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Track / Category
M. Reck
MINI 01 - Pathology (ID 93)
Event: WCLC 2015
Type: Mini Oral
Track: Biology, Pathology, and Molecular Testing
Presentations: 1
Moderators:W.A. Franklin, A.G. Nicholson
Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
MINI01.05 - Local Diagnostic Practices for Advanced Non-Small-Cell Lung Cancer in Europe and Japan: ASSESS Study (ID 2629)
10:45 - 12:15 | Author(s): M. Reck
ASSESS (a large, multicentre, non-interventional, diagnostic study; NCT01785888) evaluated local diagnostic practices for patients with advanced non-small-cell lung cancer (aNSCLC) in Europe/Japan.
Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly diagnosed/recurrent disease after resection; ineligible for curative treatment. We report diagnostic assessments and epidermal growth factor receptor (EGFR) mutation test turnaround times (secondary endpoints) associated with tissue/cytology samples from patients in Europe/Japan.
1311 patients enrolled (300 Japan). Immunohistochemistry (IHC) was used to confirm pathological diagnosis in 727/960 (76%) and 142/146 (97%) patients in Europe and Japan, respectively (where data were available); the following markers were assessed using IHC: TTF-1 (Europe 96% and Japan 79%); p65 (4% and 8%); and p40 (9% and 24%). EGFR mutation tests were not performed on samples from 110 patients and tested samples from 17 patients did not yield results. The most common reason for not testing was insufficient material provided (Europe 60% [47/78 responses]; Japan 56% [5/9 responses]). The percentages of neoplastic cells in samples (data available: Europe n=281; Japan n=20) were: <20% tumour cells: Europe 15% vs Japan 35%; 20–50% tumour cells: 23% vs 45%; >50% tumour cells: 61% vs 20%. Considering sampling methodologies, the most common sampling sites (data available: Europe n=996; Japan n=291) were the lung parenchyma (Europe 73%; Japan 79%) or lymph nodes (Europe 9%; Japan 9%); the most common sample collection method was bronchoscopy (Europe 39%; Japan 68%; Table 1). Median EGFR mutation test turnaround time was longer in Europe (11 days) versus Japan (8 days; Table 2). Mutation test success rates for Europe and Japan were 98.3% and 99.6%, respectively.
Diagnostic assessments, sampling methodologies and EGFR mutation testing practices vary between and within Europe and Japan; further understanding of local practices will drive improvements and enable more patients to receive appropriate personalised treatment. Figure 1 Figure 2
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
Track: Treatment of Advanced Diseases - NSCLC
Moderators:G.J. Riely, M.C. Garassino
Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
MINI16.10 - Discussant for MINI16.06, MINI16.07, MINI16.08, MINI16.09 (ID 3348)
Abstract not provided
MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)
Moderators:R. Feld, R. Dziadziuszko
Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
MINI17.07 - Efficacy of Nintedanib/Docetaxel after Bevacizumab, Pemetrexed or Taxanes Therapy (ID 1521)
Nintedanib is a triple angiokinase inhibitor of receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor and fibroblast growth factor. The randomized, placebo-controlled, Phase III LUME-Lung 1 study (NCT00805194; 1199.13) investigating nintedanib/docetaxel was the first trial of an antiangiogenic agent to demonstrate significant overall survival (OS) benefit in previously treated patients with non-small cell lung cancer (NSCLC) of adenocarcinoma histology; nintedanib/docetaxel is approved in the European Union for the treatment of patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after 1[st]-line chemotherapy. Here we report LUME-Lung 1 data from the adenocarcinoma population who received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes.
In LUME-Lung 1, 1314 patients with Stage IIIB/IV recurrent NSCLC received either nintedanib/docetaxel or placebo/docetaxel. Primary endpoint was centrally assessed progression-free survival (PFS); OS was a key secondary endpoint. Prior treatment with anti-VEGF agent bevacizumab was a stratification factor. Analyses of the adenocarcinoma population (n=658) according to prior treatment with bevacizumab (n=45 in either arm), pemetrexed (1[st]-line [n=126] or maintenance [n=27]) or taxanes (n=142) were performed to determine if 1[st]-line regimens could influence subsequent outcomes for nintedanib/docetaxel.
