Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

BACKGROUND: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. PATIENTS AND METHODS: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. RESULTS: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. CONCLUSIONS: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.

A phase III, randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small-cell lung cancer.

BACKGROUND: ASP8273, a novel, small molecule, irreversible tyrosine kinase inhibitor (TKI) specifically inhibits the epidermal growth factor receptor (EGFR) in patients with activating mutations or EGFR T790M resistance mutations. The current study examines the efficacy, safety, and tolerability of ASP8273 versus erlotinib or gefitinib in patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations not previously treated with an EGFR inhibitor. PATIENTS AND METHODS: This global, phase III, open-label, randomized study evaluated ASP8273 versus erlotinib/gefitinib in patients with locally advanced, metastatic, or unresectable stage IIIB/IV NSCLC with activating EGFR mutations. They were ineligible if they received prior chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS), and secondary end points included overall survival, investigator-assessed PFS, best overall response rate (ORR), disease control rate, duration of response (DoR), and the safety/tolerability profile. RESULTS: Patients (n = 530) were randomized 1 : 1 to receive ASP8273 (n = 267) or erlotinib/gefitinib (n = 263). Patient demographics between both treatment groups were generally balanced. Median PFS was 9.3 months (95% CI 5.6-11.1 months) for patients receiving ASP8273 and 9.6 months (95% CI 8.8-NE) for the erlotinib/gefitinib group, with a hazard ratio of 1.611 (P = 0.992). The ORR in the ASP8273 group was 33% (95% CI 27.4-39.0) versus 47.9% (95% CI 41.7-54.1) in the erlotinib/gefitinib group. Median DoR was similar for both groups (9.2 months for ASP8273 versus 9.0 months for erlotinib/gefitinib). More grade ≥3 treatment-emergent adverse events (TEAEs) occurred in patients receiving ASP8273 than in those receiving erlotinib/gefitinib (54.7% versus 43.5%). An independent data monitoring committee carried out an interim safety analysis and recommended discontinuing the study due to toxicity and limited predicted efficacy of ASP8273 relative to erlotinib/gefitinib. CONCLUSIONS: First-line ASP8273 did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib. CLINICALTRIAL.GOV NUMBER: NCT02588261.

CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.

Background: Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methods: Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg od (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). Results: Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39-68] and 92% (46/50; 95% CI 81-98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1-15 months); at 9 months, 75% (95% CI 53-88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Conclusions: Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. ClinicalTrials.gov number: NCT01802632; NCT02094261.

PD-L1 protein expression assessed by immunohistochemistry is neither prognostic nor predictive of benefit from adjuvant chemotherapy in resected non-small cell lung cancer.

Background: The expression of programmed death (PD) ligand 1 (PD-L1) protein expression assessed by immunohistochemistry (IHC) has been correlated with response and survival benefit from anti-PD-1/PD-L1 immune checkpoint inhibitor therapies in advanced non-small cell lung carcinoma (NSCLC). The efficacy of several agents appears correlated with PD-L1 expression. It remains controversial whether PD-L1 is prognostic in NSCLC. We assessed the prognostic value of PD-L1 IHC and its predictive role for adjuvant chemotherapy in early stage NSCLC. Patients and methods: Tumor sections from three pivotal adjuvant chemotherapy trials (IALT, JBR.10, CALGB 9633) using the E1L3N antibody were studied in this pooled analysis. PD-L1 staining intensity and percentage in both tumor cells (TCs) and immune cells (ICs) were scored by two pathologists. The average or consensus PD-L1 expression levels across intensities and/or percent cells stained were correlated with clinicopathological and molecular features, patient survivals and potential benefit of adjuvant chemotherapy. Results: Results from 982 patients were available for analysis. Considering staining at any intensities for overall PD-L1 expression, 314 (32.0%), 204 (20.8%) and 141 (14.3%) tumor samples were positive for PD-L1 staining on TCs using cut-offs at ≥1%, ≥10% and ≥25%, respectively. For PD-L1 expressing ICs, 380 (38.7%), 308 (31.4%) and 148 (15.1%) were positive at ≥ 1%, ≥10% and 25% cut-offs, respectively. Positive PD-L1 was correlated with squamous histology, intense lymphocytic infiltrate, and KRAS but not with TP53 mutation. EGFR mutated tumors showed statistically non-significant lower PD-L1 expression. PD-L1 expression was neither prognostic with these cut-offs nor other exploratory cut-offs, nor were predictive for survival benefit from adjuvant chemotherapy. Conclusions: PD-L1 IHC is not a prognostic factor in early stage NSCLC patients. It is also not predictive for adjuvant chemotherapy benefit in these patients.

Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer.

BACKGROUND: Testing for EGFR mutations and ALK rearrangement has become standard in managing advanced nonsmall-cell lung cancer (NSCLC). However, many institutions in Europe, North America and other world regions continue to face a common challenge of facilitating timely molecular testing with rapid result turnaround time. We assessed the prevalence of biomarker testing for advanced NSCLC patients and whether testing affected the timeliness of treatment decisions. METHODS: We conducted a retrospective chart review of a random sample of one-quarter of all patients with advanced NSCLC referred to the Princess Margaret Cancer Centre from 1 April 2010 to 31 March 2013. RESULTS: Of 300 patients reviewed, 175 seen by medical oncology had nonsquamous NSCLC, 72% of whom had biomarker testing carried out. Patients tested for biomarkers were more likely to be female (47% versus 21%, P = 0.002), Asian (27% versus 6%, P = 0.005) and never smokers (42% versus 8%, P < 0.0001). Only 21% of patients with biomarker testing had results available at their initial oncology consultation. This group had a shorter median time from consultation to treatment decision (0 versus 22 days, P = 0.0008) and time to treatment start (16 versus 29, P = 0.004). Thirteen percent underwent repeat biopsy for molecular testing after the initial consultation. Of those with positive EGFR or ALK results, 19% started chemotherapy before biomarker results became available. CONCLUSIONS: Awaiting biomarker testing results can delay treatment decisions and treatment initiation for patients with advanced NSCLC. This may be avoided by incorporating reflex biomarker testing into diagnostic algorithms for NSCLC at the level of the pathologist, and further education of specialists involved in obtaining diagnostic cancer specimens to ensure they are sufficient for molecular testing.

Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses.

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. CLINICALTRIALSGOV NUMBER: NCT00409188.

Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer.

BACKGROUND: Figitumumab (CP-751,871) is a fully human IgG2 monoclonal antibody that inhibits the insulin-like growth factor 1 receptor. This multicenter, randomized, phase III study investigated the efficacy of figitumumab plus erlotinib compared with erlotinib alone in patients with pretreated, nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (stage IIIB/IV or recurrent disease with nonadenocarcinoma histology) who had previously received at least one platinum-based regimen were randomized to receive open-label figitumumab (20 mg/kg) plus erlotinib 150 mg/day or erlotinib alone every 3 weeks. The primary end point was overall survival (OS). RESULTS: Of 583 patients randomized, 579 received treatment. The study was closed early by an independent data safety monitoring committee due to results crossing the prespecified futility boundary. At the final analysis, median OS was 5.7 months for figitumumab plus erlotinib and 6.2 months for erlotinib alone [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.91-1.31; P = 0.35]. Median progression-free survival was 2.1 months for figitumumab plus erlotinib and 2.6 months for erlotinib alone (HR 1.08; 95% CI 0.90-1.29; P = 0.43). Treatment-related nonfatal serious adverse events occurred in 18% and 5% of patients in the figitumumab arm or erlotinib alone arm, respectively. There were nine treatment-related deaths (three related to both drugs, four related to erlotinib alone and two related to figitumumab). CONCLUSIONS: The addition of figitumumab to erlotinib did not improve OS in patients with advanced, pretreated, nonadenocarcinoma NSCLC. Clinical development of figitumumab has been discontinued. CLINICAL TRIAL ID: NCT00673049.

Single organ metastatic sites in non-small cell lung cancer: Patient characteristics, treatment patterns and outcomes from a large retrospective Canadian cohort.

