Conversationsin OncologyNovember 12-13Kerry HotelPudong, ShanghaiChina

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AE Management With EGFR TKI TherapyProfessor Maximilian J. Hochmair

All materials are for scientific exchanges. Afatinib and nintedanib are not launched in China yet and are still under application.

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Case 1

• 45-year-old female

• Healthy

• 10 PY

• Coughing + headache

4

X-Ray June 2015

5

CT Scan

6

MRI of the Brain

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Case

• 45-year-old female

• Healthy

• 10 PY

• Coughing + headache

• NSCLC (Adeno Ca) right lower lobe – T4 N2 M1b

• EGFR Status: Exon Del 19 (pleural effusion)

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LUX-Lung 3: Del 19

Estim

ated

OS

prob

abili

ty

LUX-Lung 3 and LUX-Lung 6: Preplanned OS Analysis by Mutation Subgroups

Yang et al. Lancet Oncol. 2015;16:141-151.

PFS in overall population

PFS in overall population

AfatinibCis/Pem

Afatinib (n=112)

Cis/Pem (n=57)

Median, months 33.3 21.1

HR (95% CI) P-value

0.54 (0.36–0.79)P=0.0015

LUX-Lung 6: Del 19

124 122 118 115 106 99 90 80 73 69 59 39 16 8 1 0Afatinib

No. at risk:

PFS in overall population

Afatinib (n=124)

Cis/Gem (n=62)

Median, months 31.4 18.4

HR (95% CI) P-value

0.64 (0.44–0.94)P=0.0229

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

OS

prob

abili

ty

Time (months)

AfatinibCis/Gem

Cis/Pem

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

62 58 53 49 44 35 30 28 26 21 18 11 4 3 0 0

1.0

0.8

0.6

0.4

0.2

0

112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 0Afatinib

No. at risk: Time (months)

Cis/Pem

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

57 55 50 46 43 37 33 27 25 22 20 16 10 6 1 1 0 0

L858RLUX-Lung 3 LUX-Lung 6

Afatinib (n=91) Cis/Pem (n=47) Afatinib (n=92) Cis/Gem (n=46)

Median, months 27.6 40.3 19.6 24.3

HR (95% CI), P-value 1.30 (0.80–2.11), P=0.2919 1.22 (0.81–1.83), P=0.3432

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Austrian Recommendations 2015

Griesinger et al. April 2015. https://www.onkopedia.com.

1. ECOG = Eastern Cooperative Oncology Group2. ALK=Anaplastic Lymphoma Kinase3. EGFR=Epidermal Growth Factor Receptor4. Afatinib=Prologation of survival time in patients

with activating exon 19 deletions5. Cytostatics 3rd Generation - Gemcitabine,

Pemetrexed, Taxane, Vinorelbine6. Preferably pemetrexed in ALK + NSCLC7. CR - complete remission, PR - partial

remission, SD - stable disease8. Preservation therapy - Bevacizumab in non-

squamous cell carcinoma and after pretreatment with bevacizumab; Erlotinibindependent of histology and pretreatment; Pemetrexed in adenocarcinoma and after pretreatment with pemetrexed

9. Only in adenocarcinoma10. BSC=Best Supportive Care

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Austrian Recommendations 2015

Griesinger et al. April 2015. https://www.onkopedia.com.

1. ECOG = Eastern Cooperative Oncology Group2. ALK=Anaplastic Lymphoma Kinase3. EGFR=Epidermal Growth Factor Receptor4. Afatinib=Prologation of survival time in patients

with activating exon 19 deletions

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Efficacy of Afatinib in TKI-pretreated NSCLC Patients With Brain Metastases or Leptomeningeal Disease

• 100 patients with brain metastases and/or leptomeningeal disease

• 35% cerebral ORR – 16% responded exclusively in brain

• 66% cerebral DCR

• TTF 3.6 mo – 4 mo for EGFR mut+ pts – Not different from those without brain metastases!

• OS 9.8 mo (31% maturity)

Hoffknecht. JTO. 2014.

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PFS in Patients With Brain Metastases (Combined Analyses From LUX-Lung 3/6)

Schuler et al. J Thorac Oncol. 2016; 11(3):380-90.

