In the relentless battle against non-small cell lung cancer (NSCLC), a new beacon of hope emerges through the strategic combination of MET tyrosine kinase inhibitors (MET-TKIs) with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs). NSCLC patients harboring EGFR mutations often exhibit initial responsiveness to EGFR-TKIs, yet the relentless evolution of resistance mechanisms, particularly those involving acquired MET alterations, has long posed a formidable challenge to clinical management. A groundbreaking systematic review and meta-analysis recently published in BMC Cancer sheds light on the potential of combining MET-TKIs with EGFR-TKIs to overcome this resistance and enhance therapeutic outcomes.
This comprehensive meta-analysis encompassed six pivotal clinical studies, aggregating data from a cohort of 562 patients afflicted with NSCLC who developed acquired MET-driven resistance after prior EGFR-TKI therapy. By meticulously analyzing response rates, survival metrics, and adverse events, the investigators endeavored to delineate the therapeutic landscape of MET-TKI and EGFR-TKI combination regimens in this complex clinical niche. The findings herald a significant stride forward in pinpointing efficacious intervention strategies tailored to molecular resistance profiles.
At the forefront of the results, the pooled objective response rate (ORR) to the combination of MET-TKIs and EGFR-TKIs approached an encouraging 49.2%, coupled with a disease control rate (DCR) of 78.6%. These figures suggest that nearly half of the patients manifested measurable tumor shrinkage, while over three-quarters achieved disease stabilization or better. Importantly, the median duration of response (mDOR) spanned approximately 6.85 months, indicating a substantive period during which tumor regression was sustained. Complementing these outcomes, the median progression-free survival (mPFS) reached 5.62 months, underscoring the regimen’s capacity to delay disease advancement.
Dissecting the data further, the investigators parsed out differences contingent on the generation of EGFR-TKIs employed alongside MET-TKIs. Notably, combining MET-TKIs with third-generation EGFR-TKIs yielded numerically superior outcomes compared to first-generation EGFR-TKI combinations in patients who were T790M-negative but exhibited MET-dependent resistance. While statistical significance narrowly eluded some efficacy endpoints—such as ORR (56.8% vs. 47.8%) and DCR (81.6% vs. 75%)—the median duration of response and median progression-free survival favored the third-generation combinations, with mPFS notably extending to 7.45 months versus 4.55 months in the first-generation groups (p=0.05). These observations underscore the clinical advantage offered by newer-generation EGFR inhibitors in overcoming complex resistance mechanisms.
Beyond the generational distinction of EGFR-TKIs, the meta-analysis juxtaposed the efficacy profiles of three prominent MET inhibitors: capmatinib, savolitinib, and tepotinib. Remarkably, the objective response rates across these agents converged around 48-51%, signaling broadly comparable anti-tumor activity. Disease control rates, while showing some variability—savolitinib achieving the highest at 84.9% and tepotinib the lowest at 63.3%—did not consistently translate to statistically significant differences (p=0.02 in some cases). Median durations of response and progression-free survival similarly demonstrated no marked distinctions, suggesting interchangeability of MET-TKIs in efficacy when paired with EGFR-TKIs.
Safety profiles, however, unveiled subtle yet clinically meaningful distinctions pivoting around hepatotoxicity. Capmatinib-based combinations were associated with numerically lower incidences of elevated liver enzymes—specifically, increased AST and ALT levels—when compared to savolitinib and tepotinib counterparts. For instance, elevated AST occurred in 12.8% of capmatinib-treated patients versus nearly 19% with savolitinib and 17.4% with tepotinib. Furthermore, the rate of severe treatment-related adverse events (grade ≥3 TRAEs) trended lower in the capmatinib subgroup (30%) relative to savolitinib (46.7%) and tepotinib (41.2%), bordering on statistical significance (p=0.07). These findings advocate for a nuanced assessment of safety and tolerability alongside efficacy in clinical decision-making.
