What’s Next in Lung Cancer Treatment

Lung cancer treatment continues to make strides.

Experts predict crizotinib, a new type of targeted therapy, will be approved by year’s end for treating an infrequent subtype of non-small cell lung cancer (NSCLC). The drug’s maker submitted crizotinib for approval with the Food and Drug Administration in mid-May, and was granted fast-track status and priority review by the agency.

Crizotinib inhibits a gene mutation called ALK, which drives about 4 percent of all lung tumors’ growth. Considering that about 85 percent of the 222,000 people diagnosed with lung cancer in 2010 belong to the subcategory of NSCLC, about 5,000 to 10,000 patients stand to benefit from the drug in the U.S. alone, and it would be the first drug of its kind to get the green light from the FDA.

The drug works by turning off the cancer-causing ALK gene—and with “extraordinary” results, says Thomas Lynch, Jr., MD, one of the drug’s investigators and director of Yale Cancer Center.

The drug made an impressive debut at the annual meeting of the American Society of Clinical Oncology (ASCO) last June. Updated results reported at this year’s meeting showed that among 82 patients with ALK-positive NSCLC, 74 percent were still alive after one year and 54 percent after two years. Although the study wasn’t randomized, researchers said survival for a similar group of patients not treated with crizotinib was 44 percent after a year and 12 percent after two years.

Most patients in the crizotinib study had already received several prior therapies, as many as seven for some patients. Side effects of the drug were mild and included nausea and diarrhea.

Lynch is one of the many who expects the FDA to approve crizotinib this year. “If they don’t, it’s a crime,” he says.

It’s about finding what gene or genes are driving the cancer and then inhibiting those specific genes. That's the key.

Chemotherapy drugs used to treat lung cancer have short-term benefits and numerous side effects, Lynch says, making crizotinib “a real advance for this patient population.”

“Like [the drugs that target] EGFR mutations, this is yet another group of lung cancer patients where we have a drug that works,” he adds.

Japanese researchers discovered the errant ALK gene in lung cancer in 2007, and it appears to be more common among younger nonsmokers.

Researchers are now comparing crizotinib to standard chemotherapy in two large studies, one in untreated patients and another in patients whose tumors progressed on chemotherapy.

Lynch, who is involved in the front-line study with newly diagnosed patients, expects initial results in 2013. The second-line study should deliver results next year in 2012, he says.

As lung cancer patients and doctors await the FDA’s decision, other promising agents are making their way through the research pipeline. Topping Lynch’s list of new agents to watch: an anti-programmed death-1 antibody called MDX-1106 and Yervoy (ipilimumab). Both drugs use the body’s own immune system to fight cancer. The FDA recently approved Yervoy as a treatment for metastatic melanoma.

Although still in the early stage of testing, the immune-targeting agents “look very exciting,” Lynch says.

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In Portland, Alan Sandler, MD, is keeping an eye on two experimental agents that target the MET pathway, a master switch that turns on cancer growth. MetMAb and tivantinibARQ 197) block signals from MET, which is to blame for one out of five NSCLCs developing a resistance to drugs that inhibit the epidermal growth factor receptor (EGFR)—a gene sometimes mutated in lung cancer cells. Dual inhibition of MET and EGFR could offer a one-two punch to shut down both pathways.

Adding MetMAb to the EGFR inhibitor Tarceva (erlotinib) resulted in patients with high MET expression living nearly twice as long without their advanced disease getting worse compared with those receiving Tarceva alone: 2.9 months versus 1.5 months. Plus, the combination tripled overall survival, reaching 12.6 months compared with 3.8 months for Tarceva alone. A phase 3 study is scheduled to start later this year.

In a study testing Tarceva with or without tivantinib, patients with advanced nonsquamous cell lung cancer lived about 14 weeks longer if they received the combination—43.1 weeks versus 29.4 weeks for Tarceva alone. Combining the drugs also delayed disease progression: 18.9 weeks versus 9.7 weeks.

In both studies, the side effects were similar between the two arms and included rash, diarrhea and fatigue.

Tivantinib is now in the final stage of testing in combination with Tarceva. “Hopefully [MET] will be the next pathway that leads to drug approval in non-small cell lung cancer,” says Sandler, chief of the hematology and medical oncology division at Oregon Health & Science University and one of the study’s researchers.

As cancer researchers better understand what makes a tumor tick, better drugs can be designed to outsmart the cancer. “It’s about finding what gene or genes are driving the cancer and then inhibiting those specific genes,” Lynch says. “That’s the key.”

For more on lung cancer advances, read “Lung Overdue” from the Spring 2010 issue. You can also read more news, articles and patient stories at curetoday.com/lungcancer.