The ALTER-L038 study has revealed promising results for a chemotherapy-free regimen of benmelstobart plus anlotinib in Chinese patients with EGFR-positive advanced non-small cell lung cancer (NSCLC) who have progressed after EGFR tyrosine kinase inhibitor (TKI) therapy. This combination demonstrated good efficacy and low toxicity, suggesting a potential new immunotherapy option for this patient population.
Efficacy and Safety Profile
The study met its primary endpoint, achieving a median progression-free survival (mPFS) of nine months. The objective response rate (ORR) was 25.5%, while the disease control rate (DCR) reached 87.3%. Notably, the median duration of response (mDoR) was 19.8 months, indicating a durable response in those who benefited from the treatment. Preliminary data also showed a median overall survival (mOS) of 28.9 months.
Comparison with Existing Therapies
Various immunotherapy combinations have been assessed in EGFR-positive advanced NSCLC patients post-EGFR-TKIs. Immunotherapy plus chemotherapy failed to demonstrate significant benefits in the CheckMate-722 (mPFS, 5.6 vs. 5.4 months, respectively; p = 0.053) and Keynote-789 (mPFS, 5.6 vs. 5.5 months, respectively; p = 0.0122) studies. The Orient-31 study, involving immunotherapy, chemotherapy, and IBI305 (bevacizumab biosimilar), showed a better mPFS compared to chemotherapy alone (6.9 vs. 4.3 months, respectively; p < 0.0001), but reported a high incidence (54.7%) of grade ≥3 treatment-related adverse events (TRAEs).
Recent ATTLAS (mPFS, 8.47 months; grade ≥3 TRAEs, 35.1%) and HARMONi-A (mPFS, 7.1 months; grade ≥3 TEAEs, 61.5%) studies have shown similar efficacy and safety profiles. The ORR observed with benmelstobart plus anlotinib therapy was numerically lower than that observed with immunochemotherapy with or without bevacizumab (25.5% vs. 33.1%–43.9%, respectively).
Impact of T790M Mutation
Interestingly, patients with the T790M mutation achieved a numerically higher mPFS (9.0 vs. 6.9 months). Significant mPFS benefits (HR, 0.24; 95% CI, 0.09–0.59) for T790M mutation patients were observed in the HARMONi-A study, whereas such benefits were not evident in the ILLUMINATE, Orient-31, and ATTLAS studies. Consistent with the findings of the IMpower151 study, mPFS (9.0–11.8 vs. 6.4 months, respectively) improved in the subpopulation that received first-/second-generation EGFR-TKIs, regardless of subsequent third-generation EGFR-TKIs.
Study Limitations
This phase I/II study was limited by its single-arm design, small sample size, and lack of a randomized controlled design. The absence of candidate biomarkers (such as PD-L1 expression) analysis and tumor microenvironment profiling limited the ability to assess the efficacy of the therapy and relationships between the study drug and tumors. It would be important to investigate tumor biomarkers in large-scale randomized trials for response to better select patients for the benmelstobart plus anlotinib therapy.
Conclusion
Benmelstobart plus anlotinib therapy demonstrates anti-tumor efficacy, low toxicity, and the convenience of oral administration, potentially filling a treatment gap for patients with EGFR-positive advanced NSCLC resistant to EGFR-TKIs.