BACKGROUND: There is a paucity of information about the characteristics, treatment patterns, and outcomes of non-small cell lung cancer (NSCLC) patients with single organ metastasis (SOM). METHODS: This retrospective cohort study includes all patients with a diagnosis of stage IV NSCLC diagnosed from 2014 to 2016 and treated at Princess Margaret Cancer Centre. We compared baseline characteristics and patterns of metastatic sites between patients with SOM versus multiple (M)OM. Additionally, we identified treatment modalities and outcomes for patients with SOM. Cox multivariable models (MVA) were utilized to evaluate differences in overall survival (OS) between the SOM and MOM cohorts. RESULTS: Of 893 pts analyzed, 457 (51 %) had SOM, while 436 (49 %) had MOM at initial diagnosis. Demographics were comparable between the two groups. Brain was the most common site of metastasis for SOM patients. When compared to the MOM group, the SOM group had lower percentages of liver and adrenal metastases. Amongst SOM patients, 54 % received single modality treatment, and 20 % did not receive any treatment for their SOM. In MVA, patients with liver (HR 2.4), bone (HR 1.8), and pleural (HR 1.7) metastasis as their SOM site had the worst outcomes, with median OS of 6.8 months, 12.1 months, and 13.0 months respectively. Patients with SOM had a significantly improved median OS compared to those with MOM (15.9 months vs. 10.6 months; HR 0.56, 95 % CI 0.47-0.66, p < 0.001). CONCLUSION: In NSCLC patients who presented with SOM, survival correlated with the initial organ involved and was better overall compared to patients with MOM. SOM NSCLC may benefit from specific management strategies and SOM patients could be considered as a specific subgroup for survival analyses in observational and non-randomized interventional studies. In clinical trials, SOM can be considered as a stratification factor in the future.

Factors associated with referral to medical oncology and subsequent use of adjuvant chemotherapy for non-small-cell lung cancer: a population-based study.

BACKGROUND: Adjuvant chemotherapy (act) for non-small-cell lung cancer (nsclc) is associated with improved survival in the general population, but may be underutilized. We explored the factors associated with referral to medical oncology and subsequent use of act among all patients with resected nsclc in Ontario, Canada. METHODS: The Ontario Cancer Registry was used to identify all incident cases of nsclc diagnosed in Ontario during 2004-2006. We linked electronic records of treatment and of physician billing to identify surgery, act, and medical oncology consultation. A multivariate logistic regression model was used to evaluate factors associated with referral to medical oncology and subsequent use of act. RESULTS: Among 3354 cases of nsclc resected in Ontario during 2004-2006, 1830 (55%) were seen postoperatively by medical oncology, and 1032 (31%) were treated with act. Patients more than 70 years of age were less likely than younger patients to have a consultation [odds ratio (or): 0.4; p < 0.001]. A higher proportion of cases with stage ii or iii nsclc than with stage i disease were referred (ors: 2.7, 2.0 respectively; p < 0.005). We observed substantial geographic variation in the proportion of surgical cases referred (range: 32%-88%) that was not explained by differences in case mix. Among cases referred to medical oncology, older patients (age 60-69 years, or: 0.4; age 70+ years, or: 0.1; p < 0.001) with greater comorbidity (Charlson comorbidity index: 3+; or: 0.5; p < 0.05) and a longer postoperative stay (median length of stay: 7+ days; or: 0.7; p = 0.001) were less likely to receive act. Use of act was greater in patients with stage ii or iii than with stage i disease (ors: 3.0, 2.7 respectively; p < 0.001); use also varied with geographic location (range: 46%-63%). CONCLUSIONS: The initial decision to refer to medical oncology is associated with age and stage of disease, and those factors have an even greater effect on the decision to offer act. Comorbidity and postoperative length of stay were not associated with initial referral, but were associated with use of act in patients seen by medical oncology.

A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours.

BACKGROUND: To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin. METHODS: Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations. RESULTS: Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ≥ 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted. CONCLUSION: The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

Cross-validation study of class III beta-tubulin as a predictive marker for benefit from adjuvant chemotherapy in resected non-small-cell lung cancer: analysis of four randomized trials.

