乌鸦传媒

Patients with operable EGFR-positive non-small cell lung cancer (NSCLC) lived twice as long without disease recurrence when they received osimertinib (Tagrisso) after surgery, according to results of a potentially paradigm-changing study.

The phase III placebo-controlled ended early after an interim analysis revealed a compelling disease-free survival (DFS) advantage for the osimertinib arm. At that point, with median follow-up of about 2 years, the results showed median DFS of 20.4 months for placebo-treated patients with stages II-IIIa disease, whereas the median value had yet to be reached in the osimertinib arm. However, the confidence intervals suggested median DFS would reach at least 40 months.

Analysis of the overall study population (stages Ib-IIIa) showed a similar difference in favor of osimertinib. Both analyses suggested at least 80% reduction in the risk of recurrence or death when patients received the third-generation EGFR inhibitor after surgery. Landmark analyses showed more than twice as many patients treated with osimertinib remained alive and disease free after 2 and 3 years, Roy S. Herbst, MD, PhD, of the Yale Cancer Center in New Haven, Conn., .

"These are extraordinary results," Herbst said in a prerecorded presentation. "The [survival] curves separate early on, and the distance between the curves continues to separate throughout the course of follow-up, resulting in a hazard ratio of 0.17, which means there is an 83% reduced chance of disease recurrence. This was much better than expected and certainly is something that's going to help patients."

"What I've shown you is that osimertinib is the first targeted agent, in a global randomized trial, to show statistically significant and clinically meaningful improvement in disease-free survival in patients with stage Ib, II, and III EGFR mutation-positive non-small cell lung cancer," he added. "Consistent improvement was seen regardless of whether patients received prior chemotherapy. Osimertinib provides a highly effective, practice-changing treatment for patients ... after complete tumor resection."

Reaction, Implications

ASCO President Howard A. "Skip" Burris, MD, commented that the trial design reflected the strong interest among oncologists to use newer, more effective therapies earlier in the course of cancer treatment.

"Obviously, with a median follow-up of only 2 years, it's too early to comment on overall survival, but certainly the trends look very favorable," said Burris, of Vanderbilt University Medical Center in Nashville. "These are very impressive results and really follow the paradigm that the earlier we can use these new therapies, the greater impact we can have."

The findings almost certainly will be practice changing but may also represent an early step toward a broader paradigm shift for treatment of resectable NSCLC, said John Heymach, MD, of the University of Texas MD Anderson Cancer Center in Houston. The current approach to therapy for early NSCLC consists of neoadjuvant chemotherapy, followed by surgery, and then adjuvant chemotherapy, as necessary. Molecular testing for actionable mutations is not performed in these patients. That could change, he said, as a result of the ADAURA trial.

"With molecular testing, we'll discover not only EGFR mutations but other mutations that could potentially be targeted with other therapies," Heymach told 乌鸦传媒. "This is the first study that really creates a compelling need for molecular testing for these early-stage patients, and that will benefit not only patients with EGFR mutations but with other mutations that could benefit from targeted therapies down the road."

Already approved as first-line treatment for advanced/metastatic EGFR mutation-positive NSCLC, osimertinib targets the resistance-conferring T790M mutation in the EGFR gene. The drug's rationale in the adjuvant setting came from multiple studies evaluating the clinical course of surgically treated NSCLC. Although many patients with stages Ib-IIIa NSCLC initially appear disease free, the ranges from 45% for stage Ib to 76% for stage IIIa, even with adjuvant chemotherapy.

In ADAURA, investigators on four continents randomized 682 patients with newly diagnosed EGFR-positive stage Ib-III NSCLC to osimertinib or placebo following surgery with or without platinum-based chemotherapy (stages II-IIIa only). Randomized treatment continued for a maximum of three years. The primary endpoint was investigator-assessed DFS in patients with stages II-IIIa disease. DFS in the entire study population was a secondary endpoint, along with landmark DFS analyses, OS, safety, and quality of life.

Key Findings

When the trial was halted after the first interim analysis, patients randomized to osimertinib had median treatment duration of 22 months versus 18 months in the placebo group. All patients had been followed for at least a year, said Herbst.

The primary analysis yielded a hazard ratio of 0.17 for disease recurrence or death in favor of the osimertinib (95% CI 0.12-0.23. P<0.0001). Osimertinib-treated patients had a large DFS advantage at 12 months (97% vs 61%), 24 months (90% vs 44%), and 36 months (80% vs 28%).

Analysis of DFS in the overall population produced a DFS HR of 0.21 (95% CI 0.16-0.28, P<0.0001) and landmark DFS values of 97% vs 69% at 12 months, 89% vs 53% at 24 months, and 79% vs 41% at 36 months, all in favor of osimertinib.

Subgroup analysis showed a consistent benefit in favor of osimertinib treatment irrespective of sex, age (<65 vs ≥65), nationality/ethnicity, and receipt of chemotherapy. Only patients with stage Ib did not clearly benefit from the EGFR inhibitor.

Herbst reported that adverse events in the osimertinib arm were consistent with the drug's known safety profile. The most common (≥10% of patients) adverse events were diarrhea, paronychia, dry skin, pruritus, cough, stomatitis, nasopharyngitis, decreased appetite, upper respiratory infection, dermatitis acneiform, and mouth ulceration.

Comment