- Email: [email protected]
Ramucirumab: second-line therapy for gastric cancer
Comment
of The Lancet Oncology, Daniel Green and colleagues provide invaluable information by correlating semen parameters with cumulative alkylating agent exposure in adult male survivors of childhood cancer treated with chemotherapy but not radiotherapy.8 The authors report that more than half of participants had an abnormally low sperm concentration, with 53 (25%) of 214 participants having azoospermia. Although the investigators’ finding that 31 (89%) of 35 study participants who had received a cyclophosphamide equivalent dose of less than 4000 mg/m² were normospermic is informative, these data must be applied clinically with caution. More specifically, the authors reported that there was not a lower cyclophosphamide equivalent dose threshold below which azoospermia did not occur. This finding means that cyclophosphamide equivalent dose cannot serve as a definitive prognostic marker for sperm concentration after treatment, and it should thus not be the sole guiding parameter driving fertility preservation recommendations. Although Green and colleagues’ study8 is informative and laudable, prospective studies initiated at the time of cancer diagnosis provide the most meaningful insight into fertility preservation issues, and these studies should be encouraged. At baseline, even before the initiation of cancer therapy, semen parameters are significantly decreased for patients with testicular cancer and lymphoma compared with fertile controls.9,10 Such prospective studies, and research aimed at elucidation of the pathophysiological mechanisms driving the pretreatment decline in semen parameters, are needed. Finally, longitudinal studies tracking clinical infertility will deepen our
understanding of the reproductive outcomes for these patients. Collectively, this work will enable clinicians to more effectively stratify the risk of future fertility impairment in the aftermath of a cancer diagnosis and cancer therapy. Robert E Brannigan Department of Urology, Northwestern University, Feinberg School of Medicine, Galter Pavilion, Suite 20–150, 675 North St Clair Street, Chicago, IL 60611, USA [email protected] I declare no competing interests. 1
2
3
4
5
6
7
8
9
10
Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006; 24: 2917–31. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31: 2500–10. Sheth KR, Sharma V, Helfand BT, et al. Improved fertility preservation care for male patients with cancer after establishment of formalized oncofertility program. J Urol 2012; 187: 979–86. Köhler TS, Kondapalli LA, Shah A, Chan S, Woodruff TK, Brannigan RE. Results from the survey for preservation of adolescent reproduction (SPARE) study: gender disparity in delivery of fertility preservation message to adolescents with cancer. J Assist Reprod Genet 2011; 28: 269–77. Keene DJ, Sajjad Y, Makin G, Cervellione RM. Sperm banking in the United Kingdom is feasible in patients 13 years old or older with cancer. J Urol 2012; 188: 594–97. Stein DM, Victorson DE, Choy JT, et al. Fertility preservation preferences and perspectives among adult male survivors of pediatric cancer and their parents. J Adolesc Young Adult Oncol 2014; 3: 75–82. Johnson RH, Kroon L. Optimizing fertility preservation practices for adolescent and young adult cancer patients. J Natl Compr Canc Netw 2013; 11: 71–77. Green DM, Liu W, Kutteh WH, et al. Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study. Lancet Oncol 2014; published online September 17. http://dx.doi.org/10.1016/S1470-2045(14)70408-5. Bujan L, Walschaerts M, Moinard H, et al. Impact of chemotherapy and radiotherapy for testicular germ cell tumors on spermatogenesis and sperm DNA: a multicenter prospective study from the CECOS network. Fertil Steril 2013; 100: 673–80. Bujan L, Walschaerts M, Brugnon F, et al. Impact of lymphoma treatments on spermatogenesis and sperm deoxyribonucleic acid: a multicenter prospective study from the CECOS network. Fertil Steril 2014; 102: 667–74.
