Comment
In the meantime, the third-generation EGFR tyrosinekinase inhibitors that specifically inhibit mutant EGFR, including Thr790Met mutation that is present in about 50% of the resistant cases, but spare wildtype EGFR, might lead to greater efficacy and fewer toxicities for patients with acquired resistance. For example, the proportions of patients with a Thr790Met mutation who achieved an objective response treated with AZD92916 or CO-1686,7 the third-generation EGFR tyrosine-kinase inhibitors, were 65% and 58%, respectively. We do not yet know the activity of these drugs in the first-line setting but they might delay the emergence of acquired resistance and prolong progression-free survival. EGFR tyrosine-kinase inhibitors have clearly changed practice for lung cancer treatment, which has led to personalised treatment that depends on driver oncogene status. However, the more we know, the more unanswered questions emerge. These include optimal selection of the EGFR tyrosine-kinase inhibitors according to different EGFR mutation types, and effective combination with drugs of other modalities not dependent on EGFR mutations. Immune checkpoint inhibitors, heat-shock protein inhibitors, or chemotherapies are candidate partners because even with the best EGFR tyrosine-kinase inhibitors, cancer cells are smart enough to develop novel mechanisms for resistance.
Tetsuya Mitsudomi Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan [email protected] I report grants and personal fees from Pfizer and Roche, and grants and personal fees from Boehringer-Ingelheim, AstraZeneca, and Chugai, during the conduct of the study; personal fees from MSD, Eli-Lilly, Kyowa-Hakko Kirin, and Novartis, and grants and personal fees from Pfizer and Taiho, outside the submitted work. 1
2
3
4
5
6
7
Engelman JA, Zejnullahu K, Gale CM, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007; 67: 11924–32. Jänne PA, Ou S-HI, Kim D-W, et al. Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial. Lancet Oncol 2014;published online Nov 5.http://dx.doi.org/10.1016/S14702045(14)70461-9. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–34. Wu Y-L, Zhou C, Hu C-P, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15: 213–22. Yang JC-H, Sequist LV, Schuler MH, et al. Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy (CT). Proc Soc Am Clin Oncol 2014; 32 (5s suppl): abstr 8004. Jänne PA, Ramalingam SS, Yang JC-H, et al. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor-resistant non-small cell lung cancer (NSCLC). Proc Soc Am Clin Oncol 2014; 32 (5s suppl): abstr 8009. Sequist LV, Soria J-C, Gadgeel SM, et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). Proc Soc Am Clin Oncol 2014; 32 (5s suppl): abstr 8010.
The objective of treatment for poor-prognosis germ-cell cancer is cure. At present, standard therapy, consisting of four cycles of cisplatin, etoposide, and bleomycin (BEP), achieves this objective in about 50% of patients. In The Lancet Oncology, Karim Fizazi and colleagues1 present the outcome of an international, phase 3, multicentre, randomised trial in patients with poor-prognosis metastatic germ-cell cancers. The study compared four cycles of BEP with a risk-adapted approach that used early dose intensification in patients with unfavourable marker decline. Marker decline was assessed early with a logarithmic formula.2 The primary endpoint was progression-free survival. Substantial debate has surrounded the role of slow marker decline as an indicator of poor outcome after www.thelancet.com/oncology Vol 15 December 2014
chemotherapy.3 Now, for the first time, Fizazi and colleagues provide conclusive evidence that marker decline after the first treatment cycle can be used to detect patients with poor outcome and to identify those who are likely to benefit from early treatment intensification. 3-year rogression-free survival for patients with a favourable response to initial BEP was 70% (95% CI 57–81) compared with 48% (38–59) for patients who responded unfavourably and who remained on standard treatment; those patients who were randomly assigned to receive intensified treatment had a 3-year progression-free survival of 59% (49–68). In this respect, this study has helped to resolve the issue of unfavourable marker decline. After nearly
Steve Gschmeissner/Science Photo Library/Corbis
A practice-changing step forward in germ-cell cancer?
