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How should “RET positive” NSCLC be treated?
G Model
ARTICLE IN PRESS
LUNG-5299; No. of Pages 2
Lung Cancer xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Editorial
How should “RET positive” NSCLC be treated?
Thirty years ago the REarranged-during-Transfection(RET) protooncogene, located at chromosome 10q11.2 encoding a single pass transmembrane receptor tyrosine kinase (RTK), was found to be implicated in carcinogenesis [1]. Next to its original description in papillary thyroid carcinoma, genetic abberations in RET are added to a growing list of malignancies including adenocarcinoma of the lung [2–4] and more recently small cell lung cancer [5]. Under physiological circumstances, binding of the ligand, glial cell derived neurotrophic factor, leads to dimerization of RET and autophosphorylation of the tyrosine kinase domain. In turn, this leads to activation of several intracellular signalling pathways including the MAPkinase, PI3 kinase and STAT3 pathways. In lung cancer, gain-of-function point mutations have been described in a few cases of small cell lung cancer [5]. In in vitro systems these mutations lead to a constitutively active receptor kinase. Likewise, chromosomal rearrangements leading to a RET fusion gene may activate RET in a ligand independent manner and have been observed in a small subset of lung adenocarcinomas [2–4]. At least 6 fusion partner genes with RET are identified to date, of which the kinesin family member 5B (KIF5B) with 10 variations displaying a variety of breakpoints is best characterized. Along with the second most prevalent fusion partner CCDC6, these RET fusions have transforming potential in vitro and in mouse models. The true incidence of RET gene fusions in lung adenocarcinoma is unknown and may be anywhere between 0.4% and 2%. In larger series there is no specific subtype of lung adenocarcinoma associated with RET fusions [6]. As with other gene fusions, in particular Alk and ROS1, in epidemiological studies there is an association with female gender, younger age and light or never smoking. Although there is a wide held belief that RET fusions are mutually exclusive with other driver mutations such as EGFR or RAS mutations, a recent case reports suggests otherwise [7]. The preferred way to detect RET fusions is by FISH. Several novel NGS based techniques, including capture hybrid, whole genome and exosome sequencing have been reported that may also identify RET abberations. One study [8] that compared RET IHC using a rabbit anti-RET monoclonal antibody (clone EPR2871, Epitomics, Burlingame, CA,USA), RET gene amplification and RET FISH reported absence of RET IHC staining in 3 out of 7 RET FISH positives and only 1 out of these 7 were RET amplified. Thus, contrary to Alk rearranged tumors, to date there is no possibility to screen for RET fusions by IHC methods. At its initial discovery as a driver oncogene in lung adenocarcinoma, it was observed that treatment with multitargeted tyrosine kinase inhibitors such as Vandetanib, Sorafenib and Sunitinib led to
suppression of growth of RET rearranged lung cancer cells in vitro. Of course, these were obvious candidate drugs given their activity in other cancers harbouring RET rearrangments such a thyroid cancer. Since then, a number of case reports have been published highlighting the single agent activity of these and other multitargeted tyrosine kinase inhibitors such as cabozantinib, ponatinib, lenvatinib,dovitinib and alectinib. Two compounds have now completed phase II testing; cabozantinib and vandetanib and the results have been published late 2016 and early 2017 [9,10]. Drilon and collegues enrolled 26 RET fusion positive NSCLC patients in a phase II trial investigating the single agent activity of cabozantinib at a dose of 60 mg od. The objective response rate was found to be 28% (95% CI 12–49%), all partial, and the median duration of response was 7.0 months (95% CI 3.7–38.9 months). Response had the characteristics of those associated with actionable targets and the right drug: rapid, with 71% of responses observed at the first response evaluation at 4 weeks and some durable with one patient being on treatment for over 3 years. Japanese investigators screened over 1500 patients for RET rearrangements to include 19 in a phase II trial of oral vandetanib administered at 300 mg od. Of 17 evaluable patients, 9 (53%, 95% CI 28%–77%) had a partial remission for a median duration of response of 4.7 months (95% CI 2.8–8.5 months). As it is conceivable that different RET fusion partners confer different sensitivity to these drugs, an attempt was made to link responses to specific fusions. However, due to the small number of patients enrolled in both studies, no conclusions can be drawn in this respect. In both studies toxicities of treatment were associated with off target effects, mainly through inhibition of VEGFR-2, leading to hypertension. What can we learn from these studies? First, RET fusions constitute a bona fide predictive biomarker for the efficacy of targeted agents such as cabozantinib or vandetanib in lung cancer. Second, the results obtained highlight the importance of tissue context in the face of a RET rearrangement. The same drugs administered to patients with RET rearranged thyroid cancer have dramatically different clinical outcomes [11]. Third, there is a clear need for more selective and potent RET targeted agents in order to avoid undue toxicities and enhanced activity. The prime candidate to fill this gap is alectinib a drug that has at least equal potency against the RET tyrosine kinase while being void of VEGFR2/KDR targeting. Recently, Linn and collegues [12] described 4 patients treated with alectinib of whom 3 were pretreated with other RET inhibitors and observed encouraging clinical activity. Also, a number of novel compounds have already been identified that are good candidates and
http://dx.doi.org/10.1016/j.lungcan.2017.02.006 0169-5002/© 2017 Published by Elsevier Ireland Ltd.
