Measured Steps: Navigating the Path of Oligoprogressive Lung Cancer with Targeted and Immunotherapies.

PURPOSE OF REVIEW: This review discusses the definitions, treatment modalities, management, future directions, and ongoing clinical trials of oligoprogressive disease in oncogene-driven and non-oncogene-driven NSCLC. RECENT FINDINGS: During the last decades, diagnostic and treatment modalities for oligometastatic NSCLC have advanced significantly, leading to improved survival. Additionally, our understanding of the tumor biology of oligoprogressive disease has expanded. However, despite the efforts of organizations, such as EORTC, ESTRO, and ASTRO proposing definitions for oligometastatic and oligoprogressive disease, heterogeneity in definitions persists in (ongoing) trials. Recognizing the significance of subclassification within oligoprogressive disease in NSCLC and the varying risks associated with subsequent metastatic spread, there is a call for tailored management strategies. A consensus on standardized criteria for the definition of oligoprogressive disease is urgently needed and will not only facilitate meaningful comparisons between studies but also pave the way for the development of personalized treatment plans that take into account the heterogeneous nature of oligoprogressive disease.

Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients.

PURPOSE: Approximately 80% of brain metastases originate from non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting. However, concerns remain regarding the risk of radiation necrosis (RN) when SRS and ICI are administered concurrently. METHODS: A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risks analyses were utilized to identify predictors of any grade RN and symptomatic RN (SRN). RESULTS: The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2 months. The median age was 67 years. The median margin SRS dose was 19 Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95). CONCLUSION: The risk of any grade RN and symptomatic RN following single fraction SRS and ICI for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent ICI and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy.

Impact of tissue-agnostic approvals on management of primary brain tumors.

Novel tissue-agnostic therapeutics targeting driver mutations in tumor cells have been recently approved by FDA, driven by basket trials that have demonstrated their efficacy and safety across diverse tumor histology. However, the relative rarity of primary brain tumors (PBTs) has limited their representation in early trials of tissue-agnostic medications. Thus, consensus continues to evolve regarding utility of tissue-agnostic medications in routine practice for PBTs, a diverse group of neoplasms characterized by limited treatment options and unfavorable prognoses. We describe current and potential impact of tissue-agnostic approvals on management of PBTs. We discuss data from clinical trials for PBTs regarding tissue-agnostic targets, including BRAFV600E, neurotrophic tyrosine receptor kinase (NTRK) fusions, microsatellite instability-high (MSI-High), mismatch repair deficiency (dMMR), and high tumor mutational burden (TMB-H), in context of challenges in managing PBTs. Described are additional tissue-agnostic targets that hold promise for benefiting patients with PBTs, including RET fusion, fibroblast growth factor receptor (FGFR), ERBB2/HER2, and KRASG12C, and TP53Y220C.

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR).

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 µg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 µg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).

Key Clinical Principles in the Management of Glioblastoma.

Glioblastoma is the most common and aggressive primary brain tumor in the adult population and leads to considerable morbidity and mortality. It has a dismal prognosis with average survival of 15-18 months, and the current standard-of-care treatment paradigm includes maximal surgical resection and postoperative concurrent chemoradiotherapy and maintenance chemotherapy, with consideration of Tumor Treating Fields. There is a major emphasis to enroll patients onto ongoing clinical trials to further improve treatment outcomes, given the aggressive nature of the disease course and poor patient survival. Recent research efforts have focused on radiotherapy dose intensification, regulation of the tumor microenvironment, and exploration of immunotherapeutic approaches to overcome the barriers to treatment. This review article outlines the current evidence-based management principles as well as reviews recent clinical trial data and ongoing clinical studies evaluating novel therapeutic options.

DNA Methylation and Histone Modification in Low-Grade Gliomas: Current Understanding and Potential Clinical Targets.

