Editorial on “The AvaALL Randomized Clinical Trial”

Angiogenesis is essential for tumor growth and blood-borne metastasis, while pharmacological inhibition of tumor-induced angiogenesis is a strategy used in several solid tumors. In advanced non-squamous non-oncogene addicted non-small cell lung cancer (NSCLC), the use of bevacizumab—a monoclonal antibody targeting vascular endothelial growth factor (VEGF)—in addition to platinum-doublet is approved for first-line treatment (1,2).

A meta-analysis of four phase II and III randomized trials on the addition of bevacizumab to a platinum base doublet showed how bevacizumab combination was able to prolong both overall survival (OS) and PFS, compared to chemotherapy alone (HR =0.9; 95% CI: 0.81–0.99, P=0.03 and HR =0.72, 95% CI: 0.66–0.79, P<0.001) (3).

This strategy includes the possibility of continuing bevacizumab after the conclusion of platinum-based chemotherapy until progression. In continuous-maintenance setting, bevacizumab has been evaluated both as single-agent and in combination with pemetrexed (4,5).

Prolonged inhibition of angiogenesis after the conclusion of platinum-based chemotherapy has an interesting biological rationale and demonstrated to be associated with an overall favorable safety profile. Preclinical models support this rationale by showing that discontinuation of anti-angiogenic treatment leads to rapid vascular regrowth followed by increased tumor growth, whereas maintenance therapy extends survival of the mice. First observations, dating back to 2006, were obtained in the RIP-Tag2 and Lewis lung carcinoma experimental tumor models treated with the antiangiogenic multi-target kinase inhibitors AG-013736 or AG-02826 (6). More recently, Yang et al. found that discontinuation of anti-VEGF treatment creates a time-window of profound structural changes in the liver vasculature, which promotes metastasis (7).

Gridelli and colleagues recently published the first phase III clinical trial (AvaALL) addressing the issue of continuation of angiogenesis inhibition also beyond progressive disease, in association with second-line chemotherapy treatment (8).

This strategy has been successful in colorectal cancer and is grounded on a sound biological rationale, in relationship with potential detrimental effects of discontinuation angiogenesis inhibition (9,10).

As far as lung cancer is concerned, a retrospective analysis on advance-stage NSCLC patient treated with first line chemotherapy plus bevacizumab showed how the continuation of antiangiogenic treatment alone until progression might increase survival outcomes (11). This study sparked the interest for testing bevacizumab potential benefit beyond disease progression after first line combination treatment with standard chemotherapy in advanced non-squamous NSCLC.

In the AvaALL trial, patients with advanced non-squamous NSCLC treated with platinum-doublet plus bevacizumab in first-line setting followed by at least two cycles of bevacizumab maintenance treatment were randomized to receive, at the time of radiological progression, either standard of care chemotherapy or standard of care plus bevacizumab. The primary end-point was overall survival (since randomization).

The primary end-point was unmet but it was underpowered according to statistical assumptions.

The slow accrual has been a problem also in the previously reported phase II trial (12). This reflects the limited diffusion of first-line treatments including an anti-angiogenic agent in the field of lung cancer. The addition of bevacizumab to first-line treatment is thus limited to non-squamous NSCLC without baseline conditions that may affect the safety profile of the treatment.

Patients with uncontrolled hypertension, hemoptysis, hemorrhagic disorders or under treatment with anticoagulant therapy are not considerable eligible for bevacizumab, as well patients with a tumor invading major blood vessels, based on a radiological assessment. This last feature has become with time far more debatable: Barlesi and colleagues demonstrated how the consistency in evaluating eligibility of patients with central tumors for bevacizumab was weak among trained radiologists (13).

The presence of brain metastases was another contraindication of antiangiogenic treatment, due to the fear of fatal cerebral hemorrhagic events. A large retrospective analysis and a prospective study, however, showed no difference of the rate of cerebral haemorrhage between patients receiving bevacizumab and patients treated only with chemotherapy (14,15).

Furthermore, additional factors can ground bevacizumab prescription in lung cancer. This is the case of presence of liver metastasis: in a non-preplanned exploratory analysis in the E4599 trial the subgroup of patients with hepatic involvement was associated with marked benefit in terms of OS (1).

Secondary end-points, progression-free survival from first to second (PFS2) and from second to third progression (PFS3), suggested the potentiality of anti-angiogenesis beyond progression. Even though not formally statistically significant, the trend for improvement in PFS following the subsequent lines of treatment suggests that prolonged inhibition of angiogenesis may have an increased impact in a clinically and/or molecularly selected population. Clinical selection based on above-mentioned toxicity-related exclusion criteria already outlines a subgroup of patients who may have better prognosis, due to the limited comorbidity and the exclusion of bulky mediastinal involvement. In addition, in the present study, patients with ECOG performance status (PS) superior to 1 and aged 75 or older seem not to benefit from continuation of bevacizumab beyond progression. Even considering the limits of the subgroup analysis, this may underline the role of clinical selection in this setting.

Remarkably, until now no molecular predictive markers of sensitivity to antiangiogenic treatment are available in clinical practice. Many potential predictive biomarkers have been studied, including both components of the angiogenic pathway and others related to the capacity of tumor cells to respond to metabolic changes induced by inhibition of angiogenesis (16-20).

On this basis, we believe that future studies on the topic should include biomarkers’ based preplanned analyses.

Even though, as the authors acknowledge, their findings have no direct applications in clinical practice, due to the statistical limitations and, above all, to the changing clinical standard, the concept of continuation of anti-angiogenesis beyond progression might be considered in emerging clinical settings for bevacizumab.

