Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or

without erlotinib : Final results of the international phase III LAP 07 study

Pascal Hammel*, Florence Huguet, Jean-Luc van Laethem, David Goldstein, Bengt Glimelius, Pascal Artru, Ivan Borbath, Olivier Bouché, Jenny Shannon, Thierry André, Laurent Mineur,

Benoist Chibaudel, Franck Bonnetain, and Christophe Louvet

*Hopital Beaujon (APHP), Clichy & Faculty Denis Diderot, Paris VII, France

France, Belgium, Australia, Sweden

Background

• Locally advanced pancreatic cancer (LAPC) is a non-metastatic, but non-resectable cancer due to involvement of a major arterial axis (superior mesenteric artery, celiac trunk)

• Overall median survival (9-12 months) higher than in metastatic form

• Treatment of LAPC is a matter of debate, particularly the role of chemoradiotherapy (CRT)

Chauffert B et al, Ann Oncol 2008

GemChemoRT

Frontline CRT versus chemotherapy in LAPC

Loehrer P et al, J Clin Oncol 2011

Krishnan S et al, Cancer 2007Huguet F et al, J Clin Oncol 2007

CRT after 2.5-3 months of chemotherapy

Induction chemotherapy : promising option

Induction CT followed by CRT in LAPC

Objectives of the study

• Primary objective: to assess whether administering CRT increases overall survival in patients whose tumor is controlled after 4 months induction chemotherapy

• Secondary objectives: - Role of erlotinib - Impact of radiation therapy quality assessment (RTQA) - Tolerance - Predictive molecular markers, CTC (1)

(1) Clément-Bidard F et al, Ann Oncol 2013

Design of LAP07 study

RT

CapeEV

ALU

ATIO

N :

non

prog

ress

ive

1 month = Gemcitabine 1000 mg/m2/wk x 3

UntilProgression

Erlotinib with gem : 100 mg/d

150 mg/d as single agent (maintenance)

Cape RT

EVAL

UA

TIO

N

EVAL

UA

TIO

N

EVAL

UA

TIO

N

Secondary surgery allowed at any time

Random

1EV

ALU

ATIO

N :

non

prog

ress

ive

RT

Cape

Capecitabine 1600 mg/m2/d plus radiation therapy 54 Gy (5 x 1.8 Gy/d)

Random

2

StatisticsPrimary objective :

• 722 patients (392 events, deaths) required to demonstrate a median OS increase from 9 to 12 months in the CRT arm (HR 0.75, 2-sides = 5%, = 20%, taking into account 30% of progression before Random 2 and 5% of patients lost to follow-up)

• Intermediate analysis planned 21 months after the first patient randomized (projected accrual 420 patients and/or 196 events) using spending function and O’Brien Flemming boundaries (to reject H0 or H1)

• Kaplan-Meier, log rank and univariate Cox tests used

Main eligibility criteria

. Histologically proven adenocarcinoma

. De novo LAPC (stage III, according to UICC 2002)

. Measurable or evaluable disease

. No prior abdominal radiotherapy or chemotherapy

. Performance status WHO 0-2

. Adequate biological tests (blood, liver and renal)

Interim analyses - IDMC 1st advice

January 2012: 1st planned interim analysis (22 months, 442 patients included, 125 events)

Number of included patients could be sufficient to conclude (superiority or futility), but data not mature enough Inclusion of additional patients will not be informative for the study and would increase the time of enrollment and delay the final results

Need to continue to perform Random 2 for the included patients

March 2013:

- 269 patients reached Random 2

- 221 deaths, median follow-up 36 months

This second analysis showed that it could be the final one for the primary objective of the study

IDMC - 2nd advice

Flow Chart

Assessed for eligibility(n= 449)

1st Randomization

Intent-to-treat principle(n= 442)

Gemcitabine(n= 223)

Gemcitabine + erlotinib(n= 219)

Excluded

(n= 7)

Excluded(n= 173, 39%)

Progressive disease 114 Toxicity 16Delay 14

Patients' decision 11Investigators’ decision 11

Intercurrent disease 4Surgery 3

2nd RandomizationIntent-to-treat principle

(n= 269, 61%)

Chemotherapy(n= 136)

Chemoradiotherapy(n= 133)

Patients characteristics, Random 1Gemcitabine(n= 223)

Gemcitabine + erlotinib(n= 219)

Age - years (SD) 63.4 (9.6) 63.6 (9.7) ns

Gender - n (%) Male Female

117 (52.5)106 (47.5)

111 (50.7) ns108 (49.3)

