Carol A. Sherman

Alectinib Salvages CNS Relapses in ALK-Positive Lung Cancer Patients Previously Treated with Crizotinib and Ceritinib

Background: Leptomeningeal metastases (LM) are an increasingly frequent and devastating complication of anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC). Currently, the optimal management of LM in ALK-positive patients remains poorly understood as these patients have been routinely excluded from clinical trials. Methods: We describe four ALK-positive patients with LM who were treated with the next-generation ALK inhibitor alectinib through single-patient, compassionate use protocols at two institutions. All patients had previously been treated with both FDA-approved ALK inhibitors—crizotinib and ceritinib. Patients received alectinib at a starting dose of 600 mg twice daily. Results: Four ALK-positive NSCLC patients with symptomatic leptomeningeal disease were identified. Three of four patients experienced significant clinical and radiographic improvements in LM upon treatment with alectinib. A fourth patient had stable intracranial disease for 4 months before eventual systemic disease progression. Overall, alectinib was well tolerated. One patient required dose reduction due to grade 2 hyperbilirubinemia. Conclusions: Alectinib is active in ALK-rearranged NSCLC patients with LM, including in patients previously treated with crizotinib and ceritinib. Additional prospective studies of alectinib in ALK-positive patients with LM are warranted.

Lunx Is a Superior Molecular Marker for Detection of Non-Small Lung Cell Cancer in Peripheral Blood

The clinical management of non-small cell lung cancer (NSCLC) would benefit greatly by a test that was able to detect small amounts of NSCLC in the peripheral blood. In this report, we used a novel strategy to enrich tumor cells from the peripheral blood of 24 stage I to IV NSCLC patients and determined expression levels for six cancer-associated genes (lunx, muc1, KS1/4, CEA, CK19, and PSE). Using thresholds established at three standard deviations above the mean observed in 15 normal controls, we observed that lunx (10 of 24, 42%), muc1 (5 of 24, 21%), and CK19 (5 of 24, 21%) were overexpressed in 14 of 24 (58%) peripheral blood samples obtained from NSCLC patients. Patients who overexpressed either KS1/4 (n = 2) or PSE (n = 1) also overexpressed either lunx or muc1. Of patients with presumed curable and resectable stage I to II disease (n = 7), at least one marker was overexpressed in three (43%) patients. In advanced stage III to IV patients (n = 17), at least one marker was overexpressed in 11 patients (65%). These results provide evidence that circulating tumor cells can be detected in NSCLC patients by a high throughput molecular technique. Further studies are needed to determine the clinical relevance of gene overexpression.

The role of molecular analyses in the era of personalized therapy for advanced NSCLC

Platinum-based doublet chemotherapy is the traditional treatment of choice for advanced non-small cell lung cancer (NSCLC); however, the efficacy of these regimens has reached a plateau. Increasing evidence demonstrates that patients with sensitizing mutations in the epidermal growth factor receptor (EGFR) experience improved progression-free survival and response rates with first-line gefitinib or erlotinib therapy relative to traditional platinum-based chemotherapy, while patients with EGFR-mutation negative tumors gain greater benefit from platinum-based chemotherapy. These results highlight the importance of molecular testing prior to the initiation of first-line therapy for advanced NSCLC. Routine molecular testing of tumor samples represents an important paradigm shift in NSCLC therapy and would allow for individualized therapy in specific subsets of patients. As these and other advances in personalized treatment are integrated into everyday clinical practice, pulmonologists will play a vital role in ensuring that tumor samples of adequate quality and quantity are collected in order to perform appropriate molecular analyses to guide treatment decisions. This article provides an overview of clinical trial data supporting molecular analysis of NSCLC, describes specimen acquisition and testing methods currently in use, and discusses future directions of personalized therapy for patients with NSCLC.

Cisplatin/Irinotecan Versus Carboplatin/Paclitaxel as Definitive Chemoradiotherapy for Locoregionally Advanced Esophageal Cancer

Objective:To compare toxicities, disease control, and survival outcomes for patients treated with either cisplatin/irinotecan versus carboplatin/paclitaxel concurrent chemoradiotherapy for locally advanced esophageal cancer. Methods:Single-institution retrospective comparison between treatment groups: the cisplatin/irinotecan group was treated with 2 cycles of induction chemotherapy followed by concurrent chemoradiotherapy, whereas the carboplatin/paclitaxel group began with chemoradiotherapy followed by 2 additional cycles of chemotherapy. Acute toxicities, response rates, disease control, survival outcomes, and patterns of failure were compared between the groups. Results:Between January 2000 and December 2007, 57 patients were identified for inclusion in the present study (38 cisplatin/irinotecan and 19 carboplatin/paclitaxel). Groups were well-balanced by clinical-, pathologic-, staging-, and treatment-related factors. Thirty-five patients (92%) in the cisplatin/irinotecan group and 18 patients (95%) in the carboplatin/paclitaxel group completed the concurrent phase of chemoradiotherapy. There were no significant differences in hematologic or nonhematologic toxicities between the groups. At a median survivor follow-up of 37.6 months (range: 7.3–59.3 months) for the entire population, 22 patients were alive (16 without evidence of disease). The 3-year overall survival estimates was 19.7% for the cisplatin/irinotecan group versus 56.1% for the carboplatin/paclitaxel group (P = 0.022). Estimated 3-year cancer-specific survivals were 24.6% for the cisplatin/irinotecan group versus 59.3% for the carboplatin/paclitaxel group (P = 0.033). Conclusion:Concurrent chemoradiotherapy with carboplatin/paclitaxel is well-tolerated and provided superior overall and disease-specific survival compared with cisplatin/irinotecan chemoradiotherapy in the present study population. Further investigation is warranted.

