Tom Lynch reflects on discovery of EGFR mutations’ role in lung cancer

On Nov. 24, 2003, an article in The Boston Globe told the story of a patient’s remarkable response to gefitinib, a drug that had recently been approved by FDA.

Kate Robbins, a patient of Tom Lynch’s, then a lung cancer expert at Massachusetts General Hospital, remarkably appeared to be disease-free after a year on gefitinib (Iressa). She was one of the lucky few—in most patients, the drug didn’t seem to work.

Before she received gefitinib, Robbins had 16 tumors. After gefitinib, they vanished. “It’s the most amazing thing,” 46-year-old Robbins said to The Globe reporter Raja Mishra, who described Robbins as a woman with “big eyes and a round, girlish face” who talked with “energy and enthusiasm.”  

Robbins lived another 18 years. She died in 2021, at age 64. 

Reading that news story sparked an idea in Lynch’s colleague Daniel Haber, director of the Mass General Cancer Center, a position he holds today. 

“He’s the one who had the aha moment that, ‘I think Tom’s patient’s response is due to a mutation in EGFR kinase domain,’” recalled Lynch, who is now president, director, and holder of the Raisbeck Endowed Chair at the Fred Hutchinson Cancer Center. 

At that time, chemotherapy was the main approach to treating lung cancer. 

“Chemotherapy produced responses in about 20% of patients, and the responses were almost always short-lived,” Lynch said. “So, when gefitinib and erlotinib (Tarceva) were developed, not only were they better tolerated—less toxic than chemotherapy—occasionally, in some patients, they created these unbelievable responses. 

“The problem we had when we first developed them was, we just didn’t know who was responding and why. And it was a big unknown at that point,” Lynch said. 

Haber’s suspicions about EGFR led him to sequence several lung cancer specimens from Lynch’s patients who had bounced back after taking gefitinib. Eight of the nine patients had EGFR mutations, a finding reported in the New England Journal of Medicine. 

Lynch and Haber’s colleague Jeff Settleman, who is now chief scientific officer for oncology research and development at Pfizer, confirmed how EGFR kinase domain mutation created “an oncogene addiction that underlies the growth of the cancer, and why gefitinib as an inhibitor of the EGFR tyrosine kinase was so effective in that setting,” Lynch said. 

More than 20 years later, scientists’ understanding of EGFR-mutated lung cancer has progressed immensely. The field now has many options for patients, including drugs that target rarer mutations, Lynch said.  

“The catch is, we still haven’t found a way to cure most patients with EGFR-mutated lung cancer,” he said. “The major gap is resistance—the typical patient still becomes resistant after one to two years, and we need new options.” 

Gefitinib received a nod from the FDA Oncologic Drugs Advisory Committee in Sept. 2002, two years before scientists understood why some patients responded to the drug while others didn’t (The Cancer Letter, June 21, 2024). The landmark papers describing the role of EGFR mutations were published in April 2004 (The Cancer Letter, April 30, 2004).

Today, as a cancer center director, Lynch is concerned about the ability to make future discoveries due to decreased funding—both in the governmental and pharmaceutical sectors. 

“I worry about the cancer drug landscape becoming more crowded and complex, and the attention of pharma moving to other areas that might be less competitive—such as inflammation, auto-immunity, and obesity—at the same time that the federal government is cutting research funding for cancer,” Lynch said. “The NCI budget is what fuels innovation, and it is very much at risk.”