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A new chapter in treating lung cancer

Patients with non-small-cell lung cancer who initially respond to front-line designer therapies but later relapse may soon have another option — a gene-based drug called HKI-272.  At 14 centers worldwide, a phase 2 trial led by DF/HCC has been launched to study the impact of this second-line drug.

The phase 2 trial comes on the heels of a phase 1 study led by Kwok Kin Wong, MD, PhD (DFCI), of the Lung Cancer Program, who will report his team’s findings in June at the annual meeting of the American Society of Clinical Oncology. This trial was, in part, motivated by work done in the laboratory of Daniel Haber, MD, MS, PhD, leader of the Cancer Genetics Program and director of the MGH Cancer Center.

“At this stage, the second-line approach of using HKI-272 is showing a lot of promise,” says Wong, whose study focused on 70 patients. The international phase 2 study is now accruing 144 patients, with Thomas Lynch, MD (MGH), of the Lung Cancer Program and Translational Pharmacology and Early Therapeutics Program, serving as overall principal investigator for the MGH/DFCI/BWH/BIDMC clinical investigation sites being used in the HKI-272 trial.

It’s all part of an exciting research drama that continues to unfold at DF/HCC. The plot centers on genes that govern epidermal growth factor receptor (EGFR).

“EGFR research has gone through an elegant “bedside-to-bench” cycle several times across DF/HCC member institutions — beginning with clinical observations supported by laboratory discoveries, which led to further clinical and laboratory findings,” says Haber.

The need for novel treatments is urgent. Each year, 170,000 people are diagnosed with non-small-cell lung cancer (NSCLC). Treatments involving chemotherapeutic agents are relatively ineffective, and most die within 1 year. In fact, NSCLC is the leading cause of cancer deaths in the U.S. for both men and women. To achieve a meaningful impact, scientists are turning to molecular biology. Among the key questions: What genes are involved, and how can their activity be controlled?

Insights began to emerge in 2002 with clinical observations. “We knew drugs like Iressa (gefitinib) and Tarceva (erlotinib) worked dramatically in 10-15 percent of patients, but didn’t know why,” says Bruce Johnson, MD (DFCI/BWH), leader of the Lung Cancer Program. Such results prompted two DF/HCC groups to search for the answer in lung cancer cell lines and in patient lung cancer DNA samples. One team, at DFCI, was led by Johnson, Matthew Meyerson, MD, PhD, of the Lung Cancer and Cancer Genetics programs, and Williams Sellers, MD, of the Cancer Genetics and Prostate Cancer programs. The other team, at MGH, was led by Lynch and Haber.

Independently and simultaneously, the two teams identified a gene mutation in EGFR associated with kinase overproduction — a signal for cancer cells to thrive. “It started to come together. We went back to the tumor samples of our NSCLC patients,” says Pasi Janne, MD (DFCI) of the Lung Cancer program. “Every patient who had responded to Iressa had the EGFR mutation. It was a ‘Eureka’ moment. For the first time in treating lung cancer, we could link a genetic event to the effectiveness of a drug.”

The research went back to the clinic. Within four months, a clinical test was developed by the Laboratory for Molecular Medicine within the Harvard Partners Center for Genetics and Genomics, which has supported clinical trials at all DF/HCC institutions. Because investigators had already observed that Iressa and Tarceva were more effective in certain population subsets — people who had never smoked, women, of Asian ethnicity, or history of adenocarcinoma — the DFCI and MGH groups sequenced these patients’ tumors for the EGFR mutation.

They found that tumors with the EGFR mutation responded much better to Iressa and Tarceva, taken orally, than to traditional chemotherapy. But although the response was often dramatic, most relapsed within 6 months to 3 years.

Then back to the laboratory. Studying the tumors of patients who relapsed from Iressa treatment, a team led by Daniel Tenen, MD (BIDMC and a member of the DFHCC Leukemia program), identified a secondary EGFR mutation present only in the relapsed tumor. This mutation rendered Iressa ineffective against the EGFR. Further laboratory studies demonstrated that newer EGFR inhibitors could still be effective against tumors with this secondary mutation. Haber’s team proved the drug, HKI-272, acts on this second mutation by irreversibly binding with the receptor, putting it permanently out of commission.

Scientists now had a promising second-line drug to try in patients whose tumors developed resistance to front-line therapies. That’s where DF/HCC investigators stand today, with phase 1 findings nearly ready to report and phase 2 just underway. There are three groups of patients enrolled in the new study: patients who relapsed after receiving either Iressa or Tarceva, and patients who relapsed after receiving just chemotherapy. All are receiving HKI-272.

“We hope this promising new therapy will provide key answers,” says DF/HCC’s principal investigator Lynch. “Cancer treatments that target specific cell activity are the wave of the future.”

Image: The laboratory of Michael Eck, MD, PhD (DFCI), is studying the three-dimensional structure of the lung cancer-derived mutants of the EGFR kinase. Shown here is the structure of L858R, the most common mutation, in complex with the drug Iressa.