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FDA Advisory Panel recommends Tarceva approval for pancreatic cancer

The FDA’s Oncologic Drug Advisory Committee ( ODAC ) voted 10 to 3 in favor of recommending approval of Tarceva ( Erlotinib ) in combination with Gemcitabine for the treatment of advanced pancreatic cancer in patients who have not received previous chemotherapy.

Pancreatic cancer has the highest one-year mortality rate of any cancer.
The average life expectancy for a patient diagnosed with metastatic pancreatic cancer is three to six months, according to The Pancreatic Cancer Action Network ( PanCAN ).

A multi-center, double-blind, placebo-controlled Phase III trial evaluating Tarceva in patients with unresectable locally advanced or metastatic pancreatic cancer.
The study randomized 569 patients to receive Gemcitabine plus concurrent Tarceva or Gemcitabine plus placebo; 521 patients were randomized to receive 100 mg/day of Tarceva or placebo, and 48 patients were randomized to receive 150 mg/day of Tarceva or placebo.

The ODAC review focused on the 100 mg/day cohort.

Compared to Gemcitabine plus placebo, those patients receiving Gemcitabine plus Tarceva 100 mg/day demonstrated a statistically significant ( 23 percent ) improvement in overall survival ( hazard ratio = 0.81, p = 0.028 ), which can also be referred to as a 19 percent reduction in the risk of death.
After one year, 23 percent of patients receiving Tarceva plus Gemcitabine were alive compared to 17 percent of patients receiving Gemcitabine plus placebo.
A statistically significant improvement in progression-free survival ( hazard ratio = 0.77; p = 0.006 ) was also demonstrated.
Although no difference in tumor response was observed ( 8.6 percent in patients receiving Tarceva plus Gemcitabine versus 7.9 percent in the Gemcitabine plus placebo arm ), the disease control rate ( complete response + partial response + stable disease ) was significantly improved ( 59 percent in patients receiving Tarceva plus Gemcitabine versus 49 percent in the Gemcitabine plus placebo arm, p = 0.036 ).
Rash and diarrhea were the principal Tarceva-related side effects seen in the study and were generally characterized as mild-to-moderate.

Safety findings were generally consistent with previous studies of Tarceva in both monotherapy and combination settings.
Rash was reported in 69 percent of patients who received Tarceva plus Gemcitabine and in 30 percent of patients who received Gemcitabine plus placebo.
Diarrhea was reported in 48 percent of patients who received Tarceva plus Gemcitabine and in 36 percent of patients who received Gemcitabine plus placebo.
Two percent of the patients discontinued Tarceva because of rash and two percent because of diarrhea.
Possible interstitial lung disease ( ILD ) was experienced in 2.3 percent of patients in the Tarceva plus Gemcitabine arm compared with 0.4 percent in the Gemcitabine plus placebo arm.
The incidence of serious ILD-like events in the Tarceva and Gemcitabine arm was higher than the 0.8 percent incidence reported for both the Tarceva monotherapy and placebo arms in the Tarceva pivotal study in advanced NSCLC.
The incidence of possible ILD from all clinical studies with Tarceva is 0.7 percent.

Tarceva target the human epidermal growth factor receptor 1 ( HER1 ) pathway, which is one of the factors critical to cell growth in a number of different cancer types.
HER1, also known as EGFR, is a component of the HER signaling pathway, which plays a role in the formation and growth of numerous cancers.
Tarceva is designed to inhibit the tyrosine kinase activity of the HER1 signaling pathway inside the cell, which may block tumor cell growth.

FDA's chief investigator, Adrian Senderowicz, said:

“… the very small increase in median overall survival ( 12.8 days ) and median PFS ( 11 days ) raises the question whether the difference is clinically important. In addition, there is lack of differential response rate , along with a significant increase in toxicity associated with toxic death and SAEs (e.g. > 6 fold increase in strokes) leading to drug discontinuation and worse quality of life, suggesting that the benefit with Erlotinib/Gemcitabine ( EG ) combination in the treatment of advanced or metastatic pancreatic carcinoma may not outweigh the risks associated with this therapy. Although diarrhea and skin rash are the most frequent EG toxicities in relation to placebo/Gemcitabine, there are several serious toxicities that, while low in frequency, are more frequent in the EG arm. These include stroke, cardiac ischemia/infarction, stent occlusion, infections, ILD-like events and GI bleeding. A confirmatory second well-controlled and well-conducted trial may help to discern whether Erlotinib adds a clinically significant improvement to Gemcitabine with an acceptable toxicity profile in the therapy of locally advanced or metastatic pancreatic adenocarcinoma.”


1) Osi Pharmaceuticals, 2005

2) FDA, 2005