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Current Status of EGFR Tyrosine Kinase Inhibitor Combination Therapy in the Treatment of Newly Diagnosed EGFR-Mutated Advanced NSCLC

David Planchard, MD, PhD

Head of Thoracic Group
Department of Medical Oncology
Gustave Roussy
Villejuif, France

David Planchard, MD, PhD, has disclosed that he has received consulting fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Pfizer, Roche, and Samsung.

View ClinicalThoughts from this Author

Released: December 3, 2021

EGFR tyrosine kinase inhibitor (TKI) therapy is the current first-line standard of care for advanced EGFR-mutated non-small-cell lung cancer (NSCLC). However, progression inevitably occurs, thus there is a push to explore combination therapy in the frontline setting as a means of preventing―or at least delaying―EGFR TKI resistance. In this commentary, I will provide an overview of the current status of EGFR TKI combination therapy in the treatment of newly diagnosed EGFR-mutated advanced NSCLC, including a review of available clinical trial data on EGFR TKI combination therapy with antiangiogenic agents and an introduction to other EGFR TKI combination strategies being explored.

Combining EGFR TKIs With Antiangiogenic Agents
There is sound rationale for combining EGFR TKI therapy with antiangiogenic agents in the treatment of EGFR-mutated NSCLC. Preclinical data have demonstrated costimulation of the EGFR and VEGF signaling pathways in EGFR-positive disease, with upregulated EGFR signaling leading to upregulation of VEGF, a key mediator of angiogenesis, to support tumorigenesis. EGFR and VEGFR-2 signaling both can trigger activation of the PI3K/AKT and RAS/RAF/ERK pathways, and EGFR activation leads to HIF-1α upregulation, which may lead to VEGF gene expression and a positive feedback loop. VEGF signaling in turn contributes to the emergence of resistance to EGFR TKIs. Furthermore, therapeutic agents targeting VEGF and VEGFR already are approved and in use for the treatment of advanced NSCLC, including bevacizumab, a VEGF inhibitor, and ramucirumab, a VEGFR2 antagonist. The approach of combining an EGFR TKI with an antiangiogenic therapy is being explored in several trials in the first-line setting for patients with advanced EGFR-mutated NSCLC, which I will discuss next.

Combinations With the First-Generation EGFR TKI Erlotinib
The phase III RELAY trial (N = 449; NCT02411448) is evaluating the combination of erlotinib and ramucirumab in patients with untreated metastatic EGFR mutation–positive (either an exon 19 deletion or exon 21 L858R mutation) NSCLC. At a follow-up of 20.7 months, this combination conferred a progression-free survival (PFS) benefit compared with erlotinib plus placebo (median PFS: 19.4 months vs 12.4 months, respectively; HR: 0.59; 95% CI: 0.46-0.76; P <.0001). These results led to the FDA approval of this combination in the United States for the first-line treatment of metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R mutations. The RELAY trial is ongoing, so we have to wait to see if this improvement in PFS will translate into an overall survival (OS) benefit.

Erlotinib also is being evaluated in combination with bevacizumab for the first-line treatment of metastatic EGFR-mutated advanced NSCLC. In an interim analysis of the phase III NEJ026 trial (N = 228), this combination improved PFS compared with erlotinib monotherapy in a population of Japanese patients (median PFS: 16.9 months vs 13.3 months; HR: 0.605; 95% CI: 0.417-0.877; P = .016). However, at a median follow-up of 39.2 months, the combination of erlotinib and bevacizumab did not show an OS improvement (median OS: 50.7 months vs 46.2 months; HR: 1.00; 95% CI: 0.68-1.48), which was quite disappointing. In the open-label, randomized, multicenter phase III BEVERLY trial (N = 160; NCT02633189), erlotinib plus bevacizumab improved overall response rate (70% vs 50% with erlotinib alone) and median PFS (15.4 months vs 9.6 months; HR: 0.66; 95% CI: 0.47-0.92; P = .015), but again, this did not translate to a significant improvement in median OS (33.3 months vs 22.8 months; HR: 0.72; 95% CI: 0.47-1.10; P = .132). However, the OS was numerically higher in patients who received the combination.

In the BEVERLY trial, investigators performed subgroup analyses of PFS and OS with erlotinib plus bevacizumab by age, type of EGFR mutation, and smoking history, among other patient and disease characteristics. Of interest, there was a trend toward both a PFS and OS benefit with the combination in patients who were current or former smokers but no benefit for those who never smoked. Keeping in mind that this was an exploratory subgroup analysis―so we can’t make any definitive conclusions―these are data to keep in mind when selecting patients who might benefit from the addition of an antiangiogenic agent to EGFR TKI therapy.

Together, these data show that dual targeting of the EGFR and VEGF signaling pathways is a promising approach in the treatment of newly diagnosed advanced EGFR-mutated NSCLC, but without an improvement in OS, questions remain about the utility of combining first-generation EGFR TKIs and antiangiogenic agents in the first-line setting.