BACKGROUND: The IALT, JBR.10, ANITA and Cancer and Leukemia Group B 9633 trials compared adjuvant chemotherapy with observation for patients with resected non-small-cell lung cancer (R-NSCLC). Data from the metastatic setting suggest high tumor class III beta-tubulin (TUBB3) expression is a determinant of insensitivity to tubulin-targeting agents (e.g. vinorelbine, paclitaxel). In 265 patients from JBR.10 (vinorelbine-cisplatin versus observation), high TUBB3 was an adverse prognostic factor and was associated (nonsignificantly) with 'greater' survival benefit from chemotherapy. We explored this further in additional patients from JBR.10 and the other three trials. PATIENTS AND METHODS: TUBB3 immunohistochemical staining was scored for 1149 patients on the four trials. The original JBR.10 cut-off scores were used to classify tumors as TUBB3 high or low. The prognostic and predictive value of TUBB3 on disease-free survival (DFS) and overall survival (OS) was assessed by Cox models stratified by trial and adjusted for clinical factors. RESULTS: High TUBB3 expression was prognostic for OS [hazard ratio (HR)=1.27 (1.07-1.51), P=0.008) and DFS [HR=1.30 (1.11-1.53), P=0.001). TUBB3 was not predictive of a differential treatment effect [interaction P=0.20 (OS), P=0.23 (DFS)]. Subset analysis (n=420) on vinorelbine-cisplatin gave similar results. CONCLUSIONS: The prognostic effect of high TUBB3 expression in patients with R-NSCLC has been validated. We were unable to confirm a predictive effect for TUBB3.

An economic analysis of the INTEREST trial, a randomized trial of docetaxel versus gefitinib as second-/third-line therapy in advanced non-small-cell lung cancer.

BACKGROUND: The INTEREST (IRESSA NSCLC Trial Evaluating Response and Survival against Taxotere) trial compared gefitinib with docetaxel (Taxotere) in pretreated advanced non-small-cell lung cancer (NSCLC). Noninferiority for overall survival was concluded. Gefitinib had a better toxicity profile and greater improvements in quality of life (QoL). We undertook a cost-consequence analysis to estimate the direct medical costs of gefitinib compared with docetaxel. PATIENTS AND METHODS: Summary data from INTEREST were used to derive resource utilization and direct costs from treatment start until drug discontinuation. Costs for treatment, adverse events, outpatient visits and investigations were calculated. Mean total cost-per-patient-per-arm was determined, and incremental cost was calculated. Utility values were generated from Functional Assessment of Cancer Therapy - Lung scores and compared between arms. RESULTS: Incremental mean overall cost per patient for gefitinib over docetaxel was CAD $5161. Drug was the major contributor to overall cost in both arms. Longer mean duration of gefitinib therapy (134 versus 91 days) contributed to the incremental cost difference. The cost per 21-day cycle was similar in both arms ($1963 docetaxel, $2095 gefitinib). CONCLUSION: The modest increase in cost associated with gefitinib supports its use as an alternative to docetaxel as second-line treatment of advanced NSCLC, particularly given the improvements in QoL, patient preference for oral therapy and better toxicity profile with gefitinib.

The strength of female sex as a prognostic factor in small-cell lung cancer: a pooled analysis of chemotherapy trials from the Manchester Lung Group and Medical Research Council Clinical Trials Unit.

BACKGROUND: Previous studies reported that women survive longer than men, but experience greater toxicity, when treated for small-cell lung cancer (SCLC). METHODS: Individual patient data from six randomized phase II/III chemotherapy trials, from the Manchester Lung Group and UK Medical Research Council, were pooled for analysis. End points included overall survival, response rate, toxicity, dose intensity (DI) and transfusion rates. RESULTS: Of 1707 patients analyzed, 44% were women. At baseline, women had poorer performance status (PS) (57% versus 67% Eastern Cooperative Oncology Group PS 0-1/Karnofsky PS 80-100, P = 0.0004) and more were of normal weight or underweight (57% versus 48%, P = 0.003), but fewer were anemic (25% versus 62%, P < 0.0001). Response rates between women and men were similar (77% versus 76%, P = 0.64). In univariate [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.76-0.96, P = 0.006] and multivariate (HR 0.88, 95% CI 0.79-0.99, P = 0.04) analyses, female sex predicted for longer survival. Women experienced more grade 3/4 emesis (18% versus 9%, P < 0.0001) and grade 3/4 mucositis (13% versus 8%, P = 0.005) than men. There were no differences in DI, infections, transfusions or treatment-related deaths. CONCLUSION: Data from >1700 patients in randomized SCLC chemotherapy trials confirm that women survive modestly longer than men but may experience greater toxicity.

