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Introduction: Analyses of circulating tumor DNA (ctDNA) have shown promise in capturing tumor burden dynamics during immune checkpoint blockade (ICB), with the potential to allow patients with primary resistance to be rapidly identified and redirected to alternative therapies. Methods: BR.36 is an international multicenter, open label, biomarker-directed, phase II trial of molecular response-adaptive immuno-chemotherapy for patients with treatment-naïve non-small cell lung cancer-NSCLC (NCT04093167). The trial consists of two stages; stage 1 was a single-arm study to validate the ctDNA approach, with stage 2 focusing on ctDNA guided treatment selection. Key eligibility criteria included EGFR and ALK mutation negative, ICB and chemotherapy-naïve metastatic NSCLC with PD-L1 expression ≥1%. Primary objectives were to ascertain ctDNA molecular response, determine its timing and concordance with radiologic RECIST/iRECIST response. Secondary objectives included the evaluation of time to ctDNA molecular response and its correlation with progression-free (PFS) and overall survival (OS). Liquid biopsy analyses utilized a validated tumor-agnostic white blood cell (WBC) DNA-informed 33-gene panel approach. Ultra-sensitive error-correction ctDNA next-generation sequencing (NGS) was performed at baseline/cycle 1 (C1D1), cycle 2 (C2D1) and cycle 3 (C3D1) of pembrolizumab (200mg IV q3 weeks). The maximum variant allele fraction (maxVAF) of tumor-derived variants was tracked from the pre-treatment to on-therapy timepoints. Results: Activated October 17, 2019, stage 1 completed accrual of 50 patients on April 5, 2022; data lock date was September 20, 2022. Most patients were ever-smokers (98%), had no prior systemic therapy (92%), stage IV NSCLC (98%), adenocarcinoma (76%) with PD-L1 tumor proportion score of ≥ 50% (96%); cohort consisted of 82% white, 52% female, 56% age>65 and 76% ECOG PS 1 participants. Median follow-up was 13.5 months (range 2.5-23.0). Best overall response rate (ORR) by RECIST was 32% with a median duration of 10.1 months. Matched WBC DNA analyses allowed for effective removal of germline and clonal hematopoiesis variants, followed by evaluation of ctDNA response. MaxVAF clearance signified molecular response (mR), while maxVAF persistence indicated molecular disease progression (mPD). Among 35 evaluable patients (77.8%), 15 were classified in the mR category, with an evaluable mR rate of 43% (90% CI: 0.29-0.58). The median time to molecular response was 2.1 months (90% CI: 1.5-2.6). The sensitivity of ctDNA molecular response for RECIST and iRECIST response was 82% (90% CI: 52%-97%) and 83% (90% CI: 56%-97%), with a specificity of 75% (90% CI: 56.5%-88.5%) and 78% (90% CI: 60%-91%) respectively. Patients with mR attained longer PFS (5.03 vs 2.6 months,) and OS (not reached vs 7.23 months); ctDNA response also provided prognostic information for patients with RECIST stable disease. Conclusions: ctDNA molecular responses were concordant with radiologic response assessments, but importantly better predicted PFS and OS for patients with stable disease or better. These findings are now incorporated into the interventional second stage of the trial. Citation Format: Valsamo K. Anagnostou, Cheryl Ho, Garth Nicholas, Rosalyn Anne Juergens, Adrian Sacher, Andrea Fung, Paul Wheatley-Price, Scott Laurie, Benjamin Levy, Julie Brahmer, Archana Balan, Noushin Niknafs, Egor Avrutin, Liting Zhu, Mark Sausen, Penelope Bradbury, Jill O'Donnell-Tormey, Pierre-Olivier Gaudreau, Keyue Ding, Janet Dancey. A ctDNA-directed, multi-center phase II study of molecular response adaptive immuno-chemotherapy in patients with non-small cell lung cancer: Analysis of Stage 1 of CCTG BR.36 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT212.

