Correlation of Hand-Foot Skin Reaction (HFS) with Treatment Efficacy in Pancreatic Cancer (PC) Patients (pts) Treated with Gemcitabine/Capecitabine plus Erlotinib: A Subgroup Analysis

from the AIO-PK0104 Randomized, Cross-Over Phase III Trial in Advanced PC M. Haas1, S. Boeck1, R. P. Laubender2, D. P. Modest1, U. Vehling-Kaiser3, D. Waldschmidt4, E. Kettner5, A. Märten6, C. Winkelmann7, S. Klein8, G. Kojouharoff9, T. C. Gauler10, L. Fischer von Weikersthal11,

M. Clemens12, M. Geissler13, T. F. Greten14, S. Hegewisch-Becker15, O. Rubanov16, U. Mansmann2 and V. Heinemann1

1Department of Hematology and Oncology, Klinikum Grosshadern and Comprehensive Cancer Center, LMU Munich; 2Institute for Medical Informatics, Biometry and Epidemiology, LMU Munich; 3Practice for Medical Oncology, Landshut; 4Department of Hematology and Oncology, University of Cologne; 5Department of Hematology and Oncology, Klinikum Magdeburg; 6University of Heidelberg; 7Department of Internal Medicine, Krankenhaus Lutherstadt-Wittenberg; 8Department of Internal Medicine IV, Klinikum Bayreuth; 9Practice for Medical Oncology, Darmstadt; 10West German Tumor Center, University Hospital Essen; 11Gesundheitszentrum St. Marien, Amberg; 12Mutterhaus der Boromaeerinnen, Trier;

13Department of Gastroenterology and Oncology, Klinikum Esslingen; 14Medical School Hannover; 15Private Practice for Oncology, Hamburg; 16Practice for Medical Oncology, Hameln; all in Germany

Background:AIO-PK 0104 investigated the efficacy and safety of gemcitabine/erlotinib (G/E) followed by capecitabine (C) vs. C/E followed by G. The present subgroup analysis evaluated the correlation between C-associated skin toxicity and outcome parameters in PC.Methods:Within this multicenter phase III trial, pts with confirmed advanced PC were randomly assigned to 1 st-line treatment with either C (2,000 mg/m2/d, d1-14 q d21) plus E (150 mg/d, arm A) or G (1,000 mg/m2 over 30 min weekly x 7, then d1, 8, 15 q d28) plus E (150 mg/d, arm B). A cross-over to either G (arm A) or C (arm B) was performed after treatment failure (e. g. disease progression or unacceptable toxicity). Time to treatment failure after 1st- and 2nd-line therapy (TTF2) was the primary study endpoint. Treatment-related skin toxicity was evaluated separately for each treatment arm/each regimen based on NCI-CTCv2.Results:Of 279 eligible pts, 47 had locally advanced, 232 had metastatic disease and 141 pts received second-line chemotherapy. For the present subgroup analysis data on skin toxicity were available from 255 pts. For the 73 pts (29%) with a HFS (any grade documented at any time during the treatment strategy), TTF2 and OS both were significantly prolonged compared to pts without HFS (7.4 vs 4.0 months, p<0.001 and 9.7 vs 5.5 months, p=0.002, respectively). Considering HFS during 1 st-line treatment in 123 pts within the CE arm, these results could be confirmed for the 47 pts (38%) with a documented HFS of any grade (TTF2: 7.6 vs. 3.2 months, p<0.001; OS: 10.2 vs. 4.4 months, p=0.001). In pts receiving 1st-line treatment with G/E (n=132) no difference in outcome was observed for pts with (n=13) or without (n=119) HFS of any grade (TTF2: 5.7 vs. 4.2 months, p=0.375; OS: 8.4 vs. 6.6 months, p=0.505).Conclusions:The current subgroup analysis of AIO-PK0104 supports the assumption of a correlation between HFS in PC pts treated with capecitabine or capecitabine/erlotinib and efficacy endpoints like TTF2 and OS. A capecitabine-associated HFS thus might be predictive for efficacy in patients with advanced PC.

Trial Design and Treatment

Patient Characteristics Correlation of HFS with Efficacy – 1st Line Therapy

Cumulative Number of Patients with HFS During Treatment with Capecitabine –

1st Line Therapy

Treatment cycle 1 2 3 4 5 6 7 12

New pts. with HFS 9 20 7 3 2 4 1 1

1st line: capecitabine + erlotinib

1st line: gemcitabine + erlotinib

2nd line: gemcitabine

2nd line: capecitabine

TTF 1

TTF 2

R

Patients with data on HFS (n=255, safety population)

Correlation of HFS During 1st LineTherapy with Efficacy - TTF2

Conclusions

Frequency of HFS - 1st Line Therapy

Delay of Chemotherapy and Dose Reductions Due to HFS –

1st Line Therapy

Correlation of HFS with Efficacy – 1st and 2nd Line Therapy

Parameter

Arm ACap + E

Gem (n=123)

Arm BGem + E Cap (n=132)

Overall(n=255)

No % No % No %

Age (years)

