Erlotinib Therapy in Non Small Cell Lung Cancer Patients - Survival of Patients on Reduced Erlotinib Doses M. Pesek 1, J. Krejci 1, J. Skrickova 2, P. Zatloukal 3, V. Kolek 4, F. Salajka 5, L. Koubkova 6, D. Sixtova 7, L. Petruzelka 8, J. Roubec 9, R. VyzulaT 10, T. Pavlik 11 1 Department of Pneumology, University Hospital Plzen, 2 Dep. of Pneum., University Hospital Brno, 3 Dep. of Pneum., Univesity Hospital Praha Bulovka 4 Dep. of Pneum., Univesity Hospital Olomouc 5 Dep. of Pneum., University Hospital Hradec Kralove, 6 Dep. of Pneum., University Hospital Praha Motol, 7 Dep. of Pneum., Thomayer Univesity Hospital Praha, 8 Dep. of Oncology, Charles University Hospital Praha, 9 Dep. of Pneum., University Hospital Ostrava, 10 Masaryk Memorial Cancer Institute, Brno 11 Institute of Biostatistics and Analyses, Masaryk University Brno

Background Erlotinib is a standard treatment of recurrent/metastatic non-small cell lung cancer (NSCLC) in second and subsequent lines. Rash and diarrhea are the most common side effect of erlotinib and might be a reason of dose reduction from standard dose 150mg/day to 100mg/day. We‘ve investigated whether this dose reduction was not associated with decreased effect of treatment.

Methods All patients with NSCLC treated in 10 pulmooncology centers with erlotinib are followed in the Czech Tarceva Registry. We‘ve compared patients in which the Erlotinib dose was reduced to 100 mg whenever during the treatment with patients without dose reduction in our retrospective study.

Split II Patients with decline of the Erlotinib dosage during the treatment (from 150 mg/day to 100 mg/day) The Erlotinib dosage was decreased for 90 patients (for 84 patients because of adverse events). Split I Patients without decline of the Erlotinib dosage during the treatment Patients' stratification according to the Erlotinib dosage

Gender according to the Erlotinib dosage % of patients N = 682 without dosage decline with dosage decline No of pts without dosage decline with dosage decline Female20233 Male39057 All59290

Smoking according to the Erlotinib dosage % of patients No of pts without dosage decline with dosage decline Non-smoker13620 Former smoker23249 Smoker22421 All59290 p = (Tested by Pearson Chi-Square test) N = 682 without dosage decline with dosage decline

Patients’ age according to the Erlotinib dosage % of patients Age (years) without dosage decline with dosage decline No. of patients58989 Mean63 yrs65 yrs Median63 yrs66 yrs Min27 yrs43 yrs Max87 yrs85 yrs % of patients < 65 years 57.2 %43.8 % Age (years) N = 678 N = 678 1) Age categories according to date of diagnosis 1) Date of primary diagnosis is missing for 4 patients. p = (Tested by Mann-Whitney U test)

Histology of primary tumor according to the Erlotinib dosage % of patients Number of patients without dosage decline with dosage decline Adenocarcinoma without BAC27435 Epidermoid20940 Nonspecific NSCLC343 Large-cell130 Bronchioloalveolar carcinoma202 Other4210 All59290 N = 682 without dosage decline with dosage decline

Type of treatment before the Erlotinib treatment initiation % of patients Surgery RT Neoadjuvant CHT Adjuvant CHT CHT I. line Patients with Erlotinib treatment in the first line Without Erlotinib dosage decline (N = 65) With Erlotinibdosage decline (N = 10) % of patients CHT I. line RT Surgery Adjuvant CHT Neoadjuvant CHT CHT II. line Patients with Erlotinib treatment in the second line Without Erlotinib dosage decline (N = 269) With Erlotinib dosage decline (N = 40)

Type of treatment before the Erlotinib treatment initiation % of patients CHT I. line CHT II. line RT Surgery Adjuvant CHT Neoadjuvant CHT Patients with Erlotinib treatment in the third line Without Erlotinib dosage decline (N = 258) With Erlotinib dosage decline (N = 40)

Duration of the Erlotinib treatment % of patients N = 90 Duration of Erlotinib treatment before the dosage decline Duration of treatment No. of patients90 Mean11.8 weeks Median5.0 weeks Min1.0 week Max85.6 weeks time (weeks)

Adverse events leading to the Erlotinib dosage decline N% Rash Rash + Diarrhoea Diarrhoea56.0 Rash + Others56.0 Infection of soft tissues33.6 Other Unknown56.0 Total % of patients N = 84 N = 84 1) The Erlotinib dosage was decreased because of rash for 59 patients (70.3%). 1) The Erlotinib dosage was decreased for 90 patients (for 84 patients because of adverse events).

