original articles
Annals of Oncology 5. NCCN Clinical Practice Guidelines in Oncology—Non-Small Cell Lung Cancer. NCCN 2014. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site (10 February 2016, date last accessed). 6. Portrazza™ (necitumumab). US Prescribing Information. Eli Lilly and Company. 2015. 7. Portrazza™ (necitumumab). EU Prescribing Information. Eli Lilly and Company. 2016. 8. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002; 20: 1s–13s. 9. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 2002; 7(Suppl 4): 2–8. 10. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183–232. 11. Veale D, Ashcroft T, Marsh C et al. Epidermal growth factor receptors in non-small cell lung cancer. Br J Cancer 1987; 55: 513. 12. Fontanini G, Vignati S, Bigini D et al. Epidermal growth factor receptor (EGFr) expression in non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal lymph nodes in the squamous subtype. Eur J Cancer 1995; 31: 178–183. 13. Veale D, Kerr N, Gibson G et al. The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival. Br J Cancer 1993; 68: 162. 14. Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009; 373: 1525–1531. 15. Li S, Kussie P, Ferguson KM. Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8. Structure 2008; 16: 216–227.
16. Liu M, Zhang H, Jimenez X et al. Identification and characterization of a fully human antibody directed against epidermal growth factor receptor for cancer therapy. Cancer Res 2004; 64: 163. 17. Paz-Ares L, Mezger J, Ciuleanu TE et al. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-smallcell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 328–337. 18. Thatcher N, Hirsch FR, Luft AV et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 763–774. 19. Meert AP, Martin B, Delmotte P et al. The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis. Eur Respir J 2002; 20: 975–981. 20. Sheng J, Yang YP, Zhao YY et al. The efficacy of combining EGFR monoclonal antibody with chemotherapy for patients with advanced nonsmall cell lung cancer: a meta-analysis from 9 randomized controlled trials. Medicine (Baltimore) 2015; 94: e1400. 21. Dacic S, Flanagan M, Cieply K et al. Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma. Am J Clin Pathol 2006; 125: 860–865. 22. Hirsch FR, Herbst RS, Olsen C et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 2008; 26: 3351–3357. 23. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-smallcell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13: 33–42.
Annals of Oncology 27: 1579–1585, 2016 doi:10.1093/annonc/mdw188 Published online 8 June 2016
Efficacy of the nanoparticle–drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I–IIa clinical trial S. M. Keefe1, J. Hoffman-Censits2, R. B. Cohen1, R. Mamtani1, D. Heitjan3, S. Eliasof4, A. Nixon5, B. Turnbull6, E. G. Garmey4, O. Gunnarsson7, M. Waliki1, J. Ciconte1, L. Jayaraman4, A. Senderowicz4, A. B. Tellez4, M. Hennessy4, A. Piscitelli4, D. Vaughn1, A. Smith1 & N. B. Haas1* 1 Abramson Cancer Center, University of Pennsylvania, Philadelphia; 2Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia; 3Southern Methodist University, Dallas; 4Cerulean Pharma Inc., Waltham; 5Duke University School of Medicine, Durham; 6BioBridges LLC, Boston, USA; 7Landspitali University Hospital, Reykjavik, Iceland
Received 18 March 2016; revised 24 April 2016; accepted 26 April 2016
Background: Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle–drug conjugate (NDC), which durably *Correspondence to: Dr Naomi B. Haas, Division of Hematology/Oncology, University of Pennsylvania, 3400 Civic Center Blvd, Perelman Center for Advanced Medicine, Philadelphia, PA 19104, USA. Tel: +1-215-662-7402; E-mail: [email protected]. edu
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
original articles
Annals of Oncology
inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. Patients and methods: Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m2) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. Results: Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. Conclusions: CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol’s predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing. Key words: renal cell carcinoma, angiogenesis, hypoxia-inducible factor, nanoparticle–drug conjugate, recommended phase II dose, CRLX101
introduction Most new cases of renal cell carcinomas (RCCs) diagnosed in the United States are of clear cell (ccRCC) histology [1]. Inactivation of the von Hippel Lindau tumor suppressor gene in ccRCC leads to higher intracellular levels of hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α), and in tumorigenesis and disease progression of many RCCs, aberrant angiogenesis is an early pathophysiologic step [2]. Multiple VEGF tyrosine kinase inhibitors (TKIs), mammalian target of rapamycin inhibitors, and bevacizumab, a monoclonal antibody to circulating VEGF, are approved for the treatment of metastatic RCC (mRCC) [3]. Although benefits of progression-free survival (PFS) and overall survival (OS) are achieved with these agents, patients with mRCC have a 5-year survival rate of 1 year of PFS time at the time of final PFS analysis.
