Autor/a Dr. Jordi Remón V Jornada de Revisión del Congreso Mundial de Cáncer de Pulmón. ARCO MEDITERRANEO. Valencia 8-Nov-2013

1. Targeted Therapies
15th World Conference on Lung Cancer
IASLC 2013 - Sydeny
Jordi Remon Masip
Servei Oncologia Mèdica

2. Agenda
• First-Line
• Second-Line
• KRAS / MEK inhibitors
• EGFR. Acquired resistance to EGFR TKI.
• ALK. Crizotinib refractory

3. O03.02: Randomized phase-3 trial (INSPIRE) of Necitumumab plus cisplatinpemetrexed versus cisplatin-pemetrexed alone as first-line therapy in stage IV
non-squamous NSCLC - Paz-Ares L, et al.
Screening
Entry criteria:
Stage IV
nonsquamous
NSCLC1
ECOG PS 0-2
Open-label,
1:1 randomization
Stratified for:
Smoking status
ECOG PS
Disease histology
Geographic region
Pem-Cis + Neci q3w
Pemetrexed (500 mg/m², D1)
Cisplatin (75 mg/m², D1)
Necitumumab (800 mg D1, D8)
PR
CR
SD
Neci
PD
PD
Maximum of 6 cycles
Pem-Cis q3w
PD
Pemetrexed (500 mg/m², D1)
Cisplatin (75 mg/m², D1)
Primary endpoint
• OS
Secondary endpoints
• PFS, ORR, Biomarkers (minimum 4 slides of paraffin-embedded per patient)
Imbalance Thrombotic Events during 2 first cycles
Actually enrolled: 633 patients
Planned: 947 patients

4. O03.02: Randomized phase-3 trial (INSPIRE) of Necitumumab plus cisplatinpemetrexed versus cisplatin-pemetrexed alone as first-line therapy in stage IV
non-squamous NSCLC - Paz-Ares L, et al.
Necitumumab
ChT Alone
RR (%)
31.1
32.1
PFS (mo)
5.6
OS (mo)
P
5.6
0.96
0.664
11.3
OS (mo) by EGFR IHC*
HR
11.5
1.01
0.956
High: 15
Low: 9
High: 13.3
Low: 9.7
Interaction Test:
0.857
No differences in efficacy according: Age, Gender, Race, Smoking history
*EGFR1 high: H-score ≥200 to 300 / EGFR1 low: H-score 0 to <200
Main Side Effects Grade ≥ 3 (%)
Neci-ChT
ChT
Fatigue
11.2
6.1
Hypomagnesaemia
7.6
2.2
Rash
14.8
0.3
Venous Thrombotic event
7.6
0.3
Sudden or unexplained death
3.6
1.6

5. O03.02: Randomized phase-3 trial (INSPIRE) of Necitumumab plus cisplatinpemetrexed versus cisplatin-pemetrexed alone as first-line therapy in stage IV
non-squamous NSCLC - Paz-Ares L, et al.
13.08.2013: The trial met its primary end point: OS. Final Results in ASCO 2014

6. O16.01: Impact of tumor burden on the overall survival analysis of the LumeLung 1 study: A randomized, double-blind phase 3 trial of nintedanib (BIBF
1120) + Docetaxel in NSLCLC patients progressing after first-line
chemotherapy– Reck M , et al.
BVZ was allowed
Nintedanib
HR / p
Placebo
PFS (mo)
3.4
0.79 / 0.0019
2.7
OS (mo)
10.1
0.94 / 0.27
9.1
- ADC
12.6
0.83 / 0.036
10.3
- SQC
8.6
1.01 / 0.8907
8.7

7. O16.01: Impact of tumor burden on the overall survival analysis of the LumeLung 1 study: A randomized, double-blind phase 3 trial of nintedanib (BIBF
1120) + Docetaxel in NSLCLC patients progressing after first-line
chemotherapy– Reck M , et al.
Squamous ≥ 7.5 cm (NS)
ADC < 9 mo since Dx
ADC with PD 1st Line

8. st
1
&
nd
2
Line Conclusions
• INSPIRE, lack of efficacy or excess of toxicity?.
• Are anti-EGFR mAb a good target in non-Sqc?.
– FLEX study: better outcome in Sq than non-Sq
• SQUIRE. Is it a real positive trial? Is the control
arm the standard of care?.
• Lume-Lung1. Increased OS in ADC influenced by
driver mutations?. Docetaxel-BIBF1120 
Standard in refractory patients?