Ramucirumab: second-line therapy for gastric cancer Published Online September 18, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70464-4 See Articles page 1224
1182
In The Lancet Oncology, Hansjochen Wilke and colleagues report the results of the RAINBOW trial,1 a randomised phase 3 trial comparing ramucirumab plus paclitaxel combination with placebo plus paclitaxel for the second-line treatment of advanced gastric or gastro-oesophageal junction adenocarcinoma. Overall survival, the primary endpoint, and progression-free survival, the secondary endpoint, for the ramucirumab plus paclitaxel group were
significantly longer than those for the placebo plus paclitaxel group (hazard ratio [HR] 0·807 [95% CI 0·678–0·962], p=0·017, and 0·635 [0·536–0·752], p<0·0001, respectively). Therefore, ramucirumab is the first molecularly targeted agent proven to be effective in second-line therapy for advanced gastric or gastro-oesophageal junctional adenocarcinoma in combination with chemotherapy. Recently published results of another randomised phase 3 trial (REGARD),2 www.thelancet.com/oncology Vol 15 October 2014
Comment
www.thelancet.com/oncology Vol 15 October 2014
(4·2–5·7) for non-Asian and Asian patients, respectively, and in the placebo plus paclitaxel group 2·9 months (95% CI 2·6–3·5) and 2·8 months (2·8–4·1) for nonAsian and Asian patients, respectively. Therefore, not only patients in the ramucirumab plus paclitaxel group, but also those in the placebo plus paclitaxel group lived much longer after disease progression in Asia than in other regions. Since the geographical difference in the progression-free survival was much smaller than that in the overall survival, we cannot attribute the difference in survival time to differences in tumour biology in the two regions, and to a higher proportion of patients having gastro-oesophageal adenocarcinoma. Wilke and colleagues speculated this regional difference might be due to the much higher use of post-study treatment in Asia (about 70%) than in other regions (about 40%). This seems to be caused by differences in the health care and social security systems and cultural differences about end of life and death. The higher use of third-line or even fourth-line treatment in Asia, especially in Japan, makes the interpretation of the results of this study clinically difficult. Since the cost of the new treatment, including a new targeted agent, might be much higher than other conventional chemotherapy in the third or fourth line, application of ramucirumab might be different by regions and countries. However, an economical assessment of the treatment for patients with advanced gastric or gastro-oesophageal junctional adenocarcinoma is likely to be difficult because the longer survival of patients will increase the total cost of medical care.
Astrid & Hanns-Frieder Michler/Science Photo Library
comparing ramucirumab alone versus placebo (best supportive care) for previously treated advanced or relapsed gastric or gastro-oesophageal junctional adenocarcinoma, showed marginally but significantly better overall survival with ramucirumab (HR 0·776, 95% CI 0·603–0·998, p=0·047). After several reports of phase 3 trials comparing drug treatment with best supportive care, it is no longer ethical to compare second-line treatment with best supportive care.3–5 In this regard, the RAINBOW trial is a more practical and ethical study that also takes into consideration the patients’ needs. In the preplanned subgroup analyses of both progression-free survival and overall survival, large differences were noted between gastric cancer and gastro-oesophageal junctional adenocarcinoma. The HR for progression-free survival was 0·387 (95% CI 0·256–0·587) for patients with gastro-oesophageal junctional adenocarcinoma and 0·694 (0·575–0·838) for those with gastric cancer. Similarly the HR for overall survival was 0·521 (95% CI 0·348–0·781) and 0·899 (0·736–1·096), respectively. Such large differences in treatment effect were not noted in the AVAGAST trial,6 comparing chemotherapy with or without bevacizumab in the first-line treatment of advanced gastric and gastro-oesophageal junctional adenocarcinoma, which is another molecular targeting agent that blocks the VEGF signalling pathway.6 This difference might be due to chance or possibly to a difference between the VEGF-ligand antibody and VEGF-receptor antibody. There is an urgent need to investigate the molecular difference between the VEGF-ligand antibody and the VEGF-receptor antibody and between gastric cancer and gastro-oesophageal adenocarcinoma. The geographical difference in the overall survival was remarkable, whereas that in the progressionfree survival was small. In the ramucirumab plus paclitaxel group, median overall survival was 8·5 months (95% CI 7·4–9·8) and 12·1 (10·0–13·3) months for non-Asian and Asian patients, respectively. In the placebo plus paclitaxel group, median overall survival was 5·9 months (95% CI 5·2–7·1) and 10·5 months (7·8–14·1) for non-Asian and Asian patients, respectively. However, median progressionfree survival in the ramucirumab plus paclitaxel group was 4·2 months (95% CI 3·9–4·9) and 5·5 months
Mitsuru Sasako Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Japan [email protected] I declare no competing interests. 1
2
3
Wilke H, Muro K, Van Cutsem E, et al, for the RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014; published online Sept 18. http://dx.doi.org/10.1016/ S1470-2045(14)70420-6. Fuchs CS, Tomasek J, Yong CJ, et al, for the REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383: 31–39. Kang JH, Lee SI, Lim DH, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care versus best supportive care. J Clin Oncol 2012; 30: 1513–18.
