Analysis Reveals Insights About Chemo Rechallenge After Progression on FLAURA2 Regimen in EGFR+ Advanced NSCLC

March 30, 2026 | Kristi Rosa

Chemotherapy rechallenge proved to be common after disease progression (PD) on frontline osimertinib (Tagrisso) plus platinum and pemetrexed in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), potentially because of a long chemotherapy-free interval, according to data from an exploratory analysis of the phase 3 FLAURA2 trial (NCT04035486).¹

Data shared during the 2026 European Lung Cancer Congress showed that chemotherapy-containing regimens were given as first subsequent treatment (FST) in 74% of patients who received osimertinib plus platinum/pemetrexed (n = 88) and 76% of those given single-agent osimertinib (n = 143).

Moreover, rechallenge with platinum- and non–platinum-based chemotherapy occurred in 44% and 30% of patients, respectively, in the osimertinib plus platinum/pemetrexed arm. In the osimertinib-alone arm, 72% and 3% of patients received platinum- and non–platinum-based chemotherapy, respectively, for the first time. In the osimertinib plus platinum/pemetrexed arm, the median duration of the chemotherapy-free interval was 10.4 months (range, 0.5-49.9).

Additionally, 19% of those in the osimertinib plus platinum/pemetrexed arm went on to receive a pemetrexed-containing FST. Of these patients, 41% received carboplatin/pemetrexed alone and 47% received carboplatin/pemetrexed with other agents as FST. Seventy-one percent of patients who were rechallenged with pemetrexed discontinued frontline pemetrexed because of toxicities. Eighty eight percent of patients had a pemetrexed-free interval of over 6 months; the median duration of the pemetrexed-free interval was 19.8 months (range, 0.5-42.3). Moreover, the median duration of first-line pemetrexed was 5.5 months (range, 0.0-46.7), and the median duration of second-line pemetrexed was 5.2 months (range, 0.8-11.1).

In patients who received osimertinib plus pemetrexed/platinum, the median overall survival (OS) was:

• 3 months (95% CI, 41.0-NC) in those who discontinued osimertinib because of PD and went on to receive platinum-based chemotherapy as FST;
• 5 months (95% CI, 22.9-35.0) in the subgroup who discontinued osimertinib because of PD and received non–platinum-based chemotherapy as FST;
• 7 months (95% CI, 33.4-NC) in the subgroup who discontinued osimertinib due to PD and received other treatment regimens as FST.

In these respective groups, the estimated 3-year survival rates were 77% (95% CI, 60%-87%), 27% (95% CI, 12%-44%), and 65% (95% CI, 42%-81%).

In those who received single-agent osimertinib, the median OS was:

• 8 months (95% CI, 28.8-36.7) in the subgroup who discontinued osimertinib because of PD and went on to receive platinum-based chemotherapy as FST; and
• 9 months (95% CI, 34.6-53.3) in patients who discontinued osimertinib due to PD and received other regimens as FST.

The estimated 3-year survival rate in the former subgroup was 42% (95% CI, 33%-52%); in the latter subgroup, this rate was 60% (95% CI, 43%-73%).

“Many patients who first received osimertinib plus platinum/pemetrexed in FLAURA2 later received chemotherapy again,” Carles Escriu, MBBS, MRCP Med Onc, PhD, of the Department of Medical Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, in Liverpool, UK, and coauthors, wrote. “This shows that starting with chemotherapy does not prevent patients from having chemotherapy again in later lines of treatment.”

What was the design of FLAURA2, and what data have previously been reported?

The global, open-label, phase 3 FLAURA2 study enrolled patients with untreated locally advanced or metastatic NSCLC who had at least 18 years of age with pathologically confirmed nonsquamous disease and EGFR exon 19 deletion/L858R mutations. Patients were required to have a World Health Organization (WHO) performance status of 0 or 1. Those with stable central nervous system metastases were permitted.

Patients (n = 557) were randomized 1:1 to receive osimertinib at 80 mg once daily plus pemetrexed at 500 mg/m² and carboplatin area under the curve 5 or cisplatin at 75 mg/m² every 3 weeks for 4 cycles of platinum-based treatment followed by maintenance osimertinib at 80 mg once daily plus pemetrexed at 500 mg/m² every 3 weeks or single-agent osimertinib at 80 mg once daily. Stratification factors included race (Asian Chinese vs Asian non-Chinese vs non-Asian), EGFR mutation test (local vs central), and WHO performance status (0 vs 1).

The primary end point was progression-free survival (PFS) by investigator assessment and RECIST 1.1 criteria. Key secondary end points were OS, time to first subsequent treatment or death, DOR, disease control rate, second PFS, time to second subsequent treatment or death, and health-related quality of life.

