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Antiangiogenesis May Not Be a Universal Booster of EGFR Tyrosine Kinase Inhibitors

  • Tsung-Che Wu
    Affiliations
    Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    Department of Oncology, National Taiwan University Biomedical Park Hospital, Hsinchu, Taiwan
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  • Chia-Chi Lin
    Correspondence
    Corresponding author. Address for correspondence: Chia-Chi Lin, MD, PhD, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan.
    Affiliations
    Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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      Since the concept of antiangiogenesis was introduced in oncology, various types of systemic anticancer treatment, from cytotoxic chemotherapy, molecular targeted therapy, to immunotherapy, had been attempted to be combined with antiangiogenic agents. At around 2010, cytotoxic chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) were two pillars of systemic treatments for NSCLC, and the combination of antiangiogenic agents and EGFR TKIs was thus naturally to be explored.
      Preclinically, there were several supportive evidences for synergism of antiangiogenesis and EGFR tyrosine kinase inhibition. The two pathways are intertwined, gefitinib decreased vascular endothelial growth factor (VEGF) expression through inhibition of HIF-1α,
      • Pore N.
      • Jiang Z.
      • Gupta A.
      • Cerniglia G.
      • Kao G.D.
      • Maity A.
      EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms.
      and VEGF increased in erlotinib-resistant models.
      • Naumov G.N.
      • Nilsson M.B.
      • Cascone T.
      • et al.
      Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance.
      The synergism of dual VEGF and EGFR inhibition was also shown in xenograft models. Bevacizumab plus erlotinib combination was found to have better tumor growth inhibition than erlotinib or gefitinib treatment in models with acquired resistance to erlotinib or gefitinib.
      • Naumov G.N.
      • Nilsson M.B.
      • Cascone T.
      • et al.
      Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance.
      Combination of erlotinib and DC101, a mouse VEGF receptor (VEGFR)-2 antibody, was also found to have superior efficacy than either erlotinib or DC101 alone.
      • Kayatani H.
      • Ohashi K.
      • Imao T.
      • et al.
      Abstract 5198: combination effect of anti-VEGFR-2 antibody with erlotinib on EGFR mutant non-small cell lung cancer.
      In addition, afatinib, a second-generation irreversible EGFR TKI, when combined with bevacizumab, had higher efficacy in EGFR T790M mutation containing xenograft models than monotherapy.
      • Ninomiya T.
      • Takigawa N.
      • Ichihara E.
      • et al.
      Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model.
      In clinical testing, despite the preclinical works often focused on EGFR TKI-resistant settings, randomized trials mainly compared an EGFR TKI to its combination with either anti–VEGF or anti–VEGFR-2 antibody for patients who are naive to the EGFR TKI. In a randomized phase 2 study JO25567 in Japan, the superiority of bevacizumab plus erlotinib than erlotinib in terms of progression-free survival (PFS = 16.4 mo versus 9.8 mo, hazard ratio [HR] = 0.52, p = 0.0005) was shown for the first time, with similar overall survival (OS = 47.0 mo versus 47.4 mo, HR = 0.81, p = 0.3267) and objective response rate (ORR, 69% versus 64%, p = 0.4951) between the two arms.
      • Seto T.
      • Kato T.
      • Nishio M.
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.
      ,
      • Yamamoto N.
      • Seto T.
      • Nishio M.
      • et al.
      Erlotinib plus bevacizumab vs erlotinib monotherapy as first-line treatment for advanced EGFR mutation-positive non-squamous non-small-cell lung cancer: survival follow-up results of the randomized JO25567 study.
      Despite a similar but smaller randomized phase 2 study in the United States revealed nonsignificant improvement of PFS and even numerically worse OS in the combination group,
      • Stinchcombe T.E.
      • Janne P.A.
      • Wang X.
      • et al.
      Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a phase 2 randomized clinical trial.
      subsequently three phase 3 studies conducted in Japan, People’s Republic of China, and Italy, respectively, confirmed the PFS benefit of bevacizumab plus erlotinib over erlotinib with HR at 0.55 to 0.66.
      • Saito H.
      • Fukuhara T.
      • Furuya N.
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.
      • Kawashima Y.
      • Fukuhara T.
      • Saito H.
      • et al.
      Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.
      • Zhou Q.
      • Xu C.R.
      • Cheng Y.
      • et al.
      Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated, advanced NSCLC (ARTEMIS-CTONG1509): a multicenter phase 3 study.
      • Piccirillo M.C.
      • Bonanno L.
      • Garassino M.C.
      • et al.
      Addition of bevacizumab to erlotinib as first-line treatment of patients with EGFR-mutated advanced nonsquamous non-small cell lung cancer. The BEVERLY multicenter randomized phase III trial.
      Consistently, OS and ORR were not significantly different except ORR in the BEVERLY study (bevacizumab plus erlotinib versus erlotinib, 70% versus 50%).
      • Piccirillo M.C.
      • Bonanno L.
      • Garassino M.C.
      • et al.
