In recent years, osimertinib has attracted a lot of attention among lung cancer experts.
Results from the Phase 3 LAURA trial received a standing ovation at the 2024 American Society of Clinical Oncology Annual Meeting after the trial demonstrated a progression-free survival benefit of 33.5 months in patients with EGFR-mutated, unresectable stage 3 non-small cell lung cancer (NSCLC).
Several years earlier, the FLAURA trial established AstraZeneca’s EGFR-targeted tyrosine kinase inhibitor as first-line therapy in patients with EGFR-mutated advanced NSCLC. The trial reported a median overall survival benefit of 7.2 months in patients receiving osimertinib versus other EGFR inhibitors, gefitinib or erlotinib.
In 2018, osimertinib received FDA approval based on the results of the FLAURA trial and has gained several additional indications in advanced NSCLC as well as early-stage disease in the adjuvant setting.
As of 2020, more than 90% of patients in the United States receive the drug as part of first-line treatment for locally advanced or metastatic EGFR-mutated NSCLC.
However, a recent analysis of a real-world patient population with advanced disease provided a small reality check.
The results of Phase 3, published in Lung cancer Earlier this year, the results of osimertinib as first-line therapy were evaluated in patients who would have been eligible for FLAURA and in patients who would not have been eligible.
Ineligibility was based on five main criteria: poor ECOG performance status (≥ 2); symptomatic brain metastases or ongoing steroid treatment or spinal cord compression; hemoglobin levels below 90 g/l; platelet count below 100×109/l; or creatinine levels above 1.5 times the upper limit of normal, with a clearance of
In this real-world scenario, 44% of patients (137 of 311) would have been ineligible for the FLAURA trial, mainly due to their poor general health (n = 120). Patients who would have been ineligible also had significantly higher rates of stage IV disease and were more likely to be stage IVB and have more than three metastases.
At an average follow-up of 26.5 months, 70% (96 of 137) of FLAURA-ineligible patients had died, compared with 36% (63 of 174) of FLAURA-eligible patients.
Patients who would have been eligible for FLAURA had a similar median overall survival to patients in the FLAURA trial – 34.2 months (versus 39.1 months in FLAURA). However, the ineligible cohort fared much worse, with a median overall survival of 15.8 months – more than 18 months shorter than the eligible cohort.
The median time to treatment discontinuation was 26.8 months in FLAURA-eligible patients versus 11.9 months in ineligible patients.
Because patients in the group not eligible for the FLAURA program have a worse prognosis overall, the difference between the survival rate in this group and the group of patients eligible for FLAURA was not necessarily a surprise, said study author J. Connor Wells, MD, of the BC Cancer Agency in Vancouver, British Columbia, Canada.
“A patient’s performance status is often a good predictor of prognosis, so it is not entirely unexpected that most patients in the ineligible group had a performance status of 2 or worse,” Wells said Medical news from MedscapeNevertheless, it was “a pretty stark difference compared to the voting group.”
The results should help clinicians to communicate more appropriate expectations to patients.
“When patients want to discuss expected survival, we often look to the results of the large Phase 3 clinical trial, with the caveat that every patient is different and every cancer responds differently to treatment,” Wells said. “However, our study provides more realistic numbers for patients who are worse off to begin with.”
Should FLAURA’s eligibility criteria have been broader to cover the spectrum of actual patients?
Not necessarily, says Dr. Stephen Liu, who was not involved in the analysis.
Liu explained that using more conservative inclusion criteria in clinical trials is important to get a clear picture of treatment-related issues such as toxicities. In many cases, complications in this harder-to-treat patient population occur due to comorbidities, for example, rather than directly due to the cancer or the treatment, said Liu, director of thoracic oncology and chief of developmental therapeutics at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.
And even if there were a “striking” difference in survival rates, these real-world findings would “make no difference in practice,” Liu noted.
Osimertinib remains the best option for many patients with NSCLC. What this real-world study may ultimately show is that even the best therapy is unlikely to significantly alter the course of the disease in more severely ill patients.
However, these findings should change the expectations of oncologists and patients.
The trial was “a sobering reminder that real-world outcomes often lag behind experimental results,” Liu said.
Wells had no disclosures. Two study authors reported relationships with AstraZeneca. Liu reported consulting or research relationships with AstraZeneca as well as a number of other companies, including Abbvie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck and Pfizer.
