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Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma
Santosh Kesari1,2, Naveed Wagle1,2, Jose A Carrillo1,2
1Pacific Neuroscience Institute, Santa Monica, California.
Purpose:
Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma.
Patients And Methods:
Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers.
Results:
Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms.
Conclusions:
High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.
Insights
High-dose pemetrexed demonstrated tolerable safety and antitumor activity in patients with progressive chordoma, a rare axial spine tumor. Further Phase II studies are recommended to explore this promising treatment option.
Area of Science:
- Oncology
- Pharmacology
Background:
- Chordomas are rare tumors of the axial spine and skull-base lacking approved systemic therapies.
- Negative thymidylate synthase (TS) expression in most chordomas suggests potential efficacy of TS-inhibiting antifolates like pemetrexed.
Purpose of the Study:
- To evaluate the therapeutic activity and safety of high-dose pemetrexed in patients with progressive chordoma.
- To assess objective response rate, progression-free survival, and adverse events associated with pemetrexed treatment.
Main Methods:
- An open-label, pilot clinical trial involving adult patients with previously treated, progressive chordoma.
- Intravenous pemetrexed (900 mg/m2 every 3 weeks) with supportive care, including folic acid, vitamin B12, and dexamethasone.
- Objective response rate assessed by RECIST v1.1 criteria; secondary endpoints included adverse events and progression-free survival (PFS).
Main Results:
- Of 14 response-evaluable patients, 2 (14%) achieved partial response and 10 (71%) had stable disease.
- Median PFS was 10.5 months, with a 6-month PFS rate of 67%.
- Adverse events were generally mild and expected, with no dose-limiting toxicities observed.
Conclusions:
- High-dose pemetrexed is a tolerable treatment with objective antitumor activity in chordoma patients.
- Pemetrexed shows promise as a systemic therapy for chordoma, warranting further investigation in Phase II studies.