Patient characteristics were generally well-balanced across prior-treatment subgroups. For the adenocarcinoma population, there was no interaction between 1[st]-line treatment with bevacizumab, pemetrexed or taxanes and treatment outcome with nintedanib/docetaxel. Independent of pretreatment, nintedanib/docetaxel-treated adenocarcinoma patients had an OS benefit (Table). In the overall patient population, efficacy outcomes for these subgroups were also similar regardless of prior treatment. Furthermore, there was no significant effect on nintedanib/docetaxel outcomes for the few adenocarcinoma patients who received maintenance pemetrexed. The adverse event (AE) profile for nintedanib/docetaxel in each subgroup was consistent with that reported for the adenocarcinoma population in LUME-Lung 1, with diarrhea and reversible liver enzyme elevations among the more frequently reported AEs. Among patients who received nintedanib/docetaxel, there was no difference between prior-treatment subgroups in the frequency of AEs commonly associated with the prior treatment, such as hypertension with bevacizumab, mucositis with pemetrexed and peripheral neuropathy with taxanes.
In LUME-Lung 1, regardless of whether a patient with NSCLC of adenocarcinoma histology received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes, subsequent treatment with nintedanib/docetaxel led to improved OS.
Table: OS results in patients with NSCLC of adenocarcinoma tumor histology stratified by ± prior 1st-line bevacizumab, pemetrexed or taxanes treatment
No BEV BEV No PEM PEM No TAX TAX
N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D
Patients, n 298 315 24 21 261 271 61 65 245 271 77 65
Median OS, months 12.6 10.6 14.9 8.7 13.4 10.8 12.0 8.0 12.2 10.3 15.1 11.6
HR (95% CI) 0.85 (0.71–1.01) 0.61 (0.31–1.20) 0.83 (0.68–1.00) 0.79 (0.53–1.18) 0.86 (0.71–1.05) 0.75 (0.51–1.11)
Interaction p-value p=0.24 p=0.90 p=0.61
BEV, bevacizumab; CI, confidence interval; HR, hazard ratio; N/D, nintedanib/docetaxel; NSCLC, non-small cell lung cancer; OS, overall survival; PEM, pemetrexed; Pl/D, placebo/docetaxel; TAX, taxanes.
MINI17.08 - Tumor Growth Over Time with Nintedanib/Docetaxel or Placebo/Docetaxel in Adenocarcinoma NSCLC: Analysis From the LUME-Lung 1 Study (ID 1405)
Nintedanib (N; Vargatef[®]), a triple angiokinase inhibitor, is approved in the EU in combination with docetaxel (D) for the treatment of patients with advanced NSCLC of adenocarcinoma histology (ACH) after 1[st]-line chemotherapy. In the randomized, placebo-controlled, Phase III LUME-Lung 1 study (NCT00805194; 1199.13), N+D significantly improved overall survival (OS; secondary endpoint) vs D in patients with ACH (median OS: 12.6 vs 10.3 months (m); HR: 0.83 [95% CI: 0.70–0.99]; p=0.0359) and in patients who progressed either during or within 9 m of 1[st]-line therapy (time[T]<9m) (median OS: 10.9 vs 7.9 m; HR: 0.75 [95% CI: 0.60–0.92]; p=0.0073). We explored the impact of on tumor growth over time as a treatment effect of N+D, with a specific focus on early progressors (T<9m) and patients who had progressive disease as best response to 1[st]-line therapy (PD-FLT).
Tumor growth was evaluated using all available tumor measurements. Mixed-effects models were used to quantify the non-linear individual relationships between time from randomization and tumor burden, measured as the sum of longest diameter of target lesions (SLD) and assessed by independent central review (RECIST 1.0). Analyses were conducted for the entire population of patients with ACH, T<9m and PD-FLT.
Estimated mean baseline SLD was 82.5 mm in all patients with ACH, 88.3 mm in T<9m and 98.1 mm in PD-FLT. N+D showed a significant reduction of tumor growth over time (p<0.0001) in patients with ACH compared to D. Treatment difference at 6 months (SLD D group – SLD N+D group) for patients with ACH was 9.7 mm. This treatment difference was even more pronounced in the T<9m group (16.8 mm) and in patients with PD-FLT (19.7 mm). Tumor growth over time for N+D showed a non-linear J-shaped curve, indicating a decline in SLD at the beginning of treatment, which was maintained over time followed by a linear increase (see Figure for curves for the T<9m group). This relationship was consistently observed between populations. For patients treated with D, a linear increase in SLD from baseline over time in all ACH patients, T<9m and PD-FLT was observed. Figure 1
In the LUME-Lung 1 study, N+D significantly decreased tumor burden and decelerated tumor growth over time compared to D in all patients with ACH and in the groups of patients with the poorest prognosis.
