Update über molekulare Tests beim NSCLC

Martin Früh

Onkologie und Hämatologie Kantonsspital St. Gallen

Titel der Präsentation

«Driver» Alterationen: Obligat:

EGFR

ALK

.

.

.

.

. Tissue should be prioritized for EGFR and ALK testing

EGFR and ALK results should be available within 2 weeks (10 working days)

Lindenman, J Thor Oncol 2013

RCTs vorhanden!

Titel der Präsentation

Inzidenz Onkogen-abhängiger Malignome

Randomisierte Studien mit EGFR Erstlinien-TKIs bei EGFR- Mutation

Studie Studienarm N Ansprechrate Progressionsfreies Überleben (Monate)

Gesamtüberleben (Monate)

NEJ002 1 Gefitinib Chemotherapy

114 114

74%* 31%

10.8 * 5.4

27.7 26.6

WJTOG 2 Gefitinib Chemotherapy

86 86

62%* 32%

9.2 * 6.3

36 39

OPTIMAL3 Erlotinib Chemotherapy

82 72

83%* 36%

13.7 * 4.6

NS NS

EURTAC4 Erlotinib Chemotherapy

77 76

58%* 15%

9.7 * 5.2

23 19

LUX 3 5 Afatinib Chemotherapy

230 115

60.8%* 22.1%

13.6 * 6.9

31.6 28.2

LUX 6 6 Afatinib Chemotherapy

242 122

66.9% 23%

11 * 5.6

23.6 23.5

1NEJM 2010, 2Lancet Oncol 2010, 3Lancet Oncol 2011, 4Lancet Oncol 2012, 5JCO 2013, 6Lancet Oncol 2014

*: p<0.001 NR: nicht rapportiert NS: nicht signifikant

Welches ist der beste EGFR TKI? Erlotinib vs. Gefitinib (CTONG0901)

Yang Abstr 16.13 WCLC 2015

Gefitinib 10.4 m Erlotinib 13.0 m

P 0.1, HR 0.81 (0.62-1.05)

Gefitinib 20.1 m Erlotinib 22.9 m

P 0.25, HR 0.84 (0.63-1.13)

n=240

OS PFS

LUX lung esmo

Afatinib versus gefitinib as first-line treatment for patients with advanced non-small cell lung cancer harboring activating EGFR mutations: LUX-Lung 7

of LUX-Lung 7

!

in LUX-Lung 7

Präklinische Synergie mit Angiogeneseinhibitoren

Naumov, Cancer Res 2009

Erlotinib plus bevacizumab versus erlotinib alone as first-line treatment for advanced EGFR mutation-positive nonsquamous non-small cell lung cancer: An open-label randomized trial

Seto Lancet 2014

PFS P

FS

pro

ba

bili

ty

100

80

60

40

20

0 0 2 4 6 8 10 12 14 16 18

Time (months)

20 22 24 26 28

Erlotinib +

bevacizumab Erlotinib

Median (months) 16.0 9.7

HR (95% CI) 0.54 (0.36, 0.79)

p-value* 0.0015

*log-rank test, two-sided

Number at risk

EB

E

75

77

72

66

69

57

64

44

60

39

53

29

49

24

38

21

30

18

20

12

13

10

8

5

4

2

4

1

0

0

9.7 16.0

(n=150)

A phase II trial of erlotinib (E) and bevacizumab (B) in patients with advanced non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations with and without T790M mutation.

• Median PFS: 13.8 months (m) (95% CI 10.3-16.2)

– 16 m (95% CI 13.1-not estimable) for T790M+

– 10.4 m (95% CI 9.2-15.6) for T790M-

Stahel et al. Ann Oncol 2015; 26 (suppl 6): abstr 3BA

All T790M+ T790M-

CR 7 (6.4) 3 (8.1) 4 (5.6)

PR 76 (69.7) 23 (62.2) 53 (73.6)

SD 18 (16.5) 9 (24.3) 9 (12.5)

PD 3 (2.8) 0 (0.0) 3 (4.2)

NE 5 (4.6) 2 (5.4) 3 (4.2)

Ch

an

ge

fro

m b

ase

line (

%)

100

80

60

40

20

0

PD

SD

PR

CR

-100

-80

-60

-40

-20 -30

N=109

Yu and Riely, CCR 2013 and Yano, JTO 2011; Sos, Cancer Res, 2011; Ware, PLoS one 2010, Zhang, Nat Gen 2012; Ohashi PNAS 2012; Tabara, Plos one 2012; Ng, Nat Med 2012, Akhavan, Cancer Discov 2013;

Tumor Resistenz bei EGFR Mutation

T790M Mutation

Yun PNAS 2007

Rociletinib and Osimertinib in T790+ NSCLC

Sequist and Jänne N Engl J Med 2015

N=127, ORR 61%

N=46, ORR 59%

Acquired Resistance to AZD9291 in EGFR T790M Positive Lung Cancer

• cfDNA at progression (NGS testing)

• 26 positive for an EGFR-sensitizing mutation

– 12 (46%) had NO T790M

– Seven patients had detectable C797S (27% del 19 only), all WITH T790M

– 1 BRAF V600E, 1 PIK3CA, 1 MET ampl, 1 Her2 ampl. , all with NO T790M

• Kombinationstherapien?