Gliomas, the most common type of malignant primary brain tumor, were conventionally classified through WHO Grades I-IV (now 1-4), with low-grade gliomas being entities belonging to Grades 1 or 2. While the focus of the WHO Classification for Central Nervous System (CNS) tumors had historically been on histopathological attributes, the recently released fifth edition of the classification (WHO CNS5) characterizes brain tumors, including gliomas, using an integration of histological and molecular features, including their epigenetic changes such as histone methylation, DNA methylation, and histone acetylation, which are increasingly being used for the classification of low-grade gliomas. This review describes the current understanding of the role of DNA methylation, demethylation, and histone modification in pathogenesis, clinical behavior, and outcomes of brain tumors, in particular of low-grade gliomas. The review also highlights potential diagnostic and/or therapeutic targets in associated cellular biomolecules, structures, and processes. Targeting of MGMT promoter methylation, TET-hTDG-BER pathway, association of G-CIMP with key gene mutations, PARP inhibition, IDH and 2-HG-associated processes, TERT mutation and ARL9-associated pathways, DNA Methyltransferase (DNMT) inhibition, Histone Deacetylase (HDAC) inhibition, BET inhibition, CpG site DNA methylation signatures, along with others, present exciting avenues for translational research. This review also summarizes the current clinical trial landscape associated with the therapeutic utility of epigenetics in low-grade gliomas. Much of the evidence currently remains restricted to preclinical studies, warranting further investigation to demonstrate true clinical utility.

Endoglin inhibitor TRC105 with or without bevacizumab for bevacizumab-refractory glioblastoma (ENDOT): a multicenter phase II trial.

BACKGROUND: Glioblastoma (GBM), the most lethal primary brain tumor, has limited treatment options upon recurrence after chemoradiation and bevacizumab. TRC105 (carotuximab), a chimeric anti-endoglin (CD105) antibody, inhibits angiogenesis and potentiates activity of VEGF inhibitor bevacizumab in preclinical models. This study sought to assess safety, pharmacokinetics, and efficacy of TRC105 for bevacizumab-refractory GBM. METHODS: We conducted a pre-registered (NCT01564914), multicenter, open-label phase II clinical trial (ENDOT). We administered 10 mg/kg TRC105 monotherapy (first cohort) in adults with GBM and radiographic progression following radiation, temozolomide and bevacizumab therapy. Primary outcome was median time-to-progression (TTP), amended after first cohort's enrollment to median overall survival (mOS). Secondary outcomes were objective response rate, safety and tolerability, and progression-free survival (PFS). RESULTS: 6 patients were enrolled in TRC105 monotherapy cohort. Median TTP and PFS of 5 evaluable patients receiving monotherapy was 1.4 months, in whom plasma VEGF-A levels were elevated post-therapy. Lack of response led to protocol amendment, and second cohort's addition of bevacizumab+TRC105 with primary endpoint of mOS. 16 patients were enrolled in bevacizumab+TRC105 cohort. mOS of 15 evaluable patients was 5.7 (95%CI: 4.2-9.8) months. All 22 patients had measurable disease at baseline. Median PFS of 14 evaluable patients receiving bevacizumab+TRC105 was 1.8 months (95%CI 1.2-2.1). Serum TRC105 was measurable above target concentration of 25 ug/mL in all evaluable patients. Study medications were well-tolerated in both cohorts. Combined administration did not potentiate known toxicities of either medication, with cerebral hemorrhage not observed. CONCLUSIONS: Single-agent TRC105 lacks activity in bevacizumab-refractory GBM, possibly secondary to upregulated VEGF-A expression. Meaningful mOS in bevacizumab+TRC105 cohort warrants further trials to investigate efficacy of combination therapy.

Glioblastoma is an aggressive and lethal brain tumor, with patients typically expected to survive for 14 to 16 months after diagnosis. Nearly all patients experience tumor recurrence once conventional treatment strategies fail, after which a drug called bevacizumab is used. However, subsequent treatment options are extremely limited. We performed a clinical trial in which we investigated how safe and effective a new drug called TRC105 (carotuximab) is in patients who no longer respond to chemotherapy, radiotherapy or bevacizumab. We tested TRC105 both with and without bevacizumab, since TRC105 might enhance the activity of bevacizumab. We found that patients survived for an average of 5.7 months when given TRC105 and bevacizumab in combination. These findings suggest that further clinical trials are needed to confirm whether or not this combination therapy is a useful approach in patients with glioblastoma recurrence.