Volume 27 | No. 8 | August 2016
original articles
Annals of Oncology
30%
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* New lesion † Partial response Figure 1. Waterfall plot of best net tumor change. Only 17 out of 22 patients are depicted in this plot as these patients have both baseline and at least one CT while on therapy. 40%
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AK 001
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progression
Figure 2. Spider plot of patients evaluable for response on therapy. Note that only 17 out of 22 patients are depicted in this plot, as these patients have both baseline and at least one CT scan while on therapy.
Among the patients evaluable for PFS (n = 22), the median time was 9.9 months: 11.2 months among second-line patients (n = 4) and 7.6 months among third- to sixth-line patients (n = 18). Of additional interest, 12 of 22 patients (55%) achieved PFS treatment
Volume 27 | No. 8 | August 2016
time of 16 weeks or greater. Finally, multiple patients achieved tumor reductions and duration of treatment exceeding their experience with earlier lines of RCC therapy (supplementary Figure S1, available at Annals of Oncology online).
doi:10.1093/annonc/mdw188 |
original articles correlative studies Pre- and post-treatment plasma samples were collected from all patients. Net reductions in levels of various proteins associated with poor outcome (including osteopontin, platelet-derived growth factor BB, Fibroblast Growth Factor-b, and TIE-2) were observed in patients who had decreases in tumor volume. Pharmacodynamic changes in these markers occurring between days 1 and 3 of cycle 1 are presented in supplementary Figures S2 A & B and S3, available at Annals of Oncology online.
discussion The primary objectives of this study were to define the recommended phase II dose (RP2D) of CRLX101 (15 mg/kg) when administered in combination with standard dose bevacizumab (10 mg/kg) and to establish the safety of this drug–drug combination. Importantly, no additive toxicity of the combination was observed: concomitant bevacizumab administration did not exacerbate CRLX101-associated myelosuppression. The incidence of non-infectious cystitis from CRLX101 was similar in frequency and severity to those rates observed with CRLX101 monotherapy [10]. In this study, the cystitis was not gender-specific, nor related to the number of prior therapies, histology, or duration of therapy. Interruption of both bevacizumab and CRLX101 during cystitis might accelerate recovery and should be considered in future studies. One mechanism of resistance to anti-angiogenic therapy is the induction of tumor hypoxia and up-regulation of HIF1α and HIF2α. The latter are correlated with epithelial mesenchymal transition and promotion of tumor stem cell production, angiogenesis, tumor invasiveness, and metastasis formation [2, 12–14]. Analogs of the topoisomerase-1 inhibitor, camptothecin, such as topotecan, administered with low daily dosing, have been shown to inhibit HIF1α protein levels [6, 15, 16] but are poorly tolerated. Alternatively, pegylated, liposomal, and polymeric nanoparticles of topoisomerase inhibitors, such as CRLX101, may provide a means of sustained drug exposure and extended inhibition of HIF1α protein accumulation [4]. Admittedly, another mechanism of activity could be direct DNA topoisomerase inhibition of rapid proliferation of cancer cells by CRLX101, similar to DNA damage seen with the use of gemcitabine or 5-Fluorouracil in mRCC [17, 18]. VEGF-targeted drugs demonstrate only modest success when administered to patients with progression through multiple lines of prior therapy [19]. For example, in a randomized phase III study comparing dovitinib to sorafenib in refractory mRCC, the median PFS was 3.7 months (95% CI 3.5–3.9) for dovitinib patients and 3.6 months (3.5–3.7) for sorafenib patients (hazard ratio 0·86, 95% CI 0.72–1.04; one-sided P = 0.063) [20]. The heavily pretreated patient population in our study demonstrated an ORR of 23% and an mPFS of 9.9 months. Also, nearly half of the patients (9/22) evaluable for efficacy achieved a PFS time which exceeded performance on their prior regimens of therapy. These results must be viewed in the context of the study’s small sample size and uncontrolled design. The availability of other treatments for advanced RCC, including the immune checkpoint inhibitors [21] and dual met and VEGF inhibitors [22] makes selection of first- and second-line therapy | Keefe et al.
