Comment
of these results might herald a promising new therapeutic era of risk-adapted trials incorporating novel agents for this group of children. Lindsey M Hoffman, *Maryam Fouladi Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA [email protected]
5
6
7
8
We declare no competing interests. 1
2 3
4
Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol 2009; 27: 385–89. Lee RS, Roberts CWM. Rhabdoid tumors: an initial clue to the role of chromatin remodeling in cancer. Brain Pathol 2013; 23: 200–05. Lee RS, Stewart C, Carter SL, et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 2012; 122: 2983–88. Jagani Z, Mora-Blanco EL, Sansam CG, et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med 2010; 16: 1429–33.
9
10
11
Lee S, Cimica V, Ramachandra N, Zagzag D, Kalpana GV. Aurora A is a repressed effector target of the chromatin remodeling protein INI1/ hSNF5 required for rhabdoid tumor cell survival. Cancer Res 2011; 71: 3225–35. Mora-Blanco EL, Mishina Y, Tillman EJ, et al. Activation of β-catenin/TCF targets following loss of the tumor suppressor SNF5. Oncogene 2014; 33: 933–38. Torchia J, Picard D, Lafay-Cousin L, et al. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol 2015; published online April 14. http://dx.doi.org/10.1016/S1470-2045(15)70114-2. Weingart MF, Roth JJ, Hutt-Cabezas M, et al. Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target. Oncotarget 2015; 6: 3165–77. Smith ME, Cimica V, Chinni S, et al. Therapeutically targeting cyclin D1 in primary tumors arising from loss of Ini1. Proc Natl Acad Sci USA 2011; 108: 319–24. Wetmore C, Boyett J, Li S, et al. Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children. NeuroOncology 2015; published online Feb 16. DOI:10.1093/neuonc/nov017. Knutson SK, Warholic NM, Wigle TJ, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci USA 2013; 110: 7922–27.
Visuals Unlimited/Corbis
EGFR inhibition for recurrent or metastatic HNSCC
Published Online April 17, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70178-6 See Articles page 583
488
Head and neck squamous-cell carcinoma (HNSCC) is usually localised and potentially curable at initial diagnosis, but often recurs after treatment and can be associated with distant metastasis. Systemic therapy has an integral role in the management of patients with HNSCC; however, by contrast with therapeutic advances seen in other solid tumours, systemic therapy of HNSCC has remained relatively stagnant in recent years with the notable exception of the development of EGFR inhibitors. EGFR is almost ubiquitously expressed in HNSCC although it is very rarely mutated, and it has been linked to poor prognosis. It is therefore an obvious and attractive therapeutic target.1 Several anti-EGFR monoclonal antibodies and tyrosine-kinase inhibitors have been clinically tested in HNSCC. Cetuximab, the prototype murine–human chimeric IgG1 antiEGFR monoclonal antibody, improved survival in patients with locally advanced HNSCC when added to radiotherapy,2 and in patients with recurrent or metastatic HNSCC when added to first-line platinumbased chemotherapy,3 and thus received regulatory approval for these indications in the USA and Europe. Second-line therapy for HNSCC yields poor results and no well-established evidence-based standards of care exist. The primary goal of treatment is to prolong survival; improving symptoms, minimising toxicity,
and improving or maintaining quality of life are major secondary objectives. In platinum-refractory HNSCC, cetuximab monotherapy has reproducible antitumour activity with 10–13% of patients achieving objective responses, although no data from randomised comparisons of cetuximab with best supportive care or chemotherapy are currently available. Afatinib, which has regulatory approval in EGFRmutated non-small-cell lung cancer, stands as a unique agent in the class of EGFR inhibitors because it is an orally available irreversible tyrosine-kinase inhibitor of the broader EGFR family, targeting EGFR, HER2, and HER4. Afatinib and cetuximab had comparable activity as second-line therapy in HNSCC in a phase 2 randomised trial.4 However, afatinib at a starting dose of 50 mg once-daily resulted in more frequent serious adverse events, namely rash, diarrhoea, and stomatitis, than did cetuximab.4 An important question is whether an EGFR inhibitor compares favourably with chemotherapy in the secondline therapy of HNSCC. In The Lancet Oncology, JeanPascal Machiels and colleagues report the results of the LUX-Head & Neck 1 trial,5 a phase 3 randomised trial that compared oral afatinib (40 mg daily, with an increase to 50 mg if tolerated) with intravenous methotrexate (40 mg/m² weekly) in patients with HNSCC who had progressed after a single previous www.thelancet.com/oncology Vol 16 May 2015
Comment
