Avastin & Tarceva Combination

[Deanne Jenkyns]

New Study Suggests Combining Breakthrough Therapies Tarceva® and Avastin® May Provide More Hope For Lung Cancer Patients


A new study1 suggests that treatment with the combination of the innovative cancer drugs Avastin (bevacizumab) and Tarceva (erlotinib) or Avastin with chemotherapy, improves progression-free survival in patients with recurrent or refractory non-small cell lung cancer (NSCLC), the most common form of lung cancer, when compared with standard chemotherapy alone. Progression-free survival is the time patients live without their cancer advancing. These data were presented today at the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO), Atlanta.

“These findings signal the potential for combining novel therapies that target different cancer growth pathways, to achieve better overall patient outcomes, with a low incidence of serious side effects,” said Willem Verhoofstad, Global Business Director for Roche Oncology. “We are continuing to invest and explore the safety and efficacy of the Avastin and Tarceva combination and are currently conducting Phase III trials with both products in first-line and relapsed NSCLC settings.”

The randomised, Phase II exploratory study evaluated three treatment regimens in patients with recurrent or refractory NSCLC:
• Avastin in addition to Tarceva
• Avastin in addition to chemotherapy (either pemetrexed or docetaxel)
• Chemotherapy alone (either pemetrexed or docetaxel) as control arm

The study suggests that Avastin in combination with Tarceva or chemotherapy improves progression-free survival, the primary study endpoint, compared to chemotherapy alone. Median progression-free survival in the Avastin plus chemotherapy arm was 4.8 months, and was 4.4 months in the Avastin plus Tarceva arm, compared to just 3.0 months in the chemotherapy alone arm. The study results also showed that the toxicity profile of the Avastin plus Tarceva combination was favourable, resulting in fewer serious adverse events, when compared to either chemotherapy-containing arm. Due to the exploratory nature of this randomised Phase II study, these data do not provide definitive conclusions with respect to differences between the three treatment arms.

About the Phase II Exploratory Study
120 patients with recurrent or refractory NSCLC, who had not received previous treatment with Avastin or Tarceva, were enrolled into this study. Patients in the study had histologically or cytologically confirmed non-squamous NSCLC and had experienced clinical or radiographic disease progression during or following one platinum-based chemotherapy regimen for advanced stage disease (IIIb or IV).

The key study results showed:

• Treatment with Avastin plus Tarceva reduced the risk of cancer progression or death by 28 percent compared to chemotherapy alone (based on a hazard ratio of 0.72).
• Treatment with Avastin plus chemotherapy reduced the risk of cancer progression or death by 34 percent compared to chemotherapy alone (based on a hazard ratio of 0.66),
• Treatment with Avastin plus Tarceva saw 78% of patients alive at six months (median progression-free survival 4.4 months)
• Treatment with Avastin plus chemotherapy saw 72% of patients alive at six months (median progression-free survival 4.8 months)
• Treatment with chemotherapy alone saw 62% of patients alive at six months (median progression-free survival 3.0 months)
• The toxicity profile of the Avastin plus Tarceva combination was favourable, resulting in fewer serious adverse events, when compared to either chemotherapy-containing arm
• Adverse events in the Avastin plus Tarceva arm were similar to those observed in previous clinical trials of Avastin in combination with Tarceva, and included diarrhoea and rash
• Adverse events in the Avastin plus chemotherapy arm were similar to those observed in previous clinical trials of Avastin in combination with chemotherapy, and included hypertension and bleeding

[gpawelski]

Targeted drugs (like Avastin and Tarceva) are based on a variety of biological mechanisms (pathways) that essentially stop cancer from spreading.

They interfere with specific molecules (receptors and enzymes inside and outside a cancer cell) involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth.

The most common targets on the outside of a cancer cell are receptors, which are proteins that help relay chemical messages. Many targets on the inside of a cell are enzymes, which are proteins that help speed up chemical reactions in the body.

By focusing on these molecular and cellular changes, targeted cancer drugs go after the "target" in these cells, rather than just all cells. In other words, they focus on molecular and cellular changes that are specific to cancer.

Tarceva is a small molecule (enzyme) inhibitor of tyrosine kinase. Enzymes make biologic processes happen faster and are often key junctions in the signaling pathways. It is a key intermediary in the EGF cascade pathway.

Avastin is a large molecule (monoclonal antibody) angiogenesis inhibitor. Angiogenesis is the formation of new blood vessels. Many tumors build new blood vessels to help them grow and spread. Angiogenesis inhibitors prevent new blood vessel formation.

Because many cancer cells use similar pathways, the same drug could be used to treat one person's breast cancer and another person's lung cancer, as long as each tumor contained similar targets. This is why many of these treatments are being used in a variety of cancer types.

Although targeted therapy is appealing, it is more complex than meets the eye. Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

In other words, cancer cells have "backup systems" that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to target multiple pathways in a cancer cell.

Multi-targeted drugs can be well-predicted by measuring the effect of the drugs on the "function" (is the cell being killed regardless of the mechansim) of live cells, as opposed to a "target" (does the cell express a particular target the the drug is supposed to be attacking).

While a "target" assay tells you whether or not to give "one" drug, a "functional" assay can find other compounds and combinations and can recommend them from the one assay.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007