Annals of Oncology
quite complicated. Nevertheless, the combination of CRLX101 and bevacizumab is an attractive choice for patients with rapidly proliferating RCC or those intolerant of or progressing on VEGF-TKIs or who are not candidates for the immune checkpoint inhibitors. The activity across both clear and non-clear cell RCC is also attractive, and while the number of papillary RCC patients in our study was small, this population could be further explored. The decrease in VEGFR resistance biomarkers supports the biologic hypotheses for combining CRLX101 and bevacizumab (see supplementary material, available at Annals of Oncology online). Furthermore, these results support that the addition of CRLX101 does not adversely modulate the benefits of bevacizumab monotherapy. Based on the experience described here, a well-controlled, randomized phase II clinical trial comparing the combination of CRLX101 and bevacizumab with the investigator’s choice of standard of care in advanced, unresectable mRCC patients post 2 or 3 regimens of prior therapy was launched in the second half of 2014 [23].
funding This investigator-initiated trial was supported by Cerulean Pharmaceuticals. RM is supported by National Institutes of Health (grant K23-CA 187185).
disclosure The following authors are employees of Cerulean Pharmaceuticals: SE, EGG, MH, LJ, AS, AP, and ABT. SMK is an employee of Merck & Co., Inc. All remaining authors have declared no conflicts of interest.
references 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65(1): 5. 2. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol 2003; 170(6 Pt 1): 2163–2172. 3. National Cancer Institute. Drugs Approved in Kidney Cancer. Bethesda, MD: National Cancer Institute, http://www.cancer.gov/about-cancer/treatment/drugs/ kidney (1 September 2015, date last accessed). 4. Clark AJ, Wiley DT, Zuckerman JE et al. CRLX101 nanoparticles localize in human tumors andnot in adjacent, nonneoplastic tissue after intravenous dosing. Proc Natl Acad Sci USA 2016. 5. Eliasof S, Lazarus D, Peters CG et al. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle. Proc Natl Acad Sci USA 2013; 110(37): 15127–15132. 6. Lou JJ, Chua YL, Chew JG et al. Inhibition of hypoxia-inducible factor-1alpha (HIF1alpha) protein synthesis by DNA damage inducing agents. PLoS One 2010; 5(5): e10522. 7. Ceruleanrx IB, www.ceruleanrx.com. 8. Pham E, Birrer MJ, Eliasof S et al. Translational impact of nanoparticle-drug conjugate CRLX101 with or without bevacizumab in advanced ovarian cancer. Clin Cancer Res 2015; 21(4): 808–818. 9. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228–247. 10. Weiss GJ, Chao J, Neidhart JD et al. First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies. Invest New Drugs 2013; 31(4): 986–1000.