Time (months)No. at riskAfatinib 48 39 25 19 17 13 11 6 5 3 Chemo 33 16 5 3 1 1 0 0 0 0

Combined LUX-Lung 3 / 6

Afatinib(n=48)

Chemo(n=33)

Median, months 8.2 5.4

HR (95% CI)P-value

0.50 (0.27-0.95) P=0.03

1.0

Estim

ated

PFS

pro

babi

lity

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27

AfatinibChemo

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Tumour Response Rates in Patients With and Without Brain Metastases and Common EGFR Mutations in LUX-Lung 3 and 6

0

10

20

30

40

50

60

70

80

ORR

Patie

nt (%

)

0

10

20

30

40

50

60

70

80

ORR

Patie

nt (%

)Schuler et al. J Thorac Oncol. 2016; 11(3):380-90..

LL3

Afatinib with BMCis/Pem with BM

Afatinib without BMCis/Pem without BM

LL6

Afatinib with BMCis/Gem with BM

Afatinib without BMCis/Gem without BM

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Development After 2 Weeks With Afatinib

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Development 6 Weeks With Afatinib

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Development 6 Weeks With Afatinib

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Development 6 Weeks With Afatinib

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LUX-Lung 31,2 / LUX-Lung 62,3, %Afatinib LL3 (n=229) / LL6 (n =239) Pem/Cis (n=111) / Gem/Cis (n=113)

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4Rash/acnea 89.1 / 80.8 16.2 / 14.2 0.0 / 0.4 6.3 / 8.8 0 0

Diarrhoea 95.2 / 88.3 14.4 / 5.4 0 15.3 / 10.6 0 0

Paronychia/nail effecta 56.8 / 33.9 11.4 / 0.0 0 0 / 0 0 0

Stomatitis/mucositisa 72.1 / 51.9 8.3 / 5.4 0.4 / 0.0 15.3 / 5.3 0.9 / 0.0 0

Decreased appetite 20.5 / 10.0 3.1 / 1.3 0 53.2 / 40.7 2.7 / 1.8 0

Vomiting 17.0 / 9.6 3.1 / 0.8 0 42.3 / 80.5 2.7 / 15.9 0.0 / 3.5

Fatiguea 17.5 / 10.0 1.3 / 0.4 0 46.8 / 36.3 12.6 / 0.9 0

Nausea 17.9 / 7.5 0.9 / 0.0 0 65.8 / 75.2 3.6 / 7.1 0.0 /0.9

Dry skin/pruritusb 29.3 / 10.9 0.4 / 0.4 0 1.8 / 0.0 0 0

Neutropenia 0.9 / 2.1 0.4 / 0.4 0 31.5 / 54.0 15.3 / 17.7 2.7 / 8.8

Anemia 3.1 / 5.4 0.4 / 0.4 0 27.9 / 27.4 4.5 / 7.1 1.8 / 1.8

Leukopenia 1.7 / 3.3 0.0 / 0.4 0 18.9 / 51.3 8.1 / 13.3 0.0 / 1.8

ALT increase 7.4 / 20.1 0.0 / 1.7 0 2.7 / 15.9 0.0 / 1.8 0.0 / 0.9

AST increase 5.2 / 15.1 0.0 / 0.4 0 1.8 / 10.6 0.0 / 1.8 0

Most Frequent Treatment-Related Adverse Events in LUX-Lung 3 and LUX-Lung 6

1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Data on file. Boehringer Ingelheim; 3. Wu et al. Lancet Oncol. 2014;15:213.

