By Elizabeth Whittington

The announcement by Peter Jennings that he has lung cancer brought one of the most common of cancers to the living rooms of millions of Americans. In an e-mail informing co-workers and staff at ABC News, Jennings wrote that his diagnosis was a surprise, as it is for many lung cancer patients. This country’s long history of smoking has resulted in an epidemic of lung cancer—the leading cause of cancer deaths in the United States. What’s more disconcerting is that half of all lung cancer patients are not current smokers, and about 15 percent have never smoked at all.

Advanced lung cancer may be next on the list for Avastin following positive results reported at the 2005 meeting of the American Society of Clinical Oncology.

While the five-year survival rate for lung cancer patients is only 15 percent, if caught early and before the cancer spreads from the lungs, it jumps to nearly 50 percent. Although a majority of patients diagnosed at the earliest stages of the disease can be cured with surgery followed by chemotherapy, the outlook remains unsatisfactory. Recent results have provided new hope to patients, with advances being made both in patients with early-stage disease as well as those with more advanced disease.

Catching It Early

In early-stage non—small-cell lung cancer (NSCLC), surgery offers the best chance for a cure. However, 30 to 40 percent of patients who appear to have complete tumor removal by surgery will have their cancer recur within five years. Chemotherapy given after surgery (called adjuvant chemotherapy) might eliminate the minute, undetectable metastases that are likely to remain following surgery before they have a chance to grow into tumors.

Two phase III clinical trials investigating this issue were reported in 2004 and showed that chemotherapy administered immediately after surgery increased patient survival. In a Canadian trial, one group of patients with early-stage NSCLC was treated with a chemotherapy regimen after surgery, while a second group received no treatment following surgical removal of their tumor. A comparison of the two groups showed that the patients receiving chemotherapy had a median survival time of 7.8 years, 21 months longer than the group without chemotherapy. The second trial also showed improved survival with 11 percent fewer deaths and relapses among patients receiving chemotherapy compared with the group without chemotherapy.

At the 2005 meeting of the American Society of Clinical Oncology another trial (ANITA) confirmed the benefit of chemotherapy after surgery in lung cancer.
Taken together, these trials suggest chemotherapy following surgery can prolong survival in early-stage lung cancer patients.

The Avastin Advantage

When Connie DeWitt, a 56-year-old from Laverne, Tennessee, was diagnosed with lung cancer in 2002, it caught her by surprise because she had never been a smoker. Luckily, it was caught early enough to treat with surgery, but three years later, the cancer returned.

“At first, when they told me the cancer had come back, I looked at it as a death sentence,” DeWitt says, especially after losing her mother to the disease in 1996, only six months after her mother was diagnosed.

Her doctors told her that since her mother’s death, advances in lung cancer have come a long way, including research into Avastin™ (bevacizumab). When DeWitt was offered the opportunity to enroll in a clinical trial involving Avastin in March 2004, she didn’t hesitate.

In cancer, tumors send out signals stimulating new blood vessel growth, supplying the tumor with blood and oxygen to help it grow—a process known as angiogenesis. As an antiangiogenic therapy, Avastin works to suppress this signal by binding and inhibiting the vascular endothelial growth factor (VEGF), a protein that helps stimulate the growth of blood vessels. This essentially starves the tumor and helps prevent the cancer from spreading. When Avastin is combined with conventional chemotherapy, it impedes tumor growth sufficiently to provide the chemotherapy with an improved chance to destroy the cancer cells.

Avastin was originally approved for use in combination with chemotherapy for advanced colon cancer (see CURE, Spring 2004). Now, advanced lung cancer may be next on the list for Avastin following positive results reported at the 2005 ASCO meeting.

Adding Avastin to the standard chemotherapy combination of Taxol® (paclitaxel) and Paraplatin® (carboplatin) prolonged survival in patients with advanced lung cancer by more than two months compared with those taking conventional chemotherapy alone.

Corey Langer, MD, medical director of thoracic oncology at Fox Chase Cancer Center in Philadelphia, says it’s a landmark trial in lung cancer.

“It was an important study in that it’s the first targeted therapy to show a survival benefit in combination with chemotherapy compared to chemotherapy alone in otherwise treatment-naïve advanced lung cancer patients,” Dr. Langer says. “That’s unprecedented; it represents a vindication of targeted therapy, particularly angiogenesis inhibitors. ”

Genentech, the maker of Avastin, is soon expected to file for approval as part of first-line therapy for advanced lung cancer.

Although the preliminary results are positive, the trial did not include patients with squamous cell carcinoma, patients with brain metastases or those on blood thinners such as Coumadin® (warfarin) for anticoagulation. Even though Dr. Langer says several of his patients have inquired about Avastin, he is hesitant to prescribe the drug until it’s approved. One of his concerns is the risk of lung hemorrhage, especially in patients with squamous cell carcinoma in locations near the major airways.

This group of patients who were excluded from the trial may ultimately derive benefit from Avastin, but they will not yet be candidates for its use since little is known about side effects in this population, says Dr. Langer. “We looked at the percentage of patients in our practice that would not have been eligible to even be on the trial and it was a sizable proportion, about 40 percent,” says Dr. Langer, who speculates that eventually these patient populations will have to be included in future trials.

In a small number of patients in a previous phase II trial, Avastin increased the risk of life-threatening bleeding in the lungs. Other than pulmonary hemorrhage, Avastin has few major side effects.

