second-line afatinib for advanced squamous cell carcinoma …...fgf12 33.3 33.3 44.4 26.5 55.6 60.6...

Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib

long-term responders in the phase III LUX-Lung 8 trial – Glenwood Goss

Second-line afatinib for advanced

squamous cell carcinoma of the lung:

analysis of afatinib long-term responders

in the Phase III LUX-Lung 8 trial

Glenwood Goss, Manuel Cobo, Shun Lu, Konstantinos Syrigos, Alessandro Morabito, Istvan Albert, Gabriella Herodek, Samuel Chan,

Gyula Ostoros, Veronika Sarosi, Zsolt Kiraly, Deric Savior, Rachael Barton, Francisco Medina, Sundaram Subramanian, Andrea Ardizzoni, Enriqueta Felip,

Shirish M. Gadgeel, Vassilis Georgoulias, Nicholas Dupuis, James Love, Claudia Bühnemann, Neil Gibson, Eva Ehrnrooth, Jean-Charles Soria



• Dr Goss reports advisory board participation for and honoraria from

AstraZeneca, Boehringer Ingelheim, BMS, Pfizer

Disclosure information

Presentation Number: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders

in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria

Introduction

• Overexpression/aberrations of ErbB family members (EGFR, ErbB2, ErbB4) are

implicated in the pathogenesis of SCC of the lung, providing rationale for therapeutic

targeting1-5

• The LUX-Lung 8 study compared the irreversible ErbB family blocker, afatinib, with the

reversible EGFR TKI, erlotinib, in patients with SCC of the lung6

• Afatinib significantly improved PFS and OS versus erlotinib in this setting6

‒ PFS: 2.6 months vs 1.9 months; HR=0.81 (95% CI: 0.69–0.96)

‒ OS: 7.9 months vs 6.8 months; HR=0.81 (95% CI: 0.69–0.95)

• Afatinib is approved for the treatment of metastatic SCC of the lung following

progression after platinum-based chemotherapy

OS, overall survival; PFS, progression-free survival;

SCC, squamous cell carcinoma; TKI, tyrosine-kinase inhibitor

1. Lawrence MS, et al. Nature 2013;499:214‒8; 2. Hirsch FR, et al. J Clin Oncol 2003;21:3798‒807;

3. Heinmoller P, et al. Clin Cancer Res 2003;9:5238‒43; 4. Ugocsai K, et al. Anticancer Res 2005;25:3061‒6;

5. Lopez-Malpartida AV, et al. Lung Cancer 2009; 65:25‒33; 6. Soria J-C, et al. Lancet Oncol 2015;16:897–907


in the phase III LUX-Lung 8 trial – IASLC 17th WORLD CONFERENCE ON LUNG CANCER, December 4–7, 2016 Vienna, Austria*Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted; †Dose reduction to 100 or 50 mg permitted; ‡Tumour assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter

DCR, disease control rate; ORR, objective response rate; PRO, patient-reported outcomes; qd, once daily

LUX-Lung 8: Study design

• SCC of the lung (Stage IIIB/IV)

• Progressed after ≥4 cycles of a first-line platinum-doublet chemotherapy

• ECOG PS 0–1

• Adequate organ function

Afatinib 40 mg* qd

(n=398)

Erlotinib 150 mg† qd

(n=397)

1:1

Primary endpoint: PFS by independent review‡

Key secondary endpoint: OS

Other secondary endpoints: ORR, DCR, tumour shrinkage, PRO, safety

Stratified by

east Asian vs

non-east Asian



Post-hoc analysis of LUX-Lung 8 ‘Long-term responders’ (LTRs)

• 12 and 18-month OS rates indicated that some

patients derived prolonged benefit with afatinib

• Post-hoc analysis identified 15 patients (LTRs)

who received ≥12 months of afatinib treatment

– Median treatment duration was 16.6 months

(range: 12.3–25.8 months)

• Possible molecular/clinical biomarkers indicative

of long-term response to afatinib were evaluated

– Baseline characteristics

– Efficacy/safety of afatinib

– Molecular genomic analysis

– VeriStrat® classification*

OS: primary analysis

3 6 9 12 15 3018 21 24 27

Time (months)

