Targeted Therapies

15th World Conference on Lung Cancer

IASLC 2013 - Sydeny

Jordi Remon Masip Servei Oncologia Mèdica

Agenda

• First-Line

• Second-Line

• KRAS / MEK inhibitors

• EGFR. Acquired resistance to EGFR TKI.

• ALK. Crizotinib refractory

Pem-Cis q3w

Pemetrexed (500 mg/m², D1)

Cisplatin (75 mg/m², D1)

Pem-Cis + Neci q3w

Pemetrexed (500 mg/m², D1) Cisplatin (75 mg/m², D1)

Necitumumab (800 mg D1, D8)

PRCRSD

PD

PD

PD

Maximum of 6 cycles

Open-label, 1:1 randomization

Stratified for:

Smoking status

ECOG PS

Disease histology

Geographic region

Screening

Entry criteria: Stage IV non-squamous NSCLC1

ECOG PS 0-2

Neci

O03.02: Randomized phase-3 trial (INSPIRE) of Necitumumab plus cisplatin-

pemetrexed versus cisplatin-pemetrexed alone as first-line therapy in stage IV

non-squamous NSCLC - Paz-Ares L, et al.

Imbalance Thrombotic Events during 2 first cycles

Planned: 947 patients Actually enrolled: 633 patients

Primary endpoint

• OS

Secondary endpoints

• PFS, ORR, Biomarkers (minimum 4 slides of paraffin-embedded per patient)

O03.02: Randomized phase-3 trial (INSPIRE) of Necitumumab plus cisplatin-

pemetrexed versus cisplatin-pemetrexed alone as first-line therapy in stage IV

non-squamous NSCLC - Paz-Ares L, et al.

Necitumumab ChT Alone HR P

RR (%) 31.1 32.1

PFS (mo) 5.6 5.6 0.96 0.664

OS (mo) 11.3 11.5 1.01 0.956

OS (mo) by EGFR IHC* High: 15 Low: 9

High: 13.3 Low: 9.7

Interaction Test: 0.857

*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

No differences in efficacy according: Age, Gender, Race, Smoking history

O03.02: Randomized phase-3 trial (INSPIRE) of Necitumumab plus cisplatin-

pemetrexed 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

O16.01: Impact of tumor burden on the overall survival analysis of the Lume-

Lung 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.

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

BVZ was allowed

O16.01: Impact of tumor burden on the overall survival analysis of the Lume-

Lung 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

1st & 2nd 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?

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

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.

Trametinib 1.5mg/d + Pemetrexed resulted in broad clinical activity in NSCLC regardless of: Mutation Type, KRAS mutation subtype, Squamous histology, Prior-pemetrexed

N=42 (23 KRAS +). 79% ADC. 67% ≥ 2 prior-therapies

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

• 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?

KRAS conclusions

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?

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.

MO07.09: Feasibility and clinical impact of re-biopsy in advanced non-small-

cell lung cancer: a prospective multicentric study in real world setting (GFPC

STUDY 12-01) – Vergnengre A, et al.

Tumor heterogeneity

ADENOCARCINOMA NO TREATMENT NON-SMOKER

SQUAMOUS PREVIOUS TREATMENT

HEAVY SMOKER

Does a single biopsy might represent the mutation status of the entire tumor?

Yap. Sci Transl Med 2012

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

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

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

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

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.

N=34. 50% RR in T790M+. Grade 3 toxicities: 5%

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.

P

PI3K

AKT

P

EGFR ERBB3

Survival

P

PI3K

AKT

P

Survival

TKI

M

EGFR MUTANT T790M

P

PI3K

AKT

P

Survival

P P

MET

MET AMPLIFICATION

P

PI3K

AKT

Survival

P

HGF

HGF

HGF OVEREXPRESSION

GAB1

RAS

RAF

Proliferation

MEK

Acquired Resistance to EGFR TKI

Synergistic effect inhibiing both pathways? Toxicity?

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.

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.

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

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.

n (%)

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

Phase II: Gefitinib + Olaparib vs. Gefitinib in EGFR mutant advanced NSCLC patients

Phase I: RR in EGFR TKI naïve: 37.5% PR, 37.5% SD

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?.

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

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.

MTD, maximum tolerated dose; RP2D, recommended Phase II dose

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)

Dose escalation, 3+3 design (n=30–60)

Advanced malignancies (all histologies except leukaemia)

until MTD and RP2D established

Cohort 5, NSCLC (n=25) ALK+ and naïve or resistant to

crizotinib with active brain metastases

Cohort 1, NSCLC (n=20) ALK+ and ALK inhibitor naive

Cohort 2, NSCLC (n=20) ALK+ and crizotinib-resistant

Cohort 3, NSCLC (n=20) Documented T790M and

resistant to 1 prior EGFR TKI

Cohort 4, NSCLC (n=20) Other cancers with AP26113 targets (e.g. ALK, ROS1, EGFR

ineligible for Cohort 3 and others)

Added

May 2013

Phase 1 Phase 2

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 (≥2 patients)

30, 60 mg (n=6)

90 mg (n=8)

120 mg (n=18)

180 mg* (n=45)

240 mg (n=12)

300 mg (n=2)

Total (n=91)

Dyspnea 0 0 1 (6) 1 (2) 1 (8) 1 (50) 4 (4)

Fatigue 1 (17) 0 0 1 (2) 2 (17) 0 4 (4)

Pneumonia 0 0 3 (17) 1 (2) 0 0 4 (4)

Hypoxia 0 0 0 1 (2) 1 (8) 1 (50) 3 (3)

Lung infection 0 0 1 (6) 1 (2) 0 0 2 (2)

Pneumonitis 0 0 1 (6) 1 (2) 0 0 2 (2)

Lipase increased 0 0 1 (6) 0 2 (17) 0 3 (3)

Diarrhoea 0 0 0 0 2 (17) 0 2 (2)

Hyponatraemia 0 1 (13) 0 0 1 (8) 0 2 (2)

*Preferred terms ranked by incidence at 180 mg

− 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 term (≥2 patients)

30, 60 mg (n=6)

90 mg (n=8)

120 mg (n=18)

180 mg* (n=45)

240 mg (n=12)

300 mg (n=2)

Total (n=91)

Dyspnea 0 0 1 (6) 1 (2) 1 (8) 1 (50) 4 (4)

Fatigue 1 (17) 0 0 1 (2) 2 (17) 0 4 (4)

Pneumonia 0 0 3 (17) 1 (2) 0 0 4 (4)

Hypoxia 0 0 0 1 (2) 1 (8) 1 (50) 3 (3)

Lung infection 0 0 1 (6) 1 (2) 0 0 2 (2)

Pneumonitis 0 0 1 (6) 1 (2) 0 0 2 (2)

Lipase increased 0 0 1 (6) 0 2 (17) 0 3 (3)

Diarrhoea 0 0 0 0 2 (17) 0 2 (2)

Hyponatraemia 0 1 (13) 0 0 1 (8) 0 2 (2)

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)

Be

st ch

an

ge

fro

m b

ase

line

in

ta

rge

t le

sio

n (

%)

Best overall response PD SD PR CR

• Response duration 8+ to 40+ weeks • 14 confirmed, 4 awaiting confirmation

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

b

a c b

a

a d

• 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)

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: Brain metastases activity

Discontinued

On study

Pa

tie

nts

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

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.

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

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

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)

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.

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

What is wrong?