First- versus Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases.

Introduction: Up to 50% of non-small cell lung cancer (NSCLC) harbor EGFR alterations, the most common etiology behind brain metastases (BMs). First-generation EGFR-directed tyrosine kinase inhibitors (EGFR-TKI) are limited by blood-brain barrier penetration and T790M tumor mutations, wherein third-generation EGFR-TKIs, like Osimertinib, have shown greater activity. However, their efficacy has not been well-studied in later therapy lines in NSCLC patients with BMs (NSCLC-BM). We sought to compare outcomes of NSCLC-BM treated with either first- or third-generation EGFR-TKIs in first-line and 2nd-to-5th-line settings. Methods: A retrospective review of NSCLC-BM patients diagnosed during 2010-2019 at Cleveland Clinic, Ohio, US, a quaternary-care center, was performed and reported following 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic, histopathological, molecular characteristics, and clinical outcomes were collected. Primary outcomes were median overall survival (mOS) and progression-free survival (mPFS). Multivariable Cox proportional hazards modeling and propensity score matching were utilized to adjust for confounders. Results: 239 NSCLC-BM patients with EGFR alterations were identified, of which 107 received EGFR-TKIs after diagnosis of BMs. 77.6% (83/107) received it as first-line treatment, and 30.8% (33/107) received it in later (2nd-5th) lines of therapy, with nine patients receiving it in both settings. 64 of 107 patients received first-generation (erlotinib/gefitinib) TKIs, with 53 receiving them in the first line setting and 13 receiving it in the 2nd-5th lines of therapy. 50 patients received Osimertinib as third-generation EGFR-TKI, 30 in first-line, and 20 in the 2nd-5th lines of therapy. Univariable analysis in first-line therapy demonstrated mOS of first- and third-generation EGFR-TKIs as 18.2 and 19.4 months, respectively (p = 0.57), while unadjusted mPFS of first- and third-generation EGFR-TKIs was 9.3 and 13.8 months, respectively (p = 0.14). In 2nd-5th line therapy, for first- and third-generation EGFR-TKIs, mOS was 17.3 and 11.9 months, (p = 0.19), while mPFS was 10.4 and 6.08 months, respectively (p = 0.41). After adjusting for age, performance status, presence of extracranial metastases, whole-brain radiotherapy, and presence of leptomeningeal metastases, hazard ratio (HR) for OS was 1.25 (95% CI 0.63-2.49, p = 0.52) for first-line therapy. Adjusted HR for mOS in 2nd-to-5th line therapy was 1.60 (95% CI 0.55-4.69, p = 0.39). Conclusions: No difference in survival was detected between first- and third-generation EGFR-TKIs in either first or 2nd-to-5th lines of therapy. Larger prospective studies are warranted reporting intracranial lesion size, EGFR alteration and expression levels in primary tumor and brain metastases, and response rates.

Combination of EGFR-Directed Tyrosine Kinase Inhibitors (EGFR-TKI) with Radiotherapy in Brain Metastases from Non-Small Cell Lung Cancer: A 2010-2019 Retrospective Cohort Study.

INTRODUCTION: Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM. METHODS: A retrospective review of NSCLCBM patients diagnosed during 2010-2019 at a tertiary-care US center was performed and reported following the 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other. RESULTS: A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17-0.84, p = 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82, p = 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08, p = 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09, p = 0.07). CONCLUSIONS: NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS.

Update on the Management of Brain Metastasis.

Brain metastases occur in almost one-third of adult patients with solid tumor malignancies and lead to considerable patient morbidity and mortality. The rising incidence of brain metastases has been ascribed to the development of better imaging and screening techniques and the formulation of better systemic therapies. Until recently, the multimodal management of brain metastases focused primarily on the utilization of neurosurgical techniques, with varying combinations of whole-brain radiation therapy and stereotactic radio-surgical procedures. Over the past 2 decades, in particular, the increment in knowledge pertaining to molecular genetics and the pathogenesis of brain metastases has led to significant developments in targeted therapies and immunotherapies. This review article highlights the recent updates in the management of brain metastases with an emphasis on novel systemic therapies.