Grade of adverse events leading to the Erlotinib dosage decline Type of AEGradeN% RashIV810.1% III2025.3% II1316.5% Rash + DiarrhoeaIV11.3% III78.9% II56.3% DiarrhoeaIII33.8% II22.5% Rash + OthersIV11.3% III22.5% II22.5% Infection of soft tissuesIII22.5% II11.3% OtherIII810.1% II45.1% Total % N = 79 N = 79 1) 1) Type and grade of adverse events are known for 79 patients. Grade IV Grade III N = 10; 12.7% N = 42; 53.2% Grade II N = 27; 34.1%

Progression-free survival - Erlotinib dosage Progression-free survival time with declinewithout decline Number of patients89581 Median (95% CI) 5.4 months (3.7; 7.2) 2.1 months (1.8; 2.5) PFS probability (%, 95% IS) with declinewithout decline 3-month survival73.6 (64.3; 82.9)40.0 (35.8; 44.2) 6-month survival46.0 (35.2; 56.9)20.7 (17.0; 24.3) 1-year survival29.8 (19.3; 40.3)10.1 (7.0; 13.1) p < Time (months) Progression-free survival probability The comparison of survival between the two groups of patients was tested by Log rank test. Without Erlotinib dosage decline With Erlotinib dosage decline

Overall survival - Erlotinib dosage Overall survival time with declinewithout decline Number of patients90583 Median (95% CI) 14.7 months (10.3; 19.1) 5.4 months (4.4; 6.4) Survival probability (%, 95% IS) with declinewithout decline 3-month survival93.1 (87.8; 98.4)66.6 (62.5; 70.6) 6-month survival73.5 (63.6; 83.3)47.5 (42.9; 52.1) 1-year survival54.1 (41.5; 66.8)26.3 (21.5; 31.1) Without Erlotinib dosage decline With Erlotinib dosage decline p < Time (months) Survival probability The comparison of survival between the two groups of patients was tested by Log rank test.

Exclusion of potential confounding factor: Censoring of patients with early tumour progression with no decline erlotinib doses. Other possible related factors: Skin toxicity and effectiveness of erlotinib therapy; Types of erlotinib AEs responsible to erlotinib decline; Genetic markers (EGFR mutations, EGFR amplifications, KRAS mutations); Smoking status.

(Patients with duration of Erlotinib treatment over 12 weeks) Progression-free survival - Erlotinib dosage (Patients with duration of Erlotinib treatment over 12 weeks) Progression-free survival time with declinewithout decline Number of patients77291 Median (95% CI) 5.8 months (3.9; 7.7) 3.8 months (3.5; 4.0) PFS probability (%, 95% IS) with declinewithout decline 3-month survival80.5 (71.7; 89.4)63.4 (57.8; 68.9) 6-month survival49.8 (38.3; 61.3)31.7 (26.2; 37.2) 1-year survival31.7 (20.3; 43.0)14.4 (9.7; 19.0) p < Time (months) Progression-free survival probability The comparison of survival between the two groups of patients was tested by Log rank test. Without Erlotinib dosage decline With Erlotinib dosage decline

(Patients with duration of Erlotinib treatment over 12 weeks) Overall survival - Erlotinib dosage (Patients with duration of Erlotinib treatment over 12 weeks) Overall survival time with declinewithout decline Number of patients78292 Median (95% CI) 14.7 months (10.5; 19.0) 8.3 months (7.0; 9.7) Survival probability (%, 95% IS) with declinewithout decline 3-month survival97.4 (93.9; 100.0)96.5 (94.4; 98.6) 6-month survival75.9 (65.8; 85.9)65.9 (60.1; 71.6) 1-year survival54.4 (40.9; 67.9)34.0 (27.4; 40.6) Without Erlotinib dosage decline With Erlotinib dosage decline p = Time (months) Survival probability The comparison of survival between the two groups of patients was tested by Log rank test.

