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Summary Background Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival. Methods We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab. Findings Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11–17) for all patients (n=664), 19% (15–24) for those with at least 1% PD-L1 expression, and 11% (7–16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11–18) in patients treated with nivolumab, compared with 5% (3–7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12–0·27) for nivolumab and 0·43 (0·29–0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37–0·71) for nivolumab and 0·80 (0·61–1·04) for docetaxel. Long-term data did not show any new safety signals. Interpretation Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage. Funding Bristol-Myers Squibb.

Background Cancer is a systemic catabolic condition affecting skeletal muscle and fat. We aimed to determine whether cardiac atrophy occurs in this condition and assess its association with cardiac function, symptoms, and clinical outcomes. Methods Treatment naïve metastatic non‐small cell lung cancer patients (n = 50) were assessed prior to and 4 months after commencement of carboplatin‐based palliative chemotherapy. Methods included echocardiography for left ventricular mass (LVM) and LV function [LV ejection fraction, global longitudinal strain (GLS), diastolic function], computed tomography to quantify skeletal muscle and total adipose tissue, Eastern Cooperative Oncology Group Performance Status (ECOG‐PS), validated questionnaires for dyspnoea and fatigue, plasma biomarkers, tumour response to therapy, and overall survival. Results During 112 ± 6 days, the median change in LVM was −8.9% [95% confidence interval (95% CI) −10.8 to −4.8, P < 0.001]. Quartiles of LVM loss were −20.1%, −12.9%, −4.8%, and +5.5%. Losses of muscle, adipose tissue, and LVM were frequently concurrent; LVM loss > median value was associated with loss of skeletal muscle [odds ratio (OR) = 4.5, 95% CI: 1.4–14.8, P=0.01] and loss of total adipose tissue (OR = 10.0, 95% CI: 2.7–36.7, P < 0.001). LVM loss was associated with decreased GLS (OR = 6.6, 95% CI: 1.9–22.7, P=0.003) but not with LV ejection fraction or diastolic function. In the population overall, plasma levels of C‐reactive protein (P=0.008), high sensitivity troponin T (hs‐TnT) (P=0.03), and galectin‐3 (P=0.02) increased over time, while N‐terminal pro B‐type natriuretic peptide and hs‐cTnI did not change over time. C‐reactive protein was the only biomarker associated with LVM loss but at the univariate level only. Independent predictors of LVM loss were prior weight loss (adjusted OR = 10.2, 95% CI: 2.2–46.9, P=0.003) and tumour progression (adjusted OR = 14.6, 95% CI: 1.4–153.9, P=0.02). LVM loss was associated with exacerbations of fatigue (OR = 6.6, 95% CI: 1.9–22.7, P=0.003), dyspnoea (OR = 9.3, 95% CI: 2.4–35.8, P

Nivolumab was the first immuno-oncology agent available for the treatment of lung cancer in Canada. In the present study, we evaluated the real-world benefit of nivolumab in Canadian patients with lung cancer. Patients included in the cohort were identified from a registry of patients treated through expanded access to nivolumab before and after Health Canada approval. Demographics were collected from the application forms. Outcome data for the duration of treatment and survival were collected retrospectively. In contrast to the randomized clinical trial populations, our study cohort included patients who were older (median age: 66 years, range: 36&ndash, 92 years) and who had an Eastern Cooperative Oncology Group performance status of 2 (8.9%). Despite the poorer-prognosis cohort, median overall survival was 12.0 months, which is comparable to the survival demonstrated in the randomized phase iii trials of nivolumab in lung cancer. Median time to treatment discontinuation was 3.45 months and was similar for all patient subgroups, including poorer-prognosis groups such as those with a performance status of 2, those 75 years of age and older, and those with brain metastases. Nivolumab given in a real-world clinical setting was associated with results similar to those reported in the phase iii clinical trial setting.

PURPOSE Immunotherapy has revolutionized the treatment of advanced non–small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials. METHODS Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated. RESULTS After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3–5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs. CONCLUSION At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.

Inhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update. Clinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive nsclc. Randomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-na&iuml, ve patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows: Multiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALK rearrangement.

Background Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years’ follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results After 40.3 months’ minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions After 3 years’ minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

Summary Background Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC. Methods We did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6–12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m 2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m 2 on days 1 and 8), docetaxel (75 mg/m 2 on day 1), gemcitabine (1200 mg/m 2 on days 1 and 8), or pemetrexed (500 mg/m 2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805. Findings Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9–68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82–1·19; p=0·90). Grade 3–5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3–5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment. Interpretation Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC. Funding National Cancer Institute of the National Institutes of Health.

// Lucia Kim 1,12,* , Mauro Saieg 1,13,* , Massimo Di Maio 2,14,* , Ciro Gallo 3,* , Charles Butts 4 , Fortunato Ciardiello 5 , Ronald Feld 6 , Dengxiao Cheng 6 , Vittorio Gebbia 7 , Marco Angelo Burgio 8 , Yasmin Alam 9 , Simona Signoriello 3 , Antonio Rossi 10 , Natasha Leighl 6 , Paolo Maione 10 , Alessandro Morabito 2 , Geoffrey Liu 6,** , Ming-Sound Tsao 1,** , Francesco Perrone 2,** and Cesare Gridelli 10,11,** 1 Department of Pathology, University Health Network, Princess Margaret Cancer Center and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada 2 National Cancer Institute, G. Pascale Foundation, IRCCS, Naples, Italy 3 Department of Mental Health and Preventive Medicine, Chair of Statistics, Second University of Naples, Naples, Italy 4 Medical Oncology, Cross Cancer Institute, Edmonton, Canada 5 Medical Oncology, Second University, Naples, Italy 6 Division of Hematology and Oncology, Princess Margaret Cancer Centre and Department of Medicine, University of Toronto, Toronto, Canada 7 Medical Oncology, Casa di Cura La Maddalena, Palermo, Italy 8 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy 9 Medical Oncology, Windsor Regional Cancer Centre, Windsor, Canada 10 Department of Oncology/Hematology, Division of Medical Oncology, “S.G. Moscati” Hospital, Avellino, Italy 11 On behalf of the TORCH Investigators 12 Department of Pathology, Inha University School of Medicine, Incheon, South Korea 13 Santa Casa Medical School, Sao Paulo, SP, Brazil 14 University of Turin, Turin, Italy * Co-first author ** Co-last author Correspondence to: Cesare Gridelli, email: // Keywords : NSCLC, EGFR TKI, biomarker analysis, predictive factors, prognostic factors Received : November 09, 2016 Accepted : February 01, 2017 Published : February 25, 2017 Abstract Background: The TORCH phase III trial compared the efficacy of first-line erlotinib followed by chemotherapy at progression (experimental arm) with the reverse sequence (standard arm) in unselected advanced non-small cell lung cancer (NSCLC) patients. Here we report biomarker analyses. Methods: EGFR and KRAS mutation, expression of EGFR family members and of cMET and PTEN and EGFR and ABCG2 germline polymorphisms were tested on tumor tissue or blood samples to either confirm previously proposed predictive role or describe it in an explorative setting. Progression-free survival (PFS) was the primary end-point, overall survival, response rate and side effects (diarrhoea and skin toxicity) were secondary end-points. Interactions between biomarkers and treatment were studied with multivariable models (either Cox model or logistic regression). Statistical analyses accounted for multiple comparisons. Results: At least one biomarker was assessed in 324 out of 760 patients in the TORCH study. EGFR mutation was more common in female ( P = 0.0001), East Asians ( P < 0.0001) and never smoker ( P < 0.0001) patients; low MET protein expression by IHC (H-score

