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Background: Overall response rate is frequently used as an end point in phase 2 trials of platinum-treated extensive stage (ES) small-cell lung cancer (SCLC). We hypothesized that disease control rate (DCR) would be a superior surrogate for subsequent survival outcomes., Methods: Updated patient-level data from Southwest Oncology Group (SWOG) trials in second- and/or third-line ES-SCLC patients were pooled. Landmark analysis was performed among patients alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors with DCR was assessed using logistic regression. A Cox proportional hazard model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors., Results: Of the 319 ES-SCLC patients, 263 were alive at the 8-week landmark and constituted the pooled study population. Only 8 patients had a response. Disease control at 8 weeks was seen in 98 patients. Bivariate analysis of OS from the 8-week landmark revealed that DCR (hazard ratio [HR], 0.47; P < .0001) and elevated lactate dehydrogenase (HR, 1.70; P = .0004) were significantly associated with OS. In multivariable analysis, DCR remained an independent predictor of subsequent survival from the 8-week landmark (HR, 0.50; P < .0001)., Conclusion: In this large second- and third-line ES-SCLC database, DCR at 8 weeks was found to be a significant predictor of subsequent survival in patients receiving investigational therapy. These results have critical implications in the selection of surrogate end points in future prospective ES-SCLC trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Preclinical modeling in non-small cell lung cancer (NSCLC) showed that stimulation with hepatocyte growth factor (HGF), the ligand for MET, could reverse the cytostatic and cytotoxic effects of the EGFR inhibitor erlotinib in erlotinib-sensitive cell lines. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring erlotinib activity. We conducted a phase II trial of erlotinib plus MK-2206, a highly selective inhibitor of AKT, in NSCLC patients., Experimental Design: Eligible patients must have progressed following prior benefit from erlotinib, defined as response or stable disease > 12 weeks. Treatment consisted of erlotinib 150 mg orally every day + MK-2206 45 mg orally every alternate day on a 28-day cycle. Primary endpoints were RECIST response rate > 30% (stratum 1: EGFR mutant) and disease control rate (DCR) > 20% at 12 weeks (stratum 2: EGFR wild-type)., Results: Eighty patients were enrolled, 45 and 35 in stratum 1 and 2, respectively. Most common attributable adverse events (all grade 3) were rash, diarrhea, fatigue, and mucositis. Response and DCR were, respectively, 9% and 40% in stratum 1; 3% and 47% in stratum 2. Median progression-free survival was 4.4 months in stratum 1 and 4.6 months in stratum 2., Conclusions: Combination MK-2206 and erlotinib met its primary endpoint in erlotinib-pretreated patients with EGFR wild-type NSCLC. Although activity was seen in EGFR-mutated NSCLC, this did not exceed a priori estimates. AKT pathway inhibition merits further clinical evaluation in EGFR wild-type NSCLC., (©2015 American Association for Cancer Research.)

Background: Combination blockade of human epidermal growth factor receptor (HER) family signaling may confer enhanced antitumor activity than single-agent blockade. We performed a single-arm study of pertuzumab, a monoclonal antibody that inhibits HER2 dimerization, and erlotinib in relapsed non-small cell lung cancer (NSCLC)., Methods: Patients received pertuzumab (840-mg loading dose and 420-mg maintenance intravenously every 3 weeks) and erlotinib (150-mg or 100-mg dose orally, daily). The primary endpoint was response rate (RR) by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) at day 56 in all patients and those with EGFR wild-type tumors., Results: Of 41 patients, 28 (68.3%) experienced treatment-related grade ≥3 adverse events, including pneumatosis intestinalis (3 patients), resulting in early cessation of enrollment. Tissue samples from 32 patients showed mutated EGFR status in 9 of 41 (22%) and wild-type EGFR in 23 of 41 (56%). The FDG-PET RR for patients with assessments at day 56 was 19.5% in all patients (n = 41) and 8.7% in patients with wild-type EGFR NSCLC (n = 23). Investigator-assessed computed tomography RR at day 56 was 12.2%., Conclusion: FDG-PET suggests that pertuzumab plus erlotinib is an active combination, but combination therapy was poorly tolerated, which limits its clinical applicability. More research is warranted to identify drug combinations that disrupt HER receptor signaling but that exhibit improved tolerability profiles.