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Annals of Oncology 11. Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372(9637): 449–456. 12. Rapisarda A, Melillo G. Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 2012; 9(7): 378–390. 13. Rapisarda A, Hollingshead M, Uranchimeg B et al. Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther 2009; 8(7): 1867–1877. 14. Kerbel RS. Tumor angiogenesis. N Engl J Med 2008; 358(19): 2039–2049. 15. Kummar S, Raffeld M, Juwara L et al. Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors. Clin Cancer Res 2011; 17(15): 5123–5131. 16. Rapisarda A, Zalek J, Hollingshead M et al. Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 2004; 64 (19): 6845–6848. 17. Fizazi K, Rolland F, Chevreau C et al. A phase II study of irinotecan in patients with advanced renal cell carcinoma. Cancer 2003; 98(1): 61–65.
original articles 18. Haas NB, Lin X, Manola J et al. A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol 2012; 29 (2): 761–767. 19. Hainsworth JD, Shipley DL, Reeves J Jr et al. High-dose bevacizumab in the treatment of patients with advanced clear cell renal carcinoma: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin Genitourin Cancer 2013; 11(3): 283–289. 20. Motzer RJ, Porta C, Vogelzang NJ et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15(3): 286–296. 21. Motzer RJ, Escudier B, McDermott DF et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373(19): 1803–1813. 22. Choueiri TK, Escudier B, Powles T et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373(19): 1814–1823. 23. Voss M, Coates A, Garmey E et al. Randomized phase 2 study to assess the safety and efficacy of CRLX101 in combination with bevacizumab in patients ( pts.) with metastatic renal cell carcinoma (RCC) versus standard of care (SOC). J Clin Oncol 2015; 33 (Suppl): abstr TPS4579.
Annals of Oncology 27: 1585–1593, 2016 doi:10.1093/annonc/mdw151 Published online 15 April 2016
Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial† P. M. Clement1,2*, T. Gauler3, J. P. Machiels4, R. I. Haddad5, J. Fayette6, L. F. Licitra7, M. Tahara8, E. E. W. Cohen9, D. Cupissol10, J. J. Grau11, J. Guigay12,13, F. Caponigro14, G. de Castro, Jr15, L. de Souza Viana16, U. Keilholz17, J. M. del Campo18, X. J. Cong19, E. Ehrnrooth20 & J. B. Vermorken21 on behalf of the LUX-H&N 1 investigators 1 Department of Oncology, KU Leuven, Leuven; 2Department of General Medical Oncology, UZ Leuven, Leuven, Belgium; 3Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen, Germany; 4Institut Roi Albert II, Service d’Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium; 5Departmant of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, USA; 6Departmant of Medical Oncology, Léon Bérard Center, University of Lyon, Lyon, France; 7Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 8Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan; 9 Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, USA; 10Service d’Oncologie Médicale, Institut du Cancer de Montpellier Val d’Aurelle, Montpellier, France; 11Department of Medical Oncology, Hospital Clínic and University of Barcelona, Barcelona, Spain; 12Department of Medical Oncology, Gustave Roussy, Villejuif; 13Centre Antoine Lacassagne, Nice, France; 14Department of Melanoma, Soft Tissues, Muscolo Scheletal, Head and Neck, Head and Neck Medical Oncology, National Tumor Institute of Naples, Naples, Italy; 15Oncologia Clinica, Instituto do Câncer do Estado de São Paulo, São Paulo; 16Department of Medical Oncology, Hospital de Câncer de Barretos, São Paulo, Brazil; 17Charité Comprehensive Cancer Center, Berlin, Germany; 18Department of Medical Oncology, Hospital Universitario Vall D’Hebron, Barcelona, Spain; 19Biometrics and Data Management, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA; 20Division of Oncology, Boehringer Ingelheim Danmark A/S, Copenhagen, Denmark; 21Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium
Received 6 January 2016; revised 15 March 2016; accepted 21 March 2016
Background: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) *Correspondence to: Dr Paul M. Clement, Department of Oncology, KU Leuven, Herestraat 49, Leuven 3000, Belgium. Tel: +32-16-34-69-03; E-mail: paul.clement@ uzleuven.be †
Presented, in part, at the International Conference on Innovative Approaches in Head and Neck Oncology Meeting; 12–14 February 2015, Nice, France. Abstract No. OC-005.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