Progression free survival – accordingly to rash and its grade Time (months) Progression free survival probability p < Progression free survival time no rashrash G1,2rash G3,4 Number of pts Median OS (95% CI) 1.2 months (0.6; 1.9) 2 months (1.2; 2.9) 3.8 months (3.1; 4.5) PFS probability (%, 95%CI) no rashrash G1,2rash G3,4 3months surv (13.3; 29.7) 35.7 (24.5; 47.0) 61.3 (42.5; 80.1) 6months surv (5.8; 19.3) 20.1 (10.4; 29.8) 30.1 (11.2; 49.0) 1year survivalí 7.1 (1.6; 12.7) 9.6 (2.1; 17/0) 30.1 (11.2; 49.0) no rash rash grade 1, 2* rash grade 3, 4*

Results of analysed relations - 1 In patients having tumours with EGFR sensitive mutations and amplifications Erlotinib dose reduction was in 8/23 (35%), whereas in EGFR mutation and/or amplification negative patients erlotinib dose reductions was in 28/200 pts (14%). This difference is significant, p = – (Fisher´s exact test). KRAS mutation and erlotinib decline was found in 1/13 patients (NS).

Smoking according to the Erlotinib dosage % of patients No of pts without dosage decline with dosage decline Non-smoker13620 Former smoker23249 Smoker22421 All59290 p = (Tested by Pearson Chi-Square test) N = 682 without dosage decline with dosage decline

Results of analysed relations - 2 PFS and overal survival were found significantly longer in erlotinib dose reduced pts. 1.In both sexes 2.In EGFR non mutated tumours 3.In KRAS non mutated tumours 4.In tumours without EGFR amplifications 5.In adenocarcinomas

Results of analysed relations - 3 PFS but not overal survival is longer 1.In patients younger and older than 65 years (overal survival was longer in those older than 65 years) 2.In epidermoid cancers 3.In smokers (in non and exsmokers PFS and OS are longer) Better clinical response (CR + PR) in erlotinib reduced doses was found in all analyzed subgroups.

Overall survival according to the adverse events and Erlotinib dosage Overall survival time I.II.III. Number of patients Median (95% CI) 14.7 months (10.3; 19.1) 11.2 months (0; 23.1) 3.6 months (2.5; 4.7) Survival probability (%, 95% IS) I.II.III. 3-month survival 93.1 (87.8; 98.4) 100 (100; 100) 55.6 (37.4; 73.8) 6-month survival 73.5 (63.6; 83.3) 66.7 (35.9; 97.5) 28.5 (11.3; 45.8) 1-year survival 54.1 (41.5; 66.8) 50.0 (13.5; 86.5) 19.0 (3.3; 34.8) III. Patients with finished treatment of Erlotinib due to adverse events I. Patients with Erlotinib dosage decline p < Time (months) Survival probability The comparison of survival between the three groups of patients was tested by Log rank test. II. Patients without Erlotinib dosage decline and with adverse events

Progression-free survival according to the adverse events and Erlotinib dosage Progression-free survival time I.II.III. Number of patients Median (95% CI) 5.4 months (3.7; 7.2) 3.6 months (1.8; 5.4) 2.1 months (1.2; 2.9) PFS probability (%, 95% IS) I.II.III. 3-month survival 73.6 (64.3; 82.9) 55.6 (23.1; 88.0) 43.1 (25.2; 61.1) 6-month survival 46.0 (35.2; 56.9) 33.3 (2.5; 64.1) 18.3 (3.1; 33.5) 1-year survival 29.8 (19.3; 40.3) 16.7 (0.0; 44.4) 12.2 (0.0; 26.3) p < Time (months) Progression-free survival probability The comparison of survival between the three groups of patients was tested by Log rank test. III. Patients with finished treatment of Erlotinib due to adverse events I. Patients with Erlotinib dosage decline II. Patients without Erlotinib dosage decline and with adverse events

Conclusion - 1 Patients with erlotinib dose reduction from 150mg/day to 100mg/day due to side effects surprisingly have superior progression free and overall survival than patients without dose reduction. Several analyses of patients with different cancers treated by erlotinib confirmed better results of treatments in patients who experienced rash (or higher grade of rash). This can be also explanation of our finding, because rash was the most common reason for dose reduction in our cohort of patients. In patients with side effect erlotinib can be reduced without decreasing its efficacy.

Conclusion - 2 Severe adverse events, particularly skin rash, are associated with better antitumour effectiveness of Erlotinib. The reason of this phenomenon should be either different pharmacokinetics of this drug in a subgroup of patients or/and increased sensitivity of skin and intestinal mucosa, as well as the tumour tissue to erlotinib. Pharmacogenetic factor (SNP ABCG2421C>A) is more frequently associated with gefitinib-induced diarrhea, but not with skin toxicity, in NSCLC patients.

Conclusion - 3 In patients suffering from serious adverse events of erlotinib therapy, dosage decline brings more favorable prognosis then finishing of erlotinib therapy. In such cases, dosage decline should be considered rather than interruption of therapy or even finishing of erlotinib treatment.