MINI 30 - New Kinase Targets (ID 157)
Moderators:K. Park, M. Villalona
MINI30.03 - Smoking Predicts Sensitivity to PARP Inhibitor, Veliparib, in Advanced NSCLC Patients (ID 1279)
Tobacco-related non-small cell lung cancer (NSCLC) is associated with reduced survival and greater genomic instability. Veliparib (V) is a PARP inhibitor that augments platinum-induced DNA damage in preclinical studies, and a recent Phase 2 trial of advanced NSCLC trended to improved survival (HR 0.80; CI 0.54–1.18) when V was added to carboplatin (C) and paclitaxel (P). Here we report outcomes based on smoking status from this randomized Phase 2 study of CP with either V or placebo in advanced NSCLC.
Patients with previously untreated advanced/metastatic NSCLC were randomized 2:1 to CP with either V at 120mg BID or placebo (randomization stratified by histology and smoking history). Cotinine was measured in patients' plasma samples as an index of recent tobacco use.
Of 158 patients, 68% were male, and 49% had squamous NSCLC. At study entry, 60% pts were self-reported current smokers, 27% former smokers, and 13% never smoked. There were no significant differences in veliparib pharmacokinetic parameters between cotinine-high and low. Grade 3/4 AEs were elevated in current-smokers treated with VCP vs CP (66% vs. 40%, p=0.026); all-grade AEs and SAEs were similar between the two groups. The most common AEs in current-smokers were neutropenia (41% VCP; 27% CP), alopecia (36%; 33%), and anemia (31%; 40%). Figure 1 A sensitivity analysis of heavy vs light-smokers (≥ vs <39 pack-years, current or former smokers) showed advantage of veliparib in heavy-smokers: median PFS [HR(95% CI)] for VCP/CP was 7.0 vs 3.5 [0.43(0.20–0.94)] for heavy-smokers and 4.4 vs 4.2 [0.97(0.49–1.92)] for light-smokers; median OS was 12.6 vs 8.8 [0.52 (0.27–1.02)] for heavy-smokers and 9.9 vs 8.8 [0.92(0.53–1.61)] for light-smokers. A cotinine sensitivity analysis found that outcomes in cotinine-high were similar to current-smokers: PFS, cotinine-high HR was 0.38 (0.19–0.73) and cotinine-low was 0.97 (0.51–1.87); OS, cotinine-high HR was 0.52 (0.29–0.92) and cotinine-low was 1.07 (0.63–1.81). In univariate analyses assessing the influence of baseline characteristics and treatment on outcomes, smoking status and treatment had a significant interaction (p=0.0301 PFS, p=0.0118 OS). Additionally, multivariate analysis including all factors also identified current smoking as predictive of improved outcomes with VCP.
Smoking status was a strong predictor of efficacy for veliparib-chemotherapy combination in advanced NSCLC. No differences in pharmacokinetics of V were seen based on plasma cotinine; toxicity of VCP was acceptable regardless of smoking history. A Phase 3 study has been initiated in patients with smoking history (M14-359).
MS 16 - Novel SCLC Therapies (ID 34)
Type: Mini Symposium
Track: Small Cell Lung Cancer
Moderators:C. Barrios, N. Saijo
MS16.04 - Immunotherapy (Checkpoint Inhibitors) (ID 1919)
Small cell lung cancer (SCLC), which accounts for 15 – 20% of all lung cancer cases, represents one of the most aggressive subtypes based on rapid growth and early metastasis. Only limited therapeutic progress has been achieved in the recent decades and despite multiple mutations no targeted therapy for SCLC has been available by now. Based on preclinical data that revealed a relevant correlation between the immune system and SCLC the exploration of immune modulating agents appears to be attractive. First signals coming from randomized phase II trials showed an enhanced activity for the combination of the anti cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab with chemotherapy compared to chemotherapy alone. This combination is now under investigation in a couple of extended randomised trials. Besides ipilimumab also antibodies inhibiting the axis of programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) like nivolumab or pembrolizumab have shown encouraging results either alone or in combination with ipilimumab in heavily pre-treated patients with advanced SCLC. Ongoin or planned randomised trials will validate these signals in various therapeutic lines. A confirmation of these attractive early outcomes would have an substantial clinical impact. In particular in SCLC identification of new potential biomarkers will become of great importance because the PDL-1 status might not be the optimal predictive marker in this tumor entity.