Taken together, these data coalesce into a compelling argument for integrating MET-TKI plus EGFR-TKI combination therapy into the treatment paradigm for NSCLC patients exhibiting acquired MET alterations after EGFR-TKI resistance. The synergy harnessed by targeting both molecular drivers simultaneously appears instrumental in circumventing resistance, enhancing tumor response, and prolonging progression-free intervals.
Mechanistically, resistance to EGFR-TKIs in NSCLC frequently arises via MET amplification or mutation, which reactivate downstream signaling pathways such as PI3K/AKT and MAPK, circumventing EGFR inhibition. By introducing MET-TKIs, clinicians can abrogate these bypass tracks, reinstating susceptibility to EGFR inhibition. This rationale finds tangible validation in the analyzed clinical outcomes and underscores the value of comprehensive molecular profiling in tailoring targeted therapies.
Third-generation EGFR-TKIs, exemplified by osimertinib, offer refined selectivity and efficacy, particularly against resistant T790M mutations. Their preferential pairing with MET-TKIs may optimize blockade of divergent resistance pathways. This meta-analysis hints that such combinations might amplify survival benefit compared to earlier-generation EGFR-TKIs, though further confirmatory trials are warranted.
In addition to addressing resistance, safety remains paramount given the potential toxicities intrinsic to kinase inhibitors. Hepatotoxicity, manifesting as elevated aminotransferase levels, constitutes a notable adverse effect with MET-TKIs. The observed relative hepatoprotective profile of capmatinib could influence therapeutic choices, especially in patients with pre-existing hepatic concerns or when long-term treatment is anticipated.
Despite this promising therapeutic horizon, several limitations temper the current landscape. The pooled studies exhibit heterogeneity in patient selection, MET alteration definitions, and treatment regimens, necessitating cautious interpretation. The lack of randomized head-to-head comparisons between different MET-TKIs or optimized EGFR-TKI combinations leaves gaps for future research.
Nevertheless, these insights mark a pivotal advance in NSCLC management, offering a beacon of hope to patients confronting resistance to frontline EGFR-targeted therapies. Continued exploration through large-scale prospective trials, paired with real-world evidence, will be crucial to refine these regimens and solidify their role in personalized lung cancer care.
In the era of precision oncology, the marriage of MET and EGFR inhibitors epitomizes a rational, mechanism-driven approach to overcoming drug resistance. This meta-analysis not only illuminates the therapeutic promise but also charts a course for future investigation aimed at maximizing patient outcomes amidst the molecular complexity of NSCLC.
As lung cancer remains a leading cause of cancer-related mortality worldwide, innovations that extend survival and preserve quality of life have profound clinical and societal impact. The emergence of MET-TKI plus EGFR-TKI combinations represents a tangible stride toward transforming resistance from an insurmountable barrier into a manageable challenge, rekindling hope for patients and clinicians alike.
Ongoing studies are poised to delve deeper into biomarkers predicting response, optimal sequencing strategies, and combination regimens potentially incorporating immunotherapy. This integrative approach may unlock synergistic effects, further propelling survival gains and redefining standards of care in NSCLC.
Ultimately, the convergence of translational research, molecular diagnostics, and targeted therapeutics embodied by these findings underscores the dynamic evolution of cancer treatment from empirical to exquisitely tailored intervention. The future of NSCLC therapeutics promises continued breakthroughs fueled by such rigorous scientific inquiry.
Subject of Research: Combination therapy using MET tyrosine kinase inhibitors and EGFR tyrosine kinase inhibitors in NSCLC patients with EGFR mutations and acquired MET alterations.
Article Title: MET tyrosine kinase inhibitors in combination with EGFR tyrosine kinase inhibitors in NSCLC patients with EGFR mutations and acquired MET alterations: a systematic review and meta-analysis.
Article References:
Hu, D., Hu, Y., Lei, S. et al. MET tyrosine kinase inhibitors in combination with EGFR tyrosine kinase inhibitors in NSCLC patients with EGFR mutations and acquired MET alterations: a systematic review and meta-analysis. BMC Cancer 25, 732 (2025). https://doi.org/10.1186/s12885-025-14145-5
Image Credits: Scienmag.com