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LUX-Lung 7: Related AEs Occuring With >10%Afatinib Gefitinib

All Gr Gr3 Gr4 All Gr Gr3 Gr4

Diarrhoea 144 (90.0) 19 (11.9) 1 (0.6) 97 (61.0) 2 (1.3)

Rash/Acne* 142 (88.8) 15 (9.4) 129 (81.1) 5 (3.1)

Stomatitis* 103 (64.4) 7 (4.4) 38 (23.9)

Paronychia* 89 (55.6) 3 (1.9) 27 (17.0) 1 (0.6)

Dry skin 52 (32.5) 59 (37.1)

Pruritus 37 (23.1) 36 (22.6)

Fatigue* 33 (20.6) 9 (5.6) 23 (14.5)

Decr. appetite 26 (16.3) 1 (0.6) 19 (11.9)

Nausea 26 (16.3) 2 (1.3) 22 (13.8)

Alopecia 17 (10.6) 24 (15.1)

Vomiting 17 (10.6) 6 (3.8) 1 (0.6)

ALT increase 15 (9.4) 38 (23.9) 12 (7.5) 1 (0.6)

AST increase 10 (6.3) 33 (20.8) 4 (2.5)

4 cases of ILD with gefitinib, 3 of them ≥ grade 3No case of ILD with afatinib.

*Preferred terms of AEs. Park et al. Ann Oncol. 2015;26:(suppl 9; abstract LBA2).

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Key Considerations for Proactive AdverseEvent Management

• Regularly monitor for AE• Consider degree and duration of AEsEvaluate

• Proactive supportive careTreat

• Dose interruption and/or• Dose modification

Tolerability-guided dose adjustment

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• Grade ≥3 adverse events• Prolonged grade 2 (≥7 consecutive days)• Diarrhoea grade 2 >48 hours despite optimal care• Worsening of renal function grade 2

Resume treatment at dose REDUCED by 10 mg

Standard dose of 40 mg/d

Dose Modification

• Absence of drug-related events >CTCAE grade 1 within first 3 weeks of treatment

Continue with 50-mg/d dose

PAUSE until recovery to grade ≤1 or baseline

GIOTRIF® summary of product characteristics. Boehringer Ingelheim International GmbH.

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Despite longer treatment exposure at lower doses, tolerability-guided dose reduction led to decreases in the incidence and severity of treatment-related AEs

Key treatment-related AEs in patients requiring tolerability-guided dose modification

Median treatment exposure for dose-reduced patients

48.5

140

276.5

0 200 400

40 mg (n=122)

30 mg (n=120)

20 mg (n=40)

Median treatment exposure (days)

0

10

20

30

40

50

60

70

80

90

100

Pre Post Pre Post Pre Post Pre Post Pre Post

Any Diarrhoea Rash/acne Stomatitis Nail effects

Patie

nts

(%)

Grade ≥3

Grade 1/2

Pre: AEs before dose reduction from 40 mgPost: AEs after first dose reduction from 40 mg

Influence of Dose Adjustment on Afatinib Safety and Efficacy

Yang et al. J Clin Oncol. 2015;(suppl). Abstract 8073 and poster.

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PFS in LUX-Lung 3 Patients Who Had Dose Reductions Within the First 6 Months and Those Who Remained on Afatinib 40 mg Daily

Yang et al. J Clin Oncol. 2015;(suppl). Abstract 8073 and poster.

Median PFS similar in patients who had afatinib dose reductions in the first 6 months and those who remained on afatinib 40 mg once daily

No. at risk<40 mg in first 6 months≥40 mg for first 6 months

105124

8793

7576

5862

4136

2624

1516

64

21

00

Time (months)

1.0

0.6

0.4

0.2

0

Estim

ated

PFS

pro

babi

lity

0 3 6 9 12 15 18 21 24 27

0.8<40 mg in first 6 months≥40 mg in first 6 months

<40 mg in first 6 months (n=105)

≥40 mg for first 6 months (n=124)

Median PFS, months 11.3 11.0HR (95% CI), P value 1.25 (0.91–1.72), 0.175

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Afatinib Plasma Levels in Patients Who Dose Reduced and Those Who Remained on Afatinib 40 mg

Patients who remained on 40 mg until C3V1 (n=126) Patients whose dose was reduced to 30 mg before C3V1 (n=38; only 10 of these patients had valid trough concentrations on 40 mg afatinib at C2V1. The rest had either no PK sampling due to dose interruption, were already on 30 mg afatinib or were excluded due to invalid sampling).Yang et al. J Clin Oncol. 2015;(suppl). Abstract 8073 and poster.