ORAL 31 - PD1 Axis Inhibition (ID 143)
Type: Oral Session
Moderators:J. Weiss, B. Luey
ORAL31.03 - Evaluation of Disease-Related Symptoms in Patients with Advanced Squamous Non-Small Cell Lung Cancer Treated with Nivolumab or Docetaxel (ID 743)
The CheckMate 017 (NCT01642004) randomized, open-label, global phase 3 study evaluated efficacy and safety of second-line nivolumab vs docetaxel in patients with advanced squamous (SQ) non-small cell lung cancer (NSCLC). Overall survival was significantly superior and duration of treatment longer for nivolumab vs docetaxel. The study also evaluated disease-related symptoms using the Lung Cancer Symptom Scale (LCSS).
The LCSS includes 100 mm visual analog scales for 6 major lung cancer symptoms plus three global items evaluating the impact of symptoms; 0 represents the least severity and 100 the greatest severity. Assessment was performed every 4 weeks for nivolumab and every 3 weeks for docetaxel for the first 6 months on treatment, followed by every 6 weeks for the remainder of the treatment period for both study arms. Following treatment discontinuation, the LCSS also was assessed at two follow-up visits. The LCSS average symptom burden index (ASBI) was computed from the 6 individual symptom scores. Mean baseline and mean change from baseline of the LCSS ASBI at each assessment were summarized by treatment group. A study secondary endpoint was to estimate the proportion of patients whose LCSS ASBI showed a clinically meaningful improvement by week 12 (10 point or greater decrease, the minimally important difference [MID]), which was based on all randomized patients.
Patient baseline characteristics were generally balanced across treatment groups. LCSS completion rates for baseline and at least one subsequent assessment were 68.9% and 62.8% for nivolumab and docetaxel, respectively. Completion rates remained relatively consistent throughout assessments and by treatment arm. Baseline LCSS ASBI values were similar for nivolumab (29.6; standard deviation [SD] 16.4) and docetaxel (29.6; SD 14.7). By week 12, 20.0% (27/135; 95% CI: 13.6, 27.7) of nivolumab patients demonstrated clinically meaningful symptom improvement compared to 21.9% (30/137; 95% CI: 15.3, 29.8) of docetaxel patients. Examining mean changes from baseline in patients' LCSS ASBIs at each assessment, the nivolumab group demonstrated statistically significant improvements from baseline at each assessment from week 12 through week 54, after which sample sizes dropped to fewer than 10 patients; from week 40 through 54, the mean improvements exceeded the MID. In contrast, docetaxel patients remaining on treatment had no statistically significant changes in LCSS ASBI through week 18, after which the sample dropped to fewer than 10 patients. In the two follow-up visits after treatment discontinuation, the mean of the LCSS ASBI for both nivolumab and docetaxel patients indicated similar worsening of symptoms relative to baseline (range, 5.5–9.5); for docetaxel patients, the differences from baseline were statistically significant.
By week 12, the proportion of patients showing meaningful symptom improvement was similar for both the nivolumab and docetaxel groups. However, the overall average symptom burden while on nivolumab improved from baseline over most of the year of available follow up, while average symptom burden for docetaxel patients remained stable relative to baseline during their shorter time on treatment. These results show statistically and clinically significant reductions from baseline in lung cancer symptoms for patients with squamous NSCLC treated with second-line nivolumab.
P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
P1.01-062 - Rash as a Marker for the Efficacy of Necitumumab in the SQUIRE Study (ID 97)
SQUIRE, a randomized, phase III study (n=1,093), demonstrated that the addition of the EGFR monoclonal antibody necitumumab (N) to gemcitabine-cisplatin (GC) improved overall survival in patients with stage IV squamous NSCLC. Rash is an established class side-effect associated with EGFR-targeting agents. Previous studies have suggested a positive association between rash and clinical outcomes with EGFR-targeted therapy.
Pre-emptive treatment for rash was not allowed per protocol until completion of the first cycle of study therapy. For the purpose of this analysis, patients randomized to the N+GC arm were categorized and grouped according to whether or not they experienced rash during the first two cycles of study therapy. Patients who died or were lost to follow-up before completing two cycles of study therapy were not included in this analysis. Overall survival (OS) and progression-free survival (PFS) were measured from the date of randomization, with parameters estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs between subgroups were estimated from stratified Cox proportional hazards models, with comparisons between arms using a stratified log-rank test.
505 patients were evaluable in the N+GC arm at the end of cycle 2 of which 69% experienced rash during cycle 1 and/or cycle 2. Patients experiencing rash in the N+GC arm had improved OS (HR=0.738, p=0.0001) and PFS (HR=0.808, p=0.0066) compared with patients in the GC arm. Patients experiencing rash in the N+GC arm had improved OS (HR=0.656, p=0.0001) compared with patients in the N+GC arm who did not experience rash. The difference in PFS between patients in the N+GC arm experiencing rash versus those not experiencing rash was not statistically significant. Median PFS and OS for patients experiencing rash in the N+GC arm was 6.2 mo and 13.6 mo respectively, as compared to 5.6 and 10.2 mo for patients in the N+GC arm without rash and 5.6 and 10.6 mo for patients in the GC arm.