Background: Anaplastic thyroid cancer (ATC), a rare highly vascularized tumor, has a dismal outcome. We conducted an open-label study of doublet carboplatin/paclitaxel chemotherapy with or without fosbretabulin in patients with ATC., Methods: Patients were randomly assigned in a 2:1 ratio to 6 cycles of paclitaxel 200 mg/m(2) followed by carboplatin AUC 6 on day 1 every 3 weeks (CP), or these drugs were given on day 2 after fosbretabulin 60 mg/m(2) (CP/fosbretabulin) on days 1, 8 and 15. After 6 cycles, patients on the fosbretabulin arm without progression could continue to receive fosbretabulin on days 1 and 8 of a 3-week schedule until progression. The primary end point was overall survival (OS)., Results: Eighty patients were assigned (planned, 180) when enrollment was stopped due to rarity of disease and very low accrual. Median OS was 5.2 months [95% confidence interval (CI) 3.1, 9.0] for the CP/fosbretabulin arm (n=55; hazard ratio 0.73 [95% CI 0.44, 1.21]) and 4.0 months [95% CI 2.8, 6.2] for the CP arm (n=25; p=0.22 [log rank test]). One-year survival for CP/fosbretabulin versus CP was 26% versus 9%, respectively. There was no significant difference in progression-free survival between the two arms. Grade 1-2 hypertension and grade 3-4 neutropenia were more common with CP/fosbretabulin. There were no significant adverse cardiovascular side effects., Conclusions: Although the study did not meet statistical significance in improvement in OS with the addition of fosbretabulin to carboplatin/paclitaxel, it represents the largest prospective randomized trial ever conducted in ATC. The regimen is well tolerated, with AEs and deaths primarily related to ATC and disease progression.

Background: Chemotherapy in combination with small-molecule epidermal growth factor receptor inhibitors has yielded inconsistent results. Based on preclinical models, we conducted a phase I trial of two schedules of lapatinib and vinorelbine., Patient and Methods: Patients had advanced solid tumors and up to two prior chemotherapeutic regimens. Patients were enrolled on two dose-escalating schedules of lapatinib, continuous (arm A) or intermittent (arm B), with vinorelbine on days 1, 8, and 15 of a 28-day cycle. Tumors from a subset of patients were evaluated for gene mutations and expression of targets of interest., Results: Fifty-one patients were treated. The most common grade 3/4 toxic effects included leukopenia, neutropenia, and fatigue. Dose-limiting toxic effects were grade 3 infection, febrile neutropenia, and diarrhea (arm A) and bone pain and fatigue (arm B). The maximum tolerated dose was vinorelbine 20 mg/m(2) weekly and lapatinib 1500 mg daily (arm A) and vinorelbine 25 mg/m(2) weekly and lapatinib 1500 mg intermittently (arm B). One patient on each arm had a complete response; both had human epidermal growth factor receptor 2-positive breast cancer. In a subset of patients, lack of tumor PTEN expression correlated with a shorter time to progression., Conclusion: In an unselected population, two schedules of lapatinib and vinorelbine were feasible and well tolerated.

Purpose: Clusterin (CLU), an antiapoptotic, stress-associated protein, confers resistance to therapy when overexpressed. This trial tested custirsen (OGX-011), an inhibitor of CLU protein production, combined with gemcitabine/platinum in patients with advanced non-small cell lung cancer (NSCLC)., Patients and Methods: This was a single-arm, multicenter, phase I/II study in chemotherapy-naive stage IIIB/IV NSCLC. Custirsen was infused during a loading dose period and weekly in combination with gemcitabine (1250 mg/m) on days 1 and 8 and with cisplatin (75 mg/m) or carboplatin (area under the curve 5) on day 1 of each 21-day cycle. Ten patients were treated in a phase I lead-in and 71 in the phase II component. The primary efficacy endpoint was response rate, with exploratory analyses of other efficacy outcomes and biomarker relationships., Results: Eighty-one patients received custirsen and were included in the primary analysis. The median age was 61 years; 82% had stage IV disease. Overall response was 25 of 81 (31%; 95% confidence interval 21-42). The 1- and 2-year survivals were 54 and 30%, respectively. Toxicity of the combination was not appreciably different from what is reported for gemcitabine/platinum combinations. Custirsen treatment decreased serum CLU levels in 95% of patients evaluated. Patients who achieved a minimum median CLU level for the population of ≤38 μg/ml during treatment had a median survival of 27.1 compared with 16.1 months for patients who did not (p = 0.02)., Conclusion: Based on the above results, a randomized phase 3 trial to evaluate the survival benefit of custirsen in patients with NSCLC is warranted.

