CNS Downstaging: An Emerging Treatment Paradigm for Extensive Brain Metastases in Oncogene-Addicted Lung Cancer.

INTRODUCTION: For extensive brain metastases (BrM) presentations arising from oncogene-addicted lung cancer, tyrosine kinase inhibitors (TKIs) with high response rates in the central nervous system (CNS) could potentially downstage the CNS disease burden, allowing for the avoidance of upfront whole-brain radiotherapy (WBRT) and the conversion of some patients into candidates for focal stereotactic radiosurgery (SRS). METHODS: We describe the outcomes of patients with ALK, EGFR, and ROS1-driven NSCLC with extensive BrM presentations (defined as > 10 BrMs or leptomeningeal disease) treated with upfront newer generation CNS-active TKIs alone, including osimertinib, alectinib, brigatinib, lorlatinib, and entrectinib, from 2012 to 2021 at our institution. All BrMs were contoured at study entry, best CNS response (nadir), and first CNS progression. RESULTS: Twelve patients met criteria including 6 with ALK, 3 with EGFR, and 3 with ROS1-driven NSCLC. The median number and volume of BrMs at presentation were 49 and 19.6 cm3, respectively. Eleven patients (91.7 %) achieved a CNS response by modified-RECIST criteria to upfront TKI (10 partial responses, 1 complete response, 1 stable disease) with nadir observed at a median of 5.1 months. At nadir, the median number and volume of BrMs were 5 (median 91.7 % reduction per-patient) and 0.3 cm3(median 96.5 % reduction per-patient), respectively. Eleven patients (91.6 %) developed subsequent CNS progression (7 local failures, 3 local + distant, 1 distant) at a median of 17.9 months. At CNS progression, the median number and volume of BrMs were 7 and 0.7 cm3, respectively. Seven patients (58.3 %) received salvage SRS and no patients received salvage WBRT. The median overall survival from initiation of TKI for the extensive BrM presentation was 43.2 months. CONCLUSION: In this initial case series, we describe CNS downstaging as a promising multidisciplinary treatment paradigm involving the upfront administration CNS-active systemic therapy and close MRI surveillance for extensive BrMs as a strategy to avoid upfront WBRT and to convert some patients into SRS candidates.

Short communication: The activity of brigatinib in patients with disease progression after next generation anaplastic lymphoma tyrosine kinase inhibitors and an exploratory analysis of circulating tumor DNA.

BACKGROUND: Brigatinib, a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is central nervous system (CNS) penetrant and active against anaplastic lymphoma kinase (ALK) resistance mutations. We prospectively studied the activity of brigatinib in patients with disease progression after second generation ALK TKIs. METHODS: Patients with stage IIIB/IV ALK + non-small cell lung cancer (NSCLC), and progressive disease after second ALK TKIs were eligible. Cohort A enrolled patients with disease progression on any second ALK TKI, cohort B enrolled patients with disease progression after first-line therapy with alectinib, and cohort C enrolled patients who experienced disease progression on standard dose brigatinib. Brigatinib treatment was 90 mg daily for seven days and then escalated to 180 mg daily in cohorts A and B, and 240 mg daily in cohort C. The primary endpoint was objective response rate (ORR), and a 2-stage design was used. The intended enrollment was 20 patients in stage 1, and 20 patients in stage 2. RESULTS: The study was closed due to slow accrual. Between March 2017 and June 2020, 32 patients received study therapy; three patients in cohort A moved to cohort C after initial progression for a total of 35 study subjects. Of the 32 patients, 16 (50%) were male, the median age was 55 years (range 32-76), and patients received a median number of 2 prior ALK TKI's (range 1-3). Cohort A enrolled 27 patients, cohort B enrolled four patients, and cohort C enrolled four patients. The ORR in cohorts A, B, and C was 33% (95% confidence interval (CI: 16% to 54%), 25% (95% CI: 0.63% to 81%), and 0%, respectively. CONCLUSION: Brigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs.

Veliparib and nivolumab in combination with platinum doublet chemotherapy in patients with metastatic or advanced non-small cell lung cancer: A phase 1 dose escalation study.

OBJECTIVES: Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC. MATERIALS AND METHODS: Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m2 (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m2 (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. RESULTS: Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80-240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80-240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%. CONCLUSION: Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug-drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.

Impact of lorlatinib on patient-reported outcomes in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer.