Patients alive and under follow-up after Cycle 2
N+GC with rash N=350 N+GC no rash N=155 GC N=508
Overall Survival, mo (CI) 13.6 mo (11.6, 15.2) 10.2 (8.7, 11.6) 10.6 (9.5, 11.9)
HR* (95% CI) 0.656 (0.529, 0.813) 0.738 (0.631, 0.864)
Stratified log-rank p value* 0.0001 0.0001
PFS, mo (CI) 6.2 mo (5.7, 6.9) 5.6 (5.0, 5.7) 5.6 (5.3, 5.6)
*In comparison to the N+GC group with rash
Rash occurring during the first two cycles of treatment with necitumumab (N+GC) is associated with improved OS in patients with advanced squamous NSCLC.
P1.01-075 - Phase III, Randomized, Double-Blind Trial of Bavituximab Plus Docetaxel in Previously Treated Stage IIIb/IV Non-Squamous NSCLC (SUNRISE) (ID 1581)
Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. PS binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages leads to production of anti-inflammatory cytokines such as TGF-β and IL-10. Bavituximab, a first-in-class PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines such as TNF-α and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte (CTL) immunity. Docetaxel has also been shown to suppress MDSCs while increasing tumor antigens and T-cell mediated cytotoxicity, thereby enhancing bavituximab's immunomodulatory effects. In a prior double-blind Phase II trial in 2nd line non-squamous non-small cell lung cancer, bavituximab 3 mg/kg plus docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 month) in median overall survival (OS) compared to control.
SUNRISE is a Phase III, double-blind trial where patients with previously treated Stage IIIb/IV non-squamous, non-small cell lung cancer are randomized in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab or placebo, followed by maintenance with weekly bavituximab or placebo until progression or toxicity. Patients will be stratified by region (North America, Europe, or Rest of World), disease stage (IIIb or IV), and previous maintenance/targeted therapy (yes or no). This trial was initiated in December 2013 and accrual of 582 patients across 160+ sites in 14 countries is planned over 24 months. The primary endpoint is OS and two interim analyses are planned. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR) and safety. Radiographic tumor response is centrally assessed every two cycles during combination therapy and every nine weeks during maintenance. Exploratory analysis will include the assessment of changes in circulating immune cells and cytokines to better understand the immunotherapeutic mechanism.
Trial in progress
P1.01-080 - Treatment Rationale and Study Design for the Phase 3 JUNIPER Study: Abemaciclib vs Erlotinib in Patients with Stage IV NSCLC and KRAS Mutation (ID 1438)
Abemaciclib (LY2835219) is a potent, selective small molecule inhibitor of CDK4/6, which has been shown to inhibit cell cycle progression by preventing the phosphorylation and functional inactivation of the Rb tumor-suppressor protein. Cell cycle dysfunction due to abnormalities in the CDK4/6 pathway occurs in NSCLC. KRAS mutant xenografts predict for greater sensitivity to CDK4/6 inhibitors. In a phase 1 study with abemaciclib (Goldman ASCO 2014), 16 patients with KRAS mutant tumors (N=29) had a response of stable disease (SD) or better (disease control rate [DCR]=55.2%), and 9 patients with KRAS wild-type tumors (N=24) had a response of SD or better (DCR=37.5%).
JUNIPER (NCT02152631) is a randomized, phase 3 study of abemaciclib (200 mg orally q12hrs) + best supportive care (BSC) versus erlotinib (150 mg orally q24hrs) + BSC in patients with stage IV NSCLC whose tumors have detectable KRAS mutations and who have progressed after platinum-based chemotherapy and one other prior therapy or who are not eligible for further chemotherapy. About 550 patients will be randomized to abemaciclib or erlotinib 3:2 ratio using following factors: number of prior chemotherapy regimens (1 vs. 2), ECOG PS (0 vs. 1), gender (male vs. female) and KRAS mutation (G12C vs. others). This design has 80% power to detect overall survival (OS) hazard ratio (HR) of 0.75 (type I error 0.045) and progression-free survival (PFS) HR of 0.67 (type I error 0.005). Erlotinib was chosen as the control arm, as it is the only agent indicated for both 2nd and 3rd line therapy in advanced NSCLC. Treatment will continue until disease progression or unacceptable toxicity occurs, with assessments every 28 days, followed by short-term and long-term follow-up. Primary objectives are to compare OS and PFS of the treatment arms. Enrollment began December 2014. If the primary objectives are achieved, this study will provide results on an alternative treatment option, abemaciclib + BSC, for patients with NSCLC whose tumors have detectable KRAS mutations, currently a patient population with few treatment options.
