HER2-Targeted Drugs Useful in Some Lung Cancer Patients

Zosia Chustecka

April 23, 2013

HER-2–targeted drugs, such as trastuzumab (Herceptin), may be useful in a small percentage of cases of lung cancer, the 2% to 3% of non-small cell lung cancers (NSCLCs) that harbor HER2 mutations, according to a study published online April 22 in Journal of Clinical Oncology.

Drugs such as trastuzumab have already transformed the treatment of breast cancer, showing dramatic improvements in overall survival in patients with breast tumors that show HER2 protein overexpression, about 20% of the total patient population.

Trastuzumab has also found a niche in the treatment of gastric cancer, in the 15% to 18% of patients whose gastric tumors show HER2 overexpression. The Trastuzumab for Gastric Cancer (ToGA) trial showing a significantly improved survival was hailed as practice changing, and the drug was approved for this new indication in 2010.

Now come new results on HER2 in lung cancer — but here, there is a big difference. While about 20% of patients with NSCLC have tumors that show HER-2 overexpression, this "appears to be clinically irrelevant" because these tumors do not respond to the HER-2–targeting drugs as had been hoped. Instead, it is lung cancers that harbor a HER2 protein mutation, which are found in far fewer patients, that respond to these drugs, explained Joyti Patel, MD, from the Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine, Chicago, Illinois.

This illustrates the complexity of genetic mutations in cancer: What is true for one type of cancer may not hold in another, she commented in an interview with Medscape Medical News.

But even if the proportion of patients is smaller than had originally been hoped for, this research is still good news for patients, she said, because several drugs that target this mutation are already available on the market.

In addition to trastuzumab, there is pertuzumab (Perjeta), lapatinib (Tykerb), and trastuzumab emanstine (also known as TDM-1; Kadcyla). Another 2 such drugs are in late stages of development: afatanib and masatinib.

"Although HER2 mutations occur in only 2 percent of cases, this still equates to several thousand US lung cancer patients annually," Dr. Patel said in a statement. "We are finding more and more important mutations that drive lung cancer and matching them to targeted drugs. While confirmatory data are certainly needed, it appears that HER2 mutations represent another ‘druggable’ target, and drugs such as trastuzumab that are already available may be a reasonable treatment option for patients who harbor these mutations."

Largest Study to Date

The finding comes from a retrospective study conducted in Europe, the largest study to date to explore the effect of anti-HER2 drugs among patients with these rare mutations. The researchers, led by Julien Mazières, MD, PhD, professor of pulmonology at Larrey Hospital in Toulouse, France, tested 3800 patients with NSCLC in France, Spain, and Switzerland and found the HER2 mutation in 65 patients (1.7%).

All 65 patients with the mutations had the adenocarcinoma form of lung cancer, most (45 of 65) were women, and roughly half were never-smokers (34 of 65). About 50% of those patients had stage IV disease.

The researchers treated 16 patients (all with stage IV lung cancer and prior therapy consisting of platinum-based doublet with or without bevacizumab) with 1 or more anti-HER2 drugs: afatinib, trastuzumab, lapatinib, and masatinib. Trastuzumab was always used in combination with chemotherapy (carboplatin, paclitaxel, vinorelbine, or docetaxel), whereas the other 3 anti-HER2 agents were given as monotherapy.

Overall, 9 of 16 patients experienced some tumor shrinkage after 1 round of treatment with trastuzumab, and an additional 2 patients experienced shrinkage after a second round of treatment (1 with trastuzumab and 1 with afatinib). Disease stabilized in 3 additional patients, the researchers reported.

Among the patients who benefited from anti-HER2 treatments, median progression-free survival was 5.1 months, which is about twice what would be expected in such patients who had undergone 2 or 3 rounds of conventional chemotherapy, the researchers commented. Two patients received lapatinib and 1 masatinib, but those treatments did not prevent disease worsening.

"Our study suggests that many patients with HER2 mutations may benefit from anti-HER2 drugs," Dr. Mazières commented in a statement. "While this benefit still needs to be confirmed in a prospective clinical trial, we hope that, based on this and other studies, HER2 status will be taken into account when making treatment decisions."

Already in clinical practice, NSCLC tumors are being tested for epidermal growth factor mutations (which respond to such drugs as erlotinib [Tarceva]) and gefitinib [Iressa]), and also for the ALK rearrangements (which respond to crizotinib [Xalkori]). In clinical trials, they are also being tested for many other mutations that can be targeted by novel drugs under development.

J Clin Oncol. Published online April 22, 2013. Abstract

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