Aims Very little is known regarding the time required to diagnose and treat patients with non-small cell lung cancer (NSCLC) in Canada. We sought to quantify diagnostic and treatment intervals for NSCLC care in Alberta and identify risk factors for delays. Materials and methods The Alberta Cancer Registry identified all cases of stage I–III NSCLC diagnosed and treated in Alberta, Canada from 2004 to 2011. Diagnostic data were obtained from physician billing, inpatient/outpatient hospital data and electronic medical records to quantify the duration of diagnostic and treatment intervals and their sum (system interval). Multivariable logistic regression was carried out to identify factors associated with delays. Results Of the 3009 eligible patients included, the median and 90th percentile system interval was 78 (95% confidence interval 76–80) and 185 days (95% confidence interval 178–195), respectively. The treatment interval was longer than the diagnostic interval, with medians of 51 (95% confidence interval 49–53) and 38 (95% confidence interval 36–40) days, respectively. After adjustment, age > 60 years and treatment by modalities other than supportive care (especially surgery) were associated with delays. Factors associated with prompt care included high acuity presentations and stage III disease. Conclusion The majority of Albertans with potentially curable NSCLC exceeded guidelines for the timeliness of their care.

Introduction Activation of the RAS/RAF/MEK/ERK pathway may confer resistance to chemotherapy in non-small cell lung cancer (NSCLC). Selumetinib (AZD6244, ARRY142886), a MEK1/2 inhibitor combined with chemotherapy in patients with NSCLC was evaluated in two schedules to evaluate efficacy and toxicity. Methods IND.219 was a three-arm study of first line pemetrexed/platinum chemotherapy with two schedules of selumetinib (Arm A: intermittent given on days 2–19; Arm B: continuous given on days 1–21) versus chemotherapy alone (Arm C). The primary endpoint was objective response rate (ORR); secondary objectives were tolerability, progression-free survival (PFS), overall survival (OS). The trial was stopped at the planned interim analysis. Results Arms A/B/C enrolled 20/21/21 patients, ORR was 35% (95% CI 15–59% median duration 3.8 months), 62% (95% CI 38–82%; median duration 6.3 months), 24% (95% CI 8–47%; median duration 11.6 months) respectively. The PFS (months Arm A, B, C) was 7.5, 6.7, 4.0 respectively (hazard ratio (HR) PFS Arm A over Arm C: 0.76 [95% CI, 0.38–1.51, 2-sided p = 0.42]; Arm B over Arm C 0.75 [95% CI 0.37–1.54, p = 0.43]. Skin and gastrointestinal adverse events were more common with the addition of selumetinib. A high incidence of venous thromboembolism was seen in all arms. Conclusions Selumetinib combined with chemotherapy was associated with a higher response rate. Continuous selumetinib appeared to be superior to an intermittent schedule. PFS was prolonged with the addition of selumetinib, however this was not statistically significant.

Currently, there is no approved therapy for cancer cachexia. According to European and American regulatory agencies, physical function improvements would be approvable co-primary endpoints of new anti-cachexia medications. As physical functioning is in part dependent on cardiac functioning, we aimed to explore the cardiac status of a group of patients meeting current criteria for inclusion in cachexia clinical trials. Seventy treatment-naive patients with metastatic NSCLC [36 (51.4%) male; 96% ECOG 0–1; eligible for carboplatin-based therapy and meeting eligibility criteria for cachexia clinical trials] were recruited before the start of first-line carboplatin-based chemotherapy. Patients were evaluated by echocardiography, electrocardiography, and scales for fatigue and dyspnea. Computed tomography cross-sectional images were utilized for body composition analysis. In 9/70 patients (12.8%), echocardiography allowed discovery of clinically relevant cardiac disorders [seven patients with left ventricular ejection fraction (LVEF) 32%–47%; one patient with severe right ventricular dilation and severe pulmonary hypertension and one patient with severe pericardial effusion warranted hospitalization and drainage]. Another 10/70 (14.3%) patients had diastolic dysfunction with preserved LVEF. The cardiac conditions were associated with aggravated fatigue (p

Background Tecemotide is a MUC1-antigen-specific cancer immunotherapy. The phase III START study did not meet its primary end point but reported notable survival benefit with tecemotide versus placebo in an exploratory analysis of the predefined patient subgroup treated with concurrent chemoradiotherapy. Here, we attempted to gain further insight into the effects of tecemotide in START. Patients and methods START recruited patients who did not progress following frontline chemoradiotherapy for unresectable stage III non-small-cell lung cancer. We present updated overall survival (OS) data and exploratory analyses of OS for baseline biomarkers: soluble MUC1 (sMUC1), antinuclear antibodies (ANA), neutrophil/lymphocyte ratio (NLR), lymphocyte count, and HLA type. Results Updated OS data are consistent with the primary analysis: median 25.8 months (tecemotide) versus 22.4 months (placebo) (HR 0.89, 95% CI 0.77–1.03, P = 0.111), with ∼20 months additional median follow-up time compared with the primary analysis. Exploratory analysis of the predefined subgroup treated with concurrent chemoradiotherapy revealed clinically relevant prolonged OS with tecemotide versus placebo (29.4 versus 20.8 months; HR 0.81, 95% CI 0.68–0.98, P = 0.026). No improvement was seen with sequential chemoradiotherapy. High sMUC1 and ANA correlated with a possible survival benefit with tecemotide (interaction P = 0.0085 and 0.0022) and might have future value as biomarkers. Interactions between lymphocyte count, NLR, or prespecified HLA alleles and treatment effect were not observed. Conclusion Updated OS data support potential treatment benefit with tecemotide in patients treated with concurrent chemoradiotherapy. Exploratory biomarker analyses suggest that elevated sMUC1 or ANA levels correlate with tecemotide benefit. ClinicalTrials.gov number NCT00409188.

