Advantages and disavantages of irreversible EGFR-TKI

Lucio Crinò, MDMedical Oncology Department

University Hospital Perugia, Italy

Evolution of Knowledge in NSCLCFrom Histology to Molecular Classification

Li, et al. J Clin Oncol 2013

EGFR mutations in NSCLC

Second generation EGFR TKIs

• The second-generation of EGFR TKIs has the advantage of forming covalent, irreversible bonds with the target, which should increase their effectiveness through a prolonged inhibition of EGFR signaling

• Furthermore, the prolonged and irreversible inhibition of the receptor has the potential for further improvement in response to treatment over the first-generation TKIs such as erlotinib and gefitinib

• To date, irreversible oral TKIs that target simultaneously multiple members of the EGFR family are currently in clinical development for NSCLC, including afatinib, dacomitinib and neratinib.

• Preclinical studies showed that irreversible TKIs killed cells with acquired resistance to first-generation TKIs.

Becker K et al., World J Clin Oncol. 2014

Afatinib Is the First Irreversible ErbB Family Blocker

• Afatinib selectively, covalently binds and irreversibly blocks ErbB family receptors EGFR, HER2, and ErbB4

• Afatinib prevents ligand-dependent ErbB3 phosphorylation in preclinical studies

Solca et al. J Pharmacol Exp Ther. 2012;343:342. Li et al. Oncogene. 2008;27:4702; Köhler J et al. Onkologie 2013;36:510-518

Dacominitinb mechanism of action

• Dacomitinib is an irreversible pan-HER tyrosine kinase inhibitor with activity against EGFR, HER2 and HER4.

• Preclinical activity against– EGFR sensitising mutations– EGFR T790M– wild-type HER2– mutant HER2

Peters S., Cancer Treatment Review, 2014

Pharmacokinetics of afatinib and dacomitinib

• Afatinib undergoes minimal metabolism by the cytochrome P450 system but is a substrate of p-glycoprotein. P-glycoprotein inducers (rifampicin,carbamazepine, phenytoin, phenobarbital, St. John’s Wort ) may therefore lower systemic drug concentrations of afatinib.

• Coadministration of a P-glycoprotein inhibitor (ritonavir, cyclosporine, ketoconazole, erythromycin, verapamil, and others) can increase afatinib exposure.

• As oral drugs, gastric contents and pH may also impact bioavailability. Afatinib absorption is reduced when taken with a high fat meal whereas erlotinib absorption is increased and patients are directed to take both medications on an empty stomach

USA: Boehringer Ingelheim Pharmaceuticals, Inc Ridgefield 2013.

Potency and inhibition of cell proliferation of oral EGFR tyrosine kinase inhibitors

Peters S et al. Cancer Treatment Reviews (2014)

Studies of EGFR TKIs versus chemotherapy as first-line therapy in EGFR Act Mut+ NSCLC

Study EGFR TKI

Median PFS in TKI

arm (months)

Median PFS in chemotherapy arm (months)

Median OS in TKI arm

(months)

Median OS in chemotherapy arm (months)

OPTIMAL Erlotinib 13.1 4.6 22.7 28.9

First Signal Gefitinib 8.4 6.3 27.2 25.6

IPASS Gefitinib 9.5 6.3 21.6 21.9

WJTOG 3405

Gefitinib 8.4 5.3 36 39

NEJSG 002 Gefitinib 10.8 5.4 27.7 26.6

EURTAC Erlotinib 10.4 5.2 19.3 19.5

LUX-3 Afatinib 11.1 6.7 28.1 28.2

LUX-6 Afatinib 11.0 5.6Not

reported, immature

Not reported, immature

LUX-Lung 3 and 6: OS in common mutations

Presented By James Yang at 2014 ASCO Annual Meeting

Combined OS analysis: common mutations (n=631)

Presented By James Yang at 2014 ASCO Annual Meeting

Combined OS analysis in common mutations: subgroups

Presented By James Yang at 2014 ASCO Annual Meeting

Combined OS analysis: mutation categories

Presented By James Yang at 2014 ASCO Annual Meeting

LUX-Lung 3 and LUX-Lung 6:Summary of Adverse Events

aIncludes 3 patients (1%) who discontinued due to diarrhoea, no discontinuations for rash.bIncludes 3 patients (1%) with ILD-like events (1 grade 1, 1 grade 3; 1 grade 5).cIncluding 1 patient with ILD.dPreferred terms: dyspnoea, sepsis, ARDS, death (unknown cause).eSudden death (afatinib) and cardiac failure (Gem/Cis).SAE = serious adverse event; ILD = interstitial lung disease; ARDS = acute respiratory distress syndrome.1. Sequist et al. J Clin Oncol. 2013;31:3327; 2.Yang ASCO 2013 ; 3. Wu et al. Lancet Oncol. 2014;15:213.