9. KRAS mutant in NSCLC
Selemutinib
Placebo
HR / p
OS (mo)
9.4
5.2
0.8 / p=0.21
PFS (mo)
5.3
2.1
0.58 / p=0.014
RR (%)
37
0
< 0.0001
BATTLE study: KRAS codon G12C or G12V  poorer outcome
Jänne – Lancet oncol 2013 * Ihle – JNCI 2012

10. MO18.10: Oral mEK1/MEK2 inhibitor Trametinib (GSK1120212) in combination
with pemetrexed in a phase 1/1B involving KRAS mutant and wild type
advanced NSCLC: Efficacy and biomarker results– Mazieres J, et al.
N=42 (23 KRAS +). 79% ADC. 67% ≥ 2 prior-therapies
Trametinib 1.5mg/d + Pemetrexed resulted in broad clinical activity in NSCLC regardless of:
Mutation Type, KRAS mutation subtype, Squamous histology, Prior-pemetrexed

11. MO18.11: Oral MEK1/MEK2 inhibitor Trametinib (GSK1120212) in combination
with docetaxel in a phase 1/1B involving KRAS mutant and wild type advanced
NSCLC: Efficacy and biomarker results– Bennouna J, et al.
N=47 (27 KRAS +). 79% ADC. 64% ≥ 2 prior-therapies
Trametinib 2mg/d + Docetaxel (+GCSF) resulted in clinical activity in NSCLC regardless of:
Mutation Type, but among KRAS+, achieved higher activity in G12C vs non-G12C

12. KRAS conclusions
• Are MEK inhibitors a real target only in KRAS mutant patients?
• SELECT 1 &2 Trials ongoing.
• MEKi may enhance ChT effect regardless KRAS status. (Jänne – O16.02)
• Which is the best chemotherapeutic partner?
• Is there any KRAS mutation subtype predictive?

13. PL03.07: Treatment with therapies matched to oncogenic drivers improves
survival in patients with lung cancers: results from the lung cancer
consortium – Kris M , et al.
Fase III randomized trials?

14. PL03.07: Treatment with therapies matched to oncogenic drivers improves
survival in patients with lung cancers: results from the lung cancer
consortium – Kris M , et al.

15. MO07.09: Feasibility and clinical impact of re-biopsy in advanced non-smallcell lung cancer: a prospective multicentric study in real world setting (GFPC
STUDY 12-01) – Vergnengre A, et al.

16. Tumor heterogeneity
Yap. Sci Transl Med 2012
ADENOCARCINOMA
NO TREATMENT
NON-SMOKER
SQUAMOUS
PREVIOUS TREATMENT
HEAVY SMOKER
Does a single biopsy might represent the mutation status of the entire tumor?

17. O03.06: First in human evaluation of CO-1686, an irreversible, highly, selective
TKI of mutations of EGFR (activating T790M) - Soria J-Ch, et al.
Primary T790M population (≈ 3%) defines a resistant EGFR-TKI population
Acquired T790M population defines a clinical subset with a favourable prognosis
Irreversible TKI-EGFR exert effect in T790M mutation cell lines, but NOT in clinical studies

18. O03.06: First in human evaluation of CO-1686, an irreversible, highly, selective
TKI of mutations of EGFR (activating and T790M) - Soria J-Ch, et al.
High preclinical-activity
Reduced toxicity risk

