Sequential Erlotinib Plus Ramucirumab Prior to Osimertinib Fails to Improve Outcomes in EGFR L858R–Mutant NSCLC

June 1, 2026 | Caroline Seymour

The combination of erlotinib (Tarceva) and ramucirumab (Cyramza) prior to treatment with osimertinib (Tagrisso) failed to deliver an improvement in time to failure of strategy (TFS) vs osimertinib (Tagrisso) alone in patients with untreated advanced or recurrent non–small cell lung cancer (NSCLC) harboring an EGFR L858R mutation, according to data from the phase 3 REVOL858R/WJOG14420L trial (jRCTs051200142) that were presented at the 2026 ASCO Annual Meeting.¹

The median TFS was 16.6 months (95% CI, 13.3-19.6) with the combination approach vs 14.8 months (95% CI, 11.6-20.9) with osimertinib alone (HR, 1.03; 95% CI, 0.78-1.38; P = .49). Median follow-up was 40.3 months in the combination arm vs 37.1 months in the monotherapy arm. The landmark TFS rates at 12, 24, and 36 months in the combination arm were 65%, 30%, and 13%, respectively, vs 58%, 36%, and 19% in the single-agent arm.

Additionally, no clear advantage in favor of the combination was seen according to baseline prognostic factors.

“Erlotinib plus ramucirumab followed by osimertinib did not improve TFS vs upfront osimertinib in untreated advanced EGFR L858R–mutant NSCLC, showing a numerically lower median PFS than that reported in [the phase 3] RELAY [trial (NCT02411448)], while its safety profile was consistent with prior reports,” lead study author Naoki Haratake, MD, PhD, of the Department of Thoracic Oncology at NHO Kyushu Cancer Center in Fukuoka, Japan, said in a presentation of the data.

Why re-evaluate a frontline standard of care in EGFR-mutant NSCLC?

Despite producing a median overall survival (OS) of 38.6 months (95% CI, 34.5-41.8) in the pivotal phase 3 FLAURA trial (NCT02296125) of EGFR-mutant advanced NSCLC, efficacy outcomes appear worse in the L858R population vs the exon 19 deletion population.²

Investigators hypothesized that the introduction of erlotinib and ramucirumab prior to osimertinib therapy could improve outcomes vs osimertinib alone in this population.¹

The open-label, randomized phase 3 trial was designed to evaluate the comparative efficacy of such an approach. Investigators enrolled 230 patients at least 20 years old with untreated advanced nonsquamous NSCLC with an EGFR L858R mutation, and performance status of 0 or 1. Patients with asymptomatic brain metastases were eligible.

Patients were randomly assigned 1:1 to 80 mg of osimertinib per day, or 150 mg of erlotinib per day plus 10 mg/kg of ramucirumab every 2 weeks, and if T790M positive, the same dose and schedule of osimertinib.

Stratification factors included disease stage (stage IIIB to IV vs postoperative recurrence), brain metastasis (present or absent), and sex.

The primary end point was TFS, which was defined as the time from randomization to disease progression or death during osimertinib, or during treatment with the combination when osimertinib was not administered. Secondary end points included OS, progression-free survival (PFS), time to second progression or death, objective response rate, time to treatment failure, time to treatment discontinuation of TKI, and safety.

What were the baseline characteristics of the enrolled population?

Overall (n = 232), most patients were female (n = 143; 62%) and had a median age of 73 years (range, 36-91). ECOG performance status was primarily 0 (n = 130; 66%) and most patients had stage IIIB to IV disease (n = 171; 73%) vs postoperative recurrence (n = 61; 26%). The minority of patients were smokers (n = 80; 35%) and had brain metastases (n = 67; 29%).

What were the PFS and OS data?

Analysis of the key secondary end points also revealed no advantage for the combination. The median PFS was 14.9 months (95% CI, 12.2-17.8) with the combination vs 14.8 months (95% CI, 11.6-20.9) with osimertinib alone (HR, 1.08; 95% CI, 0.81-1.44). The median OS was 38.4 months (95% CI, 33.3-not reached [NR]) with the combination vs 44.0 months (95% CI, 31.1- NR) with osimertinib alone (HR, 0.98; 95% CI, 0.66-1.45).