OBJECTIVES: To evaluate patient-reported outcomes (PROs) from a phase 1/2 study (NCT01970865) in patients with anaplastic lymphoma kinase (ALK)- or ROS1-positive advanced non-small cell lung cancer (NSCLC) treated with lorlatinib 100 mg once daily. MATERIALS AND METHODS: PRO measures, including global quality of life (QoL), functioning domains and symptoms, were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module. Mean changes of absolute scores from baseline were assessed. Percentages of patients showing improvement, stability or worsening on each scale were reported, with a change of ≥10 points considered clinically meaningful (CM). RESULTS: 255 patients completed baseline and ≥1 post-baseline PRO assessment. Most patients had CM improvement (42.4 %) or stable (38.0 %) scores for global QoL. Functioning domains with the greatest proportion of patients with improved scores were role (37.6 %) and emotional (36.9 %); only one domain had more patients showing worsening than improving function (cognitive [24.3 % vs 22.4 %]). Most patients showed improved or stable scores for disease-related symptoms. No QLQ-C30 symptom domains had more patients worsening than improving. Symptoms on the QLQ-C30 scale with the greatest proportion of patients with improved scores were fatigue (49.4 %) and insomnia (46.3 %). Four QLQ-LC13 domains had more patients worsening than improving (two most affected were peripheral neuropathy [37.3 % vs 13.7 %] and alopecia [19.2 % vs 13.3 %]). Symptoms on the QLQ-LC13 scale with the greatest proportion of patients with improved scores were cough (42.7 %) and pain in other parts (32.9 %). CONCLUSIONS: Lorlatinib treatment showed CM improvement from baseline in global QOL that was maintained over time. Additionally, there were improvements in physical, emotional, social, and role functioning. Improvements were shown in appetite loss and key symptoms such as pain, dyspnea, cough and fatigue; a worsening in peripheral neuropathy was noted.

Detection of oligoprogressive disease in oncogene-addicted non-small cell lung cancer using PET/CT versus CT in patients receiving a tyrosine kinase inhibitor.

OBJECTIVES: In oncogene-addicted non-small cell lung cancer (NSCLC), oligoprogressive disease (OPD) can be treated with local ablative therapy (LAT) to prolong benefit from tyrosine kinase inhibitors (TKIs). A comparison of PET/CT vs. CT for the detection of OPD at first extra central nervous system (eCNS) progression was performed to determine which modality was more sensitive for OPD detection. MATERIALS AND METHODS: Patients with metastatic EGFR-MT, ALK + or ROS-1+ NSCLC on a relevant TKI from 2010 to 2016 were identified. Scan methodology at first eCNS progression (index scan) was noted and progression was categorized as OPD (≤ 4 lesions) or non-OPD (> 4 lesions). RESULTS: Of the 67 analyzable patients (EGFR-MT = 37, ALK+ = 28, ROS1+ = 2), OPD was detected in 81.3% (26/32) by PET/CT vs. 68.6% (24/35) by CT (p = 0.363). Of these, 17/26(65.4%) in PET/CT and 5/24(20.8%) in CT group had LAT (p = 0.004). Among patients receiving an alternate modality scan within 6 weeks of the index scan that showed first eCNS progression, 91.7% (11/12) had CT prior to index PET/CT, 75% (6/8) had post-index PET/CT showing further progression, whereas 0% (0/5) had post-index CT showing further progression. Time to progression (TTP), Post-progression TKI benefit (TTP2) and overall survival (OS) were longer in the PET/CT-detected group (p = 0.001, p = 0.032, and p = 0.01, respectively). In both PET/CT (N = 26) and CT-detected (N = 24) OPD subgroups, TTP2 and OS were longer in those that received LAT (65.4% [17/26] and 20.8% [5/24]) versus those that did not, although the difference was not statistically significant. CONCLUSION: PET/CT demonstrated a non-significant trend to detect more eCNS OPD and a significantly higher rate of OPD suitable for LAT than CT. Peri-progression alternate modality scans were also consistent with PET/CT being more sensitive. A prospective randomized study is required to assess the long-term impact of PET/CT vs CT in oncogene-addicted NSCLC patients on TKI therapy.

Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer.

PURPOSE: Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC. PATIENTS AND METHODS: PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients' tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13. RESULTS: 1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK-status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life. CONCLUSION: The efficacy, safety and PRO profiles of crizotinib in this cohort of 1066 patients with ALK-positive NSCLC are consistent with previous reports. TRIAL REGISTRATION NUMBER: Phase 2 trial (NCT00932451); Results.

Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.

Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m2 was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.