Experts Provide Insight Into Novel EGFR Inhibitors for Lung Cancer

H. Jack West, MD

A faculty of experts presented a compelling discussion on the state of the art for endothelial growth factor receptor (EGFR)—targeted tyrosine kinase inhibitors (TKIs) during a satellite event that took place during the 2016 ASCO Annual Meeting.

Among the topics of discussion were two spirited debates, one on whether there are meaningful differences between first- and second-generation drugs, and one on the value of liquid biopsies to assess the origin of acquired resistance.¹

The speakers also discussed treating patients with and without T790M mutations, and the use of TKIs in treating EGFR wild-type patients.

The symposium, “EGFR and Non—Small Cell Lung Cancer 3.0,” was neither sponsored nor endorsed by ASCO or the Conquer Cancer Foundation, nevertheless ran concurrently with the opening of the ASCO Annual Meeting.²

The event also coincided with a number of new developments in the field from recent weeks, as the FDA announced its approval of the first liquid biopsy for activating mutations. Additionally, developers of the third generation drug rociletinib pulled it from development last month following developments subsequent to the TIGER-X trial.

First and Second Generation Drugs Considered Interchangeable

          

While faculty members seemed in agreement that the third generation of EGFR inhibitors has dramatically changed treatment options for many cancer patients who have tumors with activating mutations, the first debate considered the relationship between first and second generation drugs such as afatinib, erlotinib, and gemcitabine.     

H. Jack West, MD, argued that data has shown that afatinib has marginal to modest superiority over the other drugs, while Karen Kelly, MD, argued that the drugs are all interchangeable. (It was Kelly’s argument that ultimately swayed the audience, 60% of whom agreed with her.)

“There have been two head-to-head clinical trials of these drugs, LUX-Lung 7 and LUX-Lung 8,” which showed that afatinib alone provided a benefit over the other agents, said West, medical director of the thoracic oncology program at the Swedish Cancer Institute in Seattle. “If we are switching out one EGFR inhibitor for another, we can choose the one that has data behind it, or not.” (LUX-Lung 8 was a study conducted in squamous cell cancer patients, most of whom lack EGFR activating mutations, West said.³)

“LUX-Lung 7 looks like a randomized phase III trial, but there is no adjustment for multiple co-primary endpoints,” replied Kelly, professor of medicine at UC Davis Comprehensive Cancer Center in Sacramento. “The trial used time to treatment failure, a very soft endpoint, which is not linked to treatment efficacy. There’s a lot of bias these days in this endpoint,” she explained.

“I don’t want to criticize LUX-Lung 7 except to say that it was an exploratory trial

with a unique statistical design, but no definitive answer could be drawn from its data,” explained Kelly in an exclusive interview withTargeted Oncology. “Time to treatment failure is not black and white like response rate or progression-free survival (PFS). This is a situation where patients staying on the drug after progressing is a new clinical option with these targeted therapy drugs that we’ve not seen before.

“There was a hint that PFS was improved with afatinib, meaning that progression or drug resistance was delayed, but we will never have the answer. This study will never be done, and the window of opportunity is closed. We have more important questions to be addressed, because now we’re on to third-generation TKIs,” she said.

“The onus is not on whether there’s an irrefutable benefit, or a strong suggestion of a benefit,” replied West in the debate. “You have to choose one thing, and you can choose the one that’s superior or inferior. I wouldn’t say it’s unconscionable to give gefitinib. The only question is whether another drug is an egregiously or modestly inferior choice.”

Divided Over Liquid Biopsies

The second lively debate involved the use of tissue versus liquid biopsies in assessing whether the T790M mutation is present in patients with cancer that has demonstrated acquired resistance to an EGFR inhibitor. Heather Wakelee, MD, assistant professor at the Stanford Cancer Institute, argued that liquid biopsies (using blood plasma or urine) should be the first choice.

“I’m on the side of the patients in this debate: no more biopsies,” said Wakelee. “A positive result from a liquid biopsy is treatment changing, but a negative result should not be the end of the analysis,” she said.

This month, the FDA granted the first approval to a liquid biopsy to Roche for the cobas EGFR Mutation Test, which Wakelee supported in her later presentation in support of liquid biopsies in the TIGER-X trial.⁴(The approval is for activating mutations that first give rise to the cancer, not T790M, which comes into play after resistance to EGFR TKIs is acquired).

However, the opposite point of view was argued by Giorgio Scagliotti, MD, PhD, who co-chaired the symposium. “I would ask Dr. Wakelee, are you really ready to tell all these pathologists that a tissue biopsy is completely worthless?” said Scagliotti, head of the thoracic oncology unit at the University of Turin in Orbassano, Italy.

“Circulating tumor DNA can be extremely different from one patient to another. It is also highly unstable, and requires rapid processing,” added Scagliotti, who is also the president-elect of the International Association for the Study of Lung Cancer (2017-2019).

“Liquid biopsy is one potential tool, but not the main tool. In clinical research, for a better understanding of the tumor beyond EGFR and T790M, we need to get tissue,” he explained in an exclusive interview.

Following the debate, audience opinion was divided evenly between preference for liquid versus tissue biopsies.

Other Topics Discussed

In addition to the 2 debates, faculty discussed other topics, such as using TKIs to target patients with the T790M mutation who have developed drug resistance. Third-generation TKIs provide improved treatment for these patients, Dr. West encouraged.

“EGFR wild type is in the gut and skin of patients, even if they don’t have the mutation,” he explained. “But the new drugs bind to the mutated form of EGFR, the part you’re trying to hit, which means lower rates of toxicity.”

Dr. Wakelee also discussed the role of TKIs in treating patients with acquired drug resistance that did not arise from T790M, who comprise 40% of those with acquired resistance. “There are some patients who have an addicted tumor, and when you stop the TKI, they can have a flare,” she warned.

Additionally, co-chair Gregory Riely, MD, PhD, discussed the use of EGFR inhibitors in wild-type patients. “EGFR TKIs have modest benefit even in patients without EGFR mutations,” said Riely, a medical oncologist at Memorial Sloan Kettering Cancer Center. “Regarding the choice of which one to use, there are rational arguments on either side, and the choice is driven largely by patient considerations. Some don’t like intravenous therapy, while others don’t like oral therapy of any kind,” he said.

“EGFR and Non—Small Cell Lung Cancer 3.0,” a symposium given in Chicago on June 3, 2016. The symposium, with audio and slides, is available online athttp://www.liveeventstream.com/bmli/bmli.html. Visited June 5, 2016.

Slides available athttp://www.bmli.com/BMLI_EGFR_Presentations.pdf. Visited June 5, 2016.

Soria J, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial.Lancet Oncol.2015;16(8):897-907.

Wakelee H, Gadgeel S, Goldman J, et al. Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib. J Clin Oncol 34, 2016 (suppl; abstr 9001).