Annals of Oncology 5. NCCN Clinical Practice Guidelines in Oncology—Non-Small Cell Lung Cancer. NCCN 2014. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site (10 February 2016, date last accessed). 6. Portrazza™ (necitumumab). US Prescribing Information. Eli Lilly and Company. 2015. 7. Portrazza™ (necitumumab). EU Prescribing Information. Eli Lilly and Company. 2016. 8. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002; 20: 1s–13s. 9. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 2002; 7(Suppl 4): 2–8. 10. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183–232. 11. Veale D, Ashcroft T, Marsh C et al. Epidermal growth factor receptors in non-small cell lung cancer. Br J Cancer 1987; 55: 513. 12. Fontanini G, Vignati S, Bigini D et al. Epidermal growth factor receptor (EGFr) expression in non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal lymph nodes in the squamous subtype. Eur J Cancer 1995; 31: 178–183. 13. Veale D, Kerr N, Gibson G et al. The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival. Br J Cancer 1993; 68: 162. 14. Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009; 373: 1525–1531. 15. Li S, Kussie P, Ferguson KM. Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8. Structure 2008; 16: 216–227.
16. Liu M, Zhang H, Jimenez X et al. Identification and characterization of a fully human antibody directed against epidermal growth factor receptor for cancer therapy. Cancer Res 2004; 64: 163. 17. Paz-Ares L, Mezger J, Ciuleanu TE et al. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-smallcell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 328–337. 18. Thatcher N, Hirsch FR, Luft AV et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 763–774. 19. Meert AP, Martin B, Delmotte P et al. The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis. Eur Respir J 2002; 20: 975–981. 20. Sheng J, Yang YP, Zhao YY et al. The efficacy of combining EGFR monoclonal antibody with chemotherapy for patients with advanced nonsmall cell lung cancer: a meta-analysis from 9 randomized controlled trials. Medicine (Baltimore) 2015; 94: e1400. 21. Dacic S, Flanagan M, Cieply K et al. Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma. Am J Clin Pathol 2006; 125: 860–865. 22. Hirsch FR, Herbst RS, Olsen C et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 2008; 26: 3351–3357. 23. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-smallcell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13: 33–42.
Annals of Oncology 27: 1579–1585, 2016 doi:10.1093/annonc/mdw188 Published online 8 June 2016
Efficacy of the nanoparticle–drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I–IIa clinical trial S. M. Keefe1, J. Hoffman-Censits2, R. B. Cohen1, R. Mamtani1, D. Heitjan3, S. Eliasof4, A. Nixon5, B. Turnbull6, E. G. Garmey4, O. Gunnarsson7, M. Waliki1, J. Ciconte1, L. Jayaraman4, A. Senderowicz4, A. B. Tellez4, M. Hennessy4, A. Piscitelli4, D. Vaughn1, A. Smith1 & N. B. Haas1* 1 Abramson Cancer Center, University of Pennsylvania, Philadelphia; 2Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia; 3Southern Methodist University, Dallas; 4Cerulean Pharma Inc., Waltham; 5Duke University School of Medicine, Durham; 6BioBridges LLC, Boston, USA; 7Landspitali University Hospital, Reykjavik, Iceland
Received 18 March 2016; revised 24 April 2016; accepted 26 April 2016
Background: Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle–drug conjugate (NDC), which durably *Correspondence to: Dr Naomi B. Haas, Division of Hematology/Oncology, University of Pennsylvania, 3400 Civic Center Blvd, Perelman Center for Advanced Medicine, Philadelphia, PA 19104, USA. Tel: +1-215-662-7402; E-mail: [email protected]. edu
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
original articles
Annals of Oncology
inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. Patients and methods: Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m2) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. Results: Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. Conclusions: CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol’s predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing. Key words: renal cell carcinoma, angiogenesis, hypoxia-inducible factor, nanoparticle–drug conjugate, recommended phase II dose, CRLX101
introduction Most new cases of renal cell carcinomas (RCCs) diagnosed in the United States are of clear cell (ccRCC) histology [1]. Inactivation of the von Hippel Lindau tumor suppressor gene in ccRCC leads to higher intracellular levels of hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α), and in tumorigenesis and disease progression of many RCCs, aberrant angiogenesis is an early pathophysiologic step [2]. Multiple VEGF tyrosine kinase inhibitors (TKIs), mammalian target of rapamycin inhibitors, and bevacizumab, a monoclonal antibody to circulating VEGF, are approved for the treatment of metastatic RCC (mRCC) [3]. Although benefits of progression-free survival (PFS) and overall survival (OS) are achieved with these agents, patients with mRCC have a 5-year survival rate of 1 year of PFS time at the time of final PFS analysis.
