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Molecular Discoveries Pave Way for Rapid Advances in Lung Cancer

Published Online: Friday, October 5, 2012
Dr. Giorgio V. Scagliotti

Giorgio V. Scagliotti, MD

In less than a decade, lung cancer has evolved from a disease state with relatively few treatment options to tumor types whose molecular characteristics have become increasingly well defined.

Giorgio V. Scagliotti, MD, has played a prominent role in researching and developing therapies to attack molecular targets. He is a professor and chair of Medical Oncology at the University of Torino in Italy, and director of the Thoracic Oncology Division at the San Luigi Gonzaga University Hospital in Turin.

At the 13th International Lung Cancer Congress, Scagliotti discussed progress in identifying the driver mutations in lung cancer, noting that researchers have been able to characterize those mutations for approximately 50% of lung tumor types. In NSCLC, there are two FDA-approved therapies with definitive targets: erlotinib (Tarceva) for tumors that harbor EGFR mutations and crizotinib (Xalkori) for ALK-translocated tumors.

“We have made much more progress over the last 10 years than during the previous 20 years in the systemic treatment of non–small cell lung cancer,” Scagliotti said in an interview with Oncology & Biotech News. “I’ll give you a very straightforward example. Tell me if, 10 years ago, just in 2002, it was possible to imagine a patient wit h stage IV non–small cell lung cancer surviving more t han 2 years. And now that is the case for the vast majority of our patients having a tumor harboring EGFR-sensitizing mutations.”

Scagliotti noted that it has been only 4 years since the first lung cancer genome was “fully codified, fully explored, and fully analyzed,” and that the impact of genetic mutations will come more sharply into focus as the tumors of more patients are sequenced.

The key to making substantial gains in life expectancy for patients with lung cancer is defining “homogenous genetic subgroups of tumors” and developing individualized strategies, Scagliotti indicated in his presentation. The onset of resistance to targeted therapies in patients with an “oncogene addiction” is inevitable, Scagliotti said, and research to overcome mechanisms of resistance is ongoing.

Scagliotti elaborated upon emerging research and treatment strategies in this interview.

OBTN: Please describe the current landscape for targeted therapies in patients with lung cancer?

Dr Scagliotti: Cancer research is getting close to a big roundabout, because we have clear evidence that cancer is a genetic somatic disease in the vast majority of cases and that it is quite likely that it originates in cancer stem cells. For any tumor type, there are genes that are really important in cancer cell initiation and progression. For some of the genes, we are already able to do a molecular diagnosis.

Only when you are able to make a molecular diagnosis and you have an effective targeted therapy for that specific abnormality, are you able to make a difference in the natural history of the disease. In lung cancer, the overall landscape is still incomplete because we have much more information in adenocarcinoma and much less information in squamous cell carcinoma.

In adenocarcinoma, we have at least three or four druggable targets. One, starting in 2004, is the story of the EGFR mutation, with gefitinib in Europe and in Japan, and more recently erlotinib, that are effective agents when you detect the EGFR mutation in the tumor.

Secondly is the ALK translocation story that is quantitatively less relevant than the EGFR mutation, but it is equally important. Crizotinib, the first-in-class agent to hit that molecular diagnosis, is able to extend, significantly, the time to progressive disease. You can improve the symptoms related to the neoplastic disease and you can get, in the vast majority of the cases, a tumor shrinkage.

Now, another piece of information has been added recently, the ROS1 translocation. Those patients with ROS1 translocation are also sensitive to crizotinib. So you have another piece of the story that is consistent with the other two.

But it is an incomplete story because we still don’t know if there is additional room in these oncogene-addicted tumors for the combination of targeted therapies. And that is exactly what we are currently exploring.

What has been the experience in combining a targeted therapy with chemotherapy?

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