1183
Comment
4
5
Ford HER, Marshall A, Bridgewater JA, et al, on behalf of the COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol 2014; 15: 78–86. Thuss-Patience PC, Kretzschmar A, Biches D, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer – a randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 2011; 47: 2306–14.
6
Ohtsu A, Shah MA, Van Custum E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2011; 29: 3968–76.
Zephyr/Science Photo Library
What new therapeutic targets exist for EGFR-mutant NSCLC?
Published Online August 28, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70386-9 See Articles page 1236
1184
EGFR mutations are a crucial therapeutic target in nonsmall-cell lung cancer (NSCLC) harbouring somatic mutations in the tyrosine kinase domain of EGFR. These EGFR mutations provoke activation of the STAT and Akt signalling pathways, and both promote cell survival.1 Additionally, downregulation of pro-apoptotic BH3-only proteins (eg, BCL2L11) can occur through modulation of ERK signalling.2 EGFR tyrosine-kinase inhibitors, such as erlotinib or gefitinib, are standard treatment for patients with EGFR-mutant NSCLC.2 However, median progression-free survival still does not exceed 10 months3 and no combination therapies have yet been incorporated into clinical practice to overcome potential mechanisms of resistance to monotherapy with EGFR tyrosine-kinase inhibitors—eg, the EGFR Thr790Met mutation2,4 and MET amplification.2 Intriguingly, erlotinib has been reported to induce MET-independent activation of STAT3 survival signalling in EGFR-mutant lung cancer cells.5 STAT3 promotes expression of genes that suppress apoptosis, such as BCL2 and BCL-XL, and several other genes involved in angiogenesis, such as HIF1A. Anti-VEGF antibodies, such as bevacizumab, are approved by the European Medicine Agency for use in several cancer types. In The Lancet Oncology, Takashi Seto and colleagues6 report a randomised phase 2 study in patients with EGFR-mutant NSCLC that investigated the potential benefit of adding bevacizumab to erlotinib compared with erlotinib alone. Important differences in progression-free survival were noted in patients given erlotinib alone: 9·7 months (95% CI 5·7–11·1) compared with 16·0 months (13·9–18·1) for patients assigned to erlotinib plus bevacizumab (hazard ratio 0·54 [95% CI 0·36–0·79]; p=0·0015). The increase in progression-free survival constitutes a new landmark in the treatment of patients with EGFR-mutant NSCLC; side-effects related to bevacizumab, such as hypertension and proteinuria, were manageable. Therefore, this study6
represents a novel therapeutic approach for optimising treatment for patients with EGFR-mutant NSCLC. The authors6 postulate that the benefit of bevacizumab could be partly related to the antiangiogenic effect normalising the tumour vasculature and potentially enhancing access of erlotinib to the tumour. Additionally, it is plausible that inhibition of VEGF signalling by bevacizumab could contribute to attenuating induction of STAT3 phosphorylation by erlotinib.7 The paradoxical activation of STAT3 by erlotinib is a new and surprising observation that warrants further research to improve standard EGFR tyrosine-kinase inhibitor therapy. The study by Seto and colleagues6 presents compelling evidence that the combination of erlotinib and bevacizumab significantly increases the duration of progression-free survival compared with erlotinib alone.3 This new therapeutic strategy targeting VEGF could also lead to new forms of resistance because VEGF directly and negatively regulates tumour cell invasion by creating a MET/VEGFR2 hetero-complex that suppresses HGF-dependent MET phosphorylation and tumour cell migration.8 In glioblastoma multiforme, inhibited VEGF restores and increases MET activity.8 Interestingly, triple inhibition of EGFR, MET, and VEGF reverses resistance to erlotinib in EGFR-mutant cell lines.9 The triplet of erlotinib, crizotinib (a MET and ALK inhibitor), and bevacizumab successfully inhibits tumour growth in erlotinib-resistant EGFR-mutant cell lines.9 Therefore, the complexity of crosstalk between signalling pathways,2 and preclinical and clinical findings, opens the gates to novel therapies including oral pan-tyrosinekinase inhibitors targeting mainly VEGF and MET. Other studies, such as BELIEF,2 are being undertaken with the combination of erlotinib and bevacizumab with the primary objective to clarify the role of this combination in patients with EGFR-mutant NSCLC who also harbour the EGFR Thr790Met mutation.4 The study www.thelancet.com/oncology Vol 15 October 2014