Volume 27 | No. 8 | August 2016
original articles
Annals of Oncology
30%
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20% 10% 0% –10% –20% –30%
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–40%
† †
–50% –50% Clear cell histology Non clear cell histology
* New lesion † Partial response Figure 1. Waterfall plot of best net tumor change. Only 17 out of 22 patients are depicted in this plot as these patients have both baseline and at least one CT while on therapy. 40%
30%
*
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% Change in target lesions
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* 0
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–10%
* *
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*
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* New lesion * Off study but not for
AK 001
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GS 006
DW 007
OW 010
AW 012
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Bno 020
JS 021
BG 22
RL 023
HR 024
JH 011
progression
Figure 2. Spider plot of patients evaluable for response on therapy. Note that only 17 out of 22 patients are depicted in this plot, as these patients have both baseline and at least one CT scan while on therapy.
Among the patients evaluable for PFS (n = 22), the median time was 9.9 months: 11.2 months among second-line patients (n = 4) and 7.6 months among third- to sixth-line patients (n = 18). Of additional interest, 12 of 22 patients (55%) achieved PFS treatment
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time of 16 weeks or greater. Finally, multiple patients achieved tumor reductions and duration of treatment exceeding their experience with earlier lines of RCC therapy (supplementary Figure S1, available at Annals of Oncology online).
doi:10.1093/annonc/mdw188 |
original articles correlative studies Pre- and post-treatment plasma samples were collected from all patients. Net reductions in levels of various proteins associated with poor outcome (including osteopontin, platelet-derived growth factor BB, Fibroblast Growth Factor-b, and TIE-2) were observed in patients who had decreases in tumor volume. Pharmacodynamic changes in these markers occurring between days 1 and 3 of cycle 1 are presented in supplementary Figures S2 A & B and S3, available at Annals of Oncology online.