Factors associated with severe acute esophagitis from hyperfractionated radiotherapy with concurrent chemotherapy for limited-stage small-cell lung cancer.

PURPOSE To describe incidence and identify factors associated with development of severe acute esophagitis during hyperfractionated radiotherapy with concurrent chemotherapy (BID-CRT) in patients with limited-stage small-cell lung cancer (SCLC). METHODS AND MATERIALS Retrospective cohort analysis of patient-, tumor-, and treatment-related variables was performed to identify factors associated with Radiation Therapy Oncology Group (RTOG) Grade 3 acute esophagitis. Twice-daily chemoradiotherapy (BID-CRT) involved 45 Gy at 1.5 Gy per fraction, treated twice daily with concurrent platinum-based chemotherapy. Logistic regression analyses were used to identify factors associated with esophagitis. RESULTS Between June 1999 and June 2007, 48 patients underwent curative intent BID-CRT for SCLC and were included in the analysis. Median radiotherapy dose was 45 Gy (range, 42-51 Gy) delivered with a median 4 cycles of chemotherapy (range, 2-6). RTOG Grade 3 acute esophagitis developed in 11 patients. No patient developed Grade 4 or 5 esophagitis. Simple logistic regression analyses demonstrated a highly significant association between Grade 3 acute esophagitis and mean esophageal dose (p = 0.002) as well as relative volume dosimetric area under curve (RV-AUC; p = 0.004). Using multiple regression analysis, RV-AUC was identified as the only factor associated with Grade 3 esophagitis (p = 0.004). The most strongly associated dosimetric volume was the V15 (Grade 3 esophagitis rates of 15% vs. 64% for V15 <60% versus >or=60%, respectively). CONCLUSIONS RV-AUC is the factor most associated with development of Grade 3 acute esophagitis in limited stage SCLC patients receiving BID-CRT.

Influence of celiac axis lymph nodes in the definitive treatment of esophageal cancer.

The management of patients with cancer of the distal thoracic esophagus is often made difficult by the presence of disease in the celiac axis lymph nodes. We investigated the outcome of such patients treated for cure in an attempt to better define the best treatment. The charts of all patients with esophageal cancer treated at the Department of Radiation Oncology at the Medical University of South Carolina between 1990 and 1998 were reviewed. Three groups of patients were analyzed: NoMo, N1Mo, and patients with positive celiac axis lymph nodes (M1a). Among 217 patients, 56 patients received radiotherapy with intent to cure, along with surgery, chemotherapy, or some combination of these modalities. Of these, 14 had disease of the distal esophagus with the celiac axis as their only site of distant disease. Comparison of survival curves in the three analyzed groups revealed no statistically significant differences in terms of overall survival (p = 0.3458 by the log-rank test) or disease-free survival (p = 0.5509 by the log-rank test). Patients with positive celiac axis lymph nodes as their only site of “M1” disease experienced a 2-year survival rate similar to “Mo” patients when treated with curative intent.

Once-daily radiotherapy to ≥59.4 Gy versus twice-daily radiotherapy to ≥45.0 Gy with concurrent chemotherapy for limited-stage small-cell lung cancer: a comparative analysis of toxicities and outcomes

PurposeThe aim of this study was to compare toxicities, disease control, survival outcomes, and patterns of failure between groups of limited-stage small-cell lung cancer patients treated with once-daily versus twice-daily radiotherapy and concurrent chemotherapy.Materials and methodsThis single-institution retrospective analysis included a comparison of two of radiotherapy regimens to planned doses of (1) ≥59.4 Gy at 1.8–2.0 Gy per once-daily fraction or (2) ≥45 Gy at 1.5 Gy per twice-daily fractions with concurrent platinum-based chemotherapy. Comparative analyses of toxicities and disease control were performed.ResultsA total of 71 patients were included in the present study (17 once-daily, 54 twice-daily). Patient, tumor, staging, and treatment factors were similar between the two treatment groups. Median planned radiotherapy doses were 60 Gy (range 59.4–70.0 Gy) and 45 Gy (range 45–51 Gy) for the once-daily and twice-daily groups, respectively. Acute toxicities were similar between the groups (∼20% grade 3 esophagitis). At a median survival follow-up of 26.2 months (range 3.4–85.5 months), 42 patients had died. The 2-year overall survival estimates were similar at 43% and 49% for the once-daily versus twice-daily groups, respectively. Isolated in-field failures were similar between the two groups (∼17%).ConclusionThe present analysis did not detect a statistically significant difference in acute toxicities, disease control, or survival outcomes in limited-stage small-cell lung cancer patients treated with concurrent chemotherapy and once-daily versus twice-daily radiotherapy.

Involved-field radiotherapy with concurrent chemotherapy for limited-stage small-cell lung cancer: Disease control, patterns of failure and survival

Introduction: Major randomised trials have employed elective nodal irradiation as part of combined modality therapy for limited‐stage small‐cell lung cancer (SCLC). The present investigation describes patterns of failure, disease control, and survival outcomes for involved‐field radiotherapy with concurrent chemotherapy, without elective irradiation of uninvolved mediastinal nodal regions.

Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial

BackgroundCOX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-κB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors.MethodsPatients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily.ResultsNo dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease.ConclusionThe combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated.Trial registration numberNCT00290680.

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

BACKGROUND Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.