P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
P1.04-044 - Local Diagnostic Practices for Advanced Non-Small-Cell Lung Cancer in Asia-Pacific and Russia: IGNITE Study (ID 2650)
IGNITE (a large, multicentre, interventional, non-comparative diagnostic study; NCT01788163) evaluated local diagnostic practices for patients with advanced non-small-cell lung cancer (aNSCLC) in Asia-Pacific/Russia.
Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly diagnosed/recurrent disease after resection; ineligible for curative treatment. We report diagnostic assessments and epidermal growth factor receptor (EGFR) mutation test turnaround times (secondary endpoints) associated with tissue/cytology samples from patients in Asia-Pacific/Russia.
3382 patients enrolled (972 Russia). Immunohistochemistry (IHC) analysis was used to confirm diagnosis in 989/2093 (47%) and 165/949 (17%) patients in Asia-Pacific and Russia, respectively (where data were available). Where IHC was used, the markers assessed were: TTF-1 (Asia-Pacific 95% and Russia 90%); p65 (3% and 5%); and p40 (17% and 4%). EGFR mutation tests were not performed on samples from 262 patients and tested samples from 23 patients did not yield results. The most common reason for not testing was insufficient material provided to test (Asia-Pacific 93% [100/108 responses], Russia 67% [24/36]). The percentages of neoplastic cells in samples (data available: Asia-Pacific n=1042; Russia n=187) were: <20% tumour cells: Asia-Pacific 33% vs Russia 6%; 20–50% tumour cells: 28% vs 33%; and >50% tumour cells: 40% vs 61%. Considering sampling methodologies (data available: Asia-Pacific n=2410; Russia n=972), the most common sampling sites were the lungs (Asia-Pacific 68%; Russia 80%) or lymph nodes (Asia-Pacific 14%; Russia 10%); the most common sample collection method was bronchoscopy (Asia-Pacific 22%; Russia 45%; Table 1). Median EGFR mutation test turnaround time was within 2 weeks for all countries except Thailand (70 days; Table 2). Mutation test success rates were high for Asia-Pacific (99.5%) and Russia (98.7%).
Diagnostic assessments, sampling methodologies and EGFR mutation testing practices vary between and within Asia-Pacific and Russia; further understanding of local practices will drive improvements and enable more patients to receive appropriate personalised treatment. Figure 1 Figure 2
P2.01-091 - Multicenter, Randomized, Double-Blind Study of Erlotinib plus Ramucirumab or Placebo in Patients with EGFR Mutation-Positive Metastatic NSCLC (ID 1560)
Ramucirumab, a human IgG1 monoclonal antibody, binds to Vascular Endothelial Growth Factor (VEGF) Receptor 2, preventing binding of VEGF-A, C and D. Ramucirumab in combination with docetaxel has demonstrated improvement in overall survival, progression free survival (PFS), objective response rate and disease control rate in 2nd line treatment of NSCLC patients in the phase III REVEL study, which included non-squamous and squamous cell carcinoma patients. Although erlotinib is recognized as one of the standard of care options in the frontline treatment of patients whose tumors harbor an Epidermal Growth Factor Receptor (EGFR) mutation, it is hypothesized that the duration of disease control would be greater when an antiangiogenic agent such as ramucirumab is added to erlotinib. This global phase Ib/III trial will assess safety, tolerability and efficacy (phase III) of the combination of ramucirumab with erlotinib in previously untreated stage IV NSCLC patients harboring activating EGFR mutations. The trial is planned to be conducted in ~120 sites in the Americas, Europe, and Asia and is currently open for enrollment. (RELAY, NCT02411448)
In part A (phase Ib) approximately 12 patients (6 Japan + 6 US/EU) will receive ramucirumab (10mg/kg on day 1) every two weeks + erlotinib (150 mg/day). DLT assessment will be performed after patients complete four weeks of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every two weeks with erlotinib until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary endpoint is PFS. There are 3 planned interim analyses that will evaluate safety, futility and efficacy, respectively. Other secondary endpoints include overall survival, objective response rate, disease control rate, duration of response, safety and quality of life.