Please cite this article in press as: E.F. Smit, How should “RET positive” NSCLC be treated? Lung Cancer (2017), http://dx.doi.org/10.1016/j.lungcan.2017.02.006
G Model LUNG-5299; No. of Pages 2
ARTICLE IN PRESS Editorial / Lung Cancer xxx (2017) xxx–xxx
2
may enter clinical evaluation in the short term [13]. Finally, the responses and survival obtained are far away from those obtained with EGFR TKI’s in EGFR mutated adenocarcinomas or with ALK inhibitors in Alk rearranged lung cancers. Combination therapies may be key here as is the case with treatment of B-RAF V600E mutated lung cancer where treatment with single agent dabrafenib is associated with less than half the response rate of the combination of dabrafenib and trametinib [14]. In view of the biology of RET signalling obvious candidates for combination therapies are MEK and/or PI3 kinase inhibitors. The international lung cancer research community has made the first steps on a road to succesful treatment of RET rearranged lung cancer that still may be very long. Conflicts of interest None. References [1] A. Fusco, M. Grieco, M. Santoro, et al., A new oncogene in human thyroid papillary carcinomas and their lymph node metastases, Nature 328 (1987) 170–172. [2] T. Kono, H. Ichikawa, Y. Totoki, et al., KIF5B-RET fusions in lung adenocarcinoma, Nat. Med. 18 (2012) 375–377. [3] K. Tageuchi, M. Soda, Y. Tokashi, et al., RET, ROS1 and ALK fusions in lung cancer, Nat. Med. 18 (2012) 378–381. [4] D. Lipson, M. Capelletti, R. Yelenski, et al., Identification of new Alk and RET gene fusions from colorectal and lung cancer biopsies, Nat. Med. 18 (2012) 382–384. [5] S. Dabir, S. Babakoohi, A. Kluge, et al., RET mutation and expression in small cell lung cancer, J. Thorac. Oncol. 9 (2014) 1316–1323. [6] K. Tsuta, T. Kohno, A. Yoshida, et al., RET-rearranged non-small-cell lung cacrinoma: a clinicopathological and molecular analysis, Br. J. Cancer 110 (2010) 1571–1578.
[7] F. Hirai, M. Takenoyama, K. Taguchi, et al., Experience with erlotinib in lung adenocarcinoma harbouring a coexisting KIB5B-RET fusion gene and EGFR mutation, J. Thorac. Oncol. 9 (2014) e37–e39. [8] A. Platt, J. Morten, Q. Ji, et al., A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized phase III studies, BMC Cancer 15 (2015) 171. [9] A. Drilon, N. Rekhtman, M. Arcila, et al., Cabozantinib in patients with RET-rearranged non-small-cell lung cancer: an open label, single center, phase 2, single arm trial, Lancet Oncol. 17 (2016) 1653–1660. [10] K. Yoh, T. Seto, M. Satouchi, et al., Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open label, multicenter phase 2 trial, Lancet Respir. Med. 5 (2017) 42–50. [11] V. Ernani, M. Kumar, A.Y. Chen, et al., Systemic treatment and management approaches for medullary thyroid cancer, Cancer Treat. Rev. 50 (2016) 89–98. [12] J.J. Linn, E. Kennedy, L.V. Sequist, et al., Clinical activity of alectinib in advanced RET rearranged non-small cell lung cancer, J. Thorac. Oncol. 11 (2016) 2027–2032. [13] A. Watson, G.V. Hopkins, S. Hitchin, et al., Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade, F1000 Res. 5 (2016) 1005. [14] D. Planchard, B. Besse, H.J. Groen, et al., Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open label, multicenter phase 2 trial, Lancet Oncol. 17 (2016) 984–993.
Egbert F. Smit Dept. Thoracic Oncology, Netherlands Cancer Institute & Dept. Pulmonary Diseases, Vrije Universiteit VU Medical Center, Amsterdam, The Netherlands E-mail address: [email protected] 31 January 2017
Please cite this article in press as: E.F. Smit, How should “RET positive” NSCLC be treated? Lung Cancer (2017), http://dx.doi.org/10.1016/j.lungcan.2017.02.006
ARTICLE IN PRESS
LUNG-5299; No. of Pages 2
Lung Cancer xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Editorial
How should “RET positive” NSCLC be treated?