Background: Historically, 5-y overall survival (OS) with chemotherapy for pts with metastatic lung cancer was ~5%; with the advent of immunotherapy, this has increased to ~15%. CheckMate (CM) 017, 057, 063, and 003 are NIVO studies with extensive follow-up in pts with previously treated advanced NSCLC. Using pooled data from these studies, we evaluated the long-term benefit (up to 4 y) of NIVO and impact of early response or disease control on subsequent long-term OS. Methods: Progression-free survival (PFS) and OS were estimated for pts with NSCLC across histologies treated with NIVO in pooled analyses of CM 017, 057, 063, and 003 (n=664), and for pts randomized to NIVO (n=427) or docetaxel (DOC; n=427) in pooled analyses of CM 017/057. Other analyses for CM 017/057 included estimation of OS in pts alive at 6 mo by response status at 6 mo, and OS in all responders (complete or partial response [CR/PR]) from time of response. Results: In pooled analyses of the 4 studies, 4-y OS rates for NIVO in all pts and those with PD-L1 ≥1% and Conclusions: These large pooled analyses show pts with CR/PR or SD with NIVO at 6 mo derived marked OS benefit; this long-term benefit was improved vs pts with DOC with the same response status at 6 mo. The NIVO safety profile was consistent with prior reports. Table.6-Month Landmark Analysis of OS by Response Status at 6 months in Pooled CM 017/057aPts alive at mo 6Response status at 6 mo, %bPost-landmark 1-y OS rate, %Post-landmark 2-y OS rate, %Post-landmark 3-y OS rate, %Post-landmark 4-y OS rate, %NIVO 3 mg/kg Q2W (n = 280)CR/PR, 2581636158SD, 2458352419PD, 51401384DOC 75 mg/m2 Q3W (n = 264)CR/PR, 1362382612SD, 39351872PD, 48221285aThe 6-month landmark timepoint was used to allow sufficient time for the majority of responses with NIVO to occur, while allowing meaningful time to assess OS post landmark: median time to response, 2.1 mo; 75th quartile, 3.5 mo.b% of pts alive at 6 mo. Citation Format: Julie Brahmer, Hossein Borghaei, Suresh S. Ramalingam, Leora Horn, Esther Holgado, Adam Pluzanski, Marco A. Burgio, Marina Garassino, Laura Q. Chow, Scott Gettinger, Lucio Crino, David Planchard, Charles Butts, Alexander Drilon, Joanna Wojcik-Tomaszewska, Gregory Otterson, Vinny Hayreh, Ang Li, John R. Penrod, Scott J. Antonia. Long-term survival outcomes with nivolumab (NIVO) in pts with previously treated advanced non-small cell lung cancer (NSCLC): Impact of early disease control and response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT195.

Purpose Survival of patients with completely resected non–small-cell lung cancer (NSCLC) is unsatisfactory, and in 2002, the benefit of adjuvant chemotherapy was not established. This phase III study assessed the impact of postoperative adjuvant gefitinib on overall survival (OS). Patients and Methods Patients with completely resected (stage IB, II, or IIIA) NSCLC stratified by stage, histology, sex, postoperative radiotherapy, and chemotherapy were randomly assigned (1:1) to receive gefitinib 250 mg per day or placebo for 2 years. Study end points were OS, disease-free survival (DFS), and toxicity. Results As a result of early closure, 503 of 1,242 planned patients were randomly assigned (251 to gefitinib and 252 to placebo). Baseline factors were balanced between the arms. With a median of 4.7 years of follow-up (range, 0.1 to 6.3 years), there was no difference in OS (hazard ratio [HR], 1.24; 95% CI, 0.94 to 1.64; P = .14) or DFS (HR, 1.22; 95% CI, 0.93 to 1.61; P = .15) between the arms. Exploratory analyses demonstrated no DFS (HR, 1.28; 95% CI, 0.92 to 1.76; P = .14) or OS benefit (HR, 1.24; 95% CI, 0.90 to 1.71; P = .18) from gefitinib for 344 patients with epidermal growth factor receptor (EGFR) wild-type tumors. Similarly, there was no DFS (HR, 1.84; 95% CI, 0.44 to 7.73; P = .395) or OS benefit (HR, 3.16; 95% CI, 0.61 to 16.45; P = .15) from gefitinib for the 15 patients with EGFR mutation-positive tumors. Adverse events were those expected with an EGFR inhibitor. Serious adverse events occurred in ≤ 5% of patients, except infection, fatigue, and pain. One patient in each arm had fatal pneumonitis. Conclusion Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, these results indicate that it is unlikely to be of benefit.

Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered.

Adjuvant chemotherapy for early stage non-small cell lung cancer was approved for provincial insurance coverage in Alberta, Canada in 2004. The purpose of this study was to measure factors related to uptake of chemotherapy in eligible patients and compare toxicity and survival outcomes in the Alberta population with those found in clinical trials. All Alberta residents diagnosed with stage IB–IIB NSCLC from 2004 to 2006 who had surgery and a consultation with an oncologist to discuss initial treatment were included in the study. Diagnostic, demographic, and vital statistics data were obtained from the Alberta Cancer Registry; chart reviews were conducted to identify details related to treatments discussed, refused, co-morbidities, and toxicity. Analyses were conducted to identify factors associated with discussion and receipt of chemotherapy and toxicity. Toxicity and survival were calculated and compared to clinical trial results. 226 patients were included in the study. Adjuvant chemotherapy was not recommended to 57 patients (25%) and 30 patients (13%) refused chemotherapy. Primary reasons for not recommending chemotherapy were co-morbidities and/or frailty (24 patients). Of the 139 patients who began chemotherapy, 47 (34%) stopped treatment early. Stage II patients who received adjuvant chemotherapy had over a 2-fold decrease in risk of death compared to those who did not receive chemotherapy after adjusting for age and co-morbidities. Efforts to improve uptake of adjuvant chemotherapy in patients with stage II NSCLC should be made as the survival advantage appears to be comparable to that found in clinical trials.

PurposeThis double-blind randomized phase II trial examined whether vandetanib, an inhibitor of vascular endothelial and epidermal growth factor receptors, could prolong progression-free survival in responding patients with small-cell lung cancer.Patients and MethodsEligible patients with complete response (CR) or partial response (PR) to combination chemotherapy (± thoracic or prophylactic cranial radiation) received oral vandetanib 300 mg/d or matched placebo. With 100 patients and 77 events, the study had 80% power to detect an improvement in median progression-free survival from 4 to 6.5 months (one-sided, 10%-level test).ResultsBetween May 2003 and March 2006, 107 patients were accrued; 46 had limited disease and 61 extensive disease. There were fewer patients with a performance status of 0 (n = 11 v 20), and fewer had CR to initial therapy (n = 4 v 8) in the vandetanib arm. Vandetanib patients had more toxicity and required more dose modifications for gastrointestinal toxicity and rash. Asymptomatic Corrected QT interval (QTC) prolongation was observed in eight vandetanib patients. Median progression-free survival for vandetanib and placebo was 2.7 and 2.8 months, respectively (hazard ratio [HR], 1.01; 80% CI, 0.75 to 1.36; one-sided P = .51). Overall survival for vandetanib was 10.6 versus 11.9 months for placebo (HR, 1.43; 80% CI, 1.00 to 2.05; one-sided P = 0.9). In planned subgroup analyses, a significant interaction was noted (P = .01): limited-stage vandetanib patients had longer overall survival (HR, 0.45; one-sided P = .07) and extensive-stage vandetanib patients shorter survival compared with placebo (HR, 2.27; one-sided P = .996).ConclusionVandetanib failed to demonstrate efficacy as maintenance therapy for small-cell lung cancer.

