Frontline EGFR/VEGF Inhibition Slows Advanced EGFR-Positive Lung Cancer

Adding the VEGF inhibitor ramucirumab (Cyramza) to the EGFR inhibitor osimertinib (Tagrisso) slowed progression of untreated EGFR-positive non-small cell lung cancer (NSCLC) by 9 months compared with osimertinib alone, an interim analysis of the randomized RAMOSE trial showed.

The combination produced a median progression-free survival (PFS) of 24.8 months versus 15.6 months with single-agent osimertinib. The 12-month PFS rates were 76.7% and 61.9%, respectively.

Adverse events (AEs), treatment-related AEs (TRAEs), and grade 3 TRAEs occurred in a similar proportion of patients in the two treatment arms, reported Xiuning Le, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and co-authors in the Journal of Clinical Oncology.

“The study is not powered for OS [overall survival] analysis and the data are immature at the interim analysis,” the authors acknowledged. “Therefore, additional time for events to accumulate for final analysis will be important to confirm these findings, and further validation of the ramucirumab with osimertinib combination in the first-line setting in a larger study will be necessary.”

“Data from the phase II, randomized, multicenter RAMOSE trial indicate that the addition of ramucirumab to osimertinib significantly prolongs PFS in TKI [tyrosine kinase inhibitor]-naive patients with NSCLC harboring classical EGFR mutations,” they added. “The combination demonstrated a safety profile in line with each drug without new safety signals, presenting a promising intensification strategy.”

The findings added to an accumulation of evidence that led to approval of single-agent osimertinib as first-line treatment for EGFR-mutated NSCLC. Beginning at least 7 years ago, lung cancer specialists advocated for osimertinib as first-line treatment for EGFR-mutated NSCLC. That position has carried over in the evaluation of combination strategies to intensify treatment.

These results aligned with earlier trials of first-generation EGFR TKIs such as the phase III NEJ026 and ARTEMIS trials, which showed that combination therapy with erlotinib (Tarceva) and bevacizumab (Avastin) significantly prolonged PFS versus erlotinib alone. Similarly, the phase III RELAY trial showed that erlotinib plus ramucirumab significantly improved PFS versus single-agent erlotinib.

More recently, the MARIPOSA trial showed a statistically significant 7-month improvement in PFS over single-agent osimertinib with the bispecific antibody amivantamab (Rybrevant) and the third-generation EGFR inhibitor lazertinib (Lazcluze) as first-line treatment for EGFR-mutated NSCLC.

The phase III FLAURA2 trial showed a median PFS of 25.2 months when osimertinib was added to chemotherapy as first-line treatment for EGFR-mutated NSCLC. Data from the trial provided principal support for FDA approval of the first-line combination.

Not all trials of osimertinib-VEGF inhibitor combinations have shown improved PFS versus the EGFR inhibitor alone, such as the WJOG9717L trial of osimertinib and bevacizumab and the TORG1833 trial of osimertinib and ramucirumab. Both trials had relatively short exposure to osimertinib, which likely was the principal reason for the lack of superiority for the combination, according to Le and colleagues.

A sound biological rationale exists for combining VEGF and EGFR inhibitors. Preclinical and clinical studies have suggested that EGFR-mutated NSCLC appears particularly sensitive to VEGF inhibition. Combined VEGF/EGFR inhibition delayed emergence of EGFR TKI resistance in preclinical models of EGFR-mutated NSCLC. EGFR signaling increases VEGF in EGFR-mutated NSCLC, which in turn contributes to emergence of EGFR TKI resistance. The preclinical evidence has been supported by clinical trials that have consistently shown improved clinical outcomes in previously untreated EGFR-mutant NSCLC with anti-VEGF/EGFR TKI combinations, the authors noted.

The open-label RAMOSE trial involved patients and investigators at 11 sites in the U.S. Eligible patients had newly diagnosed advanced/metastatic NSCLC and EGFR exon 19 deletion or L858R mutations. The protocol allowed for enrollment of patients with asymptomatic brain metastases.

Patients were randomized 2:1 to osimertinib plus ramucirumab or single-agent osimertinib. The primary endpoint was investigator-assessed PFS in the evaluable patient population.

Data analysis included 139 evaluable patients. At a preplanned interim analysis after 16.6 months of follow-up, the primary analysis showed a 9.2-month difference in median PFS in favor of the combination, which translated into a 45% reduction in the hazard for disease progression or death (95% CI 0.32-0.93, P=0.023). There was a near-15% absolute difference in PFS rate at 12 months favoring the combination (P=0.026). Objective response rate and disease control rate did not differ between the treatment arms.

No grade 5 AEs had occurred at the interim analysis. A single case of hyponatremia in the combination arm was the only grade 4 TRAE. Rates of grade 3 TRAEs were 53% with the combination and 41% with single-agent osimertinib. AE-associated discontinuation rates were 9.7% with osimertinib-ramucirumab and 8.7% with osimertinib alone.

Le and colleagues acknowledged limitations to their study: a moderate sample size, the potential for bias with investigator-assessed PFS, and an imbalance in patients with brain metastases, although the difference did not reach statistical significance.