Letter: Emerging Therapeutic Targets in Chordomas: A Review of the Literature in the Genomic Era

To the Editor: We have read with great interest the article by Gill et al1 reviewing the literature on emerging therapeutic options for the treatment of chordomas in the genomic era. Hereunder, we would like to point out critical data for patient selection in routine practice, and future clinical trials (for which a critical contribution of neurosurgeons will be needed). Firstly, we agree with the authors that epidermal growth factor receptor (EGFR) inhibitors can induce objective responses in advanced chordomas.2 However, although EGFR phosphorylation has been reported, activating mutations in EGFR (similar to those observed in non-small cell lung cancer, as suggested by the authors) have never been found in chordomas.2 Hence, the mechanism of action of EGFR inhibitors in chordomas remains poorly understood, even if Magnaghi and colleagues3 have shown that afatinib inhibits not only EGFR but also brachyury.3 Therefore, no biomarker (neither EGFR mutations nor EGFR expression by immunohistochemistry) can be routinely used in this setting. Notably, as mentioned by the authors, afatinib is currently being evaluated in a phase II trial (NCT03083678). Secondly, the authors do not mention the vascular endothelial growth factor (VEGF) signaling pathway as a potential target. To date, objective responses were reported with sunitinib, pazopanib, and sorafenib (multikinase inhibitors targeting the VEGF receptors),4,5 and a phase II study of sorafenib has shown a 9-mo progression-free rate of 73%.5 Interestingly, circulating VEGF was a significant predictor of progression-free survival in this trial.6 REGOBONE,7 an ongoing randomized phase II study of regorafenib (another agent structurally close to sorafenib) vs placebo in bone tumors and chordomas, might provide additional clinical and biomarker data on VEGF pathway inhibition (NCT02389244). TABLE. - Current Clinical Trials With Targeted Agents Enrolling Patients With Advanced Chordomas Trial Phase Experimental drug Target Setting Main inclusion criteria Main exclusion criteria NCT03083678 2 Afatinib EGFR, brachyury Advanced disease, first line and over - Locally advanced or metastatic, pathologically proven, EGFR expressing chordoma, not amenable for local therapies- Patients aged 18 yr and above- Documented radiographic progression of disease according to RECIST 1.1 criteria in last 6 mo- ECOG performance status ≤ 2- Adequate bone marrow, renal and liver functions- Availability of archival tumor material for central review - Known hypersensitivity to afatinib- Major surgery within the last 28 d before the start of treatment- Previous treatment with any other investigational agents within 14 d from the first day of study drug dosing- History or presence of clinically relevant cardiovascular abnormalities- Unable to take oral medications NCT02389244 2 Regorafenib (vs placebo) VEGFR Advanced disease, first, second, or third line - Locally advanced or metastatic, pathologically proven chordoma, not amenable for local therapies- Patients aged 18 yr and above- Documented radiographic progression of disease according to RECIST 1.1 criteria in the last 6 mo- ECOG performance status ≤ 2- Adequate bone marrow, renal and liver functions- Patients not pretreated or with 1 or 2 prior chemotherapy regimens or with 1 or 2 prior molecularly targeted therapies, but no more than 2 prior lines of treatment - Prior treatment with any VEGFR inhibitor- History or presence of clinically relevant cardiovascular abnormalitiesMajor surgical procedure, open biopsy, significant trauma, within the last 28 d before randomization- Arterial or venous thrombotic or embolic events within the last 6 mo before randomization- Unable to take oral medications NCT03012620 2 Pembrolizumab PD-1 Advanced disease, first line and over - Locally advanced or metastatic, pathologically proven chordoma, not amenable for local therapies- Patients aged 18 yr and above- ECOG performance status ≤ 1- Adequate bone marrow, renal and liver functions- Availability of archival tumor material for central review - Prior treatment with an anti-PD1 or anti-PD-L1 antibody- Concurrent steroid medication at a dose greater than prednisone 10 mg/d or equivalent- Active autoimmune disease that has required systemic treatment in the past 2 yr- History of severe hypersensitivity reaction to any monoclonal antibody therapy NCT02601950 2 Tazemetostat EZH2 Advanced disease, first line and over - Locally advanced or metastatic, pathologically proven chordoma, not amenable for local therapies- Loss of INI1 confirmed by IHC, or molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is equivocal or unavailable- Patients aged 18 yr and above- ECOG performance status ≤ 2- Adequate bone marrow, renal and liver functions- Availability of archival tumor material for central review - Prior exposure to tazemetostat or other inhibitor(s) of EZH2- Major surgery within 21 d prior to enrollment- Unable to take oral medications Thirdly, the authors point out that immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have significant clinical activity in advanced chordomas.1,8 Although a vast majority of chordomas express PD-L1 by immunohistochemistry or tissue microarrays,1 not all of them respond to PD-1/PD-L1 inhibitors. In contrast, microsatellite instability is probably worth being investigated in bone tumors, including chordomas.9 Indeed, on one hand, Klinger and colleagues10 have reported microsatellite instability in 50% of the chordoma samples tested, while, on the other hand, microsatellite instability predicts a response to pembrolizumab, an anti-PD-1 agent approved by the FDA in this setting.11 An ongoing secured access program is currently evaluating pembrolizumab in advanced chordomas (NCT03012620). Finally, the authors mention epigenetic targets (including proteins of the SWI/SNF complex, such as EZH2).1 The EZH2 inhibitor tazemetostat is currently under investigation in chordoma patients in a dedicated international phase II trial (NCT02601950). Overall, we believe that the most promising agents for the treatment of advanced chordomas, to date, encompass afatinib (an EGFR and brachyury inhibitor), regorafenib (a multikinase inhibitor targeting the VEGF receptors), PD-1/L-1 inhibitors, and EZH2 inhibitors. Beyond the existing guidelines for routine management of chordomas,12 we believe that clinicians facing patients with unresectable, relapsing, and/or metastatic chordomas should be encouraged to refer them to centers involved in clinical trials, such as those summarized in the Table. We do agree that not all chordoma patients are eligible for clinical trials (due to altered general status, comorbidities and/or rapidly worsening disease-related symptoms), but we are convinced that neurosurgeons might play a critical role in improving the enrollment in clinical trials, provided that useful information on those trials (location, inclusion and exclusion criteria) are easily available for them. Whether these investigational agents could also exert clinical activity (and impact therapeutic management) at earlier phases of the diseases remains uncertain, and will also need a shared effort from neurosurgeons and oncologists. Disclosures Dr Mir has acted as a consultant for Amgen, Astra-Zeneca, Bayer, Blueprint Medicines, Bristol Myers-Squibb, Eli-Lilly, Incyte, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, and Vifor Pharma. Prof. Blay has acted as a consultant for Amgen, Bayer, Eli-Lilly, Novartis, Pfizer, and Roche. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.