Thomas J. Lynch

Ipilimumab in Combination With Paclitaxel and Carboplatin As First-Line Treatment in Stage IIIB/IV Non–Small-Cell Lung Cancer: Results From a Randomized, Double-Blind, Multicenter Phase II Study

PURPOSE Ipilimumab, which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin. PATIENTS AND METHODS Patients (N = 204) with chemotherapy-naive non-small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m(2)) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≤ 18 weeks (induction). Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Response was assessed by using immune-related response criteria and modified WHO criteria. The primary end point was immune-related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), overall survival (OS), and safety. RESULTS The study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity. CONCLUSION Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC.

Cetuximab and First-Line Taxane/Carboplatin Chemotherapy in Advanced Non–Small-Cell Lung Cancer: Results of the Randomized Multicenter Phase III Trial BMS099

PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This multicenter, open-label, phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC, without restrictions by histology or epidermal growth factor receptor expression. Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel (225 mg/m(2)) or docetaxel (75 mg/m(2)), at the investigators discretion, and carboplatin (area under the curve = 6) on day 1 every 3 weeks for < or = six cycles; cetuximab (400 mg/m(2) on day 1, 250 mg/m(2) weekly) was administered until progression or unacceptable toxicity. The primary end point was progression-free survival assessed by independent radiologic review committee (PFS-IRRC); overall response rate (ORR), overall survival (OS), quality of life (QoL), and safety were key secondary end points. PFS and ORR assessed by investigators were also evaluated. Results Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC (hazard ratio [HR] = 0.902; 95% CI, 0.761 to 1.069; P = .236). Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC (HR = 0.890; 95% CI, 0.754 to 1.051; P = .169). ORR-IRRC was 25.7% with cetuximab/TC versus 17.2% with TC (P = .007). The safety profile of this combination was manageable and consistent with its individual components. CONCLUSION The addition of cetuximab to TC did not significantly improve the primary end point, PFS-IRRC. There was significant improvement in ORR by IRRC. The difference in OS favored cetuximab but did not reach statistical significance.

Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial

BACKGROUND Ipilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab+paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC). DESIGN Patients (n=130) with chemotherapy-naïve ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m2)/carboplatin (area under the curve=6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab+paclitaxel/carboplatin followed by placebo+paclitaxel/carboplatin) or phased ipilimumab (placebo+paclitaxel/carboplatin followed by ipilimumab+paclitaxel/carboplatin). Treatment was administered every 3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR, overall survival (OS), and safety. RESULTS Phased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio)=0.64; P=0.03]. No improvement in PFS (HR=0.93; P=0.37) or OS (HR=0.75; P=0.13) occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively. CONCLUSION These results suggest further investigation of ipilimumab in ED-SCLC.

Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice

BACKGROUND Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and β-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

A Phase I Study of Erlotinib and Hydroxychloroquine in Advanced Non–Small-Cell Lung Cancer

Introduction: This investigator-initiated study explores the safety, maximum tolerated dose, clinical response, and pharmacokinetics of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non–small-cell lung cancer. Methods: Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3 + 3 dose-escalation schema. Results: Twenty-seven patients were treated, eight with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of the patients and 85% had received two or more prior therapies. Arm A had no dose-limiting toxicities, but the maximum tolerated dose was not reached as this arm closed early to increase overall study accrual. In arm B, one patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia; one had grade 4 anemia; and one developed fatal pneumonitis, all considered unrelated to HCQ. There were no dose-limiting toxicities, therefore the highest tested dose for HCQ with erlotinib 150 mg was 1000 mg daily. One patient had a partial response to erlotinib/HCQ, for an overall response rate of 5% (95% confidence interval, 1–25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the pharmacokinetics of erlotinib. Conclusions: HCQ with or without erlotinib was safe and well tolerated. The recommended phase 2 dose of HCQ was 1000 mg when given in combination with erlotinib 150 mg.

Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer

Significance A better mechanistic understanding of the survival benefits and identification of biomarkers of response would greatly enhance the optimal utilization of antiangiogenic agents such as bevacizumab in combination with chemotherapy in the treatment of cancer. This study indicates that the benefits of bevacizumab with chemotherapy in non–small cell lung cancer (NSCLC) patients may depend on tumor vascular function during treatment. These correlative studies also provide new insights into the selection of NSCLC patients most likely to benefit from the addition of bevacizumab treatment to chemotherapy. The imaging and circulating biomarker candidates should be further evaluated in larger studies. Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non–small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment—while reducing blood flow, volume, and permeability in the overall population—may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy.

Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer.