0.2

0.4

0.6

0.8

1.0

0

Estim

ate

d O

S p

rob

abili

ty

0

36.4%

28.2%

22.0%

14.4%

Afatinib

(n=398)

Erlotinib

(n=397)

*Serum protein test used to assign a ‘Good’ or ‘Poor’ classification, with

prognostic and predictive utility for EGFR-targeted agents in NSCLC1 1. Gregorc V, et al. Lancet Oncol 2014;15(7):713-21



LTRs treated with

afatinib (n=15)

All patients treated with

afatinib (n=398)

Median age, years (range) 65 (54–81) 65 (36–84)

Female/male, % 20/80 16/84

Race, %East Asian 7 22

Non-east Asian 93 78

Smoking history, %

Never smoker 7 7

Light ex-smoker* 13 3

Current and other ex-smoker 80 91

ECOG PS, % 0/1 40/60 32/68†

Clinical stage, % IIIB/IV 20/80 12/88‡

Histology, %Squamous 100 96

Mixed 0 4

Best response to

first-line

chemotherapy, %

CR/PR 53 47

SD 47 40

Unknown 0 12

Baseline characteristics

*Less than fifteen pack-years and stopped >1 year before diagnosis; †<1% were ECOG PS 2 due to protocol violations; ‡≤1% were stage IIIA



OS

CR‡ (1)

PR‡ (4)

Duration of response§

End of treatment

• Median OS was 23.1 months (range: 12.9–31.6 months)

• Median PFS (independent central review) was 16.2 months (range: 2.8–24.1 months)

Treatment response* and OS in LTRs

*SD unless noted otherwise (patient 2 was classified as non-evaluable); †Patients were ordered and numbered by treatment duration, with patient 1 being on treatment longest; ‡First observed response at time of tumour measurement; §Last observed response at time of tumour measurement; ¶Treatment ongoing until death; ‖Received ≥1 line of chemotherapy after afatinib;

CR, complete response; PR, partial response; SD, stable disease

¶

LT

Rs

†

‖

‖

‖

‖

‖

‖

‖

Time (months)

‖

SD (9)



• NGS was undertaken in 9/15 afatinib-treated LTRs and 132/398 afatinib-treated patients of the

overall LUX-Lung 8 population

• Certain SVs were more common in LTRs than in the overall population tested

Genomic aberrations in LTRs

*EGFR, ErbB2, ErbB3, and ErbB4 genes; †FGF3, FGF4, FGF6, FGF7, FGF10, FGF12, FGF14, FGF23, FGFR1, FGFR2, FGFR3, and FGFR4 genes

CNAs, copy number alterations; NGS, next generation sequencing; SVs, short variants

Gene, %

Afatinib LTRs

(n=9)

All afatinib-treated

(n=132)

SVs

TP53 88.9 84.8

ErbB family 44.4 20.5

ErbB2/3/4 22.2/0/11.1 6.8/4.5/2.3

EGFR 11.1 6.8

LRP1B 33.3 39.4

MLL2 33.3 34.1

MLL 33.3 12.1

KEAP1 33.3 10.6

PIK3CA 33.3 15.9

CNAs

SOX2 44.4 44.7

KLHL6 44.4 43.2

PIK3CA 33.3 38.6

MAP3K13 33.3 36.4

BCL6 33.3 34.8

FGF12 33.3 33.3

44.4

26.5

55.660.6

0

10

20

30

40

50

60

70

80

90

100

*ErbB+ †FGF+

ErbB and FGF family aberrations

(SVs or CNAs)

Most common aberrations observed in LTRs (≥3 patients)

LTRs (n=9)

LUX-Lung 8 afatinib-treated population (n=132)

Pro

port

ion o

f patients

with

SV

s o

r C

NA

s (

%)



0 5 10 15 20 25 30 35

15

14

13

12

11

10

9

8

7

6

5

4

3

2

1

0 5 10 15 20 25 30 35

15

14

13

12

11

10

9

8

7

6

5

4

3

2

1

LT

Rs

†

• 12/14* (86%) LTRs were VS ‘Good’ compared to 62% in the overall afatinib-treated dataset (n=336)

• 78% of LTRs with available data had aberrations more common in LTRs than in the overall population

