patients at diagnosis; > 60% following crizotinib resistance).
Currently FDA-approved: Crizotinib, Ceritinib, Alectinib, Brigatinib, (Lorlatinib).

42. ALK Inhibitors: Development

43. ALK Inhibitors: ALEX Trial
The ALEX Trial is a randomised phase III trial (N = 303) randomising ALK-positive NSCLC between crizotinib and alectinib (first-line).
Primary endpoint: PFS, secondary endpoint: OS
Results: PFS 25.7 versus 10.4 months, HR = 0.5; toxicity profile favours alectinib.
Conclusion: Alectinib will be the new first-line standard for ALK-positive NSCLC patients.

44. ALK Inhibitors: Resistance
Resistance to ALK inhibitors comprises target-dependent and target-independent mechanisms.
Target-dependent mechanisms:
- ALK amplification
- ALK secondary mutations (e.g., L1196M, G1202R)
Target-independent mechanisms:
- src or IGF-1R alterations
- conversion to SCLC (rare!)
- others

45. ALK Inhibitors: Comparison
Drug
Brand Name
Targets
Line of Treatment
Activity
Resistance Mutations
Crizotinib
Xalkori®
(Pfizer)
ALK, c-MET
1 (to date)
ORR 66% (1L)
L1196M;
G1202R***
Ceritinib
Zykladia®
(Novartis)
ALK, IGF-1R 2
ORR 44% (2L)
L1198F;
G1202R
Alectinib
Alecensa®
(Chugai)
ALK
2 → 1
PFS: 25.7 vs mo** (1L)
I1171X;
Brigatinib
Alunbrig®
(Takeda)
ALK, ROS, EGFR
ORR 54%
(2L)
Lorlatinib* NN
ALK, ROS
≥ 2 (?)
ORR 46%
(> 1L)
C1156Y
*Breakthrough designation granted by FDA
**Data from ALEX trial
***Only Lorlatinib is active in G1202R patients