4. Wu YL. et al. 2013 ASCO Annual Meeting. Oral Presentation

% of Patients

LUX-Lung 31,2 LUX-Lung 63,4

Afatinib (n=229)

Pem/Cis(n=111)

Afatinib (n=239)

Gem/Cis(n=113)

Drug-related AEs 100 96 99 99

Drug-related AE grade ≥3 49 48 36 60

Drug-related AEs leading to discontinuation 8a,b 12 6c 40

Discontinuation due to rash 0 0 2.1 (5 pts) 0

Discontinuation due to diarrhoea 1.3 (3 pts) 0 0 0

Drug-related SAE 14 14 5 7

Related SAE leading to death 1.7 (4 pts)d 0 0.4 (1 pt)e 0.9 (1 pt)e

15

LUX-Lung 31, / LUX-Lung 62, %

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 4

Rash/acnea 89.1 / 80.8 16.2 / 14.2 0.0 / 0.4 6.3 / 8.8 0 0Diarrhoea 95.2 / 88.3 14.4 / 5.4 0 15.3 / 10.6 0 0Paronychia/nail effecta 56.8 / 32.6 11.4 / 0.0 0 0 / 0 0 0Stomatitis/mucositisa 72.1 / 51.9 8.37 / 5.4 0.4 / 0.0 15.3 / 5.3 0.9 / 0.0 0Decreased appetite 20.5 / 10.0 3.1 / 1.3 0 53.2 / 40.7 2.7 / 1.8 0Vomiting 17.0 / 9.6 3.1 / 0.8 0 42.3 / 80.5 2.7 / 15.9 0.0 / 3.5Fatiguea 17.5 / 10.0 1.3 / 0.4 0 46.8 / 36.3 12.6 / 0.9 0Nausea 17.9 / 7.5 0.9 / 0.0 0 65.8 / 75.2 3.6 / 7.1 0.0 /0.9Dry skin 29.3 / NA 0.4 / NA 0 1.8 / NA 0 0Pruritus 18.8 / 10.9 0.4 / 0.4 0 0.9 / 0.0 0 0Neutropenia 0.9 / 2.1 0.4 / 0.4 0 31.5 / 54.0 15.3 / 17.7 2.7 / 8.8Anemia 3.1 / 5.4 0.4 / 0.4 0 27.9 / 27.4 4.5 / 7.1 1.8 / 1.8Leukopenia 1.7 / 3.3 0.04 / 0.4 0 18.9 / 51.3 8.1 / 13.3 0.0 / 1.8ALT increase 7.4 / 20.1 0.0 / 1.7 0 2.7 / 15.9 0.0 / 1.8 0.0 / 0.9AST 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 (>20% Difference Between Treatment Arms)

aGrouped term for closely related AEs.

ALT = alanine aminotransferase; AST = aspartate aminotransferase.1. Sequist et al. J Clin Oncol. 2013;31:3327 2. Wu et al. Lancet Oncol. 2014;15:213.

Is response rate improved with irreversible EGFR-TKIs?Comparison of best reported phase II results for EGFR TKIs in patients with EGFR-Mutant

lung cancers (Exon 19 and Exon 21)

Agent Entered, nCR+PR Rate, %

MedianPFS, months

MedianOS, months

Dacomitinib 46 74 17 NRAfatinib1 129a 66 15b 32–39Erlotinib2 33 70 14 31

Gefitinib3 27 59

Weighted pooled analysis median PFS in patients with EGFR-mutant lungcancers4

Erlotinib (95% CI) 365c 13.2 (12.0–14.7)Gefitinib (95% CI) 1069d 9.8 (9.2–10.4)

1Yang JC, et al. Lancet Oncol 2012;3: 539–48.2Janne PA, et al. J Clin Oncol 2012;epub 30April.

