Young Lung Cancer Patients: Prime for Targeted Therapies

Roxanne Nelson

September 09, 2015

DENVER ― Young patients with lung cancer may be prime candidates for "personalized medicine," because they tend to have more mutations that can be treated with existing targeted therapies, according to preliminary results of the Genomics of Young Lung Cancer Study.

Not only is this the first study to prospectively characterize the clinical characteristics and genomic alterations in young lung cancer patients, but the researchers also went "out of the box" in terms of patient recruitment methods.

Many participants were recruited from the Internet. All had developed lung cancer before age 40 years.

"People could enter through a site that had IRB [institutional review board] approval, but we had a website where people could remotely consent from anywhere in the world and participate in our clinical trial," said lead author Barbara J. Gitlitz, MD, associate professor of clinical medicine, Keck School of Medicine, University of Southern California, Los Angeles.

She presented the findings here at the 16th World Conference on Lung Cancer (WCLC).

During the past year, this has proven to be a very successful model, with people signing up from Australia, Turkey, Norway, and all over the United States. Nearly half (44%) signed up via the Web.

Dr Gitlitz and her colleagues hypothesized that a diagnosis of lung cancer in patients younger than 40 years is associated with an increased chance of a genomic alteration. Thus, the goals of this study were to identify a "genomically enriched subtype" of lung cancer, to facilitate the delivery of targeted therapy, and to lay the groundwork for further studies.

The data presented were for the 68 patients enrolled to date.

The median age of the patients at the time they were diagnosed with lung cancer was 35 years (range, 16-39 years; 33 men, 35 women). The majority had adenocarcimona ( n = 68); 10% (n = 7) had squamous cell tumors; and one patient had small cell lung cancer.

Most patients also had stage IV adenocarcinoma (n = 54) ), and genomically, "there was a huge prevalence of ALK," she noted. ALK mutations were found in 22 (44%) patients, EGFR in 13 (26%) patients, and ROS1 in three (6%) — a total of 76% of the cohort.

New Mutations Detected

For the other 24%, Dr Gitlitz noted that "we had some very interesting genomic discoveries." Mutations seen in these remaining patients included EGFR RAD1, EGFR Dup, HER2, ATM, BRCA2, p53/PTEN, and p53.

"The EGFR RAD1 fusion is being studied now to see if it is an actionable EGFR mutation," Dr Gitlitz explained. The EGFR kinase domain duplication that was discovered was investigated by another group, and the results were recently published (Gallant JN et al, Cancer Discov. 2015 Aug 18).

"It is an actonable mutation, seen with a 33-year-old male who had a 7-month partial response with afatinib [Gilotrif, Boehringer Ingelheim Pharmaceuticals, Inc], and at progression, he had increased copy number, which is the typical route of the emergence of resistance in EGFR mutations," she said. "And so this transformed to express this mutation, which was also amenable to tyrosine kinase inhibition, so a new actionable mutation has been discovered by looking at young people with lung cancer."

Dr Gitlitz added that they also greatly exceeded their statistical expectations. For patients with adenocarcinoma, they used data from the Lung Cancer Mutation Consortium. They initially sought to demonstrate an increase in actionable mutations from 35% to 50%, but they found actionable mutations in 76% of the patients.

"Thus far, in our prospective series, those diagnosed with primary NSCLC [non-small cell lung cancer] under the age of 40 tend to be never-smokers and stage IV adenocarcinoma," she said. "A website allowed for virtual consenting, so patients can participate remotely and use social networks to share information in a novel, feasible way to conduct research across continents."

Dr Gitlitz added that they plan to continue accrual for at least another year and would "appreciate more international patients."

NGS for All

Benjamin Levy, MD, medical director of the Thoracic Oncology Program at the Mt. Sinai Health System in New York City, pointed out that although the study is small, "we can glean some insight."

Acting as discussant, he commended the researchers for their innovation in using the Internet to enroll patients. "Novel trial design, including analysis of cDNA and Web-based consenting, are a welcomed change and will reshape the way we implement studies and enhance accruals."

Dr Levy also emphasized that despite the high prevalence of actionable mutations in this population of lung cancer patients, "lung cancer under the age of 40 is not necessarily a nonsmoking disease, and education and tobacco control works."

He added that next-generation sequencing should be performed routinely in the under-40 population, given the high rate of mutations. "A very high percentage of the patients had ALK mutations, and we didn't even know that existed 10 years ago," he said.

These patients are likely to harbor other mutations that may be targetable for treatment, and next-generation sequencing will enable that, Dr Levy added.

"Further studies are needed to define genetic susceptibility in both nonsmoking and smoking patients," he concluded.

The authors have disclosed no relevant financial relationships. Dr Levy reports relationships with Genentech, Celgene, Eli Lilly, Astra-Zeneca, Boehringer, and Biodesix.

16th World Conference on Lung Cancer (WCLC). Presented September 8, 2015. Abstract 22.05.

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