19. O03.06: First in human evaluation of CO-1686, an irreversible, highly, selective
TKI of mutations of EGFR (activating T790M) - Soria J-Ch, et al.
• CO-1686: Oral, selective covalent inhibitor of EGFR and T790M resistance mutations and
spares wild type receptor signaling
• Hydrobromide salt form of CO-1686 improved drug availability and reduced intra-patient
variability (strong suggestion dose-response relationship)
• N=56. 70% T790M positive. 3 median anticancer regimens (45% ≥ 2 previous TKI).
150mg QD-900mg BID. MTD not reached

20. O03.06: First in human evaluation of CO-1686, an irreversible, highly, selective
TKI of mutations of EGFR (activating T790M) - Soria J-Ch, et al.
67% RECIST RR in evaluable T790M+ patients treated at 900 mg BID (Free base)
8 out of 9 progressed on TKI immediately prior to CO-1686

21. P1.11-034: AZD9291: An irreversible, potent and selective tyrosine kinase
inhibitor of activting EGFR and resistance T790M mutations in advanced
NSCLC – Ranson M et al.
Ongoing, open-label, dose escalation, Phase I study. No DLT 20-160 mg/d
Objective: To investigate the safety and tolerability of AZD9291 in patients with advanced
NSCLC who had disease progression following treatment with an EGFR TKI.
N=34. 50% RR in T790M+. Grade 3 toxicities: 5%

22. Acquired Resistance to EGFR TKI
EGFR MUTANT
T790M
MET AMPLIFICATION
EGFR ERBB3
HGF OVEREXPRESSION
MET
HGF
HGF
P
M
P
P
P
P
P
P
P
P
P
TKI
GAB1
RAS
PI3K
PI3K
PI3K
PI3K
RAF
AKT
AKT
AKT
AKT
Survival
Survival
Survival
MEK
Survival
Proliferation Synergistic effect inhibiing both pathways? Toxicity?

23. MO07.07: Combined pan-ERBB and ALK / ROS1 / MET inhibition with
dacomitinib and crizotinib in advanced non-small-cell lung cancer: Update of a
phase I trial– Giaccone G , et al.

24. MO07.07: Combined pan-ERBB and ALK / ROS1 / MET inhibition with
dacomitinib and crizotinib in advanced non-small-cell lung cancer: Update of a
phase I trial– Giaccone G , et al.

25. MO07.07: Combined pan-ERBB and ALK / ROS1 / MET inhibition with
dacomitinib and crizotinib in advanced non-small-cell lung cancer: Update of a
phase I trial– Giaccone G , et al.
Median Progression Free Survival: 3.4 months
No Partial-Complete RR in expansion cohorts

26. P2.11-044: Phase IB study to evaluate the efficacy andd tolerability of olaparib
(AZD2281) plus gefitinib in patients with EGFR mutation positive advanced
NSCLC – García-Campelo R et al.
100 mg BID
N=3
200 mg BID
N=6
200 mg TDS
N=6
250 mg
TDS
N=7
Any AEs: All grades
Grade ≥3
15 (94)
5 (31)
14 (93)
4 (27)
15 (100)
6 (40)
15 (94)
3 (19)
Nausea
13 (81)
0
9 (60)
0
12 (80)
1 (7)
12 (75)
1 (6)
Fatigue
8 (50)
2 (13)
9 (60)
0
6 (40)
0
10 (63)
1 (6)
Vomiting
7 (44)
2 (13)
6 (40)
0
10 (67)
0
12 (75)
1 (6)
Decreased appetite
3 (19)
0
5 (33)
0
4 (27)
0
4 (25)
0
Diarrhoea
2 (13)
1 (6)
4 (27)
0
1 (7)
0
9 (56)
1 (6)
Anaemia
2 (13)
1 (6)
3 (20)
1 (7)
4 (27)
1 (7)
1 (6)
0
n (%)
Phase I: RR in EGFR TKI naïve: 37.5% PR, 37.5% SD
Phase II: Gefitinib + Olaparib vs. Gefitinib in EGFR mutant advanced NSCLC patients

27. EGFR Conclusions
• Third generation EGFR TKI in first line to
supress primary resistance?.
• Which is the best strategy: combined
treatments or sequential treatment?.
• Should we perform a head to head “2nd line
treatment” such as in 1st line?.