Thirty years ago the REarranged-during-Transfection(RET) protooncogene, located at chromosome 10q11.2 encoding a single pass transmembrane receptor tyrosine kinase (RTK), was found to be implicated in carcinogenesis [1]. Next to its original description in papillary thyroid carcinoma, genetic abberations in RET are added to a growing list of malignancies including adenocarcinoma of the lung [2–4] and more recently small cell lung cancer [5]. Under physiological circumstances, binding of the ligand, glial cell derived neurotrophic factor, leads to dimerization of RET and autophosphorylation of the tyrosine kinase domain. In turn, this leads to activation of several intracellular signalling pathways including the MAPkinase, PI3 kinase and STAT3 pathways. In lung cancer, gain-of-function point mutations have been described in a few cases of small cell lung cancer [5]. In in vitro systems these mutations lead to a constitutively active receptor kinase. Likewise, chromosomal rearrangements leading to a RET fusion gene may activate RET in a ligand independent manner and have been observed in a small subset of lung adenocarcinomas [2–4]. At least 6 fusion partner genes with RET are identified to date, of which the kinesin family member 5B (KIF5B) with 10 variations displaying a variety of breakpoints is best characterized. Along with the second most prevalent fusion partner CCDC6, these RET fusions have transforming potential in vitro and in mouse models. The true incidence of RET gene fusions in lung adenocarcinoma is unknown and may be anywhere between 0.4% and 2%. In larger series there is no specific subtype of lung adenocarcinoma associated with RET fusions [6]. As with other gene fusions, in particular Alk and ROS1, in epidemiological studies there is an association with female gender, younger age and light or never smoking. Although there is a wide held belief that RET fusions are mutually exclusive with other driver mutations such as EGFR or RAS mutations, a recent case reports suggests otherwise [7]. The preferred way to detect RET fusions is by FISH. Several novel NGS based techniques, including capture hybrid, whole genome and exosome sequencing have been reported that may also identify RET abberations. One study [8] that compared RET IHC using a rabbit anti-RET monoclonal antibody (clone EPR2871, Epitomics, Burlingame, CA,USA), RET gene amplification and RET FISH reported absence of RET IHC staining in 3 out of 7 RET FISH positives and only 1 out of these 7 were RET amplified. Thus, contrary to Alk rearranged tumors, to date there is no possibility to screen for RET fusions by IHC methods. At its initial discovery as a driver oncogene in lung adenocarcinoma, it was observed that treatment with multitargeted tyrosine kinase inhibitors such as Vandetanib, Sorafenib and Sunitinib led to
suppression of growth of RET rearranged lung cancer cells in vitro. Of course, these were obvious candidate drugs given their activity in other cancers harbouring RET rearrangments such a thyroid cancer. Since then, a number of case reports have been published highlighting the single agent activity of these and other multitargeted tyrosine kinase inhibitors such as cabozantinib, ponatinib, lenvatinib,dovitinib and alectinib. Two compounds have now completed phase II testing; cabozantinib and vandetanib and the results have been published late 2016 and early 2017 [9,10]. Drilon and collegues enrolled 26 RET fusion positive NSCLC patients in a phase II trial investigating the single agent activity of cabozantinib at a dose of 60 mg od. The objective response rate was found to be 28% (95% CI 12–49%), all partial, and the median duration of response was 7.0 months (95% CI 3.7–38.9 months). Response had the characteristics of those associated with actionable targets and the right drug: rapid, with 71% of responses observed at the first response evaluation at 4 weeks and some durable with one patient being on treatment for over 3 years. Japanese investigators screened over 1500 patients for RET rearrangements to include 19 in a phase II trial of oral vandetanib administered at 300 mg od. Of 17 evaluable patients, 9 (53%, 95% CI 28%–77%) had a partial remission for a median duration of response of 4.7 months (95% CI 2.8–8.5 months). As it is conceivable that different RET fusion partners confer different sensitivity to these drugs, an attempt was made to link responses to specific fusions. However, due to the small number of patients enrolled in both studies, no conclusions can be drawn in this respect. In both studies toxicities of treatment were associated with off target effects, mainly through inhibition of VEGFR-2, leading to hypertension. What can we learn from these studies? First, RET fusions constitute a bona fide predictive biomarker for the efficacy of targeted agents such as cabozantinib or vandetanib in lung cancer. Second, the results obtained highlight the importance of tissue context in the face of a RET rearrangement. The same drugs administered to patients with RET rearranged thyroid cancer have dramatically different clinical outcomes [11]. Third, there is a clear need for more selective and potent RET targeted agents in order to avoid undue toxicities and enhanced activity. The prime candidate to fill this gap is alectinib a drug that has at least equal potency against the RET tyrosine kinase while being void of VEGFR2/KDR targeting. Recently, Linn and collegues [12] described 4 patients treated with alectinib of whom 3 were pretreated with other RET inhibitors and observed encouraging clinical activity. Also, a number of novel compounds have already been identified that are good candidates and
http://dx.doi.org/10.1016/j.lungcan.2017.02.006 0169-5002/© 2017 Published by Elsevier Ireland Ltd.
