- Email: [email protected]
Antibody–drug conjugates in non-Hodgkin lymphoma
Comment
treatment should be the first: the most effective or the one with the fewest side-effects? Thus, while this new study7 of treatment with pazopanib shows encouraging outcomes in a subgroup of NET patients, it also presents future challenges for selection of treatment choices. Dik J Kwekkeboom Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam 3015 GD, Netherlands
3 4 5
6 7
8
I declare no competing interests. 1
2
Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371: 224–33. Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, doubleblind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009; 27: 4656–63.
9
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514–23. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 501–13. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide longacting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebocontrolled, phase 3 study. Lancet 2011; 378: 2005–12. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514-23. Phan AT, Halperin DM, Chan JA, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncology 2015; published online May 6. http://dx.doi.org/10.1016/S1470-2045(15)70136-1. Khan S, Krenning EP, van Essen M, Kam BL, Teunissen JJ, Kwekkeboom DJ. Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. J Nucl Med 2011; 52: 1361–68. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26: 2124–30.
Although the outcome of patients with non-Hodgkin lymphoma has improved over the years, patients who relapse after rituximab-based treatment often remain resistant to salvage therapy.1 As first-line therapy, immunochemotherapy such as rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) remains unsatisfactory in patients with high-risk disease. More intensive approaches, including upfront high-dose chemotherapy and autologous stem-cell transplantation, have not been shown to be beneficial and might not be tolerated by older patients.2 Because a third of patients with nonHodgkin lymphoma are older than 75 years, the safety profiles of any proposed new agents are important considerations. Polatuzumab vedotin and pinatuzumab vedotin are two new antibody–drug conjugates targeting CD79B and CD22, respectively, under investigation in nonHodgkin lymphoma. Both contain a B-cell antibody linked to a microtubule inhibitor, monomethyl auristatin E. In The Lancet Oncology, Maria Corinna Palanca-Wessels and colleagues3 report findings from a phase 1 study of polatuzumab vendotin in patients with relapsed or refractory non-Hodgkin lymphoma and chronic lymphocytic leukaemia.3 Overall, 95 patients were recruited to the study, including 77 with non-Hodgkin lymphoma and 18 with chronic lymphocytic leukaemia. www.thelancet.com/oncology Vol 16 June 2015
All patients seemed to tolerate polatuzumab vedotin. At the recommended phase 2 dose (2·4 mg/kg), the most common adverse events were neutropenia and peripheral neuropathy. Grade 3–4 toxic effects were uncommon, except for neutropenia, which occurred in up to 40% of patients with non-Hodgkin lymphoma without significant clinical complications. Not surprisingly, peripheral neuropathy was noted in more than half of patients treated at the recommended phase 2 dose but was generally manageable. Importantly, co-administration of rituximab with polatuzumab vedotin was feasible with no effect on pharmacokinetics or toxic effects. Of 25 evaluable patients with diffuse large B-cell lymphoma (DLBCL) treated at the recommended phase 2 dose, responses were noted in 14 (67%) patients (four complete responses, ten partial responses). Of 15 patients with indolent non-Hodgkin lymphoma treated at the recommended phase 2 dose, three patients had complete responses and four had partial responses. Because most patients had received at least three lines of previous therapies, these results are encouraging. As a comparison, a study assessing idelalisib (a small molecule that inhibits the PI3Kδ–AKT signalling pathway) in patients with relapsed or refractory indolent non-Hodgkin lymphoma reported an overall response in 71 (57%) of 125 patients, with 6% achieving complete remission.4
Steve Gschmeissner/Science Photo Library
Antibody–drug conjugates in non-Hodgkin lymphoma
Published Online April 27, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70161-0 See Articles page 704
607
Comment
Compared with available therapies, what might be some of the comparative advantages of polatuzumab vedotin? DLBCL, the most common subtype of nonHodgkin lymphoma, consists of at least two molecular cell of origin subtypes: germinal centre B-cell (GCB) and activated B-cell (ABC).5 Biologically, these subtypes are associated with different somatic mutations and aberrant signalling pathways.6 Drugs such as ibrutinib, proteosome inhibitors, and immunomodulatory agents work preferentially in ABC DLBCL. In a phase 2 study evaluating ibrutinib in patients with relapsed or refractory DLBC, overall responses were noted in 40% of patients with ABC DLBCL compared with 5% in GCB DLBCL.7 Clearly, accurate assignment to the correct molecular subgroup before commencing therapy is an essential requirement. Nonetheless, identification of these molecular subgroups remains challenging even in clinics using refined immunohistochemistry algorithms.8 Polatuzumab vedotin has recently been shown to induce cell death in the vast majority of ABC and GCB DLBCL cell lines, suggesting that it can be used effectively in DLBCL subtypes without the need for sophisticated molecular testing.9 Polatuzumab vedotin’s tolerable safety profile and potential for combination with rituximab makes it an ideal drug to bring forward to the first-line setting. Indeed, an ongoing study is examining polatuzumab vedotin in place of vincristine in patients with newly diagnosed DLBCL receiving R-CHOP (NCT01992653). Such a strategy could improve the outcomes of standard first-line immunochemotherapy in all DLBCL subtypes but would require definitive phase 3 data. In the relapsed setting, antibody–drug conjugates can potentially be incorporated into second-line chemotherapy regimens