      Addition of bevacizumab to erlotinib as first-line treatment of patients with EGFR-mutated advanced nonsquamous non-small cell lung cancer. The BEVERLY multicenter randomized phase III trial.
      Rather than bevacizumab plus erlotinib combination, ramucirumab plus erlotinib versus erlotinib was tested in RELAY study and a PFS benefit of similar effect size was found (19.4 mo versus 12.4 mo, HR = 0.59, p < 0.0001). Ramucirumab plus erlotinib combination had been the only U.S. Food and Drug Administration–approved antiangiogenesis plus EGFR TKI combination up to now.
      On the basis of prior success, as osimertinib emerged as the game changer of EGFR-mutant NSCLC, the addition of antiangiogenic agent to osimertinib became an attractive idea. Phase 1 studies of bevacizumab plus osimertinib combination in the first-line setting and ramucirumab plus osimertinib combination for patients with EGFR T790M mutation did not reveal unexpected toxicities beyond common toxicities of anti–VEGF antibody, anti-VEGFR antibody, or osimertinib, but the ORR (bevacizumab plus osimertinib in first-line: 80%, ramucirumab plus osimertinib for EGFR T790M: 76%) and PFS (bevacizumab plus osimertinib in first-line: 19 mo, ramucirumab plus osimertinib for EGFR T790M: 11 mo) were also not remarkable if numerically compared with historical data of osimertinib monotherapy.
      • Yu H.A.
      • Schoenfeld A.J.
      • Makhnin A.
      • et al.
      Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a phase 1/2 single-group open-label trial.
      ,
      • Yu H.A.
      • Paz-Ares L.G.
      • Yang J.C.
      • et al.
      Phase I study of the efficacy and safety of ramucirumab in combination with osimertinib in advanced T790M-positive EGFR-mutant non-small cell lung cancer.
      Two randomized phase 2 trials, WJOG8715L and BOOSTER, both revealed that there was no PFS benefit of bevacizumab plus osimertinib over osimertinib in second-line EGFR T790M mutation population.
      • Akamatsu H.
      • Toi Y.
      • Hayashi H.
      • et al.
      Efficacy of osimertinib plus bevacizumab vs osimertinib in patients with EGFR T790M-mutated non-small cell lung cancer previously treated with epidermal growth factor receptor-tyrosine kinase inhibitor: West Japan Oncology Group 8715L phase 2 randomized clinical trial.
      ,
      • Soo R.A.
      • Han J.Y.
      • Dafni U.
      • et al.
      A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10–16) BOOSTER trial.
      In this issue of the Journal of Thoracic Oncology, Kenmotsu et al.
      • Kenmotsu H.
      • Wakuda K.
      • Mori K.
      • et al.
      Randomized phase 2 study of osimertinib plus bevacizumab versus osimertinib for untreated patients with nonsquamous NSCLC harboring EGFR mutations: WJOG9717L study.
      present the first randomized study comparing bevacizumab plus osimertinib with osimertinib in the first-line setting—WJOG9717L. The primary end point, PFS, was 22.1 months in bevacizumab plus osimertinib versus 20.2 months in osimertinib arm, and there was no statistically significant difference (HR = 0.862, p = 0.213). In addition, grade 3 to 4 toxicities were numerically higher in the combination arm (56% versus 48%).
      Despite there is still ongoing phase 3 study (NCT04181060) to be expected to put on the final puzzle on the issue of whether bevacizumab could add on additional efficacy to osimertinib, repeated failures of bevacizumab plus osimertinib combination in different settings raised the questions about the reasons behind these failures. One possible explanation, like that was proposed in the discussion of WJOG9717L, was short exposure of bevacizumab (median 33.4 wk) owing to toxicities. Because the PFS of first-line osimertinib treatment was often more than 18 months, the much shorter duration of bevacizumab was unlikely to have positive impact. However, this may not explain the whole story, as in second-line setting, where the duration of bevacizumab exposure was closer to PFS of osimertinib, the combination also did not derive additional benefit.
      Have a closer look, we may find out that there is no strong evidence to support the synergistic or additive effect of antiangiogenesis agents to osimertinib. As in the summary of preclinical evidence,
      • Pore N.
      • Jiang Z.
      • Gupta A.
      • Cerniglia G.
      • Kao G.D.
      • Maity A.
      EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms.
      • Naumov G.N.
      • Nilsson M.B.
      • Cascone T.
      • et al.
      Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance.
      • Kayatani H.
      • Ohashi K.
      • Imao T.
      • et al.
      Abstract 5198: combination effect of anti-VEGFR-2 antibody with erlotinib on EGFR mutant non-small cell lung cancer.
      • Ninomiya T.
      • Takigawa N.
      • Ichihara E.
      • et al.
      Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model.
      most of the synergism demonstrations were based on erlotinib, gefitinib, or afatinib, but not on osimertinib. Another argument is that antiangiogenesis agents may endow osimertinib with better delivery, as what they did in other combinations. Nevertheless, there is no evidence that inadequate penetration is the major resistant mechanism for front-line or second-line osimertinib in the nonselective patient population, and osimertinib itself is an effective treatment for tumors in sanctuary sites, even for leptomeningeal disease.
      • Yang J.C.H.
      • Kim S.W.
      • Kim D.W.
      • et al.
      Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: the BLOOM study.