platinum-based chemotherapy regimen. Although progression-free survival was labelled as the primary endpoint, the study was powered to show a meaningful superiority of afatinib in terms of overall survival, which is highly desirable with the introduction of new and costly targeted agents. In this well-conducted global trial that enrolled 483 patients, afatinib marginally improved progression-free survival (median 2·6 months [95% CI 2·0–2·7] for afatinib vs 1·7 months [1·5–2·4] for methotrexate; HR 0·80 [95% CI 0·65–0·98], p=0·030) but not overall survival (6·8 months [95% CI 6·1–7·7] vs 6·0 months [5·2–7·8]; 0·96 [95% CI 0·77–1·19], p=0·70). Moreover, afatinib was associated with a higher incidence of serious rash and diarrhoea than methotrexate and similar rates of stomatitis; methotrexate caused expected haematological toxicities. An interesting aspect of the study was the suggestion from subset analyses that afatinib had a more pronounced effect in patients not previously treated with an EGFR inhibitor and in those with human papillomavirus-negative tumours. These observations could generate hypotheses for future prospective investigations. Several phase 3 trials have assessed second-line therapies for HNSCC. Results were disappointing when comparing gefitinib with methotrexate,6 zalutumumab with best supportive care,7 and combining gefitinib with docetaxel.8 The LUX-Head & Neck 1 trial is added to the list of studies that have failed to show an overall survival benefit with an EGFR inhibitor in HNSCC. Monotherapy with methotrexate or a taxane remains appropriate as a control treatment arm in future randomised trials in the second-line therapy of HNSCC, whereas best supportive care might be acceptable as a comparator in some clinical settings. Whether afatinib can ultimately have a role in HNSCC will be decided by the outcome of an ongoing phase 3 trial of adjuvant afatinib after chemoradiotherapy for locally advanced HNSCC. So far, EGFR inhibition has been insufficient to produce striking clinical results in HNSCC. Drug development has been hampered by the lack of predictive biomarkers in this setting. Unless new insights into EGFR biology are made, it seems unlikely that the field will move beyond the modest benefits achieved with cetuximab in HNSCC. It is noteworthy that the mechanism of action of cetuximab is partly related to antibody-dependent cell-mediated cytotoxicity and other immune mechanisms,9 which might account for its differential www.thelancet.com/oncology Vol 16 May 2015
clinical outcomes versus other anti-EGFR antibodies in this disease. Emerging data from mutational analyses of HNSCC are expected to contribute to novel therapeutic approaches. Squamous-cell carcinoma of the lung and human papillomavirus-negative HNSCC share common molecular features10 that might render them sensitive to immunotherapy. Nivolumab, a programmed death-1 receptor inhibitor, was superior to docetaxel in terms of overall survival in the second-line therapy of squamouscell carcinoma of the lung (NCT01642004), and was recently licensed for this purpose in the USA. At this time, immune checkpoint inhibitors are the most promising new agents under investigation in HNSCC, and have the potential to be combined with other treatments, including the EGFR inhibitors. It is imperative to look beyond EGFR, in addition to better understanding EGFR, as we strive to enhance our armamentarium against HNSCC. Athanassios Argiris Hygeia Hospital, Athens, Greece, and University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [email protected] I have received personal fees from Merck Serono, Roche, Bristol Myers Squibb, and Boehringer Ingelheim, and grants from Genentech. 1
2
3 4
5
6
7
8
9 10
Karamouzis MV, Grandis JR, Argiris A. Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas. JAMA 2007; 298: 70–82. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–78. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–27. Seiwert TY, Fayette J, Cupissol D, et al. A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck. Ann Oncol 2014; 25: 1813–20. Machiels J-PH, Haddad RI, Fayette J, et al, for the LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015; published online April 17. http://dx.doi.org/10.1016/S1470-2045(15)70124-5. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009; 27: 1864–71. Machiels JP, Subramanian S, Ruzsa A, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol 2011; 12: 333–43. Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized, placebocontrolled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial. J Clin Oncol 2013; 31: 1405–14. Trivedi S, Concha-Benavente F, Srivastava RM, et al. Immune biomarkers of anti-EGFR monoclonal antibody therapy. Ann Oncol 2015; 26: 40–47. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489: 519–25.