to improve salvage therapy and increase the proportion of patients who could receive autologous stem-cell transplantation. Although the role of transplantation in patients with relapsed indolent non-Hodgkin lymphoma is increasingly controversial, antibody– drug conjugates will add to the arsenal of alternative therapies. Soon Thye Lim National Cancer Centre, Singapore, Singapore [email protected] I declare no competing interests. 1
2
3
4 5
6 7
8
9
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184–90. Schmitz N, Nickelsen M, Ziepert M, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002–1). Lancet Oncol 2012; 13: 1250–59. Palanca-Wessels MCA, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 2015; published online April 27, 2015. http://dx.doi.org/10.1016/S1470-2045(15)70128-2. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370: 1008–18. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–11. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463: 88–92. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. 54th ASH annual meeting and exposition; Atlanta, GA; Dec 8–11, 2012. 686 (abstr). de Jong D, Rosenwald A, Chhanabhai M, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications—a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol 2007; 25: 805–12. Pfeifer M, Zheng B, Erdmann T, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 2015; published online Feb 24. DOI:10.1038/leu.2015.48.
Systemic therapy for advanced basal cell carcinoma Published Online May 14, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70233-0 See Articles pages 716 and 729
608
Basal cell carcinoma is the most common cancer to affect people with fair skin. Tumours develop as a result of aberrant signalling in the Hedgehog pathway, which is essential to embryonic skin development and wound repair.1 They usually occur on the head, and in most cases are amenable to treatment with topical therapy, surgery, or radiotherapy.2 Mohs’ surgery involves microscopic examination of the tumour and surrounding skin to improve clearance, and has become the gold standard
for certain high-risk facial basal cell carcinoma, including those that have recurred.3 Some basal cell carcinoma, however, are more challenging than others to manage. Patients with basal cell naevoid syndrome (Gorlin’s syndrome) develop multiple cancers from their teens onwards. Other basal cell carcinomas might be unusually aggressive, recur on the face and require potentially disfiguring surgery, or, in very rare cases, metastasise. In 2012, vismodegib, www.thelancet.com/oncology Vol 16 June 2015
treatment should be the first: the most effective or the one with the fewest side-effects? Thus, while this new study7 of treatment with pazopanib shows encouraging outcomes in a subgroup of NET patients, it also presents future challenges for selection of treatment choices. Dik J Kwekkeboom Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam 3015 GD, Netherlands
3 4 5
6 7
8
I declare no competing interests. 1
2
Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371: 224–33. Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, doubleblind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009; 27: 4656–63.
9
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514–23. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 501–13. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide longacting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebocontrolled, phase 3 study. Lancet 2011; 378: 2005–12. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514-23. Phan AT, Halperin DM, Chan JA, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncology 2015; published online May 6. http://dx.doi.org/10.1016/S1470-2045(15)70136-1. Khan S, Krenning EP, van Essen M, Kam BL, Teunissen JJ, Kwekkeboom DJ. Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. J Nucl Med 2011; 52: 1361–68. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26: 2124–30.
Although the outcome of patients with non-Hodgkin lymphoma has improved over the years, patients who relapse after rituximab-based treatment often remain resistant to salvage therapy.1 As first-line therapy, immunochemotherapy such as rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) remains unsatisfactory in patients with high-risk disease. More intensive approaches, including upfront high-dose chemotherapy and autologous stem-cell transplantation, have not been shown to be beneficial and might not be tolerated by older patients.2 Because a third of patients with nonHodgkin lymphoma are older than 75 years, the safety profiles of any proposed new agents are important considerations. Polatuzumab vedotin and pinatuzumab vedotin are two new antibody–drug conjugates targeting CD79B and CD22, respectively, under investigation in nonHodgkin lymphoma. Both contain a B-cell antibody linked to a microtubule inhibitor, monomethyl auristatin E. In The Lancet Oncology, Maria Corinna Palanca-Wessels and colleagues3 report findings from a phase 1 study of polatuzumab vendotin in patients with relapsed or refractory non-Hodgkin lymphoma and chronic lymphocytic leukaemia.3 Overall, 95 patients were recruited to the study, including 77 with non-Hodgkin lymphoma and 18 with chronic lymphocytic leukaemia. www.thelancet.com/oncology Vol 16 June 2015
