Anti-angiogenic agents for NSCLC following first-line immunotherapy: Rationale, recent updates, and future perspectives

The implementation of immune checkpoint inhibitors (ICIs), with or without chemotherapy, as first-line treat-ment for patients who do not have actionable mutations has proved to be a major paradigm shift in the man-agement of advanced non-small cell lung cancer (NSCLC). However, the transition of ICIs, such as pembrolizumab and nivolumab, to a first-line setting has left an unmet need for effective second-line treatment options, which is an area of intense research. In 2020, we reviewed the biological and mechanistic rationale for anti-angiogenic agents in combination with, or following, immunotherapy with the aim of eliciting a so called 'angio-immunogenic' switch in the tumor microenvironment. Here, we review the latest clinical evidence of the benefits of incorporating anti-angiogenic agents into treatment regimens. While there is a paucity of prospective data, several recent observational studies indicate that the marketed anti-angiogenic drugs, nintedanib or ramucirumab, are effective in combination with docetaxel following immuno-chemotherapy. Addition of anti-angiogenics, like bevacizumab, have also demonstrated clinical benefit when combined with first-line immuno-chemotherapy regimens. Ongoing clinical trials are assessing these agents in combination with ICIs, with encouraging early results (e.g., ramucirumab plus pembrolizumab in LUNG-MAP S1800A). Also, several emerging anti-angiogenic agents combined with ICIs are currently being assessed in phase III trials following immunotherapy, including lenvatinib (LEAP-008), and sitravatinib (SAPPHIRE) It is hoped that these trials will help expand second-line treatment options in patients with NSCLC. Areas of focus in the future will include further molecular dissection of the mechanisms of resistance to immunotherapy and the various response- -progression profiles to immunotherapy observed in the clinic and the monitoring of the dynamics of immuno-modulation over the course of treatment. Improved understanding of these phenomena may help identify clinical biomarkers and inform the optimal use of anti-angiogenics in the treatment of individual patients.