28. Crizotinib in ALK-rearranged NSCLC
• ALK rearrangements ≈ 4%
• Crizotinib:
– ORR: 50-65%
– DOR: 7.7-10 mo
– 46% progress in SNC, inadequate
exposure
– Systemic PD occurs later
• Many mechanisms of resistance:
ALK amplification, ALK mutation,
activation of other pathways.
Doebele – Clin Cancer Res 2012

29. MO07.06: Updated results of a first-in-human dose findings study of the ALK /
EGFR inhibitor AP26113 in patients with advanced malignancies – Camidge R ,
et al.

30. MO07.06: Updated results of a first-in-human dose findings study of the ALK /
EGFR inhibitor AP26113 in patients with advanced malignancies – Camidge R ,
et al.
Open-label, multicentre, Phase I/II dose-finding study
Objective: To evaluate safety/toxicity and identify appropriate dosing level for AP26113 (a novel
ALK/EGFR tyrosine kinase inhibitor) in patients with advanced malignancies (Phase I) and
investigate its activity in five different patient cohorts (Phase II)
Phase 1
Phase 2
Cohort 1, NSCLC (n=20)
ALK+ and ALK inhibitor naive
Cohort 3, NSCLC (n=20)
Documented T790M and
resistant to 1 prior EGFR TKI
Dose escalation,
3+3 design (n=30–60)
Advanced malignancies (all
histologies except leukaemia)
until MTD and RP2D
established
Cohort 2, NSCLC (n=20)
ALK+ and crizotinib-resistant
Cohort 4, NSCLC (n=20)
Other cancers with AP26113
targets (e.g. ALK, ROS1, EGFR
ineligible for Cohort 3
and others)
Added
May 2013
MTD, maximum tolerated dose; RP2D, recommended Phase II dose
Cohort 5, NSCLC (n=25)
ALK+ and naïve or resistant to
crizotinib with active brain
metastases

31. MO07.06: Updated results of a first-in-human dose findings study of the ALK /
EGFR inhibitor AP26113 in patients with advanced malignancies – Camidge R ,
et al.
•
Key results
– 91 patients were enrolled (median age 57 yrs, 40% male, 91% with NSCLC)
– 180 mg once daily determined as recommended Phase II dose
– Treatment-related Grade ≥3 AEs in ≥ 2 patients were: dyspnoea (4%), fatigue (3%), diarrhoea (2%),
hypoxia (2%) and pneumonitis (2%) (table)
Preferred term
Preferred term
(≥2 patients)
(≥2 patients)
30, 60 mg
30, 60 mg
(n=6)
(n=6)
90 mg
90 mg
(n=8)
(n=8)
120 mg
120 mg
(n=18)
(n=18)
180 mg*
180 mg*
(n=45)
(n=45)
240 mg
240 mg
(n=12)
(n=12)
300 mg
300 mg
(n=2)
(n=2)
Total
Total
(n=91)
(n=91)
Dyspnea
Dyspnea
00
00
11(6)
(6)
11(2)
(2)
11(8)
(8)
11(50)
(50)
44(4)
(4)
Fatigue
Fatigue
11(17)
(17)
00
00
11(2)
(2)
22(17)
(17)
00
44(4)
(4)
Pneumonia
Pneumonia
00
00
33(17)
(17)
11(2)
(2)
00
00
44(4)
(4)
Hypoxia
Hypoxia
00
00
00
11(2)
(2)
11(8)
(8)
11(50)
(50)
33(3)
(3)
Lung infection
Lung infection
00
00
11(6)
(6)
11(2)
(2)
00
00
22(2)
(2)
Pneumonitis
Pneumonitis
00
00
11(6)
(6)
11(2)
(2)
00
00
22(2)
(2)
Lipase increased
Lipase increased
00
00
11(6)
(6)
00
22(17)
(17)
00
33(3)
(3)
Diarrhoea
Diarrhoea
00
00
00
00
22(17)
(17)
00
22(2)
(2)
Hyponatraemia
Hyponatraemia
00
11(13)
(13)
00
00
11(8)
(8)
00
22(2)
(2)
−
Early onset pulmonary symptoms
− Observed in 9–12% of patients treated at 180 mg QD; not observed at 90 mg QD
− Observed in some patients post single dose, but not later in course of treatment, despite continued dosing
and higher blood concentrations
− Suggests “step up” regimen of initial lower dose followed by escalation to RP2D
*Preferred terms ranked by incidence at 180 mg

