Comparison of Patient Outcomes According to Histology Among Pemetrexed-Treated Patients With Stage IIIB/IV Non–Small-Cell Lung Cancer in Two Phase II Trials

IntroductionRecent phase III studies in advanced non–small-cell lung cancer (NSCLC) have demonstrated differential efficacy for pemetrexed according to NSCLC histology. The results of 2 phase II studies of pemetrexed and a platinum agent (carboplatin or oxaliplatin) were pooled to determine whether outcomes in the studies differed by tumor histology.Patients and MethodsChemotherapy-naive patients with stage IIIB/IV NSCLC received pemetrexed 500 mg/m² plus carboplatin area under the curve of 6 (n = 89) or pemetrexed 500 mg/m² plus oxaliplatin 120 mg/m² (n = 41); both regimens were administered every 21 days. The primary endpoint of both trials was response rate. Treatment arms were pooled, and Cox models with main effects for squamous histology were used to assess overall survival and progression-free survival. Cofactor adjustments incorporated terms for performance status, disease stage, and sex.ResultsMore than three quarters of enrolled patients had a nonsquamous histology. Mean age was 59.9 years for patients with nonsquamous histology and 63.7 years for patients with squamous histology. Response rates were 30% for patients with nonsquamous histology and 17.2% for patients with squamous histology. Overall survival was 10.5 months for patients with nonsquamous histology and 9.8 months for patients with squamous histology (hazard ratio [HR], 0.95; 95% CI, 0.52-1.74). Progression-free survival was 5.6 months for patients with nonsquamous histology and 4.7 months for patients with squamous histology (HR, 0.72; 95% CI, 0.43-1.19).ConclusionIn patients treated with pemetrexed/platinum doublets, nonsquamous histology was associated with better outcomes. The benefit of pemetrexed treatment among patients with nonsquamous histology is consistent with the results reported from previous studies.     

A Multicenter Phase II Trial of Axitinib in Patients With Recurrent or Metastatic Non–clear-cell Renal Cell Carcinoma Who Had Failed Prior Treatment With Temsirolimus

Background

The optimal treatment option for non–clear-cell renal cell carcinoma (nccRCC) is not established. We conducted a multicenter phase II trial of axitinib for patients with advanced nccRCC who had failed prior treatment with temsirolimus.

FIR: Efficacy,Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1–Selected Patients With NSCLC

Introduction

The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti–programmed death-ligand 1 (PD-L1) atezolizumab in advanced NSCLC selected by tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression.

A Multicenter Randomized Phase IIb Efficacy Study of Vx-001, a Peptide-Based Cancer Vaccine as Maintenance Treatment in Advanced Non–Small-Cell Lung Cancer: Treatment Rationale and Protocol Dynamics

We present the treatment rationale and study design of a multicenter, open-label, randomized, 2-arm, phase IIb study. Patients with stage IV or recurrent stage I to III non–small-cell lung cancer (NSCLC) whose disease does not progress after 4 cycles of first-line platinum-based chemotherapy will be randomized in a 1:1 ratio to 1 of 2 study arms. Patients will receive the cancer vaccine Vx-001 + Montanide ISA51 VG (Seppic, Paris, France) adjuvant subcutaneously, at a dose of 2 mg, or placebo + Montanide ISA51 VG adjuvant subcutaneously. The vaccination protocol comprises 2 injections with the TYR-Vx001 or placebo (1 at day 0 and another at week 3) and 4 injections with the ARG-Vx001 or placebo, at weeks 6, 9, 12, and 15. After the treatment assessment at week 18, patients will receive the ARG-Vx001 or placebo every 12 weeks starting from week 27 until disease progression, unacceptable toxicity, withdrawal of informed consent, or death. The primary end point of this study is the survival rate at 12 months. Secondary end points include time-to-event comparison of overall survival and comparison of time to treatment failure. Exploratory objectives include comparison of disease control rate after the end of subsequent second-line treatments, comparisons of vaccine immune responses, comparison of survival rate at 12 months in patients with vaccine-induced immune response detected after the second and sixth injections, identification of biomarkers on lymphocytes and on tumors, and comparison of safety and tolerability.     