VeriStrat status and biomarkers more commonly observed in LTRs

¶

*VeriStrat data for Patient 8 was not available; †Patients were ordered and numbered by treatment duration, with patient 1 being on treatment longest; ‡First observed response at time of tumour

measurement; §Last observed response at time of tumour measurement; ¶Treatment ongoing until death; VS, VeriStrat

OS

VeriStrat Good

VeriStrat Poor

VeriStrat Missing

CR (1)‡

PR (4)‡

Duration of response§

End of treatment

G

G

G

P

G

G

G

G

G

G

G

G

G

P

M

G

P

M

¶

ErbB4; KEAP1

KEAP1; PIK3CA; ErbB2

MLL

MLL; PIK3CA

KEAP1; EGFR

ErbB2

MLL; PIK3CA

G

G

G

P

G

G

G

G

G

G

G

G

G

P

M

Time (months)

SD (9)



Subsequent therapies reported for LTRs

*Tumour response was stable disease unless noted otherwise (patient 2 was classified as non-evaluable); †Patients were ordered and numbered by treatment duration, with patient 1 being on

treatment longest; ‡First observed response at time of tumour measurement; §Last observed response at time of tumour measurement; ¶Treatment ongoing until death

¶

LT

Rs*†

Navelbine

Docetaxel

Gemcitabine

Paclitaxel/carboplatin,

gemcitabineDocetaxel

Gemcitabine

Gemcitabine/carboplatin,

paclitaxel/carboplatin

Carboplatin/nanoxel

Time (months)

OSCR (1)‡

PR (4)‡Duration of response§ End of treatmentSD (9)



• The frequency of common drug-related AEs in LTRs was similar to the overall afatinib-treated population

• Afatinib 40 mg/day was maintained in 7/15 and escalated to 50 mg in 4/15 LTRs

• 4/15 dose reduced to 30 or 20 mg; dose reductions did not seem to have a negative impact on OS

• There were no treatment-discontinuations due to AEs

Common treatment-related AEs* and tolerability-guided dose adjustments

Treatment-duration (months)

*>20% in overall afatinib-treated population; †Patients were ordered and numbered by treatment duration; ‡Treatment ongoing until death

LT

Rs

† 50 mg

40 mg

30 mg

20 mg

Data unavailable

OS‡



Conclusion

• Afatinib conferred a median survival benefit of nearly 2 years in the LTR subset

• SVs of ErbB2/4, EGFR, MLL, PIK3CA and KEAP1 were more frequent in LTRs

• 86% of LTRs* were VeriStrat-Good and nearly four times as likely to survive ≥12

months as VeriStrat-Poor patients

• The approved afatinib dose (40 mg/day) was maintained or escalated in 73% of LTRs

• Small sample size limited drawing any firm conclusions concerning molecular/clinical

markers of long term response and therefore further studies are required

*12/14 patients with available VeriStrat data



• We thank all patients and their families, and investigators and staff at all clinical sites for their valuable

participation in this study

• Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by

Hannah Detering of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the

development of this oral presentation

Acknowledgements



BACK UP



Patient disposition in LUX-Lung 8

Did not meet entry criteria

or did not enter (n=182)

6 still on treatment 3 still on treatment

Assessed for eligibility (n=977)

307 died 325 died

392 treated 395 treated

Randomised (n=795)

Afatinib (n=398) Erlotinib (n=397)



Afatinib (n=398) Erlotinib (n=397)

Median age (years) 65 64

Male (%) 84 83

Race (%)Eastern-Asian 22 22

Non-eastern Asian 78 78

Smoking history (%)

Never smoker 7 5

Light ex-smoker* 3 3

Current and other ex-smoker† 91 92

ECOG‡ (%) 0/1 32/68 34/66

Clinical stage§ (%) IIIB/IV 12/88 12/87

Histology¶ (%)Squamous 96 96

Mixed 4 4

Best response to

first-line

chemotherapy (%)

CR/PR 47 47

SD 41 42

Unknown 12 11

Demographics and baseline characteristics in LUX-Lung 8

*Less than fifteen pack-years and stopped >1 year before diagnosis; †Seventy-one (17.8%) and 85 (21.4%) patients were current smokers, respectively; ‡,<1% were ECOG PS 2; § ≤1% were stage IIIA; ¶≤1% were undifferentiated (considered to be of squamous histology)



• Median PFS was significantly longer with afatinib (2.6 months) versus erlotinib

