Ramucirumab-erlotinib: a suitable first-line treatment option for EGFR-mutated NSCLC, regardless of TP53 mutation status

An exploratory analysis of the phase III RELAY trial, comparing ramucirumab-erlotinib to placebo-erlotinib as first line treatment for patients with advanced, EGFR-mutant non-small cell lung cancer (NSCLC) show that co-occurring TP53 mutations are associated with a poorer outcome, regardless of the treatment type. Importantly, ramucirumab-erlotinib was associated with a better progression free survival and more durable responses compared to placebo-erlotinib, regardless of the TP53 mutation status. As such, the RELAY regimen proves to be a suitable first-line treatment option for all patients with EGFR-mutant NSCLC, irrespective of the TP53 mutation status.

Previous evidence shows that co-occurring TP53 mutations are associated with a poorer outcome following anti-EGFR tyrosine kinase inhibitor (TKI) therapy in patient with advanced EGFR-mutant NSCLC. Especially exon 8 mutations seem to be of interest as they can exert dysfunctional effects on the TP53 protein which may be involved in primary resistance to anti-EGFR TKI therapy. In addition to this, both preclinical and clinical evidence suggests that TP53 also plays a role in angiogenesis. In fact, TP53 alterations were found to correlate with a more favourable response to vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) antagonists and may therefore serve as a predictive biomarker for a response to antiangiogenic therapy. Recently, results of the phase III RELAY trial demonstrated that dual inhibition of the EGFR and VEGF pathways using ramucirumab and erlotinib results in a synergistic treatment effect, prolonging the progression-free survival (PFS) of patients with EGFR-mutant NSCLC. During ESMO 2021, results were presented of an analysis evaluating a potential association between the TP53 mutation status and treatment outcomes in RELAY.

Study design

RELAY is a randomised, double-blind, phase 3 trial comparing the efficacy of ramucirumab (RAM) (10 mg/kg) every 2 weeks plus erlotinib (ERL) (150 mg/day) vs. placebo (PBO) and ERL in patients with untreated, metastatic EGFR-mutant NSCLC. The primary endpoint of this trial is PFS, with overall response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS) and safety as secondary objectives. The presented exploratory post-hoc analysis of this trial investigated the association between co-occurring TP53 mutations and clinical outcomes by evaluating PFS, ORR, DCR, DoR and safety in function of the baseline TP53 mutation status. In addition, the analysis looked at the relationship between TP53 and treatment-emergent gene alterations at progression.

Consistent benefit of RAM+ERL over PBO+ERL regardless of TP53 status

Overall, TP53 mutations were detected in 165 patients, representing 43% of the evaluated RELAY cohort. Compared to TP53 wild-type patients, TP53 mutant patients seemed to be somewhat younger (<65 years: 55.8% vs. 42.5%), but apart from that, all other patients and disease characteristics were comparable between TP53 subgroups. A TP53 exon 8 mutation was detected in 41 patients. In general, concurrent gene alterations were comparable between TP53 mutant and wild-type tumours. although, PIK3CA mutations were detected at a higher rate in TP53 mutant tumours (15.8% vs. 5.9%). Finally, TP53 exon 8 mutant tumours had a greater frequency of NF1 mutations compared to those with non-exon 8 mutations (12.2% vs. 4.8%).

The presence of baseline TP53 mutations (particularly on exon 8) was found to be associated with a significantly shorter PFS comparison to patients with baseline TP53 wild-type tumours, regardless of the treatment type. Importantly, however, in both patients with TP53 mutant (median PFS: 15.18 vs. 10.61 months; HR: 0.541) and TP53 wild-type (median PFS: 20.76 vs. 15.67 months; HR: 0.789) EGFR-mutant NSCLC, RAM+ERL significantly improved the PFS compared to PBO+ERL. RAM+ERL induced a significantly better PFS compared to PBO+ERL in patients with non-exon 8 TP53 mutations. For the small number of patients with TP53 mutations on exon 8, the median PFS for RAM+ERL was superior to PBO+ERL.  Both the ORR and DCR were similar for TP53 mutant and TP53 wild-type tumours in both the RAM+ERL and PBO+ERL arms. Irrespective of the baseline TP53 mutation status, RAM+ERL significantly improved the DoR over PBO+ERL. Finally, similar toxicity profiles were observed between patients with TP53 mutant and TP53 wild-type tumours.

Conclusions

The presented exploratory analysis of RELAY confirms that co-occurring TP53 alterations are a negative prognostic factor in metastatic EGFR-mutant NSCLC with poorer outcomes for patients with a TP53 mutation (especially exon 8), regardless of the treatment. The combination of RAM and ERL was associated with a better outcome than PBO plus ERL regardless of the TP53 mutation status. Safety profiles were comparable between TP53 mutant and wild-type subgroups. Baseline patient and disease characteristics and concurrent gene alterations did not reveal any phenotypic difference between TP53 mutant and TP53 wild-type tumours. As such, the investigators concluded that the RELAY regimen is a suitable first-line treatment option for all patients with EGFR-mutant NSCLC, irrespective of the TP53 mutation status.

Reference

Nishio M, Paz-Ares L, Reck M, et al. RELAY, Ramucirumab plus erlotinib (RAM+ERL) in untreated metastatic EGFR-mutant NSCLC (EGFR+ NSCLC): association between TP53 status and clinical outcome. Presented at ESMO 2021; Abstract 1209P.