Introduction: AT-101 is an oral, pan Bcl-2 family protein inhibitor that has demonstrated activity in small cell lung cancer (SCLC) models. A phase I/II study was conducted combining AT-101 with topotecan in relapsed and refractory SCLC. Methods: An open-labeled multicenter phase I/II study was conducted of oral AT-101 with intravenous topotecan in patients with SCLC who had progressed on prior platinum-containing chemotherapy. The phase II portion was a two-stage design, and two cohorts of patients, sensitive relapsed and refractory, were analyzed. Primary endpoint in the two-stage phase II portion was response rate; secondary endpoints were duration of response and time to progression. Results: Thirty-six patients were enrolled. The most common toxicities were hematologic, as would be expected with topotecan and AT-101. The recommended phase II dose was 40 mg AT-101 days 1 to 5 with topotecan 1.25 mg/m2 days 1 to 5 on a 21-day cycle. In the sensitive-relapsed cohort (n = 18), there were 0 complete response (CR), three partial response (PR), 10 stable disease (SD), and four progressive disease (PD). In the refractory cohort (n = 12), there were 0 CR/PR, five SD, and five PD. The study did not meet its prespecified endpoints to continue enrollment in the second stage of the phase II study. Median time to progression in the sensitive-relapsed cohort was 17.4 weeks and 11.7 weeks in the refractory cohort. Conclusions: AT-101 can be safely combined with topotecan at a reduced dose of 1.25 mg/m2. The response rates observed did not meet the criteria for additional enrollment; however, many patients had a best response of SD and the median time to progression in both cohorts was favorable. Additional trials of AT-101 in SCLC are ongoing.

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

OBJECTIVES Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy. MATERIALS AND METHODS The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints. RESULTS The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p=0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p=0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p<0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint. CONCLUSION The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.

Cetuximab Monotherapy in Patients with Advanced Non-small Cell Lung Cancer After Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

Introduction: Therapeutic agents directed against the epidermal growth factor receptor (EGFR) signaling pathway have been effective in the treatment of non-small cell lung cancer (NSCLC). Cetuximab is a monoclonal antibody against the EGFR receptor with antitumor activity in NSCLC. This study evaluated the efficacy of cetuximab monotherapy after prior treatment with an oral EGFR tyrosine kinase inhibitor (TKI). Methods: Eligible patients had stage IIIB, IV, or recurrent NSCLC with progression on the oral EGFR TKIs gefitinib or erlotinib. Cetuximab was administered intravenously at 400 mg/m2 on day 1 and then 250 mg/m2 weekly until disease progression or unacceptable toxicity. The primary end point was response rate. Results: Eighteen patients were enrolled. Patients were heavily pretreated with chemotherapy and TKIs (average number of treatments = 4.2). The response rate was 0/18 (0%), and 28% of patients had confirmed stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.6–5.4 months), and median overall survival was 7.5 months (95% confidence interval, 2.2–19 months). Three patients harbored activating EGFR mutations, and one of them had stable disease for nearly 6 months on cetuximab. Common toxicities were mild and included fatigue, skin rash, and nausea/vomiting. Two patients developed interstitial lung disease, life threatening in one case. Conclusions: Cetuximab monotherapy administered after prior EGFR TKI treatment in patients with advanced NSCLC does not yield clinical responses.

Safety and effectiveness of bevacizumab-containing treatment for non-small-cell lung cancer: final results of the ARIES observational cohort study.

Introduction: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor, was approved by the US Food and Drug Administration for the treatment of advanced non–small-cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. ARIES (Avastin Regimens: Investigation of Effectiveness and Safety), a prospective observational cohort study, evaluated outcomes in a large, community-based population of patients with first-line NSCLC. Methods: From 2006 to 2009, ARIES enrolled patients with locally advanced or metastatic NSCLC who were eligible for bevacizumab, excluding those with predominantly squamous histology. Patients were required to provide informed consent and to have initiated bevacizumab with chemotherapy within 4 months before enrollment. There were no protocol-defined treatments or assessments. The dosing of bevacizumab and chemotherapy, and the choice of chemotherapy regimen, was at the discretion of the treating physician. Results: ARIES enrolled 1967 patients with first-line NSCLC. At study closure, median follow-up was 12.5 months (range, 0.2–65.5). Median age was 65 years (range, 31–93), and 252 patients (12.8%) identified as never smokers. Median progression-free survival was 6.6 months (95% confidence interval, 6.3–6.9), and median overall survival was 13.0 months (95% confidence interval, 12.2–13.8) with first-line bevacizumab plus chemotherapy. Incidences of bevacizumab-associated adverse events (19.7% overall) were consistent with those in randomized controlled trials of bevacizumab in NSCLC. Conclusion: Results from ARIES demonstrate similar outcomes to randomized controlled trials of bevacizumab when added to standard chemotherapy in a real-world patient population with advanced NSCLC.