of The Lancet Oncology, Daniel Green and colleagues provide invaluable information by correlating semen parameters with cumulative alkylating agent exposure in adult male survivors of childhood cancer treated with chemotherapy but not radiotherapy.8 The authors report that more than half of participants had an abnormally low sperm concentration, with 53 (25%) of 214 participants having azoospermia. Although the investigators’ finding that 31 (89%) of 35 study participants who had received a cyclophosphamide equivalent dose of less than 4000 mg/m² were normospermic is informative, these data must be applied clinically with caution. More specifically, the authors reported that there was not a lower cyclophosphamide equivalent dose threshold below which azoospermia did not occur. This finding means that cyclophosphamide equivalent dose cannot serve as a definitive prognostic marker for sperm concentration after treatment, and it should thus not be the sole guiding parameter driving fertility preservation recommendations. Although Green and colleagues’ study8 is informative and laudable, prospective studies initiated at the time of cancer diagnosis provide the most meaningful insight into fertility preservation issues, and these studies should be encouraged. At baseline, even before the initiation of cancer therapy, semen parameters are significantly decreased for patients with testicular cancer and lymphoma compared with fertile controls.9,10 Such prospective studies, and research aimed at elucidation of the pathophysiological mechanisms driving the pretreatment decline in semen parameters, are needed. Finally, longitudinal studies tracking clinical infertility will deepen our
understanding of the reproductive outcomes for these patients. Collectively, this work will enable clinicians to more effectively stratify the risk of future fertility impairment in the aftermath of a cancer diagnosis and cancer therapy. Robert E Brannigan Department of Urology, Northwestern University, Feinberg School of Medicine, Galter Pavilion, Suite 20–150, 675 North St Clair Street, Chicago, IL 60611, USA [email protected] I declare no competing interests. 1
2
3
4
5
6
7
8
9
10
Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006; 24: 2917–31. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31: 2500–10. Sheth KR, Sharma V, Helfand BT, et al. Improved fertility preservation care for male patients with cancer after establishment of formalized oncofertility program. J Urol 2012; 187: 979–86. Köhler TS, Kondapalli LA, Shah A, Chan S, Woodruff TK, Brannigan RE. Results from the survey for preservation of adolescent reproduction (SPARE) study: gender disparity in delivery of fertility preservation message to adolescents with cancer. J Assist Reprod Genet 2011; 28: 269–77. Keene DJ, Sajjad Y, Makin G, Cervellione RM. Sperm banking in the United Kingdom is feasible in patients 13 years old or older with cancer. J Urol 2012; 188: 594–97. Stein DM, Victorson DE, Choy JT, et al. Fertility preservation preferences and perspectives among adult male survivors of pediatric cancer and their parents. J Adolesc Young Adult Oncol 2014; 3: 75–82. Johnson RH, Kroon L. Optimizing fertility preservation practices for adolescent and young adult cancer patients. J Natl Compr Canc Netw 2013; 11: 71–77. Green DM, Liu W, Kutteh WH, et al. Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study. Lancet Oncol 2014; published online September 17. http://dx.doi.org/10.1016/S1470-2045(14)70408-5. Bujan L, Walschaerts M, Moinard H, et al. Impact of chemotherapy and radiotherapy for testicular germ cell tumors on spermatogenesis and sperm DNA: a multicenter prospective study from the CECOS network. Fertil Steril 2013; 100: 673–80. Bujan L, Walschaerts M, Brugnon F, et al. Impact of lymphoma treatments on spermatogenesis and sperm deoxyribonucleic acid: a multicenter prospective study from the CECOS network. Fertil Steril 2014; 102: 667–74.
