Trial Information

Phase II Study to Evaluatate the Efficacy of Gemcitabine Plus Erlotinib for RASH-positive Patients With Metastatic Pancreatic Cancer and Friendly Risk Circumstances

The study by Burris et al. 1997 revealed a superiority of gemcitabine vs. 5-FU in terms of
improvement of general condition, pain symptoms and overall survival in patients with
locally advanced or metastatic pancreatic cancer. Subsequently, gemcitabine was established
as a standard treatment for locally advanced and metastatic pancreatic cancer.

In a series of studies gemcitabine was combined with other chemotherapeutic agents or
targeted therapies. For the first time, the PA.03 study showed a significant improvement of
overall survival. Patients who were treated with gemcitabine plus erlotinib had a survival
of 6.24 months, compared with 5.91 months for those treated with gemcitabine plus placebo
(HR 0.82, 95% CI 0.69-0.99, p=0.038). The one-year-survival rate was 23% for gemcitabine
plus erlotinib vs. 17% for gemcitabine plus placebo.

In a subgroup analysis of the PA.03 study, patients developing a skin rash NCI CTC ≥ grade 2
had an advanced survival (one-year-survival rate 43%) vs. those with grade 1 or 0
(one-year-survival rate 16% and 9%, respectively). Later studies confirmed the correlation
between skin rash and survival.

While patients developing a skin rash of any grade seem to profit most from treatment with
erlotinib, the prognosis for those without rash is rather dismal. In this population,
survival varied between 3.3 and 4.8 months in clinical trials (Verslype et al. 2009, Boeck
et al. 2010, Manzano et al. 2010). In this patients, a modification of the treatment
strategy should be considered. Which kind of treatment might lead to optimal results in
these patients is not yet clear.

In patients with excellent general condition complying with further prerequisits (age <75
years, total serum bilirubin < 1,5xULN, no history of cardiovascular diseases) the French
Prodige study-group could show a statistical superiority for the gemcitabine-free
FOLFIRINOX-scheme in terms of overall survival, progression free survival and response rate
compared to gemcitabine alone. However, this superiority was gained at the expense of
treatment tolerability. During treatment with FOLFIRINOX a grade 3-4 neutropenia was
observed in 5.4% and a grade 3-4 diarrhea in 12.7% of patients (Conroy et al. 2011). For
patients who comply with the above-named criteria FOLFIRINOX is considered an established
standard of care.

If a comparable efficacy of gemcitabine plus erlotinib with the published FOLFIRINOX data
can be seen in the selected population, this would favour, due to the worse tolerability of
FOLFIRINOX, the use of gemcitabine plus erlotinib.

In summary, the following selections are conducted during the study:

1. Selection due to the inclusion criteria for treatment with FOLFIRINOX provided by
Conroy et al.

2. Selection due to the development of a skin rash within four weeks of treatment

3. No signs of clinical tumour progression within the run-in phase within the first four
weeks of treatment

Patients who do not develope a skin rash of any grade should be treated with FOLFIRINOX. The
efficacy of FOLFIRINOX in rash-negative patients has not yet been investigated.