Combinations With the Third-Generation EGFR TKI Osimertinib
With osimertinib having emerged as the first-line EGFR TKI of choice for the treatment of advanced EGFR-mutated NSCLC based on the phase III FLAURA trial, which showed a survival benefit with osimertinib vs first-generation EGFR TKIs, we now are evaluating osimertinib in combination with antiangiogenic therapies.

At the 2021 European Society for Medical Oncology Virtual Congress, primary results were presented from the phase II WJOG9717L trial comparing osimertinib plus bevacizumab with osimertinib alone in the first-line setting. WJOG9717L was a negative study: Adding bevacizumab to osimertinib did not improve any efficacy outcomes. The response rate was high in both arms at 86% with the combination vs 82% with osimertinib alone, and there was no significant improvement in PFS (22.1 vs 20.2 months; HR: 0.862; P = .213) or OS (not reached in either arm) with the combination. However, in a subgroup analysis, a trend toward a PFS benefit with the combination was seen in patients with a smoking history (HR: 0.481; 95% CI: 0.227-1.019) but not in never smokers (HR: 1.444; 95% CI: 0.736-2.833). The PFS subgroup analysis also suggested that patients with EGFR exon 19 deletions benefited from the combination compared with monotherapy (HR: 0.622; 95% CI: 0.312-1.240), but this was not the case for patients with EGFR exon 21 L858R mutations (HR: 1.246; 95% CI: 0.621-2.502). Thus, it appears that patients with advanced EGFR-mutated NSCLC who are current or former smokers and those with EGFR exon 19 deletions may fare better with the addition of an antiangiogenic agent to osimertinib in the frontline setting, with the caveat that this is only PFS data, not OS.

Osimertinib in combination with ramucirumab also is being evaluated for the first-line treatment of advanced EGFR-mutant disease in the phase II RAMOSE trial (NCT03909334). Enrollment is ongoing, and we look forward to the report of these data.

Other EGFR TKI Combination Strategies
Clinical trials are exploring various other EGFR TKI combinations, including with other targeted therapies, other EGFR TKIs, or chemotherapy.

For example, upfront trials are evaluating strategies that block both the EGFR and MET signaling pathways based on the preliminary success of this approach in the setting of osimertinib resistance. We know that approximately 15% of patients receiving osimertinib in the first-line setting will develop resistance through MET amplification and now have promising data for the combination of the third-generation EGFR TKI lazertinib plus amivantamab, a bispecific antibody that blocks both EGFR and MET pathway activation, in osimertinib-relapsed, EGFR-mutated advanced NSCLC. The ongoing phase III MARIPOSA study is evaluating this same strategy vs osimertinib alone for the treatment of newly diagnosed EGFR-mutant advanced disease (NCT04487080).

Preclinical evidence suggests that dual EGFR inhibition with gefitinib and osimertinib may delay emergence of acquired resistance: The EGFR TKI osimertinib is active against the acquired gefitinib-resistant mutation EGFR T790M, and gefitinib is active against the osimertinib-resistant mutation EGFR C797S. In a phase I/II study that enrolled patients with untreated metastatic NSCLC and either an EGFR exon 19 deletion or exon 21 L858R mutation, the combination of gefitinib and osimertinib was tolerable. Of the 27 patients included in the analysis population, 81.5% completed ≥6 treatment cycles with an overall response rate of 88.9%. Analysis of survival outcomes and acquired resistance mechanisms are pending data maturity and will facilitate our understanding of the role of this combination in the treatment of advanced EGFR-mutated NSCLC. Early-phase trials exploring the feasibility of combining a fourth-generation EGFR TKI (eg, BLU-945) with a first-generation EGFR TKI or osimertinib as a way to avoid development of the EGFR T790M and C797S resistance mutations, respectively, are under development.

Finally, the combination of an EGFR TKI and chemotherapy as first-line therapy for EGFR-mutated advanced NSCLC also has shown promising results, with a PFS benefit being demonstrated with the combination of the first-generation EGFR TKI gefitinib plus platinum/pemetrexed vs gefitinib alone in 2 randomized phase III studies. This strategy is now being explored with osimertinib: The phase III FLAURA2 trial is evaluating osimertinib with or without platinum-based chemotherapy plus pemetrexed in the first-line setting for patients with advanced EGFR-mutated NSCLC (NCT04035486). The first results of a safety analysis showed a good tolerance without significant increase in toxicity. The study has just finished enrolling patients, and efficacy results are eagerly awaited.

Your Thoughts?
Have you ever considered EGFR TKI combination therapy in the treatment of your patients with newly diagnosed advanced NSCLC? Answer the polling question and join the conversation by posting a comment in the discussion section.

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