Purpose: High class III β-tubulin (bTubIII) expression in advanced non–small cell lung cancer is known to correlate with reduced response rates and inferior survival with anti-microtubule agents. JBR.10 showed a 12% and 15% improvement in 5-year recurrence-free survival (RFS) and overall survival (OS), respectively, with the addition of cisplatin and vinorelbine following resection of stage IB-II non–small cell lung cancer. We sought to determine the effect of bTubIII on patient outcome and benefit from adjuvant chemotherapy in the JBR.10 trial.Experimental Design: We did a semiquantitative immunohistochemical assay for bTubIII on primary tumor tissue available from 265 of the 482 patients in JBR.10. Tumors were classified as bTubIII “low” or “high” using a validated method. We examined the prognostic effect of bTubIII in patients treated with or without chemotherapy and the survival benefit from chemotherapy in low versus high bTubIII subgroups.Results: High bTubIII expression was associated with poorer RFS and OS in patients treated with surgery alone but not in patients treated with adjuvant chemotherapy. The RFS and OS benefits of adjuvant chemotherapy were greater in high versus low tubulin expressors. However, with Cox regression, the interaction between bTubIII status and chemotherapy treatment in predicting RFS or OS did not reach statistical significance.Conclusions: Chemotherapy seemed to overcome the negative prognostic effect of high bTubIII expression. Greater benefit from adjuvant chemotherapy was seen in patients with high bTubIII expression. This is contrary to what has been seen in the setting of advanced disease; possible reasons for this difference are being explored.

Purpose Information about symptomatic toxicities of anticancer treatments is not based on direct report by patients, but rather on reports by clinicians in trials. Given the potential for under-reporting, our aim was to compare reporting by patients and physicians of six toxicities (anorexia, nausea, vomiting, constipation, diarrhea, and hair loss) within three randomized trials. Patients and Methods In one trial, elderly patients with breast cancer received adjuvant chemotherapy; in two trials, patients with advanced non–small-cell lung cancer received first-line treatment. Toxicity was prospectively collected by investigators (graded by National Cancer Institute Common Toxicity Criteria [version 2.0] or Common Terminology Criteria for Adverse Events [version 3]). At the end of each cycle, patients completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaires, including toxicity-related symptom items. Possible answers were “not at all,” “a little,” “quite a bit,” and “very much.” Analysis was limited to the first three cycles. For each toxicity, agreement between patients and physicians and under-reporting by physicians (ie, toxicity reported by patients but not reported by physicians) were calculated. Results Overall, 1,090 patients (2,482 cycles) were included. Agreement between patients and physicians was low for all toxicities. Toxicity rates reported by physicians were always lower than those reported by patients. For patients who reported toxicity (any severity), under-reporting by physicians ranged from 40.7% to 74.4%. Examining only patients who reported “very much” toxicity, under-reporting by physicians ranged from 13.0% to 50.0%. Conclusion Subjective toxicities are at high risk of under-reporting by physicians, even when prospectively collected within randomized trials. This strongly supports the incorporation of patient-reported outcomes into toxicity reporting in clinical trials.

Purpose To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non–small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. Patients and Methods Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 μg). Subsequent immunizations were administered at 6-week intervals. Results The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. Conclusion L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.

background We undertook to determine whether adjuvant vinorelbine plus cisplatin prolongs overall survival among patients with completely resected early-stage non–small-cell lung cancer. methods We randomly assigned patients with completely resected stage IB or stage II non–smallcell lung cancer to vinorelbine plus cisplatin or to observation. The primary end point was overall survival; principal secondary end points were recurrence-free survival and the toxicity and safety of the regimen. results A total of 482 patients underwent randomization to vinorelbine plus cisplatin (242 patients) or observation (240); 45 percent of the patients had pathological stage IB disease and 55 percent had stage II, and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. In both groups, the median age was 61 years, 65 percent were men, and 53 percent had adenocarcinomas. Chemotherapy caused neutropenia in 88 percent of patients (including grade 3 febrile neutropenia in 7 percent) and death from toxic effects in two patients (0.8 percent). Nonhematologic toxic effects of chemotherapy were fatigue (81 percent of patients), nausea (80 percent), anorexia (55 percent), vomiting (48 percent), neuropathy (48 percent), and constipation (47 percent), but severe (grade 3 or greater) toxic effects were uncommon (

Purpose Capecitabine has demonstrated high efficacy as first-line treatment for metastatic colorectal cancer (MCRC). Oxaliplatin shows synergy with fluorouracil (FU), with little toxicity overlap. The XELOX regimen (capecitabine plus oxaliplatin), established in a previous dose-finding study, should improve on infused oxaliplatin with FU and leucovorin (FOLFOX) regimens. The present studies further characterize efficacy and safety of the XELOX regimen. Patients and Methods The antitumor activity of XELOX was investigated in a colon cancer xenograft model. Patients with MCRC received first-line XELOX in 3-week treatment cycles: intravenous oxaliplatin 130 mg/m2 (day 1) followed by oral capecitabine 1,000 mg/m2 twice daily (day 1, evening, to day 15, morning). Results A preclinical study confirmed that capecitabine has supra-additive activity with oxaliplatin. In the clinical study, 53 of 96 patients (55%) achieved an objective response, and 30 (31%) experienced disease stabilization for ≥ 3 months following treatment. After 24 months' minimum follow-up, median time to disease progression (TTP) and median overall survival were 7.7 and 19.5 months, respectively. XELOX safety was predictable and similar to the FOLFOX4 regimen, except that myelosuppression was uncommon with XELOX (grade 3 or 4 neutropenia, 7%). Most adverse events were mild to moderate, the most common being acute sensory neuropathy (85%). Sixty-day, all-cause mortality was 2%. Conclusion XELOX is a highly effective first-line treatment for MCRC. Response rates, TTP, and overall survival are similar to those observed with FU/leucovorin/oxaliplatin combinations. XELOX provides a more convenient regimen, likely to be preferred by both patients and healthcare providers. Capecitabine has the potential to replace FU/LV in combination with oxaliplatin for MCRC.