489
of these results might herald a promising new therapeutic era of risk-adapted trials incorporating novel agents for this group of children. Lindsey M Hoffman, *Maryam Fouladi Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA [email protected]
5
6
7
8
We declare no competing interests. 1
2 3
4
Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol 2009; 27: 385–89. Lee RS, Roberts CWM. Rhabdoid tumors: an initial clue to the role of chromatin remodeling in cancer. Brain Pathol 2013; 23: 200–05. Lee RS, Stewart C, Carter SL, et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 2012; 122: 2983–88. Jagani Z, Mora-Blanco EL, Sansam CG, et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med 2010; 16: 1429–33.
9
10
11
Lee S, Cimica V, Ramachandra N, Zagzag D, Kalpana GV. Aurora A is a repressed effector target of the chromatin remodeling protein INI1/ hSNF5 required for rhabdoid tumor cell survival. Cancer Res 2011; 71: 3225–35. Mora-Blanco EL, Mishina Y, Tillman EJ, et al. Activation of β-catenin/TCF targets following loss of the tumor suppressor SNF5. Oncogene 2014; 33: 933–38. Torchia J, Picard D, Lafay-Cousin L, et al. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol 2015; published online April 14. http://dx.doi.org/10.1016/S1470-2045(15)70114-2. Weingart MF, Roth JJ, Hutt-Cabezas M, et al. Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target. Oncotarget 2015; 6: 3165–77. Smith ME, Cimica V, Chinni S, et al. Therapeutically targeting cyclin D1 in primary tumors arising from loss of Ini1. Proc Natl Acad Sci USA 2011; 108: 319–24. Wetmore C, Boyett J, Li S, et al. Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children. NeuroOncology 2015; published online Feb 16. DOI:10.1093/neuonc/nov017. Knutson SK, Warholic NM, Wigle TJ, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci USA 2013; 110: 7922–27.
Visuals Unlimited/Corbis
EGFR inhibition for recurrent or metastatic HNSCC
Published Online April 17, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70178-6 See Articles page 583
488
Head and neck squamous-cell carcinoma (HNSCC) is usually localised and potentially curable at initial diagnosis, but often recurs after treatment and can be associated with distant metastasis. Systemic therapy has an integral role in the management of patients with HNSCC; however, by contrast with therapeutic advances seen in other solid tumours, systemic therapy of HNSCC has remained relatively stagnant in recent years with the notable exception of the development of EGFR inhibitors. EGFR is almost ubiquitously expressed in HNSCC although it is very rarely mutated, and it has been linked to poor prognosis. It is therefore an obvious and attractive therapeutic target.1 Several anti-EGFR monoclonal antibodies and tyrosine-kinase inhibitors have been clinically tested in HNSCC. Cetuximab, the prototype murine–human chimeric IgG1 antiEGFR monoclonal antibody, improved survival in patients with locally advanced HNSCC when added to radiotherapy,2 and in patients with recurrent or metastatic HNSCC when added to first-line platinumbased chemotherapy,3 and thus received regulatory approval for these indications in the USA and Europe. Second-line therapy for HNSCC yields poor results and no well-established evidence-based standards of care exist. The primary goal of treatment is to prolong survival; improving symptoms, minimising toxicity,
and improving or maintaining quality of life are major secondary objectives. In platinum-refractory HNSCC, cetuximab monotherapy has reproducible antitumour activity with 10–13% of patients achieving objective responses, although no data from randomised comparisons of cetuximab with best supportive care or chemotherapy are currently available. Afatinib, which has regulatory approval in EGFRmutated non-small-cell lung cancer, stands as a unique agent in the class of EGFR inhibitors because it is an orally available irreversible tyrosine-kinase inhibitor of the broader EGFR family, targeting EGFR, HER2, and HER4. Afatinib and cetuximab had comparable activity as second-line therapy in HNSCC in a phase 2 randomised trial.4 However, afatinib at a starting dose of 50 mg once-daily resulted in more frequent serious adverse events, namely rash, diarrhoea, and stomatitis, than did cetuximab.4 An important question is whether an EGFR inhibitor compares favourably with chemotherapy in the secondline therapy of HNSCC. In The Lancet Oncology, JeanPascal Machiels and colleagues report the results of the LUX-Head & Neck 1 trial,5 a phase 3 randomised trial that compared oral afatinib (40 mg daily, with an increase to 50 mg if tolerated) with intravenous methotrexate (40 mg/m² weekly) in patients with HNSCC who had progressed after a single previous www.thelancet.com/oncology Vol 16 May 2015
Comment
