Clinical Challenges: EGFR-Mutated NSCLC

Epidermal growth factor receptor (EGFR) mutations are seen in approximately 10-20% of patients with non-small cell lung cancer (NSCLC), with a higher percentage observed among Asian patients. But considering that over 200,000 people a year are diagnosed with lung cancer, that seemingly small percentage “represents a lot of patients,” said Roy Herbst, MD, PhD, chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut.

Over the past 2 decades, tyrosine kinase inhibitors (TKIs) targeting EGFR have emerged, beginning with the two first-generation EGFR-TKIs, gefitinib (Iressa) and erlotinib (Tarceva).

A series of trials evaluating first- and second-generation EGFR TKIs found that erlotinib, gefitinib, and afatinib (Gilotrif) were the best first-line treatment options for patients with advanced NSCLC with EGFR mutations because of improved response rates and progression-free survival compared with chemotherapy.

However, as described in a 2016 review, most patients developed resistance to these drugs after 9-14 months.

“These drugs worked, and response rates were high, but patients became resistant,” Herbst told MedPage Today. “It turned out that one of the main ways that patients became resistant was through a second mutation, T790M.”

Research on a third-generation EGFR-TKI, osimertinib (Tagrisso) began about a decade ago and was designed to selectively target the T790M form of the EGFR receptor. Osimertinib, Herbst pointed out, “also had the added bonus of being very penetrative to the brain.”

The FDA granted regular approval of the drug as a second-line therapy for patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Approval was based on results from the AURA3 trial.

That study randomized patients to receive either osimertinib or platinum-based doublet chemotherapy, and reported an improvement in progression-free survival among patients who received osimertinib compared with those on chemotherapy (10.1 vs 4.4 months). The objective response rate was significantly better with osimertinib, with median estimated durations of response of 11 months for osimertinib and 4.2 months for chemotherapy.

This was followed by the FLAURA trial, which evaluated osimertinib in the first-line setting. In this phase III trial, investigators randomly assigned 556 patients with previously untreated EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC to receive either osimertinib or erlotinib or gefitinib — the standard of care at the time.

The FLAURA investigators found that patients on osimertinib achieved significantly longer progression-free survival than patients on standard EGFR-TKIs (18.9 vs 10.2 months; HR 0.46, 95% CI 0.37-0.57). The objective response rates were similar in the two groups, but the median duration of response was 17.2 months (95% CI 13.8-22.0) with osimertinib vs 8.5 months (95% CI 7.3-9.8) with the two standard EGFR-TKIs.

Adverse events of grade 3 or higher were reported in 42% of patients in the osimertinib group, and in 47% of the erlotinib/gefitinib group.

This led to FDA approval of osimertinib for this indication in 2018.

“This made osimertinib the best-in-class drug,” said Herbst. “The least toxic, the most effective, and the one that had brain metastases activity — which made it perfect in the adjuvant setting because you want to have the most potent drugs, the least toxicities, and you want to be able to target the brain.”

Herbst led the phase III ADAURA trial, which evaluated osimertinib in the adjuvant setting. Here Herbst and his colleagues included patients with stage IB to IIIA EGFR-mutated NSCLC, who had their cancer completely resected, and received chemotherapy if indicated, and randomized them to receive either osimertinib or placebo.

“The endpoint was disease-free survival, and we weren’t expecting results for a few years,” Herbst noted. However, he said, the magnitude of benefit shown with osimertinib was so great that the trial’s Independent Data Monitoring Committee recommended that the trial be unblinded early due to efficacy.

Specifically, results from an interim analysis, which Herbst presented at the plenary session of the 2020 American Society of Clinical Oncology virtual annual meeting, showed that at 2 years, disease-free survival among the patients on osimertinib was 90%, compared with 44% for placebo.

“The benefit gained was just profound,” said Herbst. “We updated the data, which showed a 10:1 diminution of the brain metastases. The hazard ratio for the brain was 0.18, meaning there were 82% fewer patients in the trial who developed brain metastases.”

Based on these results, the FDA approved osimertinib as adjuvant therapy after tumor resection in NSCLC patients with EGFR exon 19 deletions or exon 21 L858R mutations.

Herbst compared the use of the osimertinib in EGFR-mutated lung cancer to trastuzumab (Herceptin) in breast cancer, which was approved for metastatic HER2+ breast cancer and then approved for an earlier stage of the disease.

“It’s the same thing here,” he said. “We’ve taken a drug that worked in the advanced setting; it helped, but no one was cured. And we’ve moved it into the early stage, and it looks like we may have some cured.”

The implications for clinical practice “are huge,” Herbst added. “This is the first time a targeted therapy in lung cancer is being used and approved in the adjuvant setting. So it’s brought the most precise guided therapies we’ve been working on for 20 years down to early disease, where it has the potential to benefit even more patients.”

He called it a “new paradigm” for treating the disease and predicted it could extend to other targets in lung cancer.

“We’re continuing to raise the bar, and bringing in new agents earlier in the disease to potentially provide more benefit,” he said. “Because the best way to keep a patient alive is to prevent metastases, and before they even have visible metastases we can prevent them with these drugs.”