Published Online November 13, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71103-9 See Articles page 1442
1409
Comment
20 years of debate, slow marker decline is finally ready to be applied to clinical practice, in which it should shape the future management of patients with poorprognosis germ-cell cancer. However, unresolved questions remain. What constitutes the optimum timepoint for the assessment of marker decline and what is the best algorithm to use to show favourable marker decline? Another issue to consider is treatment intensification. Although several phase 2 trials have reported a benefit for patients with adverse prognostic factors in incorporating upfront high-dose chemotherapy into their firstline treatment, two randomised trials failed to show a survival benefit in an unselected population of patients with intermediate or poor prognoses.4,5 By contrast, Fizazi and colleagues used a dose-dense regimen exclusively in patients with an unfavourable marker decline who were most likely to derive a benefit from this approach. At the same time, patients with favourable marker decline and a good chance of cure with standard BEP were spared the toxicities of more intensive chemotherapy. Although this strategy is reasonable, a problem lies in the unusual dose intensification regimen used, which consisted of the rapid sequential administration of a combination of drugs with known activity in germ-cell cancer, which were given with haematopoietic growth factors but without stem-cell support. The use of cisplatin, oxaliplatin, ifosfamide, and paclitaxel resulted in a high rate of nephrotoxicity, polyneuropathy, and ototoxicity. When treating a patient population with curative intent, these toxicities might not be acceptable. Furthermore, long-term effects potentially associated with these toxicities are unknown at present. Excessive polyneuropathy eventually forced the authors to modify their schedule and to reduce the doses of oxaliplatin. Part of this schedule included high doses of bleomycin which, unusually, was given as a 24 h continuous infusion. No excess in pulmonary toxicity was noted, but whether the cumbersome bleomycin schedule had any effect on the outcome of patients or interfered with subsequent resection for residual pulmonary lesions is unknown. Although no treatment-related deaths were reported, the dose-intensified regimen used in Fizazi and colleagues’ study is too complex to be used outside of specialist centres. Non-specialist staff will probably 1410
not have the experience and expertise necessary to successfully manage such an intensive and potentially toxic treatment. Highly intensive first-line regimens might also have a negative effect on salvage options if the cancer relapses. In the study,1 only six patients (6%) in the unfavourable dose-dense group received high-dose chemotherapy at relapse compared with 16 (16%) in the unfavourable BEP group. Because such chemotherapy is known to be very effective as salvage therapy, this figure is surprisingly low. The results of Fizazi and colleagues’ study suggest changes to the management of patients with poorprognosis germ-cell cancer. Serum tumour markers should be assessed after the initial treatment cycle to tailor treatment for patients with unfavourable declines. Early dose intensification might be one way to achieve this improvement. However, this study leaves the important question about the optimum regimen unanswered, because this complex and challenging regimen will probably not find many followers— not least because the study falls short of showing a significant overall survival benefit. Nevertheless, the option of early switching of patients with unfavourable marker decline to a dose-intensive regimen offers new hope in the treatment of patients with poor-prognosis germ-cell cancer and should be pursued in the future. Anja Lorch Genitourinary Medical Oncology, Heinrich-Heine Universität Düsseldorf, 40255 Düsseldorf, Germany [email protected] I declare no competing interests. 1
2
3
4
5
Fizazi K, Pagliaro L, Laplanche A, et al. Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial. Lancet Oncol 2014; published online Nov 13. http://dx.doi.org/10.1016/S1470-2045(14)70490-5. Fizazi K, Culine S, Kramar A, et al. Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors. J Clin Oncol 2004; 22: 3868–76. Toner GC, Geller NL, Tan C, Nisselbaum J, Bosl GJ. Serum tumor marker half-life during chemotherapy allows early prediction of complete response and survival in nonseminomatous germ cell tumors. Cancer Res 1990; 50: 5904–10. Motzer RJ, Nichols CJ, Margolin KA, et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol 2007; 25: 247–56. Daugaard G, Skoneczna I, Aass N, et al. A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974). Ann Oncol 2011; 22: 1054–61.
