Lenvatinib Plus Gefitinib Shows Promise in Lenvatinib-Resistant Hepatocellular Carcinoma
Key Insights
A phase I trial demonstrates that lenvatinib combined with gefitinib shows promising anti-tumor activity in hepatocellular carcinoma (HCC (search)) patients who have progressed on lenvatinib.
The combination therapy achieved an objective response rate (ORR) of 16.7% based on RECIST1.1 and 30% based on mRECIST in heavily pre-treated HCC (search) patients.
The dual targeted therapy of lenvatinib and gefitinib was generally well-tolerated, with manageable adverse events, suggesting potential clinical benefits for HCC (search).
A phase I clinical trial has revealed that combining lenvatinib with gefitinib demonstrates encouraging anti-tumor activity in patients with hepatocellular carcinoma (HCC (search)) who have developed resistance to lenvatinib. This combination offers a potential treatment strategy for a patient population with limited options.
The study, a first-in-human, proof-of-concept trial, evaluated the efficacy and safety of the combination in HCC (search) patients who had progressed after lenvatinib treatment. The results indicated an objective response rate (ORR) of 16.7% based on RECIST1.1 criteria and 30% based on mRECIST criteria. These findings are notable considering that 60% of the patients had received second or third-line systemic therapy prior to enrollment.
Rationale Behind the Combination
The rationale for combining lenvatinib and gefitinib stems from the understanding of resistance mechanisms to lenvatinib. While lenvatinib, a multi-kinase inhibitor, has shown efficacy in HCC (search), resistance often develops through EGFR (search) activation. Previous studies have indicated that lenvatinib synergizes with EGFR inhibitors by abrogating MAPK signaling mediated by FGFRs and EGFR. This synergy was not observed with sorafenib, another first-line treatment for HCC, likely due to lenvatinib's specific inhibition of FGFR (search) family members.
Clinical Implications and Tolerability
The observed ORR compares favorably to existing second-line therapies for HCC (search), such as cabozantinib (ORR 4%), regorafenib (ORR 11%), ramucirumab (ORR 5%), and pembrolizumab (ORR 18.3%). Moreover, the combination therapy was generally well-tolerated, with most patients experiencing manageable adverse events (AEs). Only one patient withdrew due to a grade 3 AE, and symptoms improved with dose reduction or temporary drug withdrawal.
Comparison to Other EGFR Inhibitors
Previous trials with other EGFR (search) inhibitors, such as erlotinib, have shown limited therapeutic efficiency in HCC (search) patients. A phase III SEARCH trial, which combined erlotinib and sorafenib as a first-line treatment, did not yield significant clinical benefits. This highlights the specificity of the synergy between lenvatinib and EGFR inhibition, as supported by in vitro studies.
Ongoing Research and Future Directions
An ongoing phase I clinical trial is evaluating the combination of lenvatinib and cetuximab, an EGFR (search) monoclonal antibody, in head and neck squamous cell carcinoma (HNSCC (search)). Preliminary results from an ASCO meeting in 2020 showed a 67% ORR in HNSCC patients treated with this combination, suggesting potential benefits across different cancer types.
Limitations and Future Studies
The study acknowledges several limitations, including the analysis of EGFR (search) expression in tumor samples taken at initial diagnosis, which may not reflect changes during HCC (search) evolution. The authors suggest that biopsies taken just prior to combination therapy could provide a more accurate assessment of EGFR expression. Additionally, the detection of EGFR alterations in circulating tumor DNA (ctDNA) could potentially aid in screening patients who may benefit from this treatment. A well-designed, randomized phase II trial is needed to further validate the efficacy of this combination therapy.
Conclusion
The combination of lenvatinib and gefitinib demonstrates an initial therapeutic effect and is well-tolerated in HCC (search) patients who have progressed on lenvatinib. These findings warrant further clinical investigation to confirm the efficacy and identify predictive biomarkers for patient selection.