Perioperative Systemic Chemotherapy,Cytoreductive Surgery,and Hyperthermic Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: Results of the Prospective Multicenter Phase 2 COMBATAC Trial

Background

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as parts of an interdisciplinary treatment concept including systemic chemotherapy can improve survival of selected patients with peritoneal metastatic colorectal cancer (pmCRC). Nevertheless, the sequence of the therapeutic options is still a matter of debate. Thus, the COMBATAC (COMBined Anticancer Treatment of Advanced Colorectal cancer) trial was conducted to evaluate a combined treatment regimen consisting of preoperative systemic polychemotherapy + cetuximab followed by CRS + HIPEC and postoperative systemic polychemotherapy + cetuximab.

Phase I/II and Pharmacokinetic Study of Intravenous Vinflunine in Combination With Cisplatin for the Treatment of Chemonaive Patients With Advanced Non–Small-Cell Lung Cancer

BackgroundA multicenter phase I/II trial of vinflunine administered in combination with cisplatin at 80 mg/m² was conducted in order to determine the dose-limiting toxicities, the maximum tolerated dose, and the recommended dose of the combination. An eventual mutual pharmacokinetic drug-drug interaction when vinflunine and cisplatin were coadministered was also evaluated. The study was also intended to define the response rate of vinflunine in combination with cisplatin as first-line chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC) at the recommended dose.Patients and MethodsPatients were required to have a histologically confirmed diagnosis of NSCLC not amenable to curable treatment or stage IV disease. Patients may have had previous surgery for NSCLC but were to be chemonaive and have at least 1 bidimensional measurable lesion outside an irradiated area.ResultsThe recommended dose was established at cisplatin 80 mg/m² combined with vinflunine 320 mg/m². No unexpected adverse events were seen. Pharmacokinetic analysis supported the absence of mutual pharmacokinetic interaction when vinflunine and cisplatin are given in combination. Treatment of 53 patients at this recommended dose demonstrated a tumor response rate of 32.1% in the intent-to-treat population; disease control was achieved in 79.2% of the patients. The median progression-free survival and overall survival were estimated at 5 months and 10.4 months, respectively, and the 1-year survival rate was 43.4%.ConclusionThese results place the vinflunine/cisplatin combination among the most active doublets in this treatment setting and warrant further development in phase III trials of first-line treatment of patients with advanced metastatic NSCLC.     

Clinical Significance of Increased FDG Uptake in the Waldeyer Ring and the Nasopharynx Region Identified by PET-CT in Postchemotherapy Follow-up in Patients With Lymphoma: When Should We Perform Biopsy?

PurposeTo identify whether fluorodeoxyglucose (FDG) uptake in the Waldeyer ring (WR)/nasopharyngeal (NP) region by positron emission tomography–computed tomography (PET-CT) was physiologic or pathologic in the follow-up of lymphoma patients receiving postchemotherapy treatment.Patients and MethodsWe retrospectively examined FDG uptake in the WR/NP region in 534 patients with lymphoma as assessed by PET-CT used for both diagnosis and follow-up.ResultsForty-nine patients had FDG uptake in the WR/NP region by PET-CT performed after completion of a chemotherapy regimen. Biopsy was performed for 11 of these patients in whom the uptake was considered to be pathologic, and results indicated the presence of reactive follicular hyperplasia. It was considered to be physiologic in 38 patients. PET-CT was repeated after 1 year, and no significant difference was identified between the standardized maximum uptake values (SUV_max; P = .107). The initial diagnosis of 20 patients was made via biopsy performed in the WR/NP region. The SUV_max for the FDG uptake in these patients, asymmetry, SUV_max of the coexisting lymphadenopathies in the neck, and FDG uptake with a counterpart finding by CT were significantly higher than other groups (P = .047, .001, and .005).ConclusionWhen deciding whether to resample after treatment completion, it should be taken into account that, in addition to the SUV_max of the lesion, asymmetry, and the SUV_max of the coexisting lymphadenopathy in the neck, a crucial criterion is whether the FDG uptake has a counterpart finding by CT.     

