The implementation of immune checkpoint inhibitors (ICIs), with or without chemotherapy, as first-line treatment for patients who do not have actionable mutations has proved to be a major paradigm shift in the management 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 immunomodulation 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.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martin Reck received fees for honoraria, consulting/advisory roles and speaker’s bureau from Boehringer Ingelheim. Sanjay Popat received personal fees from Bristol Myers Squibb, Roche, Takeda, AstraZeneca, Pfizer, Merck Sharp & Dohme, EMD Serono, Guardant Health, AbbVie, Boehringer Ingelheim, Tesaro, OncLive, Medscape. Christian Grohé has received sponsorship or research funding and payment or other financial remuneration from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, F. Hoffmann-La Roche; and payment or other financial remuneration from Lilly. Silvia Novello received personal fees for advisor/speaker’s bureaus from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Takeda, Pfizer, Roche, Merck Sharp & Dohme, Eli Lilly, AbbVie. Wolfgang M. Brueckl received lecture and educational event (personal) fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, Merck Sharp & Dohme, Pfizer, Roche Pharmaceuticals, Takeda; congress (personal) fees from Boehringer Ingelheim, AstraZeneca, Roche Pharmaceuticals; and advisory board fees (personal) from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharp & Dohme, Lilly Pharma, Bristol Myers Squibb, Roche. Dejan Radonjic and Rolf Kaiser are employees of Boehringer Ingelheim. Rolf Kaiser also has a patent EP 2994125 issued. John Heymach received fees for advisory roles from AstraZeneca, EMD Serono, Boehringer Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Hengrui Therapeutics, Eli Lilly, Spectrum, Sanofi, Takeda, Mirati Therapeutics, Bristol Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, RefleXion, Chugai Pharmaceuticals; fees for a Board of Directors role from Rexanna Foundation; corporate-sponsored research fees from AstraZeneca, Boehringer Ingelheim, Spectrum, Takeda; and royalties and licensing fees from Spectrum. Jesus Corral and Maya Gottfried report no conflicts of interest.
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