Targeting and Retargeting in Lung Cancer

Clinical studies show that epidermal growth factor receptor (EGFR)–directed treatment is better than chemotherapy in first-line treatment of non–small cell lung cancer (NSCLC) with EGFR mutations. That result holds up consistently in terms of response rate, quality of life, and progression-free survival (PFS) across eight trials, according to a recent Journal of Clinical Oncology editorial written by Corey Langer, MD, a professor of medicine at the University of Pennsylvania and director of thoracic oncology at the Abramson Cancer Center, both in Philadelphia (J Clin Oncol 2013;31:3303–6).

However, the findings about targeted therapies still leave clinicians pondering which one to choose, Langer says.

For years, the go-to drug for treatment-naïve NSCLC patients has been erlotinib (Tarceva; Astellas Pharma). The first-generation tyrosine kinase inhibitor (TKI) was used off-label until it was approved for first-line therapy by the U.S. Food and Drug Administration (FDA) in May 2013. In July, the FDA approved afatinib (Gilotrif; Boehringer Ingelheim), a second-generation TKI, for the same indication.

Afatinib is called a second-generation drug because it covalently binds to the receptor itself, as opposed to erlotinib, which is ATP-competitive at the binding site. Afatinib is also a pan-HER inhibitor, whereas erlotinib is specific for EGFR.

These two drugs have never been compared head to head, and investigators say that published results don't point to a clear advantage for afatinib over its predecessor.

Separate trials indicate that afatinib offers 11.1 months of PFS in this population (increasing to 13.6 months among patients who don't acquire TKI-resistance mutations) compared with 10.4 months with erlotinib.

However, clinical experience shows that afatinib can be more toxic. Side effects are manageable, but afatinib-treated patients are more likely to suffer from skin rashes, diarrhea, and mouth sores, says Alice Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital in Boston. “Choosing one or the other,” she says, “boils down to what you think your patients can tolerate.”

Roy Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center in New Haven, CT, raises another consideration—afatinib could be less susceptible to acquired resistance, potentially justifying second-line uses for which it is currently not approved. Preclinical studies have shown that when combined with cetuximab chemotherapy, afatinib remains effective in TKI-resistant mice.

Lecia Sequist, MD, an associate professor at Harvard Medical School in Boston, MA, comments, though, that evidence in humans doesn't support these preclinical findings. “Afatinib doesn't appear to have a lot of activity in human patients with acquired TKI resistance,” she says.

Moreover, Sequist says, “it would be difficult to get the combination treatment outside of a clinical trial—afatinib isn't approved in combination with cetuximab, and cetuximab isn't approved in lung cancer. This would also be a very expensive regimen.”

The four oncologists agree that third-generation TKIs now in phase I trials, such as Clovis Oncology's CO-1686, might offer greater benefits in TKI-resistant, EGFR-mutant–positive cancers. Unlike their first- and second-generation predecessors, these drugs are thought to bind only to mutated EGFR and not to the wild-type receptor in normal cells. “First- and second-generation TKIs are about the same,” Langer concludes, “but this story is by no means over.

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