Oxnard Abstr 17.07 WCLC 2015

2. Resistenzmutation (C797S)

Matthew CCR 2015

EML-4 ALK Gen Rearrangement

Jüngere (median 59 Jahre) Adenokarzinome

p.os.

Titel der Präsentation

18

EML-4 ALK Gen Rearrangement

Shaw N Engl J Med 2014

n= 114 ORR: 58% PFS 7.0 months

2nd Generation ALKi: Ceritinib (Zykadia)

Kwak N Engl J Med 2010

1st Generation ALKi Crizotinib (Xalkori)

56% > 2 Vortherapien!

Duruisseaux, abstr 33.01, WCLC 2015

ALK+ Patienten mit Zweitgeneration ALKi (n=141)

Titel der Präsentation

Erworbene Resistenz auf Crizotinib

Unknown(ALK-)6%

EGFRMuta on12%

KRASMuta on19%

ALKCNG13%

ALKMuta on+CNG6%

ALKMuta on31%

Unknown(ALK+)13%

Camidge , ASCO 2013

Lorlatinib

Bauer WCLC 2015

Klinisch wichtige seltene Mutationen

24

http://www.mycancergenome.org

ROS1 Rearrangement

Takeuchi Nature 2012

ROS1 in «triple negative» AdenoCa

• 23.5% to 40% of pulmonary adenocarcinomas are EGFR-/KRAS-/ALK-

Incidence of ROS1 7.4% 1 -12.1% 2

1 Mescam-Mancinia Lung Cancer 2014 2 Go J Thor Oncol 2013

Titel der Präsentation

Crizotinib in ROS1+

Shaw N Engl J Med 2014

28

N=50 ORR 72% PFS 19 months

Awad N Engl J Med 2013

G2032R Resistance Mutation

Overcoming G2032R ROS1 Recistance Mutation?

Katayama Clin Cancer Res 2015 Zou PNAS 2015

Lorlatinib Cabozantinib

BRAF Mutation

Nur ca. 50% V600E !

Dabrafenib in patients with BRAF V600E-mutant advanced

non-small cell lung cancer (NSCLC): A multicenter, open-label, phase II trial

(BRF113928)

Planchard et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA38_PR *62% of patients progressed or died

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Number of prior systemic

anti-cancer therapy

regimens for

metastatic disease: 1

≥2

Duration of treatment (months)

Responders in ≥2nd line N=25

Progressed, n (%) 12 (48)

Ongoing, n (%) 13 (52)

Duration of response

Median, months (95% CI) 11.8 (5.4, NR)

<6 months, n (%) 11 (44), 4 ongoing

>6 months, n (%) 14 (56), 9 ongoing

>9 months, n (%) 10 (40), 8 ongoing

>12 months, n (%) 6 (24), 4 ongoing

Median PFSa, months (95% CI) 5.5, (2.8, 7.3)

ORR 32% DCR 56% (n=78)

Phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer patients

Prospective Cohort with Vemurafenib in BRAF V600E mutated NSCLC (n=20)

Hyman N Engl J Med 2015

months

Dabrafenib plus trametinib in patients with BRAF V600E mutated metastatic NSCLC

ORR 63%, DCR 88%

Planchard et al. J Clin Oncol 2015; 33 (suppl): abstr 8006

MET Amplification

Crizotinib for MET amplification

Ou, J Thor Oncol 2011

Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer

1 CR and 4 PRs have been observed with crizotinib among 12 patients to date

3 categories of amplification: MET/CEP7 ratio ≥1.8-≤2.2 (Low), >2.2-<5 (Intermediate) and ≥5 (High)

Camidge et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8001)

Low MET

n=2

Intermediate MET

n=6

High MET

n=6 100

80

60

40

20

0

–20

–40

–60

–80

–100

100

80

60

40

20

0

–20

–40

–60

–80

–100

Disease progression Stable disease Partial responseb

Complete responseb

% C

ha

ng

e f

rom

ba

se

lin

e

100

80

60

40

20

0

–20

–40

–60

–80

–100

Threshold

for partial

response c

c

aConfirmed objective responses bBased on investigator assessment cTwo patients in the intermediate MET group had an unconfirmed