www.thelancet.com/oncology Vol 15 December 2014
In the meantime, the third-generation EGFR tyrosinekinase inhibitors that specifically inhibit mutant EGFR, including Thr790Met mutation that is present in about 50% of the resistant cases, but spare wildtype EGFR, might lead to greater efficacy and fewer toxicities for patients with acquired resistance. For example, the proportions of patients with a Thr790Met mutation who achieved an objective response treated with AZD92916 or CO-1686,7 the third-generation EGFR tyrosine-kinase inhibitors, were 65% and 58%, respectively. We do not yet know the activity of these drugs in the first-line setting but they might delay the emergence of acquired resistance and prolong progression-free survival. EGFR tyrosine-kinase inhibitors have clearly changed practice for lung cancer treatment, which has led to personalised treatment that depends on driver oncogene status. However, the more we know, the more unanswered questions emerge. These include optimal selection of the EGFR tyrosine-kinase inhibitors according to different EGFR mutation types, and effective combination with drugs of other modalities not dependent on EGFR mutations. Immune checkpoint inhibitors, heat-shock protein inhibitors, or chemotherapies are candidate partners because even with the best EGFR tyrosine-kinase inhibitors, cancer cells are smart enough to develop novel mechanisms for resistance.
Tetsuya Mitsudomi Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan [email protected] I report grants and personal fees from Pfizer and Roche, and grants and personal fees from Boehringer-Ingelheim, AstraZeneca, and Chugai, during the conduct of the study; personal fees from MSD, Eli-Lilly, Kyowa-Hakko Kirin, and Novartis, and grants and personal fees from Pfizer and Taiho, outside the submitted work. 1
2
3
4
5
6
7
Engelman JA, Zejnullahu K, Gale CM, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007; 67: 11924–32. Jänne PA, Ou S-HI, Kim D-W, et al. Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial. Lancet Oncol 2014;published online Nov 5.http://dx.doi.org/10.1016/S14702045(14)70461-9. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–34. Wu Y-L, Zhou C, Hu C-P, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15: 213–22. Yang JC-H, Sequist LV, Schuler MH, et al. Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy (CT). Proc Soc Am Clin Oncol 2014; 32 (5s suppl): abstr 8004. Jänne PA, Ramalingam SS, Yang JC-H, et al. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor-resistant non-small cell lung cancer (NSCLC). Proc Soc Am Clin Oncol 2014; 32 (5s suppl): abstr 8009. Sequist LV, Soria J-C, Gadgeel SM, et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). Proc Soc Am Clin Oncol 2014; 32 (5s suppl): abstr 8010.
The objective of treatment for poor-prognosis germ-cell cancer is cure. At present, standard therapy, consisting of four cycles of cisplatin, etoposide, and bleomycin (BEP), achieves this objective in about 50% of patients. In The Lancet Oncology, Karim Fizazi and colleagues1 present the outcome of an international, phase 3, multicentre, randomised trial in patients with poor-prognosis metastatic germ-cell cancers. The study compared four cycles of BEP with a risk-adapted approach that used early dose intensification in patients with unfavourable marker decline. Marker decline was assessed early with a logarithmic formula.2 The primary endpoint was progression-free survival. Substantial debate has surrounded the role of slow marker decline as an indicator of poor outcome after www.thelancet.com/oncology Vol 15 December 2014
chemotherapy.3 Now, for the first time, Fizazi and colleagues provide conclusive evidence that marker decline after the first treatment cycle can be used to detect patients with poor outcome and to identify those who are likely to benefit from early treatment intensification. 3-year rogression-free survival for patients with a favourable response to initial BEP was 70% (95% CI 57–81) compared with 48% (38–59) for patients who responded unfavourably and who remained on standard treatment; those patients who were randomly assigned to receive intensified treatment had a 3-year progression-free survival of 59% (49–68). In this respect, this study has helped to resolve the issue of unfavourable marker decline. After nearly
Steve Gschmeissner/Science Photo Library/Corbis
A practice-changing step forward in germ-cell cancer?
