2020-05-30| R&D

ASCO 2020: AZ’s Tagrisso Promises Disease-Free Survival in Postoperative EGFR Mutation-Positive NSCLC

by Sangeeta Chakraborty
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By Sangeeta Chakraborty, Ph.D.


Lung cancer (LC) leads the chart in most cancer-associated deaths worldwide, killing about one-fifth of all cancer patients. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer patients. Among them, 30% of the cases are resectable at the time of diagnosis.

As a primary treatment modality for early-stage NSCLC, invasive surgical tumor resection has only been moderately successful, with several patients eventually dying from relapse. This poses an impediment to their postoperative disease-free survival. On the other hand, the application of systemic cisplatin-based adjuvant chemotherapy in resected NSCLC has shown a minuscule survival advantage of only 5% at five years. Clearly, traditional systemic chemotherapy is no longer seen as the best course of treatment for lung cancer. With the advent of rationally designed drugs that can target specific pathways of malignancy sparing the healthy cells, it is possible to streamline and tailor treatment regimens based on the NSCLC mutation type.

Identification of major driver mutations in some advanced NSCLC tumors, most notably in EGFR, PI3/AKT/mTOR, RAS-MAPK, and NTRK/ROS1 pathways, has led to the development of specific molecular treatments for patients. EGFR inhibitors erlotinib, gefitinib, PI3K/AKT/mTOR inhibitor everolimus, and NTRK/ROS1 inhibitor entrectinib, have replaced chemotherapy as the first-line treatment. However, newly acquired tumor mutations often make cancerous cells resistant to these drugs, and the majority of patients experience tumor progression, so understanding resistance mechanisms and developing novel drugs is the need of the hour.


Tagrisso, AstraZeneca’s Blockbuster Tyrosine Kinase Inhibitor

EGFR activating mutations that were identified in lung cancer over a decade ago prompted the application of targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs) as first-line therapy for NSCLC.

The FDA currently approves Iressa (gefitinib), Tarceva (erlotinib), Gilotrif (afatinib), and Tagresso (osimertinib) as a first-line treatment for patients with metastatic NSCLC with EGFR mutations—exon 19 deletions (Ex19del) or L858R. Besides this, Tagrisso—a third-generation TKI—also selectively inhibits the acquired EGFR-T790M mutation, taking it a notch higher in improving outcomes for metastatic NSCLC patients. As a first-line agent, Tagrisso outperformed its first-generation TKI competitors (Iressa and Tarceva) in the phase III trial FLAURA, by improving the overall survival in patients with locally advanced or metastatic NSCLC.

After the success as a frontline agent, Tagrisso is now being considered for adjuvant therapy in resected NSCLC patients. In the 2020 ASCO Virtual Scientific Program, Dr. Roy S. Herbst, Ph.D., the principal investigator, discussed the overwhelmingly positive results from the phase III trial ADAURA (NCT02511106), that tested the efficacy of Tagrisso in EGFR mutations positive NSCLC patients with complete tumor resection.

Dr. Herbst added, “the improvement in disease-free survival following surgery that was seen in the ADAURA study supports the use of this targeted therapy in earlier-stage disease, which typically has a high recurrence despite surgical treatment and chemotherapy.”


Phase III ADAURA Trial

The randomized, and placebo-controlled ADAURA trial recruited a total of 682 patients with stage IB to IIIA NSCLC harboring either EGFR-exon 19 deletions or L858R, to receive either Tagrisso or placebo. The treatment continued for three years until the disease recurred.

Tagrisso, in the adjuvant setting, led to an 83% reduction in the disease recurrence or death in patients with stage II-IIIA NSCLC. In the overall study population, including patients with stage IB, it demonstrated a 79% reduction in the risk of disease recurrence or death. At two years, 89% of the patients taking the drug were found to live without any cancer relapse compared with just 53% in the placebo group. A consistent improvement in disease-free survival was seen regardless of whether patients received prior adjuvant chemotherapy.

Additionally, a low hazard ratio (which determines the occurrence of an adverse event) favored the drug across all subgroups (age, sex, race, NSCLC stage, and EGFR aberration type), making Tagrisso a highly effective treatment of choice. The drug was well-tolerated without any high-grade toxicity or death in the treatment arm.

In April 2020, AstraZeneca announced that the ADAURA trial results had been compelling enough that an independent data monitoring committee recommended early unblinding of the study. At the time of the unblinding, the trial had completed enrollment, and all patients were followed up for at least one year.

Related Article: Overwhelming Efficacy Allows AstraZeneca to End Cancer Drug Trial Sooner



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