MUC1 is a mucinous glycoprotein which is overexpressed and under or aberrantly glycosylated in many human malignancies. MUC1 is associated with cellular transformation and can confer resistance to genotoxic agents. L-BLP25 is a peptide vaccine strategy that targets the exposed core peptide of MUC1. In preclinical studies, L-BLP25 induced a cellular immune response characterized by T-cell proliferation in response to MUC1 and production of IFN-γ. Phase I and II trials have established the dose and schedule of the vaccine as well as its excellent safety profile. A randomized phase II trial of maintenance L-BLP25 versus best supportive care in patients with stage IIIB/IV non–small cell lung cancer who experienced clinical benefit from initial therapy has been reported. Updated survival analysis of this trial continues to show a strong survival trend in favor of L-BLP25 (median survival, 30.6 versus 13.3 months) in a subgroup of patients with locoregional stage IIIB disease. These promising results will be tested in a phase III trial of L-BLP25 versus placebo in patients with stage III non–small cell lung cancer after response to primary chemoradiotherapy.

The burden of cancer for Canadian citizens and society is large. New technologies have the potential to increase the use of genetic information in clinical decision-making, furthering prevention, surveillance, and safer, more effective drug therapies for cancer patients. Personalized medicine can have different meanings to different people. The context for personalized medicine in the present paper is genetic testing, which offers the promise of refining treatment decisions for those diagnosed with chronic and life-threatening illnesses. Personalized medicine and genetic characterization of tumours can also give direction to the development of novel drugs. Genetic testing will increasingly become an essential part of clinical decision-making. In Canada, provinces are responsible for health care, and most have unique policies and programs in place to address cancer control. The result is inconsistency in access to and delivery of therapies and other interventions, beyond the differences expected because of demographic factors and clinical education. Inconsistencies arising from differences in resources, policy, and application of evidence-informed personalized cancer medicine exacerbate patient access to appropriate testing and quality care. Geographic variations in cancer incidence and mortality rates in Canada—with the Atlantic provinces and Quebec having higher rates, and British Columbia having the lowest rates—are well documented. Our purpose here is to provide an understanding of current and future applications of personalized medicine in oncology, to highlight the benefits of personalized medicine for patients, and to describe issues and opportunities for improvement in the coordination of personalized medicine in Canada. Efficient and more rapid adoption of personalized medicine in oncology in Canada could help over-come those issues and improve cancer prevention and care. That taks mignth benefit from the creation of a National Genetics Advisory Panel that would review research and provide recommendations on tests for funding or reimbursement, guidelines, service delivery models, laboratory quality assurance, education, and communication. More has to be known about the current state of personalized cancer medicine in Canada, and strategies have to be developed to inform and improve understanding and appropriate coordination and delivery. Our hope is that the perspectives emphasized in this paper will stimulate discussion and further research to create a more informed response.

Objective. The purpose of this study was to assess the value in measuring specific time intervals across cancer sites to identify potentially important variation in the timeliness of cancer care that may inform needed changes and/or improvements in coordination of care. Design. Retrospective population-level study. Demographic and treatment information were obtained from the Alberta Cancer Registry. Date of oncologist-consult was obtained from cancer medical records. Setting. Alberta, Canada. Participants. All patients diagnosed in 2005 with breast, colon, rectal or lung cancer who were residents of Alberta, Canada. Main Outcome Measures. (i) Number of days from diagnosis to first treatment by treatment modality and cancer site, (ii) number of days from surgery to post-surgery consultation and subsequent treatment and (iii) relationship between clinical and demographic factors and the cancer-specific provincial median time for outcome measures (i) and (ii). Results. Time from diagnosis to surgery, if first treatment, was ∼4 months for lung cancer compared with 1–2 months for breast and colorectal cancers. Factors associated with this time interval for breast and colorectal cancers was stage at diagnosis but was region of residence for lung cancer. Conclusions. Important variation within and across cancer sites identified in the care intervals evaluated in this study provides relevant information to inform local areas for improvement. Comparisons of these intervals across healthcare systems may also provide insights into strengths of different models for coordinating care.

The treatment of elderly cancer patients is complicated by many factors. We sought to assess the uptake and tolerance of chemotherapy among patients 75 years and older diagnosed with small cell lung cancer (SCLC) in years 2004–2008 in Alberta, Canada, and assess their survival. All patients who met the above criteria and had an oncologist-consult were included. Data were obtained from the Alberta Cancer Registry and chart review. A total of 171 patients were included in the study, 117 (68%) of whom began chemotherapy. Of those, 52% completed all cycles, 66% did not have any dose reductions, and 31% completed all cycles at the recommended dose. The risk of death for patients who did not complete all cycles of chemotherapy was 2.72 (95% CI: 1.52–4.87) and for those who completed all cycles but with a reduced dose was 1.02 (95% CI: 0.57–1.82) relative to those who completed chemotherapy at full dose after adjusting for several demographic/clinical factors. Our results suggest that a significant proportion of elderly patients are able to tolerate chemotherapy and receive a survival benefit from it while those who experience toxicity may receive a survival benefit from a reduction in chemotherapy dose as opposed to stopping treatment.

To present an updated survival analysis of an open-label, parallel-group, phase IIB trial of BLP25 liposome vaccine (L-BLP25) in patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). Patients were randomized to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received subcutaneous vaccinations of L-BLP25 930 μg weekly for 8 weeks, followed by maintenance vaccinations at 6-week intervals. Median survival time was 4.2 months longer in patients receiving L-BLP25 plus BSC (n = 88) than in those receiving BSC alone (n = 83; 17.2 months vs. 13.0 months, respectively; hazard ratio [HR] 0.745, 95% confidence interval [CI] 0.533–1.042). The 3-year survival rate was 31% in patients receiving L-BLP25 plus BSC and 17% in those receiving BSC (P = 0.035). In the stratified subset of patients with stage IIIB loco-regional (LR) disease, median survival time was 17.3 months longer in patients receiving L-BLP25 plus BSC (n = 35) than in those receiving BSC (n = 30; 30.6 months vs. 13.3 months, respectively; HR 0.548, 95% CI 0.301–0.999). In this subgroup, 3-year survival was 49% in patients receiving L-BLP25 plus BSC and 27% in those receiving BSC (P = 0.070). Confirming the initial results, further follow-up continues to show that survival time for patients with stage IIIB/IV NSCLC was longer with L-BLP25 plus BSC compared with BSC alone, with the greatest difference seen in patients with stage IIIB LR disease.

Higher awareness could translate into better care for patients with breast cancer than for those with other cancers. This study examines utilization of two key oncology services across cancer sites: consultation with an oncologist and receipt of treatment.All residents of Alberta, Canada, who were diagnosed in 2005 with breast, colon, rectal, or lung cancer and had a disease stage that should be treated with chemotherapy, radiation therapy, or hormonal therapy were included. Data were obtained from the Alberta Cancer Registry and electronic cancer medical records. Percentages of patients who had a consultation and who received treatment were compared. Multivariable log-binomial regression models were used to identify patient characteristics associated with not having the outcomes.A much higher percentage of patients with breast cancer had consultations and received treatment (92% and 83%, respectively) than those with colon (83% and 59%), rectal (86% and 73%), or lung (77% and 66%) cancer. Age, disease stage, region of residence, and surgery status are related to having a consultation and/or receiving treatment but the relationship varies by cancer site.Efforts are needed to eliminate disparities in utilization of key cancer services across cancer sites.

