Piccioni, David Eric

2001 Background: PolyADP-ribose polymerase (PARP) is an important modulator of DNA repair following temozolomide (TMZ) therapy. Pre-clinical testing demonstrated significant survival benefit for the combination of TMZ and PARP inhibitor veliparib in a subset of GBM pt-derived xenografts with MGMT promoter hypermethylation. Methods: After central pathology review and MGMT testing, patients (pts) with newly diagnosed, MGMT promoter hypermethylated GBM who had completed concurrent radiation and TMZ were randomized to adjuvant therapy with TMZ (Days 1-5 q28 days) combined with either placebo or veliparib (Days 1-7 q28 days). Veliparib/placebo+TMZ treatment was continued for up to 6 cycles. Pts accrued on the phase II and III portions of the trial were included in the primary endpoint analysis of overall survival (OS), with 90% power to detect a hazard ratio of 0.71 using a one-sided log-rank test with type I error rate of 0.05. The planned phase III sample size was 400 pts with data maturity after 302 deaths. Results: The phase II and III portions of the trial were open to accrual from 12/15/2014 to 2/6/2017 and 11/8/2017 to 10/15/2018, respectively; 447 pts were accrued to the trial and used in this intention to treat analysis. The two treatment groups were well balanced for prognostic factors, 421 pts initiated treatment, median follow-up was 57.8 months (mos), 380 pts had disease progression and 335 pts have died. There was no difference in OS (p = 0.15; HR 0.89 (0.71-1.11), median OS 28.1 vs. 24.8 mo. for TMZ+veliparib vs. TMZ+placebo, respectively) and no difference in secondary endpoint progression free survival (PFS, p = 0.31; HR 1.05 (0.86-1.30), median 13.2 vs. 12.1 mo, respectively). There was a notable trend for extended OS with TMZ+veliparib treatment at intermediate time-points between 24 and 42 mos (3-year OS 36.6% vs. 28.9% with TMZ+placebo, p = 0.09). In an unplanned exploratory analysis, treatment with TMZ at the time of first recurrence was associated with extended post-recurrence OS (p = 0.03) for pts treated on the experimental arm; median post-recurrence OS with TMZ salvage was 17.0 mo in the TMZ+veliparib arm and 12.6 mo in the TMZ+placebo arm, as compared to 9.6 mo in either arm if TMZ salvage was not used. These data are consistent with a possible effect of veliparib limiting the emergence of TMZ resistance in a subset of GBM pts. Conclusions: Veliparib combined with adjuvant TMZ therapy was not associated with significant extension in OS or PFS in newly diagnosed, MGMT hypermethylated GBM pts. However, a subset of pts treated with TMZ+veliparib may have an extended survival following re-treatment with TMZ at first recurrence. Clinical trial information: NCT02152982.

Abstract Background Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma. Methods Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

2502 Background: Patients with progressive or recurrent meningiomas have limited treatment options. Clinical trials of systemic therapies for meningiomas have failed to demonstrate benefit. FAK inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically-driven phase II study in recurrent or progressive grade I-III meningiomas. Methods: Eligible patients (pts) whose tumors screened positively for NF2 mutations were treated with GSK2256098 750mg po bid until progressive disease in 2 separate cohorts: grade I or II/III meningiomas. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; per study design, the trial would be declared positive if either endpoint was met. RR was evaluated across the overall cohort; PFS6 was evaluated within each subgroup. Historical benchmark data was obtained from Kaley et al. Neuro Oncol 2014. In the grade I group, 12 evaluable pts provided >79% power to detect a PFS6 rate >65% (vs. null hypothesis of 25%; alpha=0.014). In the grade II/III group, 24 evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha=0.02). The threshold for promising results for PFS6 was: 7+/12(grade I) and 8+/24(grade II/III) pts. For RR, 36 evaluable pts provided >94% power to detect RR >20% (vs. null 2.5%; alpha= 0.012). Results: Of 322 pts screened for all mutation cohorts of the study, 36 eligible and evaluable pts with NF2 mutations were enrolled. Across all grades, one pt had a partial response and 24 had stable disease as best response to treatment. In Grade I pts, the observed PFS6 rate was 83% (10/12 pts; 95% CI: 52-98%). In Grade II/III pts, the observed PFS6 rate was 33% (8/24 pts; 95% CI: 16-55%). The study met PFS6 efficacy endpoint both for the Grade I and the Grade II/III cohorts. Treatment was well tolerated. Only 7 patients had a maximum grade-3 adverse event that was at least possibly related to treatment; toxicities across these pts included: proteinuria (2), rash (1), pain (1), ALT (1), AST (1), cholecystitis (1), hypertriglyceridemia (1), apraxia (1), and lymphopenia (1) with no grade 4 or 5 events. Conclusions: GSK2256098 had excellent tolerability andresulted in an improved PFS6 rate in pts with recurrent or progressive NF2-mutated meningiomas. Trial endpoint was met. FAK inhibition warrants further evaluation in this patient population. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org Clinical trial information: NCT02523014 .