3Sequist LV, et al. J Clin Oncol 2008;26: 2442–94Paz-Ares L, et al. J Cell Mol Med 2010;14:51–69.

a51 treated first-line; bmedian PFS: 12 months on blind review; c12 studies; d39 studies

NR, not reached; OS, overall survival

Gefitinib:IPASS

1.00.90.80.70.60.50.40.30.20.1

0

0 4 8 12 16 20 24

Gefitinib: median 9.5 months

HR 0.48, p<0.0001

Afatinib:phase III1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 5 10 15 20 25 30

Median 16.8 months

Prog

ress

ion-

free

sur

viva

l (pr

obab

ility

)

Dacomitinib:phase II

HR 0.47, p<0.0001

Afatinib: median 13.6 months

Is PFS improved with irreversible EGFR-TKIs?Indirect comparison in patients with classical EGFR mutations in first-line

Erlotinib: EURTAC

HR 0.37, p<0.0001

Erlotinib: median 9.7 months

Indirect comparison of reversible vs. irreversible EGFR-TKIs

Gefitinib

NEJSG 002n=114

IPASSn=607

First-SIGNALn=159

WJTOG3405n=87

Rash 71.0 (5.3) 66.2 (3.1) 72.3 (1.3) 74 (2)

Diarrhoea 34.2 (0.9) 46.6 (3.8) NR 47(1)

Fatigue 10.5 (2.6) NR 28.3 (0.6) 34 (2)

Anorexia NR 21.9 (1.5) 44.7 (0) NR

Stomatitis 9.6 (0) 17.0 (0.2) NR 19 (0)

Paronychia NR 13.5 (0.3) NR 28 (1)

Vomiting 6.1 (0.9) 12.9 (0.2) NR NR

Erlotinib

OPTIMALn=83

CALGB30406n=81

73.5 (2.4) NR (7.4)

25.3 (1.2) NR (4.9)

4.8 (0) NR (1.2)

NR NR

13.3 (1.2) NR

3.6 (0) NR

NR NR

Afatinib

LUX-3n=229

37 (16.2)

33 (14.4)

3 (1.3)

7 (3.1)

20 (8.7)

26 (11.4)

7 (3.1)

LUX-Lung 7 – Trial Design

LUX-Lung 7A multicentre, randomized, open-label phase IIb of afatinib vs. gefitinib as first-line treatment for patients with advanced and metastatic non-small cell lung cancer (NSCLC) harbouring EGFR activating mutations

Patients with:• Adenocarcinoma of the lung• Presence of activating EGFR mutations in the tumor tissue either by local lab or by central lab• Stage IIIB/IV• No prior treatment with chemotherapy for advanced/metastatic disease• No prior treatment with EGFR-inhibitors• ECOG 0 or 1

Oral afatinib 40 mg once daily Oral gefitinib 250 mg once daily

Primary endpoint: progression-free survival (PFS)

Randomize1:1

NCT01466660

Oral daconitinib 45 mg once daily Oral gefitinib 250 mg once daily

Archer 1050 – Trial Design

Archer 1050A multicentre, randomized, open-label phase III, clinicas study comparing dacominitinib vs. gefitinib as first-line treatment for patients with advanced and metastatic non-small cell lung cancer (NSCLC) harbouring EGFR activating mutations

Patients with:• Adenocarcinoma of the lung• Presence of activating EGFR mutations in the tumor tissue either by local lab or by central lab. EGFR mutation status•Stage IIIB/IV• No prior treatment with chemotherapy for advanced/metastatic disease• No prior treatment with EGFR-inhibitors• ECOG 0 or 1

Randomize1:1

Primary endpoint: progression-free survival (PFS)

EGFR TKIs and EGFR mutated NSCLC:<br />major mechanisms of resistance to EGFR TKIs (2)

Presented By Daniel Costa at 2014 ASCO Annual Meeting

Modest efficacy of irreversible EGFR-TKIs Against “de novo” and “acquired” T790M

NeratinibRR=0% in T790M+

LUX-LUNG 2-3-6 trials T790M

Response rate (%) 14.3

PFS (months) 2.9

OS (months) 14.9

LUX LUNG 1: RR=7% LUX LUNG 4: RR=8%

Conclusions

• No relevant differences in clinical activity between first and second generation TKIs

• Better preclinical data of irreversible TKIs do not translate in clinical practice

• Similar results in uncommon EGFR mutations• More favorable Gefitinib Erlotinib toxicity profile• Improved efficacy of Afatinib in exon 19

deletion?• Face to Face comparative trials ongoing