Median 63 65 63

Range 38-75 32-78 32-78

Gender

Male 78 63 74 56 152 60

Female 45 37 58 44 103 40

Stage of disease

Locally advanced 22 18 21 16 43 17

Metastatic 101 82 111 84 212 83

Performance status

KPS 60-80% 45 37 47 36 92 37

KPS 90-100% 77 63 82 64 159 63

Missing 1 3 4

Treatment with 2nd line chemotherapy 62 50 76 58 138 54

N=281

1:1

Arm A

Arm B

Arm A: capecitabine 2.000 mg/m2/d p.o. d1-14, q d21 plus erlotinib, 150 mg/d p.o.; followed by gemcitabine

Arm B: gemcitabine 1.000 mg/m2 over 30 min i.v. weekly x 7, then d1, 8, 15 q d28 plus erlotinib, 150 mg/d p.o.; followed by capecitabine

TTF 1: time-to-treatment failure after 1st line therapy

TTF 2: time-to-treatment failure after 1st and 2nd line therapy

Parameter

Arm ACap + E (n=123)

Arm BGem + E (n=132)

Overall(n=255)

No % No % No %

HFS-Grade

0 76 61 119 90 195 77

1 23 19 10 8 33 13

2 16 13 3 2 19 7

3 8 6 - - 8 3

Any grade (1-3) 47 38 13 10 50 19

Parameter

Arm ACap + E

Arm BGem + E

Overall

No % No % No %

No (pts) 123 132 255

Delay of treatment

- overall 47 38 66 50 113 44

- due to HFS 9 7 - - 9 4

No (pts) 122 130 252

Dose reductions

- overall 29 24 69 53 98 39

- due to HFS 10 8 - - 10 4 Treatment delays and dose reductions overall were more

common during treatment with gemcitabine and erlotinib (arm B)

HFS was responsible for delayed application or dose reductions of capecitabine in < 10%

HFS-grades

0 1-3 0 1-3

Endpoint Subgroup No Months P-value HR(95% CI)

TTF1

Arm A: Cap+E 76 47 2.0 4.0 <0.0010.42

(0.29-0.62)

Arm B: Gem+E 119 13 3.5 5.7 0.3220.75

(0.42-1.33)

TTF2

Arm A: Cap+E 76 47 3.2 7.6 <0.0010.46

(0.32-0.67)

Arm B: Gem+E 119 13 4.2 5.7 0.3750.77

(0.43-1.37)

OS

Arm A: Cap+E 76 47 4.4 10.2 0.0010.52

(0.35-0.76)

Arm B: Gem+E 119 13 6.6 8.4 0.5050.81

(0.44-1.51)

HFS during 1st line treatment with capecitabine and erlotinib was significantly correlated with efficacy endpoints

HFS-grades 0 1-3 0 1-3

Endpoint Subgroup No Months P-value HR(95% CI)

TTF2 All patients 182 73 4.0 7.4 <0.0010.61

(0.47-0.81)

OS All patients 182 73 5.5 9.7 0.0020.64

(0.48-0.86)

Methods Definition of hand-foot-skin reaction (HFS): NCI-CTC version 2

Retrospective, post-hoc subgroup analysis based on toxicity data from the prospective, multicenter randomized AIO-PK0104 study (Boeck S et al, ASCO 2010: LBA#4011)

Safety population including 255 of the 274 eligible study patients

Separate subgroups for HFS during 1st and 2nd line therapy

Correlation of HFS with the primary (TTF2) and secondary study endpoints (TTF1, OS) for treatment efficacy

Analyses were repeated for patients who were on study for at least 3 cycles and therefore had at least one tumour assessment (i.e. patients who were defined as assessable for treatment efficacy)

Median time to capecitabine-attributed HFS was two cycles

In 36 out of 47 patients (77%) HFS was documented for the first time within the first three treatment cycles

The occurrence of HFS during treatment with capecitabine plus

erlotinib was correlated with efficacy endpoints (e. g. TTF1,

TTF2 and OS)

Capecitabine-attributed HFS occurred early within the treatment

course (after a median of two cycles)

Capecitabine-associated HFS might be predictive for treatment

efficacy in patients with advanced pancreatic cancer

The occurrence of HFS documented at any time during 1st or 2nd line therapy (in both arms) also was significantly correlated with treatment efficacy

#4023

Hand-Foot Skin Reaction

Arm A: capecitabine + erlotinib →

gemcitabine

No HFS: 3.2 months

HFS grades 1-3: 7.6 months

HR 0.46 (95%CI 0.32-0.67), p<0.001

Overall: 47 pts. with HFS

Correlation of HFS During 1st Line Therapy with Efficacy – Patients on

Study for ≥ 3 Cycles Only

HFS-grades 0 1-3 0 1-3

Endpoint Subgroup No Months HR(95% CI)

TTF1 Arm A: Cap+E 36 34 3.0 4.50.49

(0.30-0.80)

TTF2 Arm A: Cap+E 36 34 4.4 8.30.53

(0.33-0.87)

OS Arm A: Cap+E 36 34 6.7 10.40.62

(0.37-1.01)

In this subgroup analysis, only patients still on protocol after completion of 3 cycles (time of first tumour assessment) were included (i.e. patients who were defined as assessable for treatment efficacy)

Differences in outcome between HFS + and HFS – patients remained apparent