Background: Tumor Treating Fields (TTFields) is a novel, anti-mitotic, physical treatment. Alternating electrical fields (TTFields) at an intermediate frequency of 200 MHz (1-3 V/cm) are delivered continuously to the brain by a patient-operated, wearable medical device (Optune™, Novocure Ltd.). An international, multicenter, prospective, randomized phase 3 trial (EF-14) is testing the efficacy of adding TTFields to standard adjuvant temozlomide (TMZ) chemotherapy in newly diagnosed GBM. We report the final and mature results of all 695 patients (pts) enrolled (median follow-up > 3 years, minimum follow-up > 24 months) including five year survival rates. Methods: Within 7 weeks after the end of concomitant chemo-radiotherapy (TMZ/RT) and stratification for extent of resection and MGMT status, pts were randomized (at a 1:2 ratio) to either standard adjuvant TMZ alone (150-200 mg/m2/d x 5d) or TMZ and TTFields. Eligible pts had a newly diagnosed GBM, non-progressive after TMZ/RT, performance status of ≥70%, adequate hematological, liver and renal function. The primary endpoint is progression free survival (PFS; determined by blinded central radiology review), with overall survival (OS) as a powered secondary endpoint. Results: 695 pts were randomized (7/09 - 11/14). Patient characteristics are balanced, median age 56 years (range 19-83), 87 % had undergone tumor resection, 13 % a biopsy only. One third of tumors were MGMT methylated. Median time from end of radiotherapy to randomization was 37 days. The median number of adjuvant (maintenance) TMZ cycles was 6 and 5 cycles, for TTFields/TMZ and TMZ alone, respectively. All analyses are intent-to-treat. The median PFS is 6.7 months (95%CI 6.1-8.1) for the pts treated with TTFields/TMZ versus 4.0 months (CI 3.8 - 4.4) for TMZ alone (hazard ratio 0.63, p=0.00005). Median OS from randomization is 20.9 months versus 16 months for the TTFields/TMZ and TMZ alone, respectively, with a hazard ratio of 0.63 (CI 0.53-0.76), p=0.00006. Median time from initial diagnosis until completion of TMZ/RT with subsequent randomization was 3.7 months, equal in both arms. The landmark 2 and 5-year survival rates are 43% (CI 39-48%) vs 31% (CI 25-38) and 13% (CI 9-18) vs 5% (CI 2-11); p=0.0008 and 0.0037, respectively. The significant improvement in OS was seen across all patient subgroups regardless of age, extent of resection, performance status, gender, geography or MGMT methylation status. Only compliance with TTFields treatment was predictive of outcome, with pts who were treated for more than 18 hours/day (monthly average) living significantly longer than pts treated for less than 18 hours/day. Conclusions: This final analysis of the EF-14 trial demonstrate consistent superior PFS and OS in pts treated with maintenance therapy including both TTFields and TMZ compared with maintenance TMZ alone. With a hazard ratio for survival of 0.63, the magnitude of improvement when adding TTFields is comparable to the benefit observed with TMZ 12 years ago. Tumor Treating Fields are a welcome addition to the treatment armamentarium in GBM, and defines a new standard of care. This innovative regional treatment modality that can due to the absence of overlapping toxicity easily be combined with standard chemotherapy holds promise as a regional tumor treatment modality in other solid tumors. Citation Format: Roger Stupp, Monika E. Hegi, Ahmed Idbaih, David M. Steinberg, Benoit Lhermitte, William Read, Steven A. Toms, Gene H. Barnett, Garth Nicholas, Chae-Yong Kim, Karen Fink, Andrea Salmaggi, Frank S. Lieberman, Jay-Jiguang Zhu, Lynne Taylor, Giuseppe Stragliotto, Andreas F. Hottinger, Eilon D. Kirson, Uri Weinberg, Yoram Palti, Zvi Ram, on behalf of the EF-14 trial investigators. Tumor treating fields added to standard chemotherapy in newly diagnosed glioblastoma (GBM): Final results of a randomized, multi-center, phase III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT007. doi:10.1158/1538-7445.AM2017-CT007

Glioblastoma multiforme (GBM) is the most aggressive and invasive form of brain tumor. From diagnosis the average survival time is about one year. While other forms of brain cancer can be successfully removed by surgical means, the invasive nature of GBM results in frequent relapses at secondary sites within the brain. PTEN loss is very common in GBM and leads to aberrant activation of the phosphoinositide 3-kinase pathway. Here we show that this event results in the constitutive phosphorylation and inactivation of the tumor suppressor lethal giant larvae (LGL). In Drosophila, loss of LGL causes both over-proliferation and increased invasiveness of epithelial and brain tissue. Studies in yeast and mammals have also shown a role for Lgl in vesicle trafficking and cell motility. Its role in the proliferation and invasiveness in human brain cancer has not been investigated previously. In both cell culture and in vivo subcutaneous mouse models, expression of a non-phosphorylatable, constitutively active form of LGL (LGL-3SA) did not significantly affect the proliferation of human U87MG glioblastoma cells. However, LGL-3SA expression did lead to a reduction in the invasiveness of U87MG cells in vitro. This appeared to be mediated in part by effects on matrix metalloproteinase trafficking, as LGL-3SA prevented the delivery of matrix metalloproteinase 14 (MMP14) to the leading edge of U87MG cells. The role of Lgl in primary glioblastoma stem-like cells was also assessed, as these cells retain their invasive properties in mouse xenografts and are therefore a more clinically relevant model of glioblastoma. All primary glioblastoma stem-like cells expressed Lgl. MMP14 expression was also detected in primary glioblastoma stem-like cells, and Lgl-3SA impaired its trafficking in these cells as well. Experiments are underway to assess the affects of Lgl-3SA expression on the in vivo invasiveness of intracranial xenograft tumours generated using glioblastoma stem-like cells. Our current in vitro data suggest that inactivation of Lgl is an essential downstream step mediating the increased invasiveness of PTEN negative glioblastoma. Inactivation of Lgl enhances invasiveness by increasing the delivery of MMP-14 to the cell surface, where it can promote the degradation of extracellular matrix directly and also indirectly by activation of other matrix metalloproteinases. Citation Format: Alexander Gont, Jennifer Hanson, Mathieu Soucie, Amin Kassam, Vasco DaSilva, John Woulfe, Garth Nicholas, Sylvie Lavictoire, Ian Restall, Ian A. Lorimer. Inactivation of the tumor suppressor Lgl via PTEN loss promotes the invasiveness of glioblastoma multiforme. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1968. doi:10.1158/1538-7445.AM2013-1968