Evolving Standards of Care in EGFR+: Evaluating the Shift from TKIs to Combinations

Key Takeaways:

• Frontline combinations now offer significantly improved survival outcomes compared to standard monotherapy.
• Certain factors, such as specific mutations, increased tumor burden, and CNS disease, are critical indicators for choosing intensified combination therapy.
• Enhanced outcomes require proactive management of more frequent and complex multi-drug adverse events.

For nearly a decade, the management of advanced EGFR-mutant non-small cell lung cancer (NSCLC) has been dominated by the success of third-generation tyrosine kinase inhibitor (TKI) monotherapy. However, the paradigm is shifting. In addition to the "monotherapy-first" approach, the clinical community may also choose from more aggressive, personalized combination strategy options in the frontline setting for certain patients.^1,2

The rationale behind combination strategies

The primary driver of this shift is the inevitability of acquired resistance. Despite the efficacy of some monotherapies, resistance typically emerges through "on-target" mutations, such as C797S, or "off-target" bypass signaling, most notably MET amplification and HER2 alterations.³

Recent data suggest that targeting some of these pathways upfront – rather than waiting for progression – can significantly delay the emergence of resistance and extend overall survival (OS).

Redefining frontline therapy

The FDA approval of osimertinib plus platinum-pemetrexed chemotherapy in early 2024 marked the first major breakthrough in the monotherapy-only wall. Updated data presented at the ESMO Congress in 2025 confirmed that this combination provides a statistically significant and clinically meaningful OS benefit.^4,5

In the final OS analysis of the FLAURA2 trial, the combination arm achieved a median OS of 47.5 months compared to 37.6 months for osimertinib alone. For clinicians, the challenge is now identifying which patients will benefit most from this intensified regimen versus those who should remain on monotherapy.⁶

The rise of bispecifics

While FLAURA2 integrates traditional cytotoxic therapy, the MARIPOSA trial introduced a chemotherapy-free combination: the bispecific antibody amivantamab (targeting EGFR and MET) plus the third-generation TKI lazertinib.⁷

As reported in late 2024 and reinforced by 2025 long-term follow-up, the amivantamab-lazertinib combination significantly prolonged OS compared to osimertinib monotherapy, with a 3-year OS rate of 60 percent versus 51 percent, respectively. This regimen is particularly compelling for patients with "high-risk" molecular features, such as TP53 co-mutations or detectable baseline circulating tumor DNA (ctDNA), which also demonstrated PFS benefit.⁸

Clinical decision-making: Balancing efficacy and toxicity

The transition to combinations is not without trade-offs. The "standard" of care is becoming increasingly individualized based on:⁹

• Toxicity profiles – FLAURA2 demonstrated increased hematologic and gastrointestinal toxicities, while the MARIPOSA regimen is associated with higher rates of infusion-related reactions, skin reactions, and venous thromboembolism.
• Quality of life – Many patients may still prefer an oral-only, relatively low-toxicity regimen like osimertinib monotherapy.
• Subgroup biology – Emerging consensus suggests that patients with specific mutations, CNS metastases, increased tumor burden, and circulating tumor DNA should be evaluated for potential combination therapy.

The era of "one size fits all" monotherapy is coming to an end. The 2025 and 2026 updates to the ASCO Living Guidelines now reflect a more nuanced landscape where chemotherapy-TKI and bispecific-TKI combinations are preferred for patients fit for intensified therapy.⁹

For clinicians, the future of EGFR+ care lies in sophisticated risk stratification – using characteristics such as baseline molecular profiling and CNS status to choose the right combination at the right time.⁹