All patients seemed to tolerate polatuzumab vedotin. At the recommended phase 2 dose (2·4 mg/kg), the most common adverse events were neutropenia and peripheral neuropathy. Grade 3–4 toxic effects were uncommon, except for neutropenia, which occurred in up to 40% of patients with non-Hodgkin lymphoma without significant clinical complications. Not surprisingly, peripheral neuropathy was noted in more than half of patients treated at the recommended phase 2 dose but was generally manageable. Importantly, co-administration of rituximab with polatuzumab vedotin was feasible with no effect on pharmacokinetics or toxic effects. Of 25 evaluable patients with diffuse large B-cell lymphoma (DLBCL) treated at the recommended phase 2 dose, responses were noted in 14 (67%) patients (four complete responses, ten partial responses). Of 15 patients with indolent non-Hodgkin lymphoma treated at the recommended phase 2 dose, three patients had complete responses and four had partial responses. Because most patients had received at least three lines of previous therapies, these results are encouraging. As a comparison, a study assessing idelalisib (a small molecule that inhibits the PI3Kδ–AKT signalling pathway) in patients with relapsed or refractory indolent non-Hodgkin lymphoma reported an overall response in 71 (57%) of 125 patients, with 6% achieving complete remission.4
Steve Gschmeissner/Science Photo Library
Antibody–drug conjugates in non-Hodgkin lymphoma
Published Online April 27, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70161-0 See Articles page 704
607
Comment
Compared with available therapies, what might be some of the comparative advantages of polatuzumab vedotin? DLBCL, the most common subtype of nonHodgkin lymphoma, consists of at least two molecular cell of origin subtypes: germinal centre B-cell (GCB) and activated B-cell (ABC).5 Biologically, these subtypes are associated with different somatic mutations and aberrant signalling pathways.6 Drugs such as ibrutinib, proteosome inhibitors, and immunomodulatory agents work preferentially in ABC DLBCL. In a phase 2 study evaluating ibrutinib in patients with relapsed or refractory DLBC, overall responses were noted in 40% of patients with ABC DLBCL compared with 5% in GCB DLBCL.7 Clearly, accurate assignment to the correct molecular subgroup before commencing therapy is an essential requirement. Nonetheless, identification of these molecular subgroups remains challenging even in clinics using refined immunohistochemistry algorithms.8 Polatuzumab vedotin has recently been shown to induce cell death in the vast majority of ABC and GCB DLBCL cell lines, suggesting that it can be used effectively in DLBCL subtypes without the need for sophisticated molecular testing.9 Polatuzumab vedotin’s tolerable safety profile and potential for combination with rituximab makes it an ideal drug to bring forward to the first-line setting. Indeed, an ongoing study is examining polatuzumab vedotin in place of vincristine in patients with newly diagnosed DLBCL receiving R-CHOP (NCT01992653). Such a strategy could improve the outcomes of standard first-line immunochemotherapy in all DLBCL subtypes but would require definitive phase 3 data. In the relapsed setting, antibody–drug conjugates can potentially be incorporated into second-line chemotherapy regimens
to improve salvage therapy and increase the proportion of patients who could receive autologous stem-cell transplantation. Although the role of transplantation in patients with relapsed indolent non-Hodgkin lymphoma is increasingly controversial, antibody– drug conjugates will add to the arsenal of alternative therapies. Soon Thye Lim National Cancer Centre, Singapore, Singapore [email protected] I declare no competing interests. 1
2
3
4 5
6 7
8
9
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184–90. Schmitz N, Nickelsen M, Ziepert M, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002–1). Lancet Oncol 2012; 13: 1250–59. Palanca-Wessels MCA, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 2015; published online April 27, 2015. http://dx.doi.org/10.1016/S1470-2045(15)70128-2. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370: 1008–18. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–11. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463: 88–92. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. 54th ASH annual meeting and exposition; Atlanta, GA; Dec 8–11, 2012. 686 (abstr). de Jong D, Rosenwald A, Chhanabhai M, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications—a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol 2007; 25: 805–12. Pfeifer M, Zheng B, Erdmann T, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 2015; published online Feb 24. DOI:10.1038/leu.2015.48.
Systemic therapy for advanced basal cell carcinoma Published Online May 14, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70233-0 See Articles pages 716 and 729
608
Basal cell carcinoma is the most common cancer to affect people with fair skin. Tumours develop as a result of aberrant signalling in the Hedgehog pathway, which is essential to embryonic skin development and wound repair.1 They usually occur on the head, and in most cases are amenable to treatment with topical therapy, surgery, or radiotherapy.2 Mohs’ surgery involves microscopic examination of the tumour and surrounding skin to improve clearance, and has become the gold standard
for certain high-risk facial basal cell carcinoma, including those that have recurred.3 Some basal cell carcinoma, however, are more challenging than others to manage. Patients with basal cell naevoid syndrome (Gorlin’s syndrome) develop multiple cancers from their teens onwards. Other basal cell carcinomas might be unusually aggressive, recur on the face and require potentially disfiguring surgery, or, in very rare cases, metastasise. In 2012, vismodegib, www.thelancet.com/oncology Vol 16 June 2015