Prior data from the study showed that PFS was significantly longer in the osimertinib plus platinum/pemetrexed arm (n = 279) vs the osimertinib-alone (n = 278) arm, at a median of 25.5 months vs 16.7 months, respectively (HR, 0.62; 95% CI, 0.49-0.79; P < .001).²

In February 2024, the FDA approved osimertinib plus platinum-based chemotherapy for use in patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations based on FLAURA2 data.³ Updated data showed that the median OS in the osimertinib plus platinum/pemetrexed arm was 47.5 months vs 37.6 months with osimertinib alone (HR, 0.77; 95% CI, 0.61-0.96; P = .02).⁴

What did these post hoc analyses examine?

In the latest analyses shared during the congress, investigators sought to examine the use of chemotherapy as FST in patients with EGFR-mutated NSCLC who discontinued frontline osimertinib plus platinum/pemetrexed because of PD in FLAURA2.¹

A total of 127 patients out of the 279 in the osimertinib plus platinum/pemetrexed arm discontinued frontline osimertinib because of PD; in the osimertinib monotherapy arm, 185 of the 278 patients discontinued first-line osimertinib due to PD. In these respective arms, 69% and 77% of patients received an FST.

In the osimertinib plus platinum/pemetrexed arm (n = 88), 44% received platinum-based chemotherapy as FST. Specifically, 16% of patients received platinum doublet chemotherapy, 15% received platinum chemotherapy with immunotherapy, 7% received platinum with EGFR inhibition, 6% received platinum and antiangiogenic therapy, and 1% received platinum and other. In the osimertinib-alone arm, these respective rates were 31%, 17%, 10%, 11%, and 1%; 1% of patients in this group received platinum with a single agent.

Moreover, in the osimertinib plus platinum/pemetrexed arm, 30% received non–platinum-based chemotherapy as FST. Seventeen percent of patients received non-platinum single-agent chemotherapy, 6% received non-platinum chemotherapy plus antiangiogenic therapy, and 7% received non-platinum chemotherapy plus EGFR inhibition; these respective rates in the osimertinib-alone arm were 1%, 1%, and 0%. One percent of patients in this group received non-platinum doublet chemotherapy.

In the osimertinib plus platinum/pemetrexed arm, 8% received EGFR-targeted therapy beyond osimertinib as a single agent or in combination as FST vs 7% of those in the osimertinib-alone arm; 5% vs 3% of patients received osimertinib plus a targeted agent or investigational drug with no chemotherapy. Lastly, 14% of patients in both arms received other FST.

The data cutoff date was June 12, 2025, for the current analyses.

What additional efforts are underway to further investigate osimertinib in NSCLC?

The phase 3 SAFFRON trial (NCT05261399) is comparing the safety and efficacy of savolitinib plus osimertinib with platinum-based doublet chemotherapy in patients with NSCLC who progressed on osimertinib.⁵ Moreover, the safety and efficacy of datopotamab deruxtecan-dlnk (Datroway) with or without osimertinib is being compared with platinum-based doublet chemotherapy in patients with EGFR-mutated locally advanced or metastatic NSCLC as part of the phase 3 TROPION-Lung15 study (NCT06417814).⁶

Disclosures: Dr Escriu disclosed serving in advisory roles for AstraZeneca, Johnson & Johnson/Janssen, and Regeneron. He served on the speaker’s bureau for AstraZeneca, MSD Oncology, and Pfizer. Travel expenses were provided by Amgen and Johnson & Johnson/Janssen.

References

Escriu C, Jänne PA, Planchard D, et al. Chemotherapy rechallenge in patients with EGFR-mutated advanced NSCLC who discontinued first-line osimertinib plus platinum–pemetrexed due to progression: FLAURA2 exploratory analysis. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Poster 27P.

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

FDA approves osimertinib with chemotherapy with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 16, 2024. Accessed March 27, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer

Jänne JA, Planchard D, Kobayashi K, et al. Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):27-38. doi:10.1056/NEJMoa2510308

Savolitinib plus osimertinib versus platinum-based doublet chemotherapy in participants with non-small cell lung cancer who have progressed on osimertinib treatment (SAFFRON). ClinicalTrials.gov. Updated January 10, 2025. Accessed March 27, 2026. https://clinicaltrials.gov/study/NCT05261399

A study to investigate the efficacy and safety of Dato-DXd with or without osimertinib compared with platinum based doublet chemotherapy in participants with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (TROPION-Lung15). ClinicalTrials.gov. Updated March 2, 2026. Accessed March 27, 2026. https://clinicaltrials.gov/study/NCT06417814