P3.01-072 - Final Efficacy and Safety Results of ECOG Performance Status (PS) Subgroup Analyses From the SQUIRE Phase III Study (ID 1660)
As previously reported, the SQUIRE study demonstrated that the addition of necitumumab (N) to gemcitabine-cisplatin (GC) chemotherapy significantly improved survival in patients with stage IV squamous NSCLC. Overall survival (OS), progression-free survival (PFS), and safety results are presented for Eastern Cooperative Oncology Group (ECOG) PS 0–1/2 subgroups.
Patients with stage IV squamous NSCLC were randomized 1:1 to N (800 mg iv, days 1 and 8) plus GC (G=1250 mg/m² iv, days 1 and 8; C=75 mg/m² iv, day 1) or GC alone every 21 days for up to six cycles in this multicenter, open-label study. N+GC patients without progression continued on N alone until progressive disease or intolerable toxicity. The study was powered for OS and PFS (previously reported). Preplanned subgroup analyses were performed for ECOG PS 0–1 and 2.
Subgroups PS 0–1/2 (n=996 [91%]/n=96 [9%]) were well balanced regarding baseline characteristics (males, 83% vs 86%; median age, 62 vs 65 yrs; smoking/ex-light smoker/nonsmoker, 91/4/5% vs 89/6/5%). GC median relative dose intensity was similar between PS 0–1/2 subgroups; N (overall) was higher for the PS 0–1 than for PS 2 subgroup (94.8% and 90.0%). Post-study therapy use was generally higher in the PS 0–1 than in the PS 2 subgroup, but was balanced between both arms. The OS hazard ratio (HR) for N+GC vs. GC was 0.85 (95% CI: 0.74, 0.98; p=0.026) for PS 0–1 and 0.78 (95% CI: 0.51, 1.21; p=0.275) for PS 2. The PFS HR (N+GC vs. GC) was 0.86 (95% CI: 0.75, 0.99; p=0.035) for PS 0–1 and 0.79 (95% CI: 0.50, 1.24; p=0.292) for PS 2. Select Grade ≥3 treatment-emergent adverse events (TEAEs) are shown in the table. The percentage of patients with adverse events leading to discontinuation of any study drug was lower in the PS 0–1 subgroup (N+GC=30%; GC=23%) than the PS 2 subgroup (N+GC=42%; GC=41%). The percentage of patients hospitalized was higher in the PS 0–1 subgroup (N+GC=43%; GC=34%) than the PS2 subgroup (N+GC=25%; GC=30%). Table. Select TEAEs
Grade ≥3 Event* PS 0-1 N+GC (%) N=490 PS 0-1 GC (%) N=495 PS 2 N+GC (%) N=48 PS 2 GC (%) N=46
Neutropenia 25.5 28.1 12.5 21.7
Febrile neutropenia 0.6 1.4 2.1 0
Anemia 11.2 10.3 4.2 17.4
Thrombocytopenia 10.4 10.5 8.3 13.0
Fatigue 7.1 7.1 8.3 6.5
Hypomagnesemia 9.8 1.0 4.2 2.2
Rash 7.8 0.4 0 0
Arterial thromboembolic events 3.7 1.8 6.3 4.3
Venous thromboembolic events 5.5 2.6 0 2.2
[*][Adverse events of possible relevance to treatment, according to either composite categories or preferred terms (febrile neutropenia only)]
OS and PFS treatment results for N+GC were consistent and considered favorable across subgroups including ECOG PS 2 patients. Administration of N+GC was well tolerated in PS 2 patients, with no evidence of an increased safety risk in this subgroup.
P3.01-089 - Nab-Paclitaxel with or without CC-486 as Second-Line Therapy for NSCLC (ABOUND.2L) (ID 719)
Many patients with advanced non-small cell lung cancer (NSCLC) will experience disease progression during first-line chemotherapy. Effective and well-tolerated second-line treatment options for this patient population are limited. In a multicenter phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the primary endpoint of overall response rate (ORR) compared with solvent-based paclitaxel plus C in patients with advanced NSCLC (33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). nab-P combined with CC-486, an oral formulation of azacitidine, resulted in promising outcomes in a phase I trial of patients with relapsed/refractory solid tumors (LoRusso et al. Mol Cancer Ther. 2013;12(11 Suppl):Abstract A120). In the open-label, multicenter phase II ABOUND.2L trial, the safety and efficacy of nab-P with or without CC-486 will be evaluated in the second-line treatment of patients with advanced nonsquamous NSCLC.