discussion The primary objectives of this study were to define the recommended phase II dose (RP2D) of CRLX101 (15 mg/kg) when administered in combination with standard dose bevacizumab (10 mg/kg) and to establish the safety of this drug–drug combination. Importantly, no additive toxicity of the combination was observed: concomitant bevacizumab administration did not exacerbate CRLX101-associated myelosuppression. The incidence of non-infectious cystitis from CRLX101 was similar in frequency and severity to those rates observed with CRLX101 monotherapy [10]. In this study, the cystitis was not gender-specific, nor related to the number of prior therapies, histology, or duration of therapy. Interruption of both bevacizumab and CRLX101 during cystitis might accelerate recovery and should be considered in future studies. One mechanism of resistance to anti-angiogenic therapy is the induction of tumor hypoxia and up-regulation of HIF1α and HIF2α. The latter are correlated with epithelial mesenchymal transition and promotion of tumor stem cell production, angiogenesis, tumor invasiveness, and metastasis formation [2, 12–14]. Analogs of the topoisomerase-1 inhibitor, camptothecin, such as topotecan, administered with low daily dosing, have been shown to inhibit HIF1α protein levels [6, 15, 16] but are poorly tolerated. Alternatively, pegylated, liposomal, and polymeric nanoparticles of topoisomerase inhibitors, such as CRLX101, may provide a means of sustained drug exposure and extended inhibition of HIF1α protein accumulation [4]. Admittedly, another mechanism of activity could be direct DNA topoisomerase inhibition of rapid proliferation of cancer cells by CRLX101, similar to DNA damage seen with the use of gemcitabine or 5-Fluorouracil in mRCC [17, 18]. VEGF-targeted drugs demonstrate only modest success when administered to patients with progression through multiple lines of prior therapy [19]. For example, in a randomized phase III study comparing dovitinib to sorafenib in refractory mRCC, the median PFS was 3.7 months (95% CI 3.5–3.9) for dovitinib patients and 3.6 months (3.5–3.7) for sorafenib patients (hazard ratio 0·86, 95% CI 0.72–1.04; one-sided P = 0.063) [20]. The heavily pretreated patient population in our study demonstrated an ORR of 23% and an mPFS of 9.9 months. Also, nearly half of the patients (9/22) evaluable for efficacy achieved a PFS time which exceeded performance on their prior regimens of therapy. These results must be viewed in the context of the study’s small sample size and uncontrolled design. The availability of other treatments for advanced RCC, including the immune checkpoint inhibitors [21] and dual met and VEGF inhibitors [22] makes selection of first- and second-line therapy | Keefe et al.
Annals of Oncology
quite complicated. Nevertheless, the combination of CRLX101 and bevacizumab is an attractive choice for patients with rapidly proliferating RCC or those intolerant of or progressing on VEGF-TKIs or who are not candidates for the immune checkpoint inhibitors. The activity across both clear and non-clear cell RCC is also attractive, and while the number of papillary RCC patients in our study was small, this population could be further explored. The decrease in VEGFR resistance biomarkers supports the biologic hypotheses for combining CRLX101 and bevacizumab (see supplementary material, available at Annals of Oncology online). Furthermore, these results support that the addition of CRLX101 does not adversely modulate the benefits of bevacizumab monotherapy. Based on the experience described here, a well-controlled, randomized phase II clinical trial comparing the combination of CRLX101 and bevacizumab with the investigator’s choice of standard of care in advanced, unresectable mRCC patients post 2 or 3 regimens of prior therapy was launched in the second half of 2014 [23].
funding This investigator-initiated trial was supported by Cerulean Pharmaceuticals. RM is supported by National Institutes of Health (grant K23-CA 187185).
disclosure The following authors are employees of Cerulean Pharmaceuticals: SE, EGG, MH, LJ, AS, AP, and ABT. SMK is an employee of Merck & Co., Inc. All remaining authors have declared no conflicts of interest.
references 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65(1): 5. 2. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol 2003; 170(6 Pt 1): 2163–2172. 3. National Cancer Institute. Drugs Approved in Kidney Cancer. Bethesda, MD: National Cancer Institute, http://www.cancer.gov/about-cancer/treatment/drugs/ kidney (1 September 2015, date last accessed). 4. Clark AJ, Wiley DT, Zuckerman JE et al. CRLX101 nanoparticles localize in human tumors andnot in adjacent, nonneoplastic tissue after intravenous dosing. Proc Natl Acad Sci USA 2016. 5. Eliasof S, Lazarus D, Peters CG et al. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle. Proc Natl Acad Sci USA 2013; 110(37): 15127–15132. 6. Lou JJ, Chua YL, Chew JG et al. Inhibition of hypoxia-inducible factor-1alpha (HIF1alpha) protein synthesis by DNA damage inducing agents. PLoS One 2010; 5(5): e10522. 7. Ceruleanrx IB, www.ceruleanrx.com. 8. Pham E, Birrer MJ, Eliasof S et al. Translational impact of nanoparticle-drug conjugate CRLX101 with or without bevacizumab in advanced ovarian cancer. Clin Cancer Res 2015; 21(4): 808–818. 9. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228–247. 10. Weiss GJ, Chao J, Neidhart JD et al. First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies. Invest New Drugs 2013; 31(4): 986–1000.
