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Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer Rebecca S. Heista,1,2, Dan G. Dudab,1, Dushyant V. Sahanic,1, Marek Ancukiewiczb, Panos Fidiasd, Lecia V. Sequista, Jennifer S. Temela, Alice T. Shawa, Nathan A. Pennelle, Joel W. Nealf, Leena Gandhig, Thomas J. Lynchh, Jeffrey A. Engelmana, and Rakesh K. Jainb,2 Departments of aMedicine, bRadiation Oncology, and cRadiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; dDepartment of Medical Oncology, University of Arizona Cancer Center at Dignity, Phoenix, AZ 85013; eDepartment of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH 44195; fDepartment of Medicine, Division of Oncology, Stanford University/Stanford Cancer Institute, Palo Alto, CA 94305; gDepartment of Adult Oncology, Dana–Farber Cancer Institute, Boston, MA 02115; and hDepartment of Medical Oncology, Yale Cancer Center, New Haven, CT 06520 Contributed by Rakesh K. Jain, December 16, 2014 (sent for review November 18, 2014; reviewed by Elisabeth G. E. De Vries and Daniel Von Hoff) Addition of anti-VEGF antibody therapy to standard chemothera- tumors (3). However, this effect would eventually lead to both pies has improved survival and is an accepted standard of care for decreased drug delivery (and hence treatment resistance) and advanced non–small cell lung cancer (NSCLC). However, the mech- increased tumor hypoxia (a major driver of tumor progression) anisms by which anti-VEGF therapy increases survival remain un- (4). Another potential mechanism of antiangiogenic therapy is clear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab Significance plus chemotherapy with carboplatin and nab-paclitaxel in ad- vanced NSCLC patients to explore potential biomarkers of treat- A better mechanistic understanding of the survival benefits ment response and resistance to this regimen. Thirty-six patients and identification of biomarkers of response would greatly were enrolled in this study. The primary end point was 6-mo pro- enhance the optimal utilization of antiangiogenic agents such gression-free survival rate, which was 74% (95% CI: 57, 97). This as bevacizumab in combination with chemotherapy in the regimen has a promising overall response rate of 36% and median treatment of cancer. This study indicates that the benefits of time to progression of 8.5 (6.0, 38.7) mo and overall survival of bevacizumab with chemotherapy in non–small cell lung can- 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sus- cer (NSCLC) patients may depend on tumor vascular function tained increase in plasma PlGF, a potential pharmacodynamic during treatment. These correlative studies also provide new marker. We also found that higher levels of soluble VEGFR1 mea- insights into the selection of NSCLC patients most likely to benefit sured before starting bevacizumab with chemotherapy were asso- from the addition of bevacizumab treatment to chemotherapy. ciated with worse survival, supporting its potential role as MEDICAL SCIENCES The imaging and circulating biomarker candidates should be fur- biomarker of treatment resistance. Our imaging biomarker stud- ther evaluated in larger studies. ies indicate that bevacizumab-based treatment—while reducing blood flow, volume, and permeability in the overall population— maybeassociatedwithimprovedsurvivalinpatientswithim- Author contributions: R.S.H., D.G.D., D.V.S., N.A.P., T.J.L., and R.K.J. designed research; R.S.H., D.G.D., D.V.S., P.F., L.V.S., J.S.T., A.T.S., N.A.P., J.W.N., L.G., T.J.L., and J.A.E. per- proved tumor vasculature and blood perfusion after treatment. This formed research; R.S.H., D.G.D., D.V.S., and R.K.J. contributed new reagents/analytic tools; hypothesis-generating study supports the notion that excessively R.S.H., D.G.D., D.V.S., M.A., P.F., L.V.S., J.S.T., A.T.S., N.A.P., J.W.N., L.G., T.J.L., J.A.E., and decreasing vascular permeability and pruning/rarefaction after R.K.J. analyzed data; and R.S.H., D.G.D., D.V.S., M.A., P.F., T.J.L., J.A.E., and R.K.J. wrote bevacizumab therapy may negatively impact the outcome of the paper. combination therapy in NSCLC patients. This hypothesis warrants Reviewers: E.G.E.D.V., University Medical Center Groningen; and D.V.H., Translational Genomics Institute. further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy. Conflict of interest statement: R.S.H. has served as a consultant for Boehringer-Ingelheim and Momenta. D.G.D. has served as a consultant for Hexal/Sandoz. P.F. has served on the speak- ers’ bureau for Boehringer-Ingelheim and Genentech/Roche, and on an advisory board for lung cancer | antiangiogenesis | bioimaging Boehringer-Ingelheim and Genentech/Roche. L.V.S. has served as a consultant (uncompen- sated) for Clovis, Astrazeneca, Boehringer Ingelheim, Genentech/Roche, Novartis, Merrimack, and Taiho. J.S.T. received travel funds from Helsinn Therapeutics. A.T.S. has served as a con- he