Ramucirumab: second-line therapy for gastric cancer Published Online September 18, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70464-4 See Articles page 1224
1182
In The Lancet Oncology, Hansjochen Wilke and colleagues report the results of the RAINBOW trial,1 a randomised phase 3 trial comparing ramucirumab plus paclitaxel combination with placebo plus paclitaxel for the second-line treatment of advanced gastric or gastro-oesophageal junction adenocarcinoma. Overall survival, the primary endpoint, and progression-free survival, the secondary endpoint, for the ramucirumab plus paclitaxel group were
significantly longer than those for the placebo plus paclitaxel group (hazard ratio [HR] 0·807 [95% CI 0·678–0·962], p=0·017, and 0·635 [0·536–0·752], p<0·0001, respectively). Therefore, ramucirumab is the first molecularly targeted agent proven to be effective in second-line therapy for advanced gastric or gastro-oesophageal junctional adenocarcinoma in combination with chemotherapy. Recently published results of another randomised phase 3 trial (REGARD),2 www.thelancet.com/oncology Vol 15 October 2014
Comment
www.thelancet.com/oncology Vol 15 October 2014
(4·2–5·7) for non-Asian and Asian patients, respectively, and in the placebo plus paclitaxel group 2·9 months (95% CI 2·6–3·5) and 2·8 months (2·8–4·1) for nonAsian and Asian patients, respectively. Therefore, not only patients in the ramucirumab plus paclitaxel group, but also those in the placebo plus paclitaxel group lived much longer after disease progression in Asia than in other regions. Since the geographical difference in the progression-free survival was much smaller than that in the overall survival, we cannot attribute the difference in survival time to differences in tumour biology in the two regions, and to a higher proportion of patients having gastro-oesophageal adenocarcinoma. Wilke and colleagues speculated this regional difference might be due to the much higher use of post-study treatment in Asia (about 70%) than in other regions (about 40%). This seems to be caused by differences in the health care and social security systems and cultural differences about end of life and death. The higher use of third-line or even fourth-line treatment in Asia, especially in Japan, makes the interpretation of the results of this study clinically difficult. Since the cost of the new treatment, including a new targeted agent, might be much higher than other conventional chemotherapy in the third or fourth line, application of ramucirumab might be different by regions and countries. However, an economical assessment of the treatment for patients with advanced gastric or gastro-oesophageal junctional adenocarcinoma is likely to be difficult because the longer survival of patients will increase the total cost of medical care.
Astrid & Hanns-Frieder Michler/Science Photo Library
comparing ramucirumab alone versus placebo (best supportive care) for previously treated advanced or relapsed gastric or gastro-oesophageal junctional adenocarcinoma, showed marginally but significantly better overall survival with ramucirumab (HR 0·776, 95% CI 0·603–0·998, p=0·047). After several reports of phase 3 trials comparing drug treatment with best supportive care, it is no longer ethical to compare second-line treatment with best supportive care.3–5 In this regard, the RAINBOW trial is a more practical and ethical study that also takes into consideration the patients’ needs. In the preplanned subgroup analyses of both progression-free survival and overall survival, large differences were noted between gastric cancer and gastro-oesophageal junctional adenocarcinoma. The HR for progression-free survival was 0·387 (95% CI 0·256–0·587) for patients with gastro-oesophageal junctional adenocarcinoma and 0·694 (0·575–0·838) for those with gastric cancer. Similarly the HR for overall survival was 0·521 (95% CI 0·348–0·781) and 0·899 (0·736–1·096), respectively. Such large differences in treatment effect were not noted in the AVAGAST trial,6 comparing chemotherapy with or without bevacizumab in the first-line treatment of advanced gastric and gastro-oesophageal junctional adenocarcinoma, which is another molecular targeting agent that blocks the VEGF signalling pathway.6 This difference might be due to chance or possibly to a difference between the VEGF-ligand antibody and VEGF-receptor antibody. There is an urgent need to investigate the molecular difference between the VEGF-ligand antibody and the VEGF-receptor antibody and between gastric cancer and gastro-oesophageal adenocarcinoma. The geographical difference in the overall survival was remarkable, whereas that in the progressionfree survival was small. In the ramucirumab plus paclitaxel group, median overall survival was 8·5 months (95% CI 7·4–9·8) and 12·1 (10·0–13·3) months for non-Asian and Asian patients, respectively. In the placebo plus paclitaxel group, median overall survival was 5·9 months (95% CI 5·2–7·1) and 10·5 months (7·8–14·1) for non-Asian and Asian patients, respectively. However, median progressionfree survival in the ramucirumab plus paclitaxel group was 4·2 months (95% CI 3·9–4·9) and 5·5 months
Mitsuru Sasako Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Japan [email protected] I declare no competing interests. 1
2
3
Wilke H, Muro K, Van Cutsem E, et al, for the RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014; published online Sept 18. http://dx.doi.org/10.1016/ S1470-2045(14)70420-6. Fuchs CS, Tomasek J, Yong CJ, et al, for the REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383: 31–39. Kang JH, Lee SI, Lim DH, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care versus best supportive care. J Clin Oncol 2012; 30: 1513–18.