Introduction: BLP25 liposome vaccine (L-BLP25) is an innovative therapeutic cancer vaccine designed to induce an immune response resulting in elimination of tumor cells expressing the MUC1 antigen, which is overexpressed in non–small-cell lung cancer (NSCLC). Manufacturing modifications have produced subtle changes to the lipid A acyl chain composition of L-BLP25. This open-label phase II study was conducted to evaluate the safety of the new formulation in patients with unresectable stage IIIA/IIIB NSCLC. Patients and Methods Twenty-two patients received L-BLP25 1000 μg every week for 8 weeks plus best supportive care. Maintenance vaccinations were given every 6 weeks, commencing at week 13, until disease progression. Results Median treatment duration was 9.9 months (range, 1-30 months), 9 patients remain on treatment, and 8 have received treatment for > 2 years. Fifteen patients (68%) had adverse events considered to be related to L-BLP25: these were all grade 1/2, except for 1 grade 3 event (pneumonia). The most common adverse events were injection-site reactions (bruising [23%], erythema [18%], pain [14%], fatigue [18%], and influenza-like illness [14%]). After a median follow-up of 26.7 months, the 1-year survival rate was 82% (95% CI, 66%-98%), and the 2-year survival rate was 64% (95% CI, 44%-84%). Conclusion The results suggest that the new formulation of L-BLP25 has a safety profile similar to the original formulation and is safe to use in the phase III clinical development program.

Herein, we present a randomized phase III Italian-Canadian trial named TORCH (Tarceva or Chemotherapy). In TORCH, we are investigating whether erlotinib as first-line therapy until progression followed by chemotherapy with cisplatin/gemcitabine will not be inferior in terms of survival to the standard arm, consisting of first-line cisplatin/gemcitabine for 6 cycles, followed at progression by erlotinib until second progression. The primary objective is overall survival, and an adjunctive primary endpoint is activity of first-line treatment with erlotinib in terms of progression-free rate after 9 weeks of treatment. Secondary objectives include response rate, progression-free survival, toxicity, quality of life, and exploratory evaluations of tumor tissue and blood samples for biologic or genomic determinants of outcome. The study design is based on a noninferiority survival comparison with about 900 patients expected to be recruited. An early analysis of activity will be performed in the experimental arm (first-line erlotinib followed by chemotherapy).

Background: To demonstrate the noninferiority of capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX-4) as second-line therapy in patients with metastatic colorectal cancer after prior irinotecan-based chemotherapy. Patients and methods: A total of 627 patients were randomly assigned to receive XELOX (n = 313) or FOLFOX-4 (n = 314) following disease progression/recurrence or intolerance to irinotecan-based chemotherapy. The primary end point was progression-free survival (PFS). Results: PFS for XELOX was noninferior to FOLFOX-4 [hazard ratio (HR) = 0.97; 95% confidence interval (CI) 0.83-1.14] in the intention-to-treat (ITT) population. Median PFS was 4.7 months with XELOX versus 4.8 months with FOLFOX-4. The robustness of the primary analysis was supported by multivariate and subgroup analyses. Median overall survival in the ITT population was 11.9 months with XELOX versus 12.5 months with FOLFOX-4 (HR = 1.02; 95% CI 0.86-1.21). Treatment-related grade 3/4 adverse events occurred in 50% of XELOX- and 65% of FOLFOX-4-treated patients. Whereas grade 3/4 neutropenia (35% versus 5% with XELOX) and febrile neutropenia (4% versus < 1%) were more common with FOLFOX-4, grade 3/4 diarrhea (19% versus 5% with FOLFOX-4) and grade 3 hand-foot syndrome (4% versus < 1%) were more common with XELOX. Conclusion: XELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.

The identification of tumor-associated/-specific antigens and an increased understanding of the ways in which antigens are processed and presented has led to a revived interest in cancer vaccines as a therapeutic strategy. BLP25 liposome (L-BLP25) vaccine is a cancer vaccine that targets the exposed core peptide of the MUC1 tumor-associated antigen. Studies in advanced-stage non-small cell lung cancer demonstrate that L-BLP25 vaccine has the potential to extend the survival of patients with Stage IIIB locoregional non-small cell lung cancer and maintain quality of life for longer. L-BLP25 vaccine also shows promise for prostate cancer patients, having the potential to prolong prostate-specific antigen doubling time in men with biochemical failure post prostatectomy. These clinically meaningful results with a relatively nontoxic therapeutic vaccine are very encouraging and suggest potential for L-BLP25 to fulfill an unmet medical need.

Background Following resection of liver metastases from colorectal cancer, 5-year survivals are reportedly 30 – 39%. It can be assumed that this clinical situation represents systemic disease. Therefore, it is postulated that systemic chemotherapy would improve outcomes, particularly in those whose disease is sensitive to the agents administered. One potential advantage of neoadjuvant chemotherapy is that it provides in vivo chemosensitivity data. Response to neoadjuvant chemotherapy could therefore guide adjuvant chemotherapy following resection of liver metastases from colorectal cancer. Methods and design This is a prospective Phase II evaluation of outcomes in patients with potentially resectable liver metastases. Patients will receive neoadjuvant chemotherapy and will undergo resection. Postoperative chemotherapy will be directed by the degree of response to preoperative chemotherapy. All patients with Stage IV colorectal adenocarcinoma isolated to the liver that have disease that is amenable to complete ablation by resection, radiofrequency ablation, and/or cryoablation will be candidates for the trial. Patients will receive CPT-11 180 mg/m2 IV (over 90 minutes) on day 1 with 5-FU 400 mg/m2 bolus and 600 mg/m2 by 22 hour infusion and calcium folinate 200 mg/m2 on days 1 and 2, every 2 weeks. Altogether, six cycles of chemotherapy will be administered. Patients will then undergo resection and/or radiofrequency ablation. Patients who had stable disease or a clinical response with preoperative chemotherapy will receive an additional 12 cycles of CPT-11 180 mg/m2 IV (over 90 minutes) on day 1 with 5-FU 400 mg/m2 bolus and 600 mg/m2 by 22 hour infusion and calcium folinate 200 mg/m2 on days 1 and 2 (given every 2 weeks). Patients with resectable disease who had progressive disease during neoadjuvant chemotherapy will receive best supportive care or an alternative agent, at the discretion of the treating physician. Those patients who are not rendered free of disease following the neoadjuvant chemotherapy and surgery will receive best supportive care or an alternative agent, at the discretion of the treating physician. The primary endpoint of the study is disease-free survival. Secondary endpoints include overall survival, safety and feasibility, response to chemotherapy, and quality of life.