advent of targeted therapies has led to an unprecedented sultant for Pfizer, Novartis, Ariad, Chugai, Ignyta, Genentech/Roche, and Daiichi-Sankyo. L.G. Tincrease in the median overall survival (OS) in advanced has served as a consultant for Merck and on an advisory board for Merck and Genentech/ non–small cell lung cancer (NSCLC), well beyond 1 y. This Roche. N.A.P. has served as a consultant for Genentech. J.W.N. has served as a consultant for Clovis. T.J.L. has served on the board of directors for BMS, on a scientific advisory board for progress included the successful development of antiangiogenic Arvinas, and has an EGFR mutation-testing patent from Partners Healthcare. J.A.E. has re- drugs such as bevacizumab or ramucirumab in combination with ceived consulting fees from Genentech, Roche, Ventana, and Chugai, and is coinventor on chemotherapy (1, 2). However, although the use of cancer cell- a patent licensed by Ventana. R.K.J. has received research grants from MedImmune and EGFR Roche for research unrelated to this study; has received consultant fees from Enlight, Ophtho- targeted drugs is guided by biomarkers (e.g., mutations, tech, and SynDevRx; owns equity in Enlight, Ophthotech, SynDevRx, and XTuit; and serves on ALK-EML4 translocations), there are currently no biomarkers the Board of Directors of XTuit and Boards of Trustees of Tekla Healthcare Investors, Tekla for antiangiogenic drugs. In advanced NSCLC, the use of the Life Sciences Investors, and Tekla Healthcare Opportunities Fund. Funding for the clinical trial anti-VEGF antibody bevacizumab in combination with platinum- was provided by Celgene and Roche/Genentech, which provided study drugs and funding for the clinical trial. All data collection and analysis were performed independently by the in- based chemotherapy is a widely accepted standard of care in vestigators of this investigator-initiated clinical trial. nonsquamous histology (1). However, the mechanism by which Freely available online through the PNAS open access option. bevacizumab improves survival over chemotherapy alone re- 1R.S.H., D.G.D., and D.V.S. contributed equally to this work. mains debated. 2To whom correspondence may be addressed. Email: [email protected] or jain@steele. Originally, it was hypothesized that antiangiogenic agents mgh.harvard.edu. would effectively starve the tumor of oxygen and nutrients by This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. pruning the blood vessel system and reducing blood perfusion to 1073/pnas.1424024112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1424024112 PNAS | February 3, 2015 | vol. 112 | no. 5 | 1547–1552 Downloaded by guest on September 23, 2021 transient vascular normalization, by which structurally and func- time, and the treating physician elected to take him off study to tionally abnormal tumor vasculature is normalized, i.e., remodeled start an EGFR inhibitor. One patient came off study to receive or modified to more closely resemble normal vasculature (4). By palliative radiation to a painful bony metastasis, which was not attenuation of vascular hyperpermeability, increasing vessel peri- detected before enrollment. The other five patients who were not cyte coverage, and normalization of the basement membrane, evaluable stopped study treatment due to adverse events (AEs): vascular normalization may lead to reduced interstitial fluid one patient came off study after one cycle due to an allergic re- pressure and improved blood perfusion. This normalization may action; one patient came off study due to abscess/diverticulitis have important consequences on drug and oxygen delivery and on and a new finding of concurrent pancreatic cancer; two patients theimmunemicroenvironment(5–8). Finally, it remains un- were taken off study as their liver function tests did not meet clear whether bevacizumab’s efficacy is dependent on the che- criteria to continue the study drug as written in the protocol and motherapeutic regimen used. therefore required dose holds (although these were grade 2 liver Unfortunately, clinical data exploring these mechanisms in function test abnormalities and were considered clinically ac- NSCLC are scarce. Van der Veldt et al. reported that bevacizumab ceptable to continue chemotherapy off study); and one patient reduced perfusion and net influx rate of radiolabeled docetaxel in came off study due to nausea/vomiting that was not tolerable. All 10 patients with advanced NSCLC (9). Bevacizumab administration of the 28 remaining patients were evaluable for response. Thirteen significantly reduced drug uptake measured by PET starting at 5 h (36%) had a partial response (PR) and 13 (36%) had stable dis- after and persisting until day 4. Whether this effect was associated ease (SD) as their best response, and 2 (6%) showed progressive with benefit or treatment resistance remains unknown.

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