platinum-based chemotherapy regimen. Although progression-free survival was labelled as the primary endpoint, the study was powered to show a meaningful superiority of afatinib in terms of overall survival, which is highly desirable with the introduction of new and costly targeted agents. In this well-conducted global trial that enrolled 483 patients, afatinib marginally improved progression-free survival (median 2·6 months [95% CI 2·0–2·7] for afatinib vs 1·7 months [1·5–2·4] for methotrexate; HR 0·80 [95% CI 0·65–0·98], p=0·030) but not overall survival (6·8 months [95% CI 6·1–7·7] vs 6·0 months [5·2–7·8]; 0·96 [95% CI 0·77–1·19], p=0·70). Moreover, afatinib was associated with a higher incidence of serious rash and diarrhoea than methotrexate and similar rates of stomatitis; methotrexate caused expected haematological toxicities. An interesting aspect of the study was the suggestion from subset analyses that afatinib had a more pronounced effect in patients not previously treated with an EGFR inhibitor and in those with human papillomavirus-negative tumours. These observations could generate hypotheses for future prospective investigations. Several phase 3 trials have assessed second-line therapies for HNSCC. Results were disappointing when comparing gefitinib with methotrexate,6 zalutumumab with best supportive care,7 and combining gefitinib with docetaxel.8 The LUX-Head & Neck 1 trial is added to the list of studies that have failed to show an overall survival benefit with an EGFR inhibitor in HNSCC. Monotherapy with methotrexate or a taxane remains appropriate as a control treatment arm in future randomised trials in the second-line therapy of HNSCC, whereas best supportive care might be acceptable as a comparator in some clinical settings. Whether afatinib can ultimately have a role in HNSCC will be decided by the outcome of an ongoing phase 3 trial of adjuvant afatinib after chemoradiotherapy for locally advanced HNSCC. So far, EGFR inhibition has been insufficient to produce striking clinical results in HNSCC. Drug development has been hampered by the lack of predictive biomarkers in this setting. Unless new insights into EGFR biology are made, it seems unlikely that the field will move beyond the modest benefits achieved with cetuximab in HNSCC. It is noteworthy that the mechanism of action of cetuximab is partly related to antibody-dependent cell-mediated cytotoxicity and other immune mechanisms,9 which might account for its differential www.thelancet.com/oncology Vol 16 May 2015
clinical outcomes versus other anti-EGFR antibodies in this disease. Emerging data from mutational analyses of HNSCC are expected to contribute to novel therapeutic approaches. Squamous-cell carcinoma of the lung and human papillomavirus-negative HNSCC share common molecular features10 that might render them sensitive to immunotherapy. Nivolumab, a programmed death-1 receptor inhibitor, was superior to docetaxel in terms of overall survival in the second-line therapy of squamouscell carcinoma of the lung (NCT01642004), and was recently licensed for this purpose in the USA. At this time, immune checkpoint inhibitors are the most promising new agents under investigation in HNSCC, and have the potential to be combined with other treatments, including the EGFR inhibitors. It is imperative to look beyond EGFR, in addition to better understanding EGFR, as we strive to enhance our armamentarium against HNSCC. Athanassios Argiris Hygeia Hospital, Athens, Greece, and University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [email protected] I have received personal fees from Merck Serono, Roche, Bristol Myers Squibb, and Boehringer Ingelheim, and grants from Genentech. 1
2
3 4
5
6
7
8
9 10
Karamouzis MV, Grandis JR, Argiris A. Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas. JAMA 2007; 298: 70–82. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–78. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–27. Seiwert TY, Fayette J, Cupissol D, et al. A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck. Ann Oncol 2014; 25: 1813–20. Machiels J-PH, Haddad RI, Fayette J, et al, for the LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015; published online April 17. http://dx.doi.org/10.1016/S1470-2045(15)70124-5. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009; 27: 1864–71. Machiels JP, Subramanian S, Ruzsa A, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol 2011; 12: 333–43. Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized, placebocontrolled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial. J Clin Oncol 2013; 31: 1405–14. Trivedi S, Concha-Benavente F, Srivastava RM, et al. Immune biomarkers of anti-EGFR monoclonal antibody therapy. Ann Oncol 2015; 26: 40–47. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489: 519–25.
489