Rationale and Design of MILES-3 and MILES-4 Studies: Two Randomized Phase 3 Trials Comparing Single-Agent Chemotherapy Versus Cisplatin-Based Doublets in Elderly Patients With Advanced Non–Small-Cell Lung Cancer

BackgroundPlatinum-based chemotherapy is the cornerstone of treatment of advanced non-small-cell lung cancer (NSCLC) patients, but the efficacy of adding cisplatin to single-agent chemotherapy remains to be demonstrated in prospective phase III trials dedicated to elderly patients. Furthermore, the superiority of cisplatin/pemetrexed over cisplatin/gemcitabine in non-squamous NSCLC has not been confirmed prospectively. We present the rationale and design of two open-label, multicenter, randomized phase III trials for elderly patients with advanced NSCLC∶ Multicenter Italian Lung cancer in the Elderly Study (MILES)-3 and MILES-4. The aim is to evaluate the efficacy of adding cisplatin to single-agent chemotherapy (both trials) and the efficacy of pemetrexed versus gemcitabine in non-squamous tumors (MILES-4).Patients and MethodsBoth trials are dedicated to first-line therapy of patients older than 70 years with advanced NSCLC, ECOG performance status 0-1. In the MILES-3 trial, patients are randomized in a 1∶1 ratio to gemcitabine or cisplatin/gemcitabine. In the MILES-4 study patients with non-squamous histology are randomized, in a factorial design with 1∶1∶1∶1 ratio, to four arms: gemcitabine (A), cisplatin/gemcitabine (B), pemetrexed (C), cisplatin/pemetrexed (D). Two comparisons are planned∶ A+C vs B+D to test the role of cisplatin; A+B vs C+D to test the role of pemetrexed. Primary endpoint of both trials is overall survival. Secondary and exploratory endpoints include progression-free survival, response rate, toxicity, and quality of life.ConclusionsMILES-3 and MILES-4 results will add important evidence about the role of cisplatin-based doublets and pemetrexed in the first-line therapy of elderly patients with advanced NSCLC.     

Bevacizumab in Combination With Either FOLFOX-4 or XELOX-2 in First-line Treatment of Patients With Metastatic Colorectal Cancer: A Multicenter Randomized Phase II Trial of the Gruppo Oncologico dell’Italia Meridionale (GOIM 2802)

IntroductionBiweekly schedule of XELOX-2 (capecitabine plus oxaliplatin) showed interesting results in first-line therapy of patients with metastatic colorectal cancer (mCRC). Bevacizumab plus FOLFOX-4 (oxaliplatin, folinic acid, and infusional 5-fluorouracil) is among standard first-line treatment options in this setting. We performed a phase II randomized trial in order to evaluate the activity of bevacizumab plus either FOLFOX-4 or XELOX-2 in first-line therapy of patients with mCRC.Materials and MethodsPatients with mCRC were randomized, in a 1:2 ratio, to first-line bevacizumab plus either FOLFOX-4 (Arm A), as calibration arm, or XELOX-2 (Arm B), up to 12 cycles. Patients without progression were further randomized to maintenance bevacizumab alone or with the same induction fluoropyrimidine. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival, overall survival, and toxicity. The study design was formally non-comparative, but exploratory comparison was performed.ResultsForty-five patients were randomized in arm A and 87 in arm B with an ORR of 55.6% versus 48.3% (P = .43), respectively. After a median follow-up of 47.2 months, progression-free survival was 10.0 versus 9.9 months (hazard ratio, 0.96; 95% confidence interval, 0.65-1.41; P = .84) and overall survival was 29.8 versus 25.0 months (hazard ratio, 1.21; 95% confidence interval, 0.77-1.92; P = .41), respectively. The main grade 3 to 4 toxicities (% A/B) were: neutropenia 15/3 and nausea 9/5.ConclusionThis exploratory analysis showed that biweekly XELOX-2 plus bevacizumab has a comparable ORR with FOLFOX-4 plus bevacizumab in patients with mCRC.     