Background: Trastuzumab provides significant clinical benefits in HER2-positive metastatic breast cancer patients when administered in combination with chemotherapy. Chemotherapy has also been shown to be beneficial in some patients with advanced non-small-cell lung cancer (NSCLC). The present randomized phase II trial examined the effect of adding trastuzumab to a standard chemotherapeutic combination (gemcitabine-cisplatin) in patients with HER2-positive NSCLC. Patients and methods: Patients with untreated stage IIIB/IV HER2-positive NSCLC received up to six 21-day cycles of gemcitabine, 1250 mg/m(2) (days 1 and 8) and cisplatin 75 mg/m(2) (day 1). Patients in the trastuzumab arm received trastuzumab 4 mg/kg intravenously (i.v.) followed by 2 mg/kg/week i.v. until progression. Results: Of 619 patients screened, 103 were eligible. Fifty-one patients were treated with trastuzumab plus gemcitabine-cisplatin and 50 with gemcitabine-cisplatin alone. Efficacy was similar in the trastuzumab and control arms: response rate 36% versus 41%; median time to progression 6.3 versus 7.2 months; and median progression-free survival (PFS) 6.1 versus 7 months. Response rate (83%) and median PFS (8.5 months) appeared relatively good in the six trastuzumab-treated patients with HER2 3+ or fluorescence in situ hybridization (FISH)-positive NSCLC. Addition of trastuzumab to gemcitabine-cisplatin was well tolerated, side-effects were as expected, and trastuzumab did not exacerbate the known toxicity of gemcitabine and cisplatin. Symptomatic cardiotoxicity was observed in one trastuzumab-treated patient. Serum trastuzumab concentrations in the presence of gemcitabine-cisplatin were comparable to those of trastuzumab alone. Conclusions: Trastuzumab plus gemcitabine-cisplatin is well tolerated. Clinical benefit was not observed. Although HER2 3+/FISH-positive patients may benefit from trastuzumab, the subgroup is too small to provide definitive information. No significant effect of gemcitabine-cisplatin on trastuzumab pharmacokinetics was observed. RI van Zandwijk, Nico/E-4177-2012

Background Chromosomal rearrangements in the receptor tyrosine kinase (RTK) ROS1 define a new molecular subset of NSCLC. ALK inhibitors can inhibit ROS1 kinase activity in cell lines. We examined the efficacy and safety of crizotinib, a small molecule inhibitor of two other RTKs, MET and ALK, in patients with advanced, ROS1-rearranged NSCLC. Methods Patients with advanced NSCLC harboring ROS1 rearrangement, as determined using a break-apart FISH assay, were recruited into an expansion cohort of the original phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg BID. The objective response rate (ORR) was determined based on RECIST v1.0. The disease control rate (DCR; stable disease [SD] + partial response [PR] + complete response [CR]) was evaluated at weeks 8 and 16. Results At the time of data cut-off on April 19, 2012, 15 patients with ROS1 NSCLC had received crizotinib and 14 were evaluable for response. The median age was 54 years (range 31–72). Fourteen patients were never-smokers and all had adenocarcinoma histology. All patients were confirmed negative for ALK rearrangement. The median number of prior treatments was 1 (range 0–6). The first ROS1 patient received crizotinib on October 19, 2010. To date, the ORR is 57% (8/14; 95% CI 28.9–82.3), with 7 PR and 1 CR. There were 4 SD, one of which was unconfirmed as PR at the time of data cut-off. The DCR at 8 weeks was 79% (11/14). Median duration of treatment was 25.7 weeks (range 0.1 + to 65.3 + ), and 12 patients continue on study. The pharmacokinetics, antitumor activity and safety profile of crizotinib in this group of patients were similar to those observed in patients with ALK-positive NSCLC. Conclusions Crizotinib is associated with clinically significant antitumor activity in patients with ROS1 NSCLC. Similar to ALK, ROS1 rearrangement defines another unique molecular subset of NSCLC patients for whom crizotinib therapy may be highly effective. Importantly, this study represents the first clinical investigation of ROS1 as a driver mutation and therapeutic target in cancer. Disclosure S.I. Ou: Advisory role: Pfizer, Genentech. Compensated Honoraria: Pfizer, Genentech, Lilly. Myself Research funding: Pfizer. Myself (institution). D.R. Camidge: Advisory role: Pfizer. Myself. Honoraria: Pfizer. Myself. L. Tye: Employment: Pfizer. Clinician. Myself. Stock Ownership; Pfizer. Myself. K. Wilner: Emplyement: Pfizer. Senior Director. Myself. Compensated. Stock ownership: Pfizer. Myself. M. Varella-Garcia: Honoraria: Abbott Molecular. Myself. funding for the trial provided by NIH - yes. A.T. Shaw: Advisory role: Pfizer, Ariad, Chugai, Novartis, Daiichi-sankyo. Myself. Compensated Research funding: Astra Zeneca, Novartis. Myself. All other authors have declared no conflicts of interest.

Introduction L-BLP25 (Stimuvax®) is an antigen-specific cancer immunotherapeutic agent targeting the mucin 1 tumour-associated antigen. Phase IIb data suggest prolonged overall survival with L-BLP25 when administered after completion of chemoradiotherapy for locally advanced non-small-cell lung cancer (NSCLC; non-significant). This study was initiated in April 2005 to obtain safety data when modifications of the adjuvant component of the immunotherapeutic were performed. Here we report an updated analysis of long-term data based on the cut-off date 18 May 2011. Methods The primary objective of this open-label phase II study was to evaluate the safety of the new formulation of L-BLP25 in patients with unresectable stage IIIA/B NSCLC, with a secondary objective of assessment of survival time. Following completion of initial chemoradiotherapy, patients with stage III NSCLC received treatment with L-BLP25 starting with weekly injections over 8 weeks, followed by injections given every 6 weeks from week 13 onwards until disease progression. A single low dose of intravenous cyclophosphamide 300 mg/m2 (maximum 600 mg) was given 3 days before first vaccination. Results Twenty-two patients were enrolled. After a median follow-up of 70.3 months (median treatment duration 9.9 months [range, 1–73]), median survival time was 51.9 months (95%CI, 17.5, not estimable [NE]) and median progression-free survival was 31.4 months (95%CI, 5.7, NE). Five-year survival was 50% (95%CI, 29–71%); previously reported 1- and 2-year survival rates, 82% (95%CI, 66–98%) and 64% (95%CI, 44–84%), respectively. Four patients survived more than 72 months. Safety findings were consistent with previous reports; adverse events (AEs) consisted mainly of fatigue (59%), injection-site reactions (55%) and mild-to-moderate influenza-like illness. Two serious treatment-emergent AEs were assessed as being treatment-related: cholecystitis and pneumonia. Conclusions Long-term follow-up of this small patient population provides encouraging survival data for L-BLP25 maintenance therapy in stage III NSCLC. Long-term safety data were consistent with previous reports and did not reveal any new safety issues. Disclosure C. Butts: Charles Butts has provided consultancy and served on Speakers' Bureaux for Merck Serono. A. Maksymiuk: Andrew Maksymiuk has some stock shares in Merck Canada ( M. Falk: Martin Falk is a Merck Serono employee. A.H. Loos: Dr Loos is a Merck employee. All other authors have declared no conflicts of interest.