For one year, DeWitt saw Avastin help shrink the tumor and was even in remission for a while. She was able to work through treatment, although she admitted she did have to give up her second full-time job. “I feel just as normal as everybody; sometimes I have to remind myself that I do have this disease,” DeWitt says. “What slows me down now is a lot of physical exertion, like running or swimming or dancing. I can tell sometimes, but to see me, you wouldn’t know that I have lung cancer.”

FDA Limits Iressa Use

As of June 17, the Food and Drug Administration limited use of Iressa® (gefitinib), an epidermal growth factor receptor (EGFR) inhibitor, to patients who have shown improvement on the drug. Newly diagnosed patients should not be given Iressa, according to the FDA’s new drug indication.

This action by the FDA was based on recent phase III trial results. Although Iressa causes tumor shrinkage in about 10 percent of patients, results of a large study announced in December 2004 failed to show survival improvement in lung cancer patients.

Patients who are either currently receiving and benefiting from Iressa, those who have shown previous benefit from Iressa, or those enrolled in a clinical trial that was approved before June 17 still may have access to the drug, provided their doctor believes it is beneficial.

Tarceva® (erlotinib), another EGFR inhibitor that works best in a small percentage of lung cancer patients with a specific mutation of the EGFR (see sidebar), is now the sole targeted agent approved for lung cancer.

In 2004, AstraZeneca quickly disclosed the trial results to the FDA and released a prompt update stating that individual patients doing well on Iressa may be part of the patient population that derives benefit from the drug. However, the company urged most patients to consider other agents, including Tarceva.

Roman Perez-Soler, MD, chief of clinical oncology at Montefiore Medical Center and professor of medicine and pharmacology at Albert Einstein College of Medicine, says the Iressa findings were unexpected. But he says patients should understand that, although the results were not statistically significant, they did show a slight survival advantage.

Cindy Bass knows she is lucky to be in the 10 percent of lung cancer patients who have had a response with Iressa.

“I’m very fortunate,” says Bass, a 67-year-old New Yorker who has been surviving with lung cancer for the past seven years by using a combination of radiation, chemotherapy, surgery and targeted therapies to control her adenocarcinoma. She responded well to Iressa for two years, but switched to Tarceva in January after the Iressa trail results were announced.

“Iressa was really working for me,” Bass says, but she followed her doctor’s advice when he when he suggested switching to Tarceva. After success on Iressa, Bass hopes Tarceva will work for her as well.

Approved in November 2004 for NSCLC, Tarceva is the first EGFR inhibitor to show a survival advantage in patients with this disease. In a phase III study, patients taking Tarceva had a significant improvement in survival over patients not taking Tarceva (6.7 months versus 4.7 months).

Looking Toward the Future

Scientists are investigating other EGFR inhibitors to see if these new drugs are superior to Tarceva and Iressa. One such drug is panitumumab (ABX-EGF), a monoclonal antibody against EGFR that is being tested in colon cancer. In preclinical models for lung cancer, panitumumab showed antitumor activity by inhibiting EGFR and another growth factor. Mild side effects, including rash and diarrhea, were reported in phase I trials. It is now being tested in phase II trials in combination with standard chemotherapy. In addition, a dual inhibitor called ZD6474 is being tested in both NSCLC and small-cell lung cancer and has shown benefit in a recent phase II trial by inhibiting angiogenesis and overexpression of EGFR.

“I’ll be more excited about new drugs that seem to be affecting new targets,” Dr. Perez-Soler says, specifically noting Velcade® (bortezomib), a proteasome inhibitor that has shown preliminary activity in lung cancer. Velcade is approved for patients with multiple myeloma but has shown activity in some patients with a type of lung cancer called bronchoalveolar carcinoma. It also has shown activity in patients whose lung cancer has progressed despite prior chemotherapy.

Other drugs in development include a new formulation of Taxol called Xyotax™ (paclitaxel poliglumex). Recent phase III studies showed Xyotax can produce survival similar to conventional chemotherapy drugs like Taxol/carboplatin and Taxotere® (docetaxel), while resulting in fewer serious side effects. Telcyta® (TLK286) also showed antitumor activity in a recent phase II trial that paired the drug with cisplatin in untreated NSCLC patients.

Dr. Langer speculates future trials will combine Avastin with other targeted agents. In a recent phase I/II trial, Avastin was paired with Tarceva in solid tumors with 20 percent of patients responding and a median survival time of 12.6 months. Since the two drugs attack different mechanisms, the combination may be more effective than either therapy by itself.

“Chemotherapy is not going to go away; it remains our platform for treatment,” Dr. Langer says. “I think you’ll see a continued integration of chemotherapy with targeted therapies. We just have to get smarter on how to do it. ”

Living with Lung Cancer

“Most patients on these drugs respond and are stable for a while. They seem to benefit from these drugs but eventually progress,” says Dr. Perez-Soler, who has seen patients live for several years while on Tarceva and Iressa. “I don’t think these treatments are curative, but in some patients, the results are quite spectacular. ”

Although Bass hasn’t beaten her cancer, she’s happy with keeping the cancer stable for now.

“At this stage, it’s livable,” Bass says. “I live a very normal, healthy life except for the fact that I have lung cancer.” And she hasn’t let lung cancer interfere with the things she loves to do, including traveling. This year she’s planning a river cruise in Europe.

“That’s really something to look forward to.”