First-Line Osimertinib Plus Chemo Demonstrates Consistent Benefit in EGFR-Mutant NSCLC

Natalia Isabel Valdiviezo Lama, MD

The addition of platinum-pemetrexed chemotherapy to osimertinib (Tagrisso) produced long-term, clinically meaningful and statistically significant survival outcomes following disease progression vs osimertinib alone in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) in the first line, according to a prespecified analysis of post-progression outcomes and updated survival data from the phase 3 FLAURA2 trial (NCT04035486).¹

Findings presented at the 2024 European Lung Cancer Congress showed that patients treated with osimertinib plus chemotherapy experienced a 27% lower risk of receiving a first subsequent treatment and a 30% lower risk of experiencing second progression after subsequent treatment vs osimertinib alone (HR, 0.73; 95% CI, 0.56-0.94 and HR, 0.70; 95% CI, 0.52-0.93, respectively). The median time to second progression (PFS2) was 30.6 months (95% CI, 29.0-not calculable [NC]) with the combination vs 27.8 months (95% CI, 26.0-NC) with osimertinib monotherapy.

Consistent benefits with the combination were seen for other post-progression outcomes in this population including progression-free survival (PFS), time to second subsequent treatment (TSST), first interim overall survival (OS), and second interim OS, with HRs of 0.62 (95% CI, 0.49-0.79), 0.69 (95% CI, 0.51-0.93), 0.90 (95% CI, 0.65-1.24), and 0.75 (95% CI, 0.57-0.97), respectively.

Additional data from the second interim OS analysis of FLAURA2 revealed that at a median follow-up of 31.7 months (range, 0.1-43.3) the median OS with the combination was not reached (95% CI, 38.0-NC). The median OS was 36.7 months with osimertinib monotherapy (95% CI, 33.2-NC) after a median follow-up of 30.5 months (range, 0.1-43.0; P = .0280). The overall maturity of these data was 41%. The probability of OS was initially higher with the monotherapy at 12 months; however, OS benefit at 24- and 36- months favored the combination.

“All post-progression results showed a consistent benefit in favor of first-line osimertinib plus chemotherapy vs osimertinib alone for patients with EGFR-mutated advanced NSCLC,” lead study author Natalia Isabel Valdiviezo Lama, MD, a medical oncologist from the National Institute of Neoplastic Diseases in Lima, Peru, stated in an oral presentation of the data. “There was [also] an encouraging trend towards an OS benefit for osimertinib plus platinum-pemetrexed chemotherapy vs osimertinib alone at the second interim analysis for OS.”

The global, open-label, randomized FLAURA2 trial enrolled patients 18 years of age or older with pathologically confirmed, nonsquamous, locally advanced or metastatic EGFR-mutated NSCLC. Patients were required to express EGFR exon 19 deletions or L858R mutations, have a World Health Organization performance status (WHO PS) of 0 or 1 at screening, and have brain scans at baseline. No prior systemic therapy for advanced NSCLC was allowed. Notably, patients with stable brain metastases who completed definitive therapy, were not on steroids, and had a stable neurological status were eligible for the study. Key stratification factors included race (Chinese Asian vs non-Chinese Asian vs non-Asian), EGFR mutation (local vs central test), and WHO PS (0 vs 1).

A total of 557 patients were enrolled onto the study and randomly assigned 1:1 to receive the combination (n = 279) or osimertinib alone (n = 278). Patients received 80 mg of oral osimertinib once per day either alone or in combination with 500 mg/m² of pemetrexed (Alimta) plus 75 mg/m² of cisplatin or area under the curve 5 of carboplatin on day 1 of each 21-day cycle for a total of 4 cycles. Maintenance therapy in the combination arm consisted of 80 mg of osimertinib per day plus 500 mg/m² of pemetrexed once every 3 weeks.

The study’s primary end point was PFS, with a sensitivity analysis featuring PFS by blinded independent central review per RECIST v1.1 criteria. Secondary end points comprised objective response rate, duration of response, disease control rate, health-related quality of life, and safety as well as the following post-progression outcomes: PFS2, time to first subsequent treatment (TFST), TSST, and OS.

Follow-up assessments were conducted using RECIST v1.1 criteria at 6 and 12 weeks and continued every 12 weeks until radiologic disease progression or other withdrawal criteria were met. Notably, patients could continue study treatment after disease progression according to the investigator’s determination of continued benefit. This was considered to be a continuation of first-line treatment. PFS2 assessment occurred every 12 weeks thereafter until the data cutoff for the primary analysis. Survival follow-up occurred every 12 weeks until the data cutoff for the final OS analysis. The data cutoff for the second interim OS analysis was January 8th, 2024.

Previously reported data from the primary analysis of the FLAURA2 study showed that first-line osimertinib plus chemotherapy significantly improved PFS vs osimertinib alone in this patient population (HR, 0.62; 95% CI, 0.49-0.79; P < 0.001). At the data cutoff of April 3, 2023, the median PFS per investigator assessment with osimertinib plus chemotherapy was 25.5 months (95% CI, 24.7-NC) vs 16.7 months (95% CI, 14.1-21.3) with osimertinib monotherapy. The percentage of patients alive and progression-free at 24 months was 57% (95% CI, 50%-63%) in the osimertinib plus chemotherapy group vs 41% (95% CI, 35%-47%) in the osimertinib group.² This PFS benefit was observed across all prespecified subgroups.

Further results from the post-progression outcomes analysis showed signals for both TFST and TSST in favor of the combination arm vs osimertinib monotherapy. With an overall data maturity of 42%, the median TFST was 30.7 months (95% CI, 27.3-NC) with the combination vs 25.4 months (95% CI, 22.8-NC) with osimertinib monotherapy. The median TSST was not reached (95% CI, NC-NC) with the combination vs 33.2 months (95% CI, 28.2-NC) with the monotherapy; the overall maturity of these data was 32%.¹

At the time of the primary analysis, 55% of patients were still being treated with the osimertinib combination, and 44% remained on treatment with osimertinib monotherapy.¹ Of the patients who discontinued therapy in the combination arm (n = 123) or monotherapy arm (n = 151), 46% and 60%, respectively, began subsequent treatment.

The most frequently observed first subsequent therapy across both the combination and monotherapy arms was chemotherapy, at 69% (platinum based, 32% vs non-platinum based, 37%) and 84% (81% vs 3%), respectively. Other common second-line regimens included non–osimertinib-containing EGFR TKI regimens (14% vs 7%), and osimertinib plus a targeted therapy (5% vs 4%).

Findings from the final OS analysis of FLAURA2 will be presented at a later date.

Disclosures: Dr Valdiviezo Lama reported no potential conflicts of interest.

References

1. Valdiviezo Lama N, Okamoto I, Hughes BGM, et al. First-line (1L) osimertinib (osi) ± platinum-pemetrexed in EGFR-mutated (EGFRm) advanced NSCLC: FLAURA2 post-progression outcomes. Ann Oncol. 2024;9(suppl 3):1-53. doi:10.1016/esmoop/esmoop102569
2. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434