Background: Apricoxib, a novel once-daily selective cyclooxygenase-2 inhibitor, was investigated in combination with erlotinib for recurrent stage IIIB/IV nonsmall cell lung cancer to determine the maximum tolerated dose, dose-limiting toxicity, and recommended phase II dose (RP2D) based on changes in urinary prostaglandin E₂ metabolite (PGE-M)., Methods: Patients received escalating doses of apricoxib (100, 200, and 400 mg/day) in combination with erlotinib 150 mg/day until disease progression or unacceptable toxicity. Urinary PGE-M was used to assess biologic activity and inform the optimal biologic dose., Results: Twenty patients were treated (3 at 100 mg; 3 at 200 mg; 14 at 400 mg apricoxib) with a median of 4 cycles (range, 2-14 cycles); 8 patients (40%) received prior EGFR-directed therapies. No dose-limiting toxicity was observed. Study drug-related adverse events (AEs) included diarrhea, rash, dry skin, anemia, fatigue, and increased serum creatinine; 4 patients had grade ≥ 3 drug-related AEs (diarrhea, perforated duodenal ulcer, hypophosphatemia, and deep vein thrombosis). The RP2D was 400 mg/day based on safety, biologic activity based on decreases in urinary PGE-M, and pharmacokinetics. One patient had a partial response, and 11 had stable disease. Stable disease was observed in patients who had received prior EGFR inhibitor therapy but was greater in patients not previously treated with an EGFR inhibitor. Seventeen patients had elevated urinary PGE-M at baseline, and 14 (70%) had a decrease from baseline, which was associated with disease control., Conclusions: Apricoxib plus erlotinib was well tolerated and yielded a 60% disease control rate. A phase II trial is currently investigating 400 mg/day apricoxib plus 150 mg/day erlotinib in patients selected based on change in urinary PGE-M., (Copyright © 2010 American Cancer Society.)

Background: The proteasome inhibitor bortezomib sensitizes tumor cells to chemotherapy-induced apoptosis. In preclinical non-small-cell lung cancer (NSCLC) models, p53-dependent growth arrest after bortezomib treatment resulted in reduced cytotoxicity if bortezomib preceded docetaxel. The reverse sequence of docetaxel before bortezomib was associated with increased apoptosis, cleavage of caspase-3 and PARP (poly [ADP-ribose] polymerase), and reduction in Bcl-2. A prospective randomized phase II trial of concurrent versus sequential docetaxel and bortezomib was conducted to assess whether administration sequence resulted in measurable clinical differences., Patients and Methods: Previously treated patients with advanced NSCLC were randomized to concurrent (CON) or sequential (SEQ) docetaxel (75 mg/m² intravenous [I.V.]) followed by bortezomib, every 3 weeks. In the CON arm, bortezomib (1.6 mg/m² I.V.) was given on days 1 and 8, and in the SEQ arm, it was given on days 2 and 8. Previous erlotinib as well as treated or controlled brain metastases were allowed. The primary endpoint was objective response rate (RR); progression-free (PFS) and overall survival (OS) were secondary endpoints., Results: Eighty-one patients were randomized (40 CON and 41 SEQ). Grade 3+ toxicities were mostly due to myelosuppression. One patient each had grade 4 hyponatremia and syncope. Toxicities were similar between the arms. There was 1 treatment-related death in the SEQ arm. There were 8 partial responders, 4 in each arm, for an overall RR of 10%. Disease control rate was similar in both arms (50% vs. 49%). Median PFS was 12 weeks in the CON arm and 11 weeks in the SEQ arm. Median OS times in the CON and SEQ arms were 13.3 and 10.5 months, respectively., Conclusion: Docetaxel plus bortezomib given sequentially or concurrently has similar RR and PFS. Median survival in the SEQ arm exceeds published survival estimates for either agent alone or in combination. Any further studies in this population would require molecular characterization of a phenotype most likely to benefit from proteasome inhibitor therapy.

PURPOSE Vorinostat, a histone deacetylase inhibitor, exerts anticancer effects by both histone and nonhistone-mediated mechanisms. It also enhances the anticancer effects of platinum compounds and taxanes in non-small-cell lung cancer (NSCLC) cell lines. This phase II randomized, double-blinded, placebo-controlled study evaluated the efficacy of vorinostat in combination with carboplatin and paclitaxel in patients with advanced-stage NSCLC. PATIENTS AND METHODS Patients with previously untreated stage IIIB (ie, wet) or IV NSCLC were randomly assigned (2:1) to carboplatin (area under the curve, 6 mg/mL x min) and paclitaxel (200 mg/m(2) day 3) with either vorinostat (400 mg by mouth daily) or placebo. Vorinostat or placebo was given on days 1 through 14 of each 3-week cycle to a maximum of six cycles. The primary end point was comparison of the response rate. Results Ninety-four patients initiated protocol therapy. Baseline patient characteristics were similar between the two arms. The median number of cycles was four for both treatment arms. The confirmed response rate was 34% with vorinostat versus 12.5% with placebo (P = .02). There was a trend toward improvement in median progression-free survival (6.0 months v 4.1 months; P = .48) and overall survival (13.0 months v 9.7 months; P = .17) in the vorinostat arm. Grade 4 platelet toxicity was more common with vorinostat (18% v 3%; P < .05). Nausea, emesis, fatigue, dehydration, and hyponatremia also were more frequent with vorinostat. CONCLUSION Vorinostat enhances the efficacy of carboplatin and paclitaxel in patients with advanced NSCLC. HDAC inhibition is a promising therapeutic strategy for treatment of NSCLC.