The first one concerns treatment of EGFR-mutated advanced NSCLC. Angiogenesis is essential for tumor growth and EGFR-related signaling axis plays an important role in its regulation. In particular, mutant EGFR seems to be able to up-regulate VEGF production, suggesting a potential synergy between antiangiogenic agents and EGFR-tyrosine kinase inhibitors (TKIs) (21). Randomized trials evaluated the association of bevacizumab with erlotinib as first line treatment and confirmed an improvement in PFS, even though an increase in OS has not been demonstrated (22,23).

The second potential field of application of bevacizumab beyond progression in lung cancer is treatment of a clinically selected population of non-oncogene addicted advanced NSCLC treated with carboplatin-paclitaxel in combination with bevacizumab and atezolizumab in first-line setting (24). Evidence accumulated about the immunosuppressive role of VEGF, including dysfunctional lymphocyte trafficking into the tumor, hampered dendritic cells maturation, higher tumoral expression of PD-L1 and recruitment of immunosuppressive immune cell subsets, such as T-regulatory cells and myeloid-derived suppressor cells (25). Interestingly the subset of patients with liver metastases seems to benefit more from this combination, thus confirming the potential existence of clinically defined subgroups of patients who may have particular benefit from antiangiogenic treatment. In conclusion, this manuscript suggests that the strategy of continuing bevacizumab beyond progression deserves further investigation in up-coming clinical applications of antiangiogenic treatment.

Acknowledgements

Funding: This work was supported by 5×1000 IOV Intramural Grants (2018).

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. [Crossref] [PubMed]
2. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27:1227-34. [Crossref] [PubMed]
3. Soria JC, Mauguen A, Reck M, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013;24:20-30. [Crossref] [PubMed]
4. Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 2013;31:3004-11. [Crossref] [PubMed]
5. Karayama M, Inui N, Fujisawa T, et al. Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer. Eur J Cancer 2016;58:30-7. [Crossref] [PubMed]
6. Mancuso MR, Davis R, Norberg SM, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006;116:2610-21. [Crossref] [PubMed]
7. Yang Y, Zhang Y, Iwamoto H, et al. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat Commun 2016;7:12680. [Crossref] [PubMed]
8. Gridelli C, de Castro Carpeno J, Dingemans AC, et al. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol 2018;4:e183486. [Crossref] [PubMed]
9. Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 2005;23:939-52. [Crossref] [PubMed]
10. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 2013;14:29-37. [Crossref] [PubMed]
11. Nadler E, Yu E, Ravelo A, et al. Bevacizumab treatment to progression after chemotherapy: outcomes from a U.S. community practice network. Oncologist 2011;16:486-96. [Crossref] [PubMed]
12. Takeda M, Yamanaka T, Seto T, et al. Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): An open-label, randomized, phase 2 trial. Cancer 2016;122:1050-9. [Crossref] [PubMed]
13. Barlesi F, Balleyguier C, Besse B, et al. Inter- and intraobserver consistency in assessing eligibility for bevacizumab (BVZ) in non-small-cell lung cancer (NSCLC) patients with centrally located tumors. Ann Oncol 2010;21:1682-6. [Crossref] [PubMed]
14. Besse B, Lasserre SF, Compton P, et al. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res 2010;16:269-78. [Crossref] [PubMed]
15. Besse B, Le Moulec S, Mazieres J, et al. Bevacizumab in Patients with Nonsquamous Non-Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized, Phase II Study. Clin Cancer Res 2015;21:1896-903. [Crossref] [PubMed]
16. Lambrechts D, Lenz HJ, de Haas S, et al. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol 2013;31:1219-30. [Crossref] [PubMed]
17. Bonanno L, De Paoli A, Zulato E, et al. LKB1 expression correlates with increased survival in advanced non-small cell lung cancer patients treated with chemotherapy and bevacizumab. Clin Cancer Res 2017;23:3316-24. [Crossref] [PubMed]
18. de Marinis F, Bria E, Ciardiello F, et al. International Experts Panel Meeting of the Italian Association of Thoracic Oncology on Antiangiogenetic Drugs for Non-Small-Cell Lung Cancer: Realities and Hopes. J Thorac Oncol 2016;11:1153-69. [Crossref] [PubMed]
19. Mok T, Gorbunova V, Juhasz E, et al. A correlative biomarker analysis of the combination of bevacizumab and carboplatin-based chemotherapy for advanced nonsquamous non-small-cell lung cancer: results of the phase II randomized ABIGAIL study (BO21015). J Thorac Oncol 2014;9:848-55. [Crossref] [PubMed]
20. Pallaud C, Reck M, Juhasz E, et al. Clinical genotyping and efficacy outcomes: exploratory biomarker data from the phase II ABIGAIL study of first-line bevacizumab plus chemotherapy in non-squamous non-small-cell lung cancer. Lung Cancer 2014;86:67-72. [Crossref] [PubMed]
21. Clarke K, Smith K, Gullick WJ, et al. Mutant epidermal growth factor receptor enhances induction of vascular endothelial growth factor by hypoxia and insulin-like growth factor-1 via a PI3 kinase dependent pathway. Br J Cancer 2001;84:1322-9. [Crossref] [PubMed]
22. 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. Lancet Oncol 2014;15:1236-44. [Crossref] [PubMed]
23. Furuya N, Fukuhara T, Saito H, et al. Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. J Clin Oncol 2018;15 suppl:9006. [Crossref]
24. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 2018;378:2288-301. [Crossref] [PubMed]
25. Manegold C, Dingemans AC, Gray JE, et al. The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC. J Thorac Oncol 2017;12:194-207. [Crossref] [PubMed]