(1.9 months; HR=0.81 [95% CI: 0.69–0.96])

LUX-Lung 8: Primary endpoint (PFS)

Afatinib 398 139 50 30 14 10 5 2 2 0

Erlotinib 397 99 34 17 10 2 1 1 1 0

1.0

0.8

0.6

0.4

0.2

0

Estim

ate

d P

FS

pro

ba

bili

ty

Time (months)3 6 9 12 15 18 21 24 27

Number at risk

0

Afatinib

(n=398)

Erlotinib

(n=397)

Median, months 2.6 1.9

HR (95% CI) 0.81 (0.69–0.96)

p value 0.0103



Treatment duration and best response in LTRs

• Median duration of treatment was 16.6 months (range: 12.3–25.8 months)

• ORR=33% (n=5)

12.3

12.9

13.1

13.2

13.7

13.8

15.9

16.6

17.5

17.6

19.0

19.6

20.3

22.825.8

0 5 10 15 20 25 30

15

14

13

12

11

10

9

8

7

6

5

4

3

2

1

Treatment duration (months)

Complete response

Partial response

Stable disease†

Non-evaluable‡

*Patients were ordered and numbered by treatment duration; †Four patients had stable non-target disease in the absence of baseline-target disease; ‡Classed non-evaluable by the assessing

oncologist due to missing baseline CTs

LT

Rs*



• NGS was undertaken in 9/15 afatinib-treated LTRs and 245/795 patients of the

overall LUX-Lung 8 population

• Certain SVs were more common in LTRs than in the overall population

Genomic aberrations in LTRs and in the overall NGS dataset

*EGFR, ErbB2, ErbB3, and ErbB4 genes; †FGF3, FGF4, FGF6, FGF7, FGF10, FGF12, FGF14, FGF23, FGFR1, FGFR2, FGFR3, and FGFR4 genes

NGS, next generation sequencing; CNAs, copy number alterations; SVs, short variants

Gene, % Afatinib LTRs (n=9) Overall (n=245)

SVs

TP53 88.9 87.3

ErbB family 44.4 23.3

ErbB2/3/4 22.2/0/11.1 4.9/6.1/5.7

EGFR 11.1 6.5

LRP1B 33.3 39.2

MLL2 33.3 33.1

MLL 33.3 12.2

KEAP1 33.3 10.2

PIK3CA 33.3 11.8

CNAs

SOX2 44.4 42.9

KLHL6 44.4 39.6

PIK3CA 33.3 36.3

MAP3K13 33.3 32.2

BCL6 33.3 30.6

FGF12 33.3 28.2

44.4

29.4

55.6 58.0

0

10

20

30

40

50

60

70

80

90

100

*ErbB+ †FGF+

ErbB and FGF family aberrations

(SV or CNA)

Most common aberrations observed in LTRs (≥3 patients)

LTRs (n=9)

LUX-Lung 8 population (n=245)

Pro

port

ion o

f patients

with S

Vs

or

CN

As (

%)



Patient

number

Line of

therapy

Additional cancer therapy

Start date,

days after last

afatinib dose

Stop date,

days after last

afatinib dose

First

compound*

Second

compound*

Third

compound*

3 3 8 69 Paclitaxel Carboplatin –

3 4 204 274 Gemcitabine – –

4 3 105 – Docetaxel – –

5 3 6 – Carboplatin Nanoxel –

6 3 2 – Navelbine – –

9 3 15 159 Gemcitabine Carboplatin Gemcitabine

9 4 223 – Paclitaxel Carboplatin –

11 3 30 110 Docetaxel – –



Details of subsequent therapy

*Dictionary term



• The frequency of drug-related AEs in LTRs was similar to the overall afatinib-treated population

• AEs generally occurred soon after treatment onset

Common treatment-related AEs*: Incidence and onset

*>20% in overall afatinib-treated population; †Grouped term

Related AEs in LTRs All grades, n (%) Grade 3, n (%)Median AE onset, days

(range)

Diarrhoea 11 (73) 1 (7) 11 (5–48)

Rash/acne† 11 (73) 1 (7) 17 (9–107)

Stomatitis 2 (13) 1 (7) 98 (11–223)

second-line afatinib for advanced squamous cell carcinoma …...fgf12 33.3 33.3 44.4 26.5 55.6 60.6...

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