What was the rate of T790M mutations and array of first subsequent therapies?

Of 116 patients receiving erlotinib plus ramucirumab, 48 (41%) were evaluated for the EGFR T790M resistance mutation at progression. Twenty-nine (25%) patients underwent tissue re-biopsy and 19 (16%) underwent plasma circulating tumor DNA (ctDNA) testing. T790M was identified in 15 (13%) patients. Most T790M-positive cases were detected by tissue re-biopsy (n = 12; 10%), with the remaining 3 (3%) detected by ctDNA analysis.
Within the combination arm (n = 116) first subsequent therapies consisted of osimertinib (n = 16; 14%), first- or second-generation EGFR TKIs (n = 28; 24%), platinum-based cytotoxic chemotherapy (n = 28; 24%), or nonplatinum cytotoxic chemotherapy (n = 3; 3%); 35% (n = 41) of patients did not receive a subsequent therapy.

In the monotherapy arm (n = 116) first subsequent therapies consisted of osimertinib (n = 23; 20%), first- or second-generation EGFR TKIs (n = 7; 6%), platinum-based cytotoxic chemotherapy (n = 34; 29%), nonplatinum cytotoxic chemotherapy (n = 1; 1%), or other (n = 3; 3%); 41% (n = 48) of patients did not receive a subsequent therapy.

How did the addition of erlotinib and ramucirumab affect the safety profile of the regimen?

Within the combination arm, adverse effects (AEs) included acneiform rash (grade 1/2, 52%; grade 3/4, 19%), diarrhea (52%; 2%), paronychia (34%; 6%), hypertension (21%; 17%), increased aspartate aminotransferase (AST) levels (31%; 7%), increased alanine aminotransferase (ALT) levels (22%; 10%), stomatitis (27%; 4%), decreased appetite (21%; 8%), bleeding or hemorrhage events (19%; 7%), dry skin (23%; 2%), proteinuria (15%; 4%), epistaxis (17%; 1%), anemia (13%; 3%), and decreased platelet counts (14%; 0%).

In the monotherapy arm AEs consisted of acneiform rash (grade 1/2, 29%; grade 3/4, 1%), diarrhea (37%; 4%), paronychia (30%; 0%), hypertension (1%; 0%), increased AST levels (15%; 2%), increased ALT levels (14%; 1%), stomatitis (16%; 2%), decreased appetite (23%; 1%), bleeding or hemorrhage events (3%; 2%), dry skin (21%; 0%), proteinuria (2%; 0%), epistaxis (3%; 0%), anemia (16%; 3%), and decreased platelet counts (11%; 0%).

Overall, in the combination arm (n = 115), all patients experienced an AE, 72% (n = 83) of which were grade 3 or greater. Any AE that led to treatment discontinuation occurred in 36% (n = 41) of patients; 23% (n = 26) discontinued therapy because of progressive disease. Grade 1 or greater interstitial lung disease (ILD) or pneumonitis occurred in 2% (n = 2) of patients.

In the monotherapy arm (n = 117), all patients experienced an AE, 44% (n = 52) of which were grade 3 or greater. Any AE that led to treatment discontinuation occurred in 21% (n = 24) of patients; 52% (n = 61) discontinued therapy because of progressive disease. Grade 1 or greater ILD or pneumonitis occurred in 10% (n = 12) of patients.

“EGFR L858R–mutant NSCLC remains an unmet clinical need, and longer follow-up is ongoing to clarify the long-term OS effect of this sequential strategy,” Haratake concluded.

Disclosures: Haratake disclosed honoraria from AstraZeneca Japan, Lilly Japan, and Merck Sharp & Dohme; and consulting or advisory roles with Lilly Japan.

References

Haratake N, Hayashi H, Tanaka K, et al. Phase 3 clinical trial of the combination of erlotinib plus ramucirumab compared with osimertinib in untreated advanced or recurrent non-small cell lung cancer with EGFR L858R mutation: the REVOL858R trial (WJOG14420L). J Clin Oncol. 2026;44(suppl 17):LBA8518. doi:10.1200/JCO.2026.44.17_suppl.LBA8518

Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662