PR that was not confirmed in a second assessment

Incidence of RET Translocation

• 7 of 944 (0.7%) unselected NSCLC

• 8 of 51 lung (15%) adenocarcinomas negative for EGFR, KRAS, ALK, ROS1

Varella-Garcia J Clin Oncol 31, 2013 (suppl; abstr 8024)

Platt J Clin Oncol 31, 2013 (suppl; abstr 8045)

• 5/32 (15%)

never-smoking history, adenocarcinomas (WT EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MEK1, AKT, ALK ROS1)

Drilon J Clin Oncol 31, 2013 (suppl; abstr 8067)

«enriched»

«unselected»

• 24 of 842 (2.8%) EGFR mut

– non-squamous cell ca. Yoh et al. Ann Oncol 2014; 25 (suppl 4):

abstr 1227PD

«semi-enriched»

Clinical response of RET+ patients

– Vandetanib: 3/3 SD (2 shrinkages) 1

– Vandetanib: 2/2 SD, Sunitinib: 2/2 PD 2

– Cabozantinib: 2/3 PR 3

39

Platt J Clin Oncol, 2013 (suppl; abstr 8045)1, Varella-Garcia J Clin Oncol, 2013 (suppl; abstr 8024)2, Drilon Cancer Discovery 20133

Vandetanib und RET (CCDC6-RET Fusion)

Falchook J Clin Oncol 2014

Phase II study of cabozantinib for patients with advanced RET-rearranged lung cancers (n=16)

Drilon et al. J Clin Oncol 2015; 33 (suppl): abstr 8007

Cabozantinib (n=16)

ORR, % (95%CI) 38 (15, 65)

PR, n (%)

Confirmed

Unconfirmed

7 (44)

6 (38)

1 (6)

Median PFS, months (95% CI) 7 (5, not reached)

Median OS, months (95% CI) 10 (8, not reached)

Her2 mutated NSCLC

Mazières J Clin Oncol 2013

• Lapatinib: 2/2 PD

• Trastuzumab 1/1 PR

• Afatinib 2/3 SD, 1/3 PR

26-30 September 2014, Madrid, Spain

esmo.org

esmo.org

PUMA trial 4201 for HER2 mutation

100

0

-50

-100

50

% c

han

ge in

su

m L

D

PD

PD PD PD SD SD PD SD

SD SD SD SD PD SD

SD SD SD SD SD SD

SD SD SD

PR PR PR

SD

12bp exon 20 insertion 3bp exon 20 insertion 9 bp exon 20 insertion A775_G776Ins YVMA Exon 20 insertion G776VC P780_Y781Ins GSP S310F Unspecified

100

0

-50

-100

50

% c

han

ge in

su

m L

D

Neratinib Neratinib + temsirolimus

Courtesy of B. Besse and J. Mazières

PFS 2.9 months PFS 4.0 months

26-30 September 2014, Madrid, Spain

esmo.org

esmo.org

ETOP NICHE Studie

MET exon 14 splicing site mutation

3/4 responders crizotinib (n=3, PR) capozantinib (n=1, SD)

Awad J Clin Oncol 2016, Shea J Thor Oncol 2016, Paik Cancer Disc 2015, Liu ASCO 2015

Gehäuft bei sarcomatoiden Karzinomen (8/36, 22%, Liu Abstr 8020)

Entrectinib bei NTRK1 Rearrangement

Farago J Thor Oncol 2015

Systemtherapie 1975-2015 Verbesserung durch SUBTYPISIERUNG

47

Ansprechrate Medianes Überleben (Monate)

Ohne Chemotherapie 0% 6

Monotherapie 15% 7

Doublet 25% 8-10

Doublet+ Bevacizumab 35% 12

Doublet+ Cetuximab 36% 12

EGFR-TKI bei EGFR+ 75% 24

Crizotinib bei ALK+ 57% 24

Osimertinib/Rociletinib bei T790M+

>50% >40?

Ceritinib bei ALK+ >50% 34

Titel der Präsentation

Zusammenfassung 30-40% der nicht-plattenepitehlialen NSCLC besitzen eine

potentiell onkogene «Driver» Mutation

Randomisierte Studien zeigen einen Benefit bezüglich ORR, PFS und QoL bei EGFR und ALK

Identifikation weiterer «selteneren» molekularen Mutation und Einschluss in Studienprotokolle ist entscheidend

Erneute molekulare Testung bei Progression ermöglicht die Behandlung mit neuen wirksamen Substanzen (z. B. 790M)