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Tumor Growth Rate (TGR) Analysis Predicts Survival in a Multicenter Phase II Study of the PARP Inhibitor Pamiparib
Benjamin M Ellingson1, Timothy F Cloughesy2, Xiaobu Ye2
1From the UCLA Brain Tumor Imaging Laboratory, Department of Radiological Sciences (B.M.E., A.T., C.R., S.O., F.S.), UCLA Brain Tumor Program, Department of Neurology (T.F.C.), David Geffen School of Medicine, University of California Los Angeles, CA; Johns Hopkins University (X.Y., S.D., N.D., S.A.G.), Baltimore, MD; Dana-Farber Cancer Institute (P.Y.W.), and Mass General Brigham Cancer Institute, Boston, MA; Hermelin Brain Tumor Center (T.W.), Henry Ford Health, Wayne State and Michigan State University, Detroit, MI, USA; Department of Medicine (J.L.C.), Division of Oncology, Washington University School of Medicine, St Louis, MO, USA; Department of Neurology (L.B.N.), University of Alabama at Birmingham, Birmingham, AB, USA; Department of Hematology and Medical Oncology (B.H.O.), Emory University School of Medicine, Atlanta, GA, USA; Department of Medical Oncology (A.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurology and Neurological Sciences (A.O.), Stanford University School of Medicine, Palo Alto, CA, USA; Department of Therapeutic Radiology (R.S.B.), Yale School of Medicine, New Haven, CT, USA and Division of Neuro-Oncology (D.S.), University of Virginia School of Medicine. bellingson@mednet.ucla.edu.
Background And Purpose:
Mutations in isocitrate dehydrogenase (IDH) lead to production of the oncometabolite 2-hydroxygluterate (2-HG), which suppresses homologous recombination and induces poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity. Preclinical studies demonstrate that IDH-mutant gliomas are sensitive to PARP inhibition. Tumor growth rate (TGR) assessment offers a novel approach to evaluate treatment effects beyond traditional response criteria. Here, we report the change in TGR in a multicenter phase Ib/II study of the PARP inhibitor pamiparib with low-dose temozolomide in recurrent IDH-mutant gliomas, and evaluate TGR as an independent prognostic biomarker for overall survival.
Materials And Methods:
In this Adult Brain Tumor Consortium multicenter phase Ib/II clinical trial (ABTC-1801; NCT03914742), patients with recurrent IDH-mutant gliomas were enrolled in three cohorts: Arm A (grade 2-3, failed ≥2 alkylators), Arm B (grade 2-3, failed single alkylator ≥12 months prior), and an exploratory cohort of grade 4 IDH-mutant patients. All patients received pamiparib 60mg twice daily with temozolomide 20mg daily. Tumor growth rates were assessed using serial MRI FLAIR measurements before and during treatment. Growth rate inhibition was defined as a decrease in TGR after treatment compared to pre-treatment growth rate.
Results:
Among evaluable patients in the dose expansion cohorts enrolled between 2020-2022, 45.5% (5/11) in Arm A, 30% (6/20) in Arm B, and 30% (3/10) in the grade 4 arm demonstrated a decrease in TGR during treatment relative to pre-treatment TGRs. Cox regression analysis showed that higher post-treatment TGR (HR=1.0065 [95%CI:1.0031-1.01], P=0.0002; Arms A-B, HR=1.0068 [95%CI:1.0027-1.011], P=0.0012) and an increase in TGR after treatment were significantly associated with shorter survival for all patients as well as when only including grades 2-3 gliomas in Arms A-B (All patients, HR=1.007 [95%CI:1.0032-1.0107], P=0.0003; Arms A-B, HR=1.008 [95%CI:1.0034-1.0126], P=0.0006). Patients with TGR change >+25 mL/6 months had significantly worse survival compared to those with TGR <+25 mL/6 months (HR=4.946, P=0.0044; Arms A-B, HR=3.210, P=0.0108).
Conclusions:
TGR changes were significantly associated with survival outcomes, suggesting that growth stabilization may be an important metric for assessing treatment benefit in IDH-mutant gliomas.
Insights
Tumor growth rate (TGR) changes in recurrent isocitrate dehydrogenase (IDH)-mutant gliomas treated with pamiparib and temozolomide correlate with survival. Stabilizing tumor growth is a key indicator of treatment benefit in these IDH-mutant gliomas.
Area of Science:
- Neuro-oncology
- Clinical trial research
- Cancer metabolism
Background:
- Isocitrate dehydrogenase (IDH) mutations produce 2-hydroxygluterate (2-HG), a metabolite that hinders DNA repair and increases sensitivity to PARP inhibitors.
- Preclinical data suggest IDH-mutant gliomas respond well to PARP inhibition.
- Tumor growth rate (TGR) offers a novel method for evaluating treatment efficacy beyond conventional criteria.
Purpose of the Study:
- To assess changes in TGR during treatment with pamiparib and low-dose temozolomide in patients with recurrent IDH-mutant gliomas.
- To investigate TGR as an independent prognostic biomarker for overall survival in this patient population.
Main Methods:
- A multicenter phase Ib/II clinical trial (ABTC-1801) enrolled patients with recurrent IDH-mutant gliomas into three cohorts.
- Patients received pamiparib (60mg BID) plus temozolomide (20mg daily).
- TGR was measured using serial MRI FLAIR before and during treatment; growth rate inhibition was defined as a post-treatment TGR decrease.
Main Results:
- A decrease in TGR was observed in 45.5% of Arm A, 30% of Arm B, and 30% of the grade 4 cohort.
- Higher post-treatment TGR and TGR increase post-treatment were significantly linked to shorter survival (P<0.0012).
- Patients with TGR change >+25 mL/6 months had significantly worse survival (HR=3.210, P=0.0108 in Arms A-B).
Conclusions:
- Changes in TGR demonstrated a significant association with survival outcomes in recurrent IDH-mutant gliomas.
- Growth stabilization, as indicated by TGR, may serve as a critical metric for evaluating treatment effectiveness.
- TGR assessment provides valuable prognostic information for patients with IDH-mutant gliomas.
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