Dose reduction was more likely in patients with higher plasma concentrations

140

120

100

80

60

40

20

0Trou

gh p

lasm

a co

ncen

trat

ions

(n

g/m

L)

C3V1 (Day 43)

40 mg(n=126)

30 mg(n=38)

C2V1 (Day 22)

40 mg(n=122)

40 mg(n=10)

Individual data with median and 25th/75th percentiles

10th/90th percentilesData points outside percentiles

After dose reduction to 30 mg ≥4 days previously (n=38)

Patients who remained on 40 mg (n=126)

Geometric mean plasma concentrations 24.4 ng/mL 23.7 ng/mL

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Case: Adverse Event Management

• Exanthema: – Grad 1 after 10 days

• Management:– Skin cream with uric acid

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Adverse Event Management

• Diarrhoea (first episode): – Onset of diarrhoea: after 12 days of afatinib treatment– First grade: Grade 2 (<48 hours)

• Management: – Continue afatinib at the same dose– Immediately started loperamide 4 mg initially (two tablets) Then 2 mg (one tablet) after each episode of diarrhoea, for 2 days, with complete resolution

– Dietary changes (no dairy products, lighter diet, BRAT diet)

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AEs From My Point of view

• Diarrhoea

• Rash/acne

• Stomatitis/mucositis

• Paronychia

Important: good education, most side effects happen in the first 3 weeks, in the beginning more time-consuming, motivation of the patients

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Diarrhoea

• Main side effect

• Occurs in the 1st and 2nd weeks

• Loperamide should be taken at home prophylactically (4 mg initially and then 2 mg)

• Interruption/early reduction of the dose (grade 3 or >48 h grade 2)

• Principally well-treatable

• Patient should follow the diet recommendation

• Can be an “advantage” for patients with opioids

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Rash/Acne

• From my point of view, rarer with afatinib compared to erlotinib

• With dose reduction of 10 mg, grade 1 rash/acne is always the maximum

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Stomatitis

• Happens more often compared with reversible TKIs

• Chamomile tea or oral lidocaine can help initially

• Easily manageable with dose reduction

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Paronychia

• A bit more common compared with reversible TKIs– Antiseptic bath– Local or systemically antibiosis– Short therapy break/dose reduction

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AEs From My Point of View

• Diarrhoea

• Rash/acne

• Stomatitis/mucositis

• Paronychia

• Fatigue

in low-weight patients (<50 kg) starting dose 30 mg

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Clinically Relevant Interactions of Oral TKIs

Peters et al. Cancer Treat Rev. 2014;40:917. Chen Y-M et al., PLoS One, 2016

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Case 2

• 56-year-old female

• Coughing + headache

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Case 2

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Case 2

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Case 2

• 56-year-old female

• Coughing + headache

• NSCLC (Adeno Ca) left upper lobe - cT3pN3cM1b

EGFR Status: Exon 21 (L861Q)

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1 Month Interval Exon 21 (L861Q) cT3pN3cM1b

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Development of CT Scans After 3 MonthsExon 21 (L861Q)

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Clear Intracerebral ActivityMRI 3 Month Interval

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Tumour Flair: Patient Stopped Treatment as Felt ‘Well’

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Conclusion

• Afatinib is a highly effective drug

• AE (especially diarrhoea) are easily manageable

• Individualised treatment possible with dose adaptation

• Be aware of tumour flair

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Thank You for Your Attention

Thanks to my colleagues from the respiratory oncology unit!!!

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Methods

• January 2010 till March 2014

• Tumour tissue from bronchoscopy, CT- and ultrasound-guided biopsies and surgical specimen

• 4 hospitals (LKH Hochegg, Wilheminenspital, KH Hietzing, OWS)

• Reflex testing in patients with NSCLC (Adeno Ca and NOS)

• Mutation detection was performed with EGFR Mutation Test Kit from ROCHE on a COBAS 4800

Hochmair et al. CELCC. 2014.

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Results EGFR1/2010 – 7/2014

1999 samples

256 (12.8%) EGFR mutations

211 (10.6%) activating mutation

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Distribution of Different EGFR Mutation Types

Exon 19 Deletion48%

Exon 21 L681Q1%

Exon 21 L858R31%

Exon 20 Insertion3%

Exon 18 G719X7%

Exon 20 S76813% different double

mutations7%