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Annals of Oncology 11. Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372(9637): 449–456. 12. Rapisarda A, Melillo G. Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 2012; 9(7): 378–390. 13. Rapisarda A, Hollingshead M, Uranchimeg B et al. Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther 2009; 8(7): 1867–1877. 14. Kerbel RS. Tumor angiogenesis. N Engl J Med 2008; 358(19): 2039–2049. 15. Kummar S, Raffeld M, Juwara L et al. Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors. Clin Cancer Res 2011; 17(15): 5123–5131. 16. Rapisarda A, Zalek J, Hollingshead M et al. Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 2004; 64 (19): 6845–6848. 17. Fizazi K, Rolland F, Chevreau C et al. A phase II study of irinotecan in patients with advanced renal cell carcinoma. Cancer 2003; 98(1): 61–65.
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Annals of Oncology 27: 1585–1593, 2016 doi:10.1093/annonc/mdw151 Published online 15 April 2016
Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial† P. M. Clement1,2*, T. Gauler3, J. P. Machiels4, R. I. Haddad5, J. Fayette6, L. F. Licitra7, M. Tahara8, E. E. W. Cohen9, D. Cupissol10, J. J. Grau11, J. Guigay12,13, F. Caponigro14, G. de Castro, Jr15, L. de Souza Viana16, U. Keilholz17, J. M. del Campo18, X. J. Cong19, E. Ehrnrooth20 & J. B. Vermorken21 on behalf of the LUX-H&N 1 investigators 1 Department of Oncology, KU Leuven, Leuven; 2Department of General Medical Oncology, UZ Leuven, Leuven, Belgium; 3Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen, Germany; 4Institut Roi Albert II, Service d’Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium; 5Departmant of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, USA; 6Departmant of Medical Oncology, Léon Bérard Center, University of Lyon, Lyon, France; 7Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 8Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan; 9 Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, USA; 10Service d’Oncologie Médicale, Institut du Cancer de Montpellier Val d’Aurelle, Montpellier, France; 11Department of Medical Oncology, Hospital Clínic and University of Barcelona, Barcelona, Spain; 12Department of Medical Oncology, Gustave Roussy, Villejuif; 13Centre Antoine Lacassagne, Nice, France; 14Department of Melanoma, Soft Tissues, Muscolo Scheletal, Head and Neck, Head and Neck Medical Oncology, National Tumor Institute of Naples, Naples, Italy; 15Oncologia Clinica, Instituto do Câncer do Estado de São Paulo, São Paulo; 16Department of Medical Oncology, Hospital de Câncer de Barretos, São Paulo, Brazil; 17Charité Comprehensive Cancer Center, Berlin, Germany; 18Department of Medical Oncology, Hospital Universitario Vall D’Hebron, Barcelona, Spain; 19Biometrics and Data Management, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA; 20Division of Oncology, Boehringer Ingelheim Danmark A/S, Copenhagen, Denmark; 21Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium
Received 6 January 2016; revised 15 March 2016; accepted 21 March 2016
Background: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) *Correspondence to: Dr Paul M. Clement, Department of Oncology, KU Leuven, Herestraat 49, Leuven 3000, Belgium. Tel: +32-16-34-69-03; E-mail: paul.clement@ uzleuven.be †
Presented, in part, at the International Conference on Innovative Approaches in Head and Neck Oncology Meeting; 12–14 February 2015, Nice, France. Abstract No. OC-005.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