Association of Circulating Tumor Cells and Tumor Molecular Profile With Clinical Outcomes in Patients With Previously Untreated Metastatic Colorectal Cancer: A Pooled Analysis of the Phase III VISNÚ-1 and Phase II VISNÚ-2 Randomized Trials

BackgroundThe bCTC count is a well-established prognostic biomarker in mCRC, as well as in other tumor types. The aim of this analysis was to evaluate the prognostic/predictive role of the bCTC count (≥3 vs. <3) in previously untreated mCRC.Patients and MethodsThe study involved 589 untreated mCRC patients included in the intention-to-treat population of 2 randomized clinical trials (phase III VISNU-1 [NCT01640405] and phase II VISNU-2 [NCT01640444] studies).ResultsOf the 589 patients, 349 (59.2%) had bCTC≥3 and 240 (40.7%) had bCTC<3. Multivariate analysis showed that the bCTC count is an independent prognostic factor for overall survival (OS) (HR 0.59, 95% CI 0.48-0.72; P = 0.000) and potential for progression-free survival (PFS) (P = 0.0549). Median OS was 32.9 and 19.5 months in patients with bCTC<3 and bCTC≥3 (P <0.001), respectively. This effect was also observed comparing OS in RASwt patients from both studies. Other prognostic factors were: ECOG-PS, primary tumor site, number of metastatic sites and surgery of the primary tumor. Median OS was lower for patients treated with anti-VEGF versus anti-EGFR (22.3 vs. 33.3 months, P <0.0001) while there were no significant differences in PFS according to the targeted treatment received.ConclusionThis post-hoc analysis of 2 randomized studies confirms the poor prognosis of patients with bCTC≥3 but this is not associated with other adverse independent prognostic factors such as RAS/BRAF mutations.     

An Open-Label,Multicenter, Randomized,Phase II Study of Cisplatin and Pemetrexed With or Without Cixutumumab (IMC-A12) as a First-Line Therapy in Patients With Advanced Nonsquamous Non–Small Cell Lung Cancer

IntroductionType 1 insulin-like growth factor receptor is deregulated in solid tumors. Cixutumumab, a monoclonal antibody that inhibits the activity of type 1 insulin-like growth factor receptor, was investigated in combination with pemetrexed/cisplatin in the frontline setting.MethodsIn this open-label, phase II study, patients with stage IV nonsquamous NSCLC and a performance status of 0 to 1 were randomized (1:1) to receive 20 mg/kg cixutumumab, 500 mg/m² pemetrexed, and 75 mg/m² cisplatin (cixutumumab [n = 87]) or pemetrexed and cisplatin (control [n = 85]). Eligible patients received pemetrexed-based maintenance therapy with cixutumumab (cixutumumab arm) or without it (control arm). The primary end point was progression-free survival. Secondary end points assessed overall survival, objective response rate, and safety. Survival was analyzed by the Kaplan-Meier method and Cox proportional hazard model. Exploratory correlative analyses were also performed.ResultsThe mean age of the intent-to-treat population (n = 172) was 59 years (range 32–83). Median progression-free survival was 5.45 months with cixutumumab versus 5.22 months in the control (hazard ratio = 1.15, 95% confidence interval: 0.81–1.61; p = 0.44). Median overall survival was 11.33 months with cixutumumab versus 10.38 months in the control (hazard ratio = 0.93, 95% confidence interval: 0.64–1.36). Objective response rate did not differ between treatments (p = 0.338). Grade 3 or 4 hyperglycemia occurred at a higher rate with cixutumumab than in the control (9.4% versus 1.2%). One death possibly related to cixutumumab occurred.ConclusionsEfficacy was not improved in patients with nonsquamous NSCLC when cixutumumab was added to pemetrexed/cisplatin. Combination therapy was well tolerated and no new safety concerns were reported.