WHO PS - n (%) 0 1 2 unknown

109 (50.7)91 (42.3)15 (7)8

88 (40.7) 112 (51.9) ns16 (7.4)3

Tumor location - n (%) Head Body + tail unknown

146 (65.5)76 (34)1 (0.5)

156 (71.2)62 (28.3) ns 1 (0.5)

Grade - n (%) Well differentiated Moderately differentiated Poorly differentiated Not assessable unknown

56 (37.1)37 (24.5)18 (11.9)40 (26.5)72

51 (32.9)38 (24.5)23 (14.8) ns43 (27.8)64

Nodal status - n (%) N0 N1 unknown

134 (61.2)85 (38.8)4

124 (56.9)94 (43.1) ns1

Overall survival by Random 2 status

Random 2, interim analyses

Futility (no chance to demonstrate a significant difference between the two arms)

PFS by Random 2 status

Toxic death 0 1 (not related to RT)

Tolerance, Random 2

Chemotherapy(n= 136)

Chemoradiotherapy(n= 133)

Adverse Events - n (%) Grade 3/4n (%)

Grade 3/4n (%)

P

Hematologic Neutrophils Platelets Hemoglobin Febrile neutropenia

8 (7)3 (2.6)1 (0.9)0 (0)

3 (3.1)0 (0)1 (1)0 (0)

0.20.21

Gastrointestinal Nausea Vomiting Diarrhea Mucositis

0 (0)0 (0)

1 (0.9)0 (0)

6 (5.9)3 (2.9)5 (4.9)0 (0)

0.0090.10.1

Pulmonary Coughing Dyspnea

3 (2.6)3 (2.6)

0 (0)0 (0)

0.60.6

Radiation Therapy Quality Assessment

• RT guidelines defined from international consensus1

1 Huguet F et al. Int J Radiat Oncol Biol Phys 2012

• Before including, each participating centre had to validate a Dummy Run to ensure that the guidelines have been understood and accepted

• Using the prospectively defined guidelines, each patient treatment graded as per protocol (PP), minor deviation (MID), or major deviation (MAD)

Among the 133 patients treated in the CRT arm :

- PP = 37 (31.6%)

- MID = 59 (50.4%)

- MAD = 21 (18%)

- non evaluable / non treated= 4/12

• Deviations of planned schedule: did not have significantly influenced unfavorably the outcome of patients

• Data of Quality Control and radiation therapy will be presented at the ASTRO meeting 2013

Radiation Therapy Quality Assessment

Overall Survival by Random 1 status

PFS by Random 1 status

Tolerance (Random 1)

Gemcitabine(n= 223)

Gem + erlotinib

(n= 219)Adverse Events - n (%) Grade 3/4 Grade 3/4 pHematologic Neutrophils Platelets Hemoglobin Febrile neutropenia

70 (32.4)3 (1.4)5 (2.3)0 (0)

78 (37.3)7 (3.3)

13 (6.2)5 (2.4)

0.30.2

0.040.03

Gastrointestinal Nausea Vomiting Diarrhea Mucositis

6 (2.8)3 (1.4)3 (1.4)0 (0)

7 (3.3)6 (2.8)

14 (6.6)2 (0.9)

0.70.3

0.0050.1

Cutaneaous Acneiform rash Photosensitivity Xerodermia

1 (0.5)0 (0)0 (0)

12 (5.7)0 (0)

1 (0.5)

0.007

0.3Pulmonary Coughing Dyspnea

0 (0)3 (1.4)

51 (32.9)38 (24.5) 1

Allergy 1 (0.5) 0 (0) 1

Overall survival combining Random 1 & Random 2 status

Interaction testP = 0.871, ns

Conclusions (1)

• Lack of superiority of CRT vs continuing chemotherapy in LAPC patients with tumor controlled after 4 months of chemotherapy

• Good tolerance in the CRT arm with this schema

• Erlotinib: not beneficial in LAPC, increased the toxicity

• Encouraging OS: 15.2 to 16.4 months in patients achieving Random 2

Conclusions (2)

• In LAPC, standard of care should remain chemotherapy, CRT being an option after tumor control by chemotherapy

• Further analyses of LAP 07 results are ongoing, with the aim to identify a subgroup of patients who could benefit from CRT

• Other schemas of radiotherapy and/or chemotherapy (i.e., FOLFIRINOX, nab-paclitaxel) should be tested in LAPC

Acknowledgements

. Patients and their families

. All professionals of medical teams

. All data managers and CRAs

. GERCOR staff : D. Notelet, A. Hadengue, N. Le Scodan and R. Moukoko

. Roche

Thanks to all investigators

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