Celebrating the 10th Anniversary
A decade of discoveries in Cancer Discovery. For the community. By the Community.
Their impactful studies. In their words.
…it led to the development of a medicine, osimertinib, that has changed the survival expectations of so many patients with varying stages of EGFRm NSCLC—approximately 215,000 of them, in fact, between clinical trial research and its approved indications.
AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer
Q: What unanswered questions in the field was this study addressing?
A: (Darren A.E. Cross) First-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib had become standard of care in first-line activating EGFR-mutant non–small cell lung cancer (EGFRm NSCLC). However, despite their benefit, they are not curative treatments, and most patients on first-generation EGFR-TKIs ultimately progress due to acquired resistance.
It was well known that a predominant mechanism in about 50% of resistance cases was due to the secondary mutation T790M in EGFR. Despite efforts to tackle this resistance—like the development of second-generation TKIs—it remained a key area of unmet need. Therefore, we set out to design and develop a new class of EGFR-TKI that could effectively target T790M and activating mutant EGFR, prolonging patients’ treatment benefit.
A: (William Pao) When we wrote this paper, we had known for a decade that first-generation EGFR tyrosine kinase inhibitors (EGFR TKIs) like gefitinib and erlotinib provided significant clinical benefit in patients with advanced EGFR-mutant (EGFRm+) non–small cell lung cancer (NSCLC), but that patients ultimately developed disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. We had been searching for ways to overcome T790M-mediated resistance. We knew it was possible from our study involving the combination of afatinib (a second-generation EGFR TKI) and cetuximab (an anti-EGFR antibody), but the combination had high rates of rash and diarrhea, making it hard for patients to tolerate. Here, we were trying to find a novel oral potent mutant-selective EGFR TKI that could target EGFRm+ sensitizing and T790M resistance mutants and spare wild-type EGFR, the latter characteristic of which would lead to lower side effects. It's worth remembering that gefitinib, erlotinib, afatinib, and other EGFR TKIs in existence at that time were developed against wild-type EGFR before the world even knew that lung cancer–associated EGFR mutations even existed! The molecule AstraZeneca chemists developed—AZD9291—therefore was the first clinically approved EGFR TKI designed to deliberately target mutant and not wild-type EGFR.
Q: What surprised or excited you most about the findings?
A: (Darren A.E. Cross) When this program was started within AstraZeneca, the idea of so-called third-generation EGFR-TKIs was completely novel and innovative. There was no previous precedent that this new type of EGFR-TKI would even be feasible.
When we successfully achieved preclinical development of AZD9291 (generic name osimertinib), as described in the paper, this was a hugely significant moment. It was the first-ever third-generation EGFR-TKI with a specifically designed profile to enter clinical development. It was potent toward activating and T790M mutant EGFR, and could harbor selectivity against wild-type EGFR to limit toxicities. The development of osimertinib was truly groundbreaking and a game changer for the treatment of metastatic EGFRm NSCLC.
A: (William Pao) When this paper was published, it was obvious that AZD9291 would become approved for the treatment of patients with metastatic EGFR T790M mutation–positive NSCLC who have progressed on or after EGFR TKI therapy. It was not a given, however, that what became osimertinib would become a first-line treatment option in EGFRm+ lung cancer, which it did in 2018. And the recent FDA approval (2020) of osimertinib as the first adjuvant treatment for patients with resected early-stage EGFRm+ NSCLC has been an even more welcome bonus for patients.
Q: What has been the paper’s greatest impact in the years that followed?
A: (Darren A.E. Cross) This paper’s greatest impact is that it led to the development of a medicine, osimertinib, that has changed the survival expectations of so many patients with varying stages of EGFRm NSCLC—approximately 215,000 of them, in fact, between clinical trial research and its approved indications.
Since publication of its preclinical development and encouraging first patient case reports, osimertinib has been approved in 89 countries for the treatment of T790M resistance, and in 87 countries for the treatment of first-line metastatic EGFRm NSCLC, a setting where osimertinib is now widely accepted as the standard of care. Most recently, osimertinib became the first targeted therapy approved in the early stages of lung cancer based on the unprecedented disease-free survival results of the ADAURA Phase III trial.
Further, since this paper was published, osimertinib has continued to demonstrate its ability to cross the blood–brain barrier to ultimately address central nervous system metastases in late-stage disease and reduce the risk of their recurrence in early-stage disease. It has been an eventful seven years for osimertinib and for patients with EGFRm NSCLC, and I can’t wait to see what comes next from this development program.
A: (William Pao) When I became a fellow in medical oncology in 2000, the median overall survival time for unselected NSCLC patients treated with the standard of care (chemotherapy) was less than a year. Today, the median overall survival of patients with EGFR mutations treated with osimertinib is more than 3 years! And in the adjuvant study, patients who received osimertinib had an 80% decrease in chance of disease recurrence compared with patients who received a placebo. Consistent with the improved outcomes for these patients, population-level mortality from NSCLC in the United States has fallen sharply from 2013 to 2016, shortly after routine testing for molecular alterations in EGFR and ALK (another target) was recommended and FDA-approved targeted therapies were introduced for commercial use. I would anticipate that these trends will continue, as osimertinib was not approved till 2015. Overall, this means that research like this can really have an impact on patients' lives. The development of transformative medicines requires the convergence of fundamental biological, clinical, and technological breakthroughs. The story of osimertinib is a great example of how all three came together to enable rapid drug development.