Approximately 160 patients who have received 1 platinum-containing chemotherapy regimen for treatment of advanced disease will be randomized 1:1 to CC-486 200 mg/day on days 1 to 14 every 21 days plus nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 8 and 15 every 21 days or nab-P 100 mg/m[2] IV (30-minute infusion) on days 1 and 8 every 21 days. Key eligibility criteria include histologically or cytologically confirmed advanced nonsquamous NSCLC, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, no prior taxane therapy, no known EGFR mutation or EML4-ALK translocation, and peripheral neuropathy grade < 2. Randomization will be stratified by ECOG performance status (0 vs 1), sex, and smoking status (yes vs no). ClinicalTrials.gov identifier NCT02250326.
Key Endpoints
Primary -Progression-free Survival
Secondary -Disease control rate -Overall Survival -ORR -Safety
Exploratory -Changes in quality of life -Healthcare resource utilization throughout the study -Correlation between pretreatment tumor characteristics and response to treatment
P3.04-005 - Discrepancies between ALK FISH and Capture Based NGS Test NEOplus and Clinical Outcome with ALK TKI Therapy (ID 2748)
Research in recent years has unraveled several gene fusions driving tumor development in lung cancer. Especially adenocarcinomas of the lung harboring ALK and ROS1 gene fusions exhibit striking sensitivity to ALK and ROS1 kinase inhibitors respectively, translating to dramatic responses in the clinic. Several different technologies are available to detect aberrant genomic structures. The most frequently used technologies include fluorescent in situ hybridization (FISH), currently considered as the "gold standard", immunohistochemistry (IHC), RT-PCR based approaches and hybrid capture based NGS sequencing.
Here, we describe a selection of tumor samples showing discrepant results between fluorescent in situ hybridization and hybrid capture based NGS sequencing. These included samples with positive FISH but negative NEOplus as well as negative FISH and positive NEOplus results. In addition, we used response data of targeted therapies to evaluate the true genetic phenotype of the tumor.
Overall, several lung adenocarcinomas showed discrepant results when FISH and NEOplus data were compared. First, one sample was tested positive for ALK rearrangement using FISH which was not confirmed using NEOplus. In line with this finding, the tumor did not respond to ALK TKI treatment. Second, a total of 4 cases were fusion negative by FISH but positive by NEOplus. Three out of 4 ALK positive cases showed clinical response to ALK kinase inhibition, the clinical results for case number 4 are pending. Interestingly, one of these responding tumors was also negative for ALK expression using IHC.
In summary, we describe a selection of tumor samples with discrepant results for fusion detecting using FISH and NEOplus. Overall, in all of the cases for which clinical response data was available, tumor sensitivity was in line with the initial diagnosis generated by the NEOplus assay.
P3.04-053 - SPECTAlung: Screening Patients with Thoracic Tumors for Efficient Clinical Trial Access (ID 1386)
The identification of molecular alteration and its targeting has completely changed the treatment and prognosis of lung cancer. However, designing and implementing clinical trials in small subsets of patients with a particular molecular alteration is challenging because of lack of uniform screening program. Across Europe, screening for molecular alterations is center or country dependent and, generally limited to a small subset of genes. SPECTAlung is the first European standardized, quality-assured molecular screening program of the European Organization for the Research and Treatment of Cancer (EORTC) in collaboration with the European Thoracic Oncology Platform (ETOP) to facilitate clinical trial access for patients with thoracic tumors. It is expected to test 500 to 1000 patients each year with the overall goal of offering patients clinical trials with targeted agents.
Patients sign the informed consent for their tumor tissue to be collected, centralized and processed according to defined international quality control standards at Gustave Roussy Biobank (Villejuif, France). Next Generation Sequencing (NGS) is performed at Sanger Institute (Cambridge, UK) where a panel of about 360 genes is analyzed for mutation, rearrangements and gene copy number. Eligible patients will be those having a pathological diagnosis of any thoracic tumor (lung cancer, malignant pleural mesothelioma and thymic malignancies) at any stage of disease, availability of tumor tissue, age at least 18 years, PS 0-2, life expectancy > 3 months, no active malignancy in the 5 years before study entry and absence of any exclusion criteria that may prevent inclusion into clinical trials. A molecular report will be released to the investigator highlighting identified molecular alterations and also the trials for which the patients might be eligible. The study has been submitted to ethical committees of 15 selected highly specialized and qualified thoracic centres in 12 countries in Europe. EORTC and ETOP will promote the implementation of clinical trials in molecularly selected groups of patients at the SPECTAlung centers. SPECTAlung offers innovative and attractive models of collaboration with commercial and research organizations, by improving patient access to novel therapeutic clinical trial and support the development of personalized medicine. Clinical trial registry number NCT02214134.
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