7501 Background: JBR.10 was one of a number of phase III trials that established adjuvant cisplatin based chemotherapy as a recommended treatment in completely resected NSCLC . Long-term follow-up of these trials is important to document persistent benefit and potential late toxicities of adjuvant therapy. We report the updated survival data for JBR.10 with more than 9 years median follow up. Methods: Patients with completely resected stage IB (T2N0) or II (T1–2N1) NSCLC were randomized to receive 4 cycles of vinorelbine/cisplatin or observation.. Kaplan-Meier curves were generated for overall (OS) and disease specific survival (DSS). Log-rank test was used to compare survival distribution and to test cause specific hazard. For the competing risk analysis, the Gray test was used to test the difference in cause specific incidences. All efficacy analyses were done on an ITT basis. Results: 482 patients were randomized. Data cut-off for this update was July 2008. Median follow-up is 9.3 years (3.2–13.8 y). 12 patients were lost to follow up, a median 4.9 years from randomization (1.5–12 years). 271 deaths have occurred, 73% due to lung cancer or its treatment. Survival analysis continues to show a benefit for chemotherapy: HR .78 (CI .61-.99, p=.04). The benefit appears to be confined to N1 patients: median OS 6.8 y versus 3.6 y, HR .68 (CI .5-.92, p=.01). N0 patients did not appear to benefit: HR 1.03 (CI .7–1.52, p=.87). Chemotherapy significantly prolonged DSS, HR.73 (CI .55-.97, p=.03) Competing risk analysis showed observation to be associated with significantly higher risk of death from lung cancer (p=.02) with no difference in incidences of death from other causes between arms (p=.62). Conclusions: Prolonged follow-up of patients in the JBR.10 trial continues to show a benefit in survival for adjuvant chemotherapy. This benefit appears to be confined to N1 patients. There was no increase in death from other causes in the chemotherapy arm. [Table: see text]

3055 Background: The BLP25 liposome vaccine (L-BLP25, Stimuvax) is an investigational innovative therapeutic cancer vaccine incorporating immunoadjuvant monophosphoryl lipid A and synthetic MUC1 lipopeptide in a liposomal delivery system. In an open-label phase IIb study in 171 pts with stage IIIB/IV NSCLC randomized to best supportive care (BSC) alone (n=83) or BSC + L-BLP25 (1000 μg lipopeptide) (n=88), L-BLP25 pts received weekly vaccinations for 8 weeks (wks) and could continue maintenance vaccinations every 6 wks from wk 13. Results were encouraging (Butts et al, JCO 2005) and a remarkable number of pts received prolonged treatment (tmt). As a result a global phase III study (START) has been initiated. Methods: Safety results for 16 pts from the phase IIb study treated for ≥2 years with L-BLP25 are reported. Results: In these 16 pts (median age 57.5 years, ECOG PS: 0 in 5/16 [31%] and 1 in 11/16 [69%]), there were more females (56% vs 44% [9/16 vs 76/171]) and locoregional stage IIIB disease at entry (81% vs 38% [13/16 vs 65/171]) vs the phase IIb study population. Pts received L-BLP25 for 2.0–7.7 years and 10 pts were treated for >5 years. Compliance with tmt was good: almost all (96%) maintenance vaccinations were given every 6 wks according to the tmt schedule. L-BLP25 was well tolerated: the most common tmt-emergent adverse events (TEAEs) were cough (n=12, 75%), fatigue (n=12, 75%), and dyspnea (n=11, 69%). The pattern of TEAEs did not change significantly over time and there was no rise in the incidence of TEAEs with increasing time on tmt. Among the most common TEAEs in years 1, 2, and >2 were nausea (44, 19, and 38%), fatigue (56, 18, and 38%), chest pain (38, 31, and 31%), and cough (38, 25, and 31%). Twelve pts (75%) had tmt-related TEAEs (grade 1/2 in 11/12 pts [92%] and grade 3 in 1/12 [8%]): the most common were injection-site reactions. The occurrence of tmt-related TEAEs decreased with increasing tmt duration. There was no evidence of any TEAEs related to autoimmunity. Analysis of laboratory data did not indicate any long-term renal, liver, or other toxicity. Conclusions: Long-term use of L-BLP25 was without any identifiable safety issues. In particular, there was no evidence of autoimmune reactions with prolonged use. [Table: see text]

8071 Background: Pts diagnosed with advanced NSCLC with good performance status typically receive platinum-based chemotherapy; however, no approved maintenance therapy exists. Tremelimumab, a fully human anti-CTLA4 mAb, is associated with durable responses in some pts with metastatic melanoma. Methods: This open-label, randomized, multicenter, phase II clinical trial evaluating efficacy and safety of tremelimumab as maintenance therapy was conducted in pts with locally advanced or metastatic NSCLC with ECOG performance status ≤1. Pts treated with ≥4 cycles of first-line platinum-based therapy resulting in either stable disease (SD) or response per RECIST were eligible and were randomized 3–6 weeks after prior therapy. Pts received 15 mg/kg IV tremelimumab Q90D or BSC until disease progression. Primary endpoint was progression-free survival (PFS) at 3 months. Secondary endpoints included safety, objective response rate, and 1-year survival. Results: Eighty-seven pts received tremelimumab (n=44) or BSC (n=43). Nine (20.9%; 90% CI: 11.4%, 33.7%) pts receiving tremelimumab and 6 (14.3%; 90% CI: 6.4%, 26.3%) pts receiving BSC were progression free at 3 months. Among pts receiving tremelimumab, there were 2 (4.8%) partial responses and 7 (16.6%) SDs, compared with 0 and 6 (14.3%) pts receiving BSC, respectively. Treatment-related adverse events (AEs) were observed in 27 (61.4%) pts receiving tremelimumab and 3 (7.0%) receiving BSC. Nine pts (20.5%) receiving tremelimumab reported grade 3 or 4 AEs compared with 0 patients receiving BSC. The most common grade 3 or 4 AEs attributed to tremelimumab were diarrhea and colitis (n=4, 9.1%). Conclusions: In pts with advanced NSCLC and good performance status receiving platinum-based first-line therapy, single-agent tremelimumab was tolerable, with safety consistent with prior studies. Although PFS analysis did not demonstrate superiority of tremelimumab over BSC, the 4.8% objective response rate seen only in the investigational arm may support future combination studies. Analysis of 1-year survival is forthcoming. [Table: see text]