Please cite this article in press as: E.F. Smit, How should “RET positive” NSCLC be treated? Lung Cancer (2017), http://dx.doi.org/10.1016/j.lungcan.2017.02.006
G Model LUNG-5299; No. of Pages 2
ARTICLE IN PRESS Editorial / Lung Cancer xxx (2017) xxx–xxx
2
may enter clinical evaluation in the short term [13]. Finally, the responses and survival obtained are far away from those obtained with EGFR TKI’s in EGFR mutated adenocarcinomas or with ALK inhibitors in Alk rearranged lung cancers. Combination therapies may be key here as is the case with treatment of B-RAF V600E mutated lung cancer where treatment with single agent dabrafenib is associated with less than half the response rate of the combination of dabrafenib and trametinib [14]. In view of the biology of RET signalling obvious candidates for combination therapies are MEK and/or PI3 kinase inhibitors. The international lung cancer research community has made the first steps on a road to succesful treatment of RET rearranged lung cancer that still may be very long. Conflicts of interest None. References [1] A. Fusco, M. Grieco, M. Santoro, et al., A new oncogene in human thyroid papillary carcinomas and their lymph node metastases, Nature 328 (1987) 170–172. [2] T. Kono, H. Ichikawa, Y. Totoki, et al., KIF5B-RET fusions in lung adenocarcinoma, Nat. Med. 18 (2012) 375–377. [3] K. Tageuchi, M. Soda, Y. Tokashi, et al., RET, ROS1 and ALK fusions in lung cancer, Nat. Med. 18 (2012) 378–381. [4] D. Lipson, M. Capelletti, R. Yelenski, et al., Identification of new Alk and RET gene fusions from colorectal and lung cancer biopsies, Nat. Med. 18 (2012) 382–384. [5] S. Dabir, S. Babakoohi, A. Kluge, et al., RET mutation and expression in small cell lung cancer, J. Thorac. Oncol. 9 (2014) 1316–1323. [6] K. Tsuta, T. Kohno, A. Yoshida, et al., RET-rearranged non-small-cell lung cacrinoma: a clinicopathological and molecular analysis, Br. J. Cancer 110 (2010) 1571–1578.
[7] F. Hirai, M. Takenoyama, K. Taguchi, et al., Experience with erlotinib in lung adenocarcinoma harbouring a coexisting KIB5B-RET fusion gene and EGFR mutation, J. Thorac. Oncol. 9 (2014) e37–e39. [8] A. Platt, J. Morten, Q. Ji, et al., A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized phase III studies, BMC Cancer 15 (2015) 171. [9] A. Drilon, N. Rekhtman, M. Arcila, et al., Cabozantinib in patients with RET-rearranged non-small-cell lung cancer: an open label, single center, phase 2, single arm trial, Lancet Oncol. 17 (2016) 1653–1660. [10] K. Yoh, T. Seto, M. Satouchi, et al., Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open label, multicenter phase 2 trial, Lancet Respir. Med. 5 (2017) 42–50. [11] V. Ernani, M. Kumar, A.Y. Chen, et al., Systemic treatment and management approaches for medullary thyroid cancer, Cancer Treat. Rev. 50 (2016) 89–98. [12] J.J. Linn, E. Kennedy, L.V. Sequist, et al., Clinical activity of alectinib in advanced RET rearranged non-small cell lung cancer, J. Thorac. Oncol. 11 (2016) 2027–2032. [13] A. Watson, G.V. Hopkins, S. Hitchin, et al., Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade, F1000 Res. 5 (2016) 1005. [14] D. Planchard, B. Besse, H.J. Groen, et al., Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open label, multicenter phase 2 trial, Lancet Oncol. 17 (2016) 984–993.
Egbert F. Smit Dept. Thoracic Oncology, Netherlands Cancer Institute & Dept. Pulmonary Diseases, Vrije Universiteit VU Medical Center, Amsterdam, The Netherlands E-mail address: [email protected] 31 January 2017
Please cite this article in press as: E.F. Smit, How should “RET positive” NSCLC be treated? Lung Cancer (2017), http://dx.doi.org/10.1016/j.lungcan.2017.02.006