A phase 2 clinical trial has provided final results demonstrating the long-term efficacy and safety of capmatinib in patients with MET exon 14 skipping mutation-positive (METex14) non-small cell lung cancer (NSCLC). The GEOMETRY mono-1 study, a non-randomized, multi-cohort, open-label trial, was conducted across 152 centers in 25 countries, with patients treated at 95 sites in 20 countries. Funded by Novartis Pharmaceuticals, the study results were published in The Lancet Oncology in October 2024.
The primary purpose of the GEOMETRY mono-1 trial was to evaluate the efficacy and safety of capmatinib, a highly selective MET inhibitor, in both treatment-naive and previously treated patients with METex14 NSCLC. The study aimed to provide further evidence supporting capmatinib as a targeted treatment option for this specific patient population.
The trial enrolled a total of 373 patients across multiple cohorts based on MET status (METex14 or MET amplification) and previous therapy lines. For the final analysis reported in this publication, researchers focused on 160 patients with METex14 NSCLC, including 60 treatment-naive patients (in cohorts 5b and 7) and 100 previously treated patients (in cohorts 4 and 6). Patients were eligible if they were aged 18 years or older with advanced or metastatic (stage IIIB/IV) NSCLC that was EGFR wild-type and ALK rearrangement-negative. They were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and at least one measurable lesion according to RECIST v1.1 criteria.
The demographic data revealed that the METex14 NSCLC population tended to be older, with a mean age of 71.3 years (SD 7.8). The majority of patients (61%) were female, and 85% were aged 65 years or older. Notably, 61% of patients had no history of smoking. These characteristics align with previous observations that METex14 mutations in NSCLC are often associated with older age and a history of never smoking.
The primary endpoint of the study was overall response rate (ORR) as assessed by blinded independent review committee (BIRC) using RECIST v1.1 criteria. Key secondary endpoints included duration of response, progression-free survival (PFS), and overall survival (OS).
Results from the trial were highly encouraging, particularly for treatment-naive patients. In the first-line setting, capmatinib demonstrated an ORR of 68% (41 out of 60 patients; 95% CI 55.0-79.7), with complete responses observed in three patients. The median duration of response was 16.6 months (95% CI 8.4-22.1), and the median PFS was 12.5 months (95% CI 8.3-18.0). Median OS in treatment-naive patients reached 21.4 months (95% CI 15.2-30.5).
For previously treated patients, the ORR was 44% (44 out of 100 patients; 95% CI 34.1-54.3), with one complete response. The median duration of response in this group was 9.7 months (95% CI 5.6-13.0), with a median PFS of 5.5 months (95% CI 4.2-8.1) and median OS of 16.8 months (95% CI 11.6-23.8).
The safety profile of capmatinib remained consistent with previous reports and was generally manageable. The most common treatment-related adverse events included peripheral edema (47%), nausea (35%), increased blood creatinine (21%), and vomiting (20%). Grade 3-4 serious adverse events occurred in 44% of patients, with dyspnea being the most frequent (5%). Treatment-related deaths were rare, occurring in only four patients (1%).
One notable finding from the study was the promising intracranial activity of capmatinib in patients with brain metastases at baseline. A post-hoc retrospective medical review based on central neuroradiological assessment found that 16 out of 28 evaluable patients (57%) with brain metastases showed intracranial complete or partial responses, including nine complete responses. This observation suggests potential benefit for patients with CNS involvement, a common and challenging aspect of NSCLC management.
The study also incorporated extensive biomarker analyses, providing valuable insights into the genomic landscape of METex14 NSCLC and potential mechanisms of resistance to capmatinib. Researchers found good concordance between tissue-based and blood-based detection of METex14 mutations, supporting the use of liquid biopsy as a less invasive option for identifying eligible patients. Analysis of circulating tumor DNA at disease progression revealed the emergence of MET kinase domain mutations and alterations in the PI3K-AKT-MAPK pathway as potential resistance mechanisms.
Gene expression analysis of baseline tumor samples showed that higher MET and MET pathway expression were associated with better responses to capmatinib, particularly in the first-line setting. Interestingly, PD-L1 gene expression did not appear to impact response to capmatinib, which may have implications for treatment sequencing decisions between targeted therapy and immunotherapy in this patient population.
The authors concluded that these final results from the GEOMETRY mono-1 trial provide robust evidence supporting capmatinib as an effective targeted therapy option for patients with METex14 NSCLC, with particularly compelling activity in the first-line setting. The durable responses and prolonged survival observed, coupled with a manageable safety profile, strengthen the case for capmatinib as a valuable treatment choice for this molecularly defined subgroup of NSCLC patients.
However, the study does have some limitations that should be considered. As a phase 2, non-randomized trial, it lacks a direct comparison to standard-of-care treatments. The authors acknowledge this limitation but note that results from a small phase 3 randomized trial of capmatinib versus docetaxel and real-world evidence reports provide supporting data for the robustness of capmatinib's activity. Additionally, the biomarker analyses were conducted on relatively small sample sizes and should be validated in larger studies.
The potential clinical impact of these findings is significant. METex14 mutations occur in approximately 3-4% of NSCLC cases, representing a distinct molecular subgroup that has historically had limited targeted treatment options. The strong efficacy signals observed with capmatinib, particularly in treatment-naive patients, suggest that upfront MET inhibition could become a preferred strategy for these patients. The high response rates and durable benefit seen in older patients with multiple comorbidities are especially noteworthy, as this population may be less suitable for aggressive chemotherapy regimens.
The biomarker findings from this study also have important clinical implications. The validation of blood-based testing for METex14 mutations could facilitate more widespread and rapid identification of eligible patients, potentially expanding access to targeted therapy. The insights gained into resistance mechanisms may guide future combination strategies or sequential treatment approaches to overcome acquired resistance to MET inhibition.
Furthermore, the observed intracranial activity of capmatinib addresses an important unmet need in NSCLC management. Brain metastases are a common and often debilitating complication of lung cancer, and therapies with CNS penetration are highly valued. The promising results seen in patients with brain metastases, even in those without prior radiation therapy, suggest that capmatinib could offer a valuable treatment option for this challenging clinical scenario.
In conclusion, the final results from the GEOMETRY mono-1 trial provide compelling evidence for the efficacy and safety of capmatinib in METex14 NSCLC. The study reinforces the importance of comprehensive molecular profiling in NSCLC to identify patients who may benefit from targeted therapies. As our understanding of resistance mechanisms and biomarkers of response continues to evolve, the management of METex14 NSCLC is likely to become increasingly personalized. Moving forward, ongoing and future studies will be crucial to further optimize the use of capmatinib and other MET inhibitors in this patient population, potentially exploring combination strategies or sequential approaches to maximize long-term benefit.
References
Wolf J, Hochmair M, Han JY, et al. Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial [published correction appears in Lancet Oncol. 2024 Nov;25(11):e542. doi: 10.1016/S1470-2045(24)00560-6]. Lancet Oncol. 2024;25(10):1357-1370. doi:10.1016/S1470-2045(24)00441-8