      In addition, there was no evidence that antiangiogenesis agents may help osimertinib to conquer the known resistant mechanisms. In previous studies,
      • Lin C.C.
      • Shih J.Y.
      • Yu C.J.
      • et al.
      Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study.
      ,
      • Ramalingam S.
      • Cheng Y.
      • Zhou C.
      • et al.
      Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study.
      common single-agent osimertinib-resistant mechanisms were described, for example, EGFR C797S, MET amplification, histologic transformation, and bypass pathways. In phase 1 studies of bevacizumab plus osimertinib and ramucirumab plus osimertinib combinations, EGFR C797S, EGFR L718Q, EGFR amplification, MET amplification, squamous cell transformation, and pleomorphic transformation were noted as resistant mechanism.
      • Yu H.A.
      • Schoenfeld A.J.
      • Makhnin A.
      • et al.
      Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a phase 1/2 single-group open-label trial.
      ,
      • Yu H.A.
      • Paz-Ares L.G.
      • Yang J.C.
      • et al.
      Phase I study of the efficacy and safety of ramucirumab in combination with osimertinib in advanced T790M-positive EGFR-mutant non-small cell lung cancer.
      This indirect comparison indicated that antiangiogenesis agents did not help conquer single-agent osimertinib-resistant mechanisms, although delayed occurrence or decreased proportion of common osimertinib-resistant mechanism could not be totally ruled out.
      To gain further insight and guide future studies, additional translational research and deeper mining of existing studies are necessary. The synergism of antiangiogenesis agents and osimertinib in osimertinib-sensitive or osimertinib-resistant settings may be investigated in models like what had been done for first- and second-generation EGFR TKIs. To evaluate the relapse pattern and resistant mechanisms in studies of bevacizumab or ramucirumab plus erlotinib combination versus erlotinib may provide hints on what is the exact role of antiangiogenesis agents in the synergism. Furthermore, subgroup analysis, especially findings consistent in different studies, may help us to generate testable hypothesis in next trials. For example, ever-smokers have a more favorable HR of PFS than never-smokers in all three randomized studies of bevacizumab plus osimertinib versus osimertinib, potential study for this specific population may be designed, and the underlying molecular characteristics (co-occurring gene alterations, programmed death-ligand 1 expression, tumor mutation burden, or mutation signatures) of this benefit may be worth exploring.
      Although antiangiogenesis may not be a booster for osimertinib according to current evidence, there are potential rooms for the combination in unique niches. Because there is potential improvement of central nervous system drug delivery by vascular normalization effect of antiangiogenesis agents,
      • Goel S.
      • Wong A.H.
      • Jain R.K.
      Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease.
      several trials are pursuing osimertinib plus bevacizumab combination in patients with brain (NCT02971501, NCT05104281) or leptomeningeal (NCT04148898) metastases. Besides the anti–VEGF partner bevacizumab, anti–VEGFR2 ramucirumab plus osimertinib versus osimertinib is also being tested in randomized study (NCT03909334). Moreover, specific molecular subgroups are being explored, including osimertinib-sensitive mutation, such as EGFR L858R mutation (NCT04988607, when the result is available, it will be informative to compare the result with WJOG 9717L, as EGFR L858R mutation was the unfavorable subgroup for the combination arm in WJOG 9717L), and traditionally osimertinib-insensitive mutations, such as EGFR exon 20 insertions (NCT04974879). Finally, there are also uncharted areas waiting for reasonable studies: ever-smokers, or an associated molecularly defined group (e.g., p53 coalteration or smoking mutation signature), on the basis of consistent subgroup analysis mentioned previously; and osimertinib-resistant setting, on the grounds that the preclinical evidence of synergism of antiangiogenesis to EGFR TKIs was actually mainly in TKI-resistant setting, but the antiangiogenic agent plus EGFR TKI combinations in TKI-resistant population had not been thoroughly evaluated in clinical trials (Table 1).
      Table 1Ongoing and Future Studies of Osimertinib Plus Antiangiogenic Agent Combinations
      Study FocusTrials
      Phase 3 study of bevacizumab plus osimertinib vs. osimertinibNCT04181060
      Different partner of antiangiogenic agent, randomized phase 2 study

      Ramucirumab plus osimertinib vs. osimertinib
      NCT03909334
      CNS metastases bevacizumab plus osimertinib vs. osimertinibBrainNCT02971501, NCT05104281
      LeptomeningealNCT04988607
      Molecularly defined population bevacizumab plus osimertinib vs. osimertinibOsimertinib-sensitive EGFR L858R mutationNCT04988607
      Osimertinib-insensitive EGFR exon 20 insertionsNCT04974879
      Ever-smokersClinical smoking historyTo be explored
      Associated molecular feature: p53 coalteration, smoking mutation signature
      Bevacizumab or ramucirumab plus osimertinib combination in osimertinib-resistant settingTo be explored
      CNS, central nervous system.

      CRediT Authorship Contribution Statement

      Tsung-Che Wu, Chia-Chi Lin: Conceptualization, Writing - review.

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