1183
Comment
4
5
Ford HER, Marshall A, Bridgewater JA, et al, on behalf of the COUGAR-02 Investigators. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol 2014; 15: 78–86. Thuss-Patience PC, Kretzschmar A, Biches D, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer – a randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 2011; 47: 2306–14.
6
Ohtsu A, Shah MA, Van Custum E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2011; 29: 3968–76.
Zephyr/Science Photo Library
What new therapeutic targets exist for EGFR-mutant NSCLC?
Published Online August 28, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70386-9 See Articles page 1236
1184
EGFR mutations are a crucial therapeutic target in nonsmall-cell lung cancer (NSCLC) harbouring somatic mutations in the tyrosine kinase domain of EGFR. These EGFR mutations provoke activation of the STAT and Akt signalling pathways, and both promote cell survival.1 Additionally, downregulation of pro-apoptotic BH3-only proteins (eg, BCL2L11) can occur through modulation of ERK signalling.2 EGFR tyrosine-kinase inhibitors, such as erlotinib or gefitinib, are standard treatment for patients with EGFR-mutant NSCLC.2 However, median progression-free survival still does not exceed 10 months3 and no combination therapies have yet been incorporated into clinical practice to overcome potential mechanisms of resistance to monotherapy with EGFR tyrosine-kinase inhibitors—eg, the EGFR Thr790Met mutation2,4 and MET amplification.2 Intriguingly, erlotinib has been reported to induce MET-independent activation of STAT3 survival signalling in EGFR-mutant lung cancer cells.5 STAT3 promotes expression of genes that suppress apoptosis, such as BCL2 and BCL-XL, and several other genes involved in angiogenesis, such as HIF1A. Anti-VEGF antibodies, such as bevacizumab, are approved by the European Medicine Agency for use in several cancer types. In The Lancet Oncology, Takashi Seto and colleagues6 report a randomised phase 2 study in patients with EGFR-mutant NSCLC that investigated the potential benefit of adding bevacizumab to erlotinib compared with erlotinib alone. Important differences in progression-free survival were noted in patients given erlotinib alone: 9·7 months (95% CI 5·7–11·1) compared with 16·0 months (13·9–18·1) for patients assigned to erlotinib plus bevacizumab (hazard ratio 0·54 [95% CI 0·36–0·79]; p=0·0015). The increase in progression-free survival constitutes a new landmark in the treatment of patients with EGFR-mutant NSCLC; side-effects related to bevacizumab, such as hypertension and proteinuria, were manageable. Therefore, this study6
represents a novel therapeutic approach for optimising treatment for patients with EGFR-mutant NSCLC. The authors6 postulate that the benefit of bevacizumab could be partly related to the antiangiogenic effect normalising the tumour vasculature and potentially enhancing access of erlotinib to the tumour. Additionally, it is plausible that inhibition of VEGF signalling by bevacizumab could contribute to attenuating induction of STAT3 phosphorylation by erlotinib.7 The paradoxical activation of STAT3 by erlotinib is a new and surprising observation that warrants further research to improve standard EGFR tyrosine-kinase inhibitor therapy. The study by Seto and colleagues6 presents compelling evidence that the combination of erlotinib and bevacizumab significantly increases the duration of progression-free survival compared with erlotinib alone.3 This new therapeutic strategy targeting VEGF could also lead to new forms of resistance because VEGF directly and negatively regulates tumour cell invasion by creating a MET/VEGFR2 hetero-complex that suppresses HGF-dependent MET phosphorylation and tumour cell migration.8 In glioblastoma multiforme, inhibited VEGF restores and increases MET activity.8 Interestingly, triple inhibition of EGFR, MET, and VEGF reverses resistance to erlotinib in EGFR-mutant cell lines.9 The triplet of erlotinib, crizotinib (a MET and ALK inhibitor), and bevacizumab successfully inhibits tumour growth in erlotinib-resistant EGFR-mutant cell lines.9 Therefore, the complexity of crosstalk between signalling pathways,2 and preclinical and clinical findings, opens the gates to novel therapies including oral pan-tyrosinekinase inhibitors targeting mainly VEGF and MET. Other studies, such as BELIEF,2 are being undertaken with the combination of erlotinib and bevacizumab with the primary objective to clarify the role of this combination in patients with EGFR-mutant NSCLC who also harbour the EGFR Thr790Met mutation.4 The study www.thelancet.com/oncology Vol 15 October 2014