32. MO07.06: Updated results of a first-in-human dose findings study of the ALK /
EGFR inhibitor AP26113 in patients with advanced malignancies – Camidge R ,
et al.
Efficacy: ALK+ NSCLC anti-tumour activity target lesions (n=34)
PD
Best change from baseline in target lesion (%)
Best overall response
•
b
SD
PR
CR
65% (22/34) objective response rate (95% CI; 47–80%)
• 61% (19/31) post-crizotinib patients (incl. 1 crizotinib intolerant)
• 100% (3/3) in TKI-naïve patients (incl. 1 complete response)
a
c b
a
•
Response duration 8+ to 40+ weeks
• 14 confirmed, 4 awaiting confirmation
d
a
All patients received prior crizotinib unless otherwise indicated; Doses ranged from 60–240 mg/day; aTKI-naïve; bReceived
prior crizotinib and LDK378; cPD by RECIST 1.1 due to 2nd primary tumour of melanoma; dCrizotinib-intolerant

33. Patients
MO07.06: Updated results of a first-in-human dose findings study of the ALK /
EGFR inhibitor AP26113 in patients with advanced malignancies – Camidge R ,
et al.
On study
Discontinued
Efficacy: Brain metastases activity
Time to treatment (weeks)
•
•
8 of 10 ALK+ NSCLC patients with active brain lesions at baseline had evidence of radiographic
improvement in brain
Duration of CNS benefita ranging from 8+ to 40+ weeks

34. O16.06: A phase I dose escalation study of a new ALK inhibitor CH5424802
/RO5424802, in ALK+ non-small-cell lung cancer patients who have failed
Crizotinib – Gadgeel S, et al.
• CH5424802 or Alectinib is a second generation highly selective ALK inhibitor.
• In preclinical models has shown superior efficacy than crizotinib.
• Clinical data, 300 mg BID in ALK+ TKI naïve patients: RR 93%, DOR 14 mo

35. O16.06: A phase I dose escalation study of a new ALK inhibitor CH5424802
/RO5424802, in ALK+ non-small-cell lung cancer patients who have failed
Crizotinib – Gadgeel S, et al.
N= 47 patients enrolled
30% patients ≥ 3 prior lines therapy

36. O16.06: A phase I dose escalation study of a new ALK inhibitor CH5424802
/RO5424802, in ALK+ non-small-cell lung cancer patients who have failed
Crizotinib – Gadgeel S, et al.
24 out of 47 received treatment for 120 days or longer
Grade 3-4: 2-4% (Increase GGT)

37. ALK refractory Conclusions
• In acquired resistance to crizotinib patients:
– Similar RR ≈ 50-60%
• Better in first line? Initial option in SNC M1+?
• Only 4% ALK+ NSCLC. Then, no head to head.
• AP26113 Upcoming Phase II registration trial
in crizotinib-resistant ALK+ NSCLC.

38. Final Remarks
• First-Line
– Necitumumab: INSPIRE- NEG+. SQUIRE – POS+
• Second-Line
– Lume-Lung 1 trial: POS+ (PFS). Subgroup analyses
• KRAS
– The main driver mutation but yet missunderstood
• EGFR
– Third generation TKI, better outcome and toxicity
• ALK
– AP26113 / Alectinib ≈50% RR in Crizo-refractory

39. What is wrong?