Published Online November 13, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71103-9 See Articles page 1442
1409
Comment
20 years of debate, slow marker decline is finally ready to be applied to clinical practice, in which it should shape the future management of patients with poorprognosis germ-cell cancer. However, unresolved questions remain. What constitutes the optimum timepoint for the assessment of marker decline and what is the best algorithm to use to show favourable marker decline? Another issue to consider is treatment intensification. Although several phase 2 trials have reported a benefit for patients with adverse prognostic factors in incorporating upfront high-dose chemotherapy into their firstline treatment, two randomised trials failed to show a survival benefit in an unselected population of patients with intermediate or poor prognoses.4,5 By contrast, Fizazi and colleagues used a dose-dense regimen exclusively in patients with an unfavourable marker decline who were most likely to derive a benefit from this approach. At the same time, patients with favourable marker decline and a good chance of cure with standard BEP were spared the toxicities of more intensive chemotherapy. Although this strategy is reasonable, a problem lies in the unusual dose intensification regimen used, which consisted of the rapid sequential administration of a combination of drugs with known activity in germ-cell cancer, which were given with haematopoietic growth factors but without stem-cell support. The use of cisplatin, oxaliplatin, ifosfamide, and paclitaxel resulted in a high rate of nephrotoxicity, polyneuropathy, and ototoxicity. When treating a patient population with curative intent, these toxicities might not be acceptable. Furthermore, long-term effects potentially associated with these toxicities are unknown at present. Excessive polyneuropathy eventually forced the authors to modify their schedule and to reduce the doses of oxaliplatin. Part of this schedule included high doses of bleomycin which, unusually, was given as a 24 h continuous infusion. No excess in pulmonary toxicity was noted, but whether the cumbersome bleomycin schedule had any effect on the outcome of patients or interfered with subsequent resection for residual pulmonary lesions is unknown. Although no treatment-related deaths were reported, the dose-intensified regimen used in Fizazi and colleagues’ study is too complex to be used outside of specialist centres. Non-specialist staff will probably 1410
not have the experience and expertise necessary to successfully manage such an intensive and potentially toxic treatment. Highly intensive first-line regimens might also have a negative effect on salvage options if the cancer relapses. In the study,1 only six patients (6%) in the unfavourable dose-dense group received high-dose chemotherapy at relapse compared with 16 (16%) in the unfavourable BEP group. Because such chemotherapy is known to be very effective as salvage therapy, this figure is surprisingly low. The results of Fizazi and colleagues’ study suggest changes to the management of patients with poorprognosis germ-cell cancer. Serum tumour markers should be assessed after the initial treatment cycle to tailor treatment for patients with unfavourable declines. Early dose intensification might be one way to achieve this improvement. However, this study leaves the important question about the optimum regimen unanswered, because this complex and challenging regimen will probably not find many followers— not least because the study falls short of showing a significant overall survival benefit. Nevertheless, the option of early switching of patients with unfavourable marker decline to a dose-intensive regimen offers new hope in the treatment of patients with poor-prognosis germ-cell cancer and should be pursued in the future. Anja Lorch Genitourinary Medical Oncology, Heinrich-Heine Universität Düsseldorf, 40255 Düsseldorf, Germany [email protected] I declare no competing interests. 1
2
3
4
5
Fizazi K, Pagliaro L, Laplanche A, et al. Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial. Lancet Oncol 2014; published online Nov 13. http://dx.doi.org/10.1016/S1470-2045(14)70490-5. Fizazi K, Culine S, Kramar A, et al. Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors. J Clin Oncol 2004; 22: 3868–76. Toner GC, Geller NL, Tan C, Nisselbaum J, Bosl GJ. Serum tumor marker half-life during chemotherapy allows early prediction of complete response and survival in nonseminomatous germ cell tumors. Cancer Res 1990; 50: 5904–10. Motzer RJ, Nichols CJ, Margolin KA, et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol 2007; 25: 247–56. Daugaard G, Skoneczna I, Aass N, et al. A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974). Ann Oncol 2011; 22: 1054–61.
www.thelancet.com/oncology Vol 15 December 2014