Treatment-emergent hypertension and outcomes in patients with advanced non-small-cell lung cancer receiving chemotherapy with or without the vascular endothelial growth factor receptor inhibitor cediranib: NCIC Clinical Trials Group Study BR24.

BACKGROUND: Hypertension (HTN), a recognized adverse effect of angiogenesis inhibitors, may be a potential biomarker of activity of these agents. We conducted a retrospective analysis to examine the incidence and predictors of the development of on-treatment HTN with the vascular endothelial growth factor receptor tyrosine kinase inhibitor cediranib, and the relationship of this adverse event with treatment outcomes. PATIENTS AND METHODS: BR24 was a double-blind placebo-controlled phase II trial of carboplatin/paclitaxel chemotherapy with either daily oral cediranib or placebo in patients (n = 296) with advanced non-small-cell lung cancer (NSCLC). Exploratory analyses characterized relationships between HTN, baseline variables, and efficacy outcomes. RESULTS: New onset or worsening of preexisting HTN (treatment-emergent HTN) was more frequent in patients receiving cediranib (68 versus 45%, P < 0.0001). Factors associated with HTN in all randomized patients were good performance status and treatment with cediranib. In both arms, treatment-emergent HTN was associated with improved efficacy outcomes, but there was no evidence of a differential treatment effect, with nonsignificant interaction P values. CONCLUSIONS: In advanced NSCLC, HTN is frequent in patients receiving chemotherapy, with or without cediranib. The development of HTN was favorably prognostic in these patients, but not predictive of a differential outcome with cediranib.

The influence of sex and histology on outcomes in non-small-cell lung cancer: a pooled analysis of five randomized trials.

BACKGROUND: Some non-small-cell lung cancer (NSCLC) surgical series have indicated that the positive prognostic effect of female sex is limited to patients with adenocarcinoma. We carried out a retrospective analysis to investigate the role of sex and histology on efficacy, toxicity, and dose delivery after chemotherapy. PATIENT AND METHODS: Individual patient data were pooled from five randomized, phase III, advanced NSCLC chemotherapy trials. Primary outcomes were response rate, overall survival (OS), toxicity, and dose delivery. A secondary analysis examined survival by sex in histological subgroups. RESULTS: Of 2349 patients, 34% were women. Women had a higher response rate to chemotherapy (42% versus 40%, P = 0.01) and longer survival than men (median OS 9.6 versus 8.6 months, P = 0.002). The difference in OS remained after adjusting for age, stage, performance status, and histology (hazard ratio 0.83, 95% confidence interval 0.74-0.92, P = 0.0005). Upon further examination, longer survival in women was only seen in patients with adenocarcinoma (test for interaction P = 0.006). There were no differences in hematological toxicity or transfusions. Women experienced more grade 3-4 emesis than men (P < 0.0001) and more dose delays (P = 0.02) or dose reductions (P < 0.0001). CONCLUSION: The positive prognostic effect among women is confirmed in patients receiving platinum-based chemotherapy but appears confined to those with adenocarcinoma histology.

A randomized trial of the electronic Lung Cancer Symptom Scale for quality-of-life assessment in patients with advanced non-small-cell lung cancer.

Introduction: Improving health-related quality of life (hrqol) is a key goal of systemic therapy in advanced lung cancer, although routine assessment remains challenging. We analyzed the impact of a real-time electronic hrqol tool, the electronic Lung Cancer Symptom Scale (elcss-ql), on palliative care (pc) referral rates, patterns of chemotherapy treatment, and use of other supportive interventions in patients with advanced non-small-cell lung cancer (nsclc) receiving first-line chemotherapy. Methods: Patients with advanced nsclc starting first-line chemotherapy were randomized to their oncologist receiving or not receiving their elcss-ql data before each clinic visit. Patients completed the elcss-ql at baseline, before each chemotherapy cycle, and at subsequent follow-up visits until disease progression. Prospective data about the pc referral rate, hrqol, and use of other supportive interventions were collected. Results: For the 95 patients with advanced nsclc who participated, oncologists received real-time elcss-ql data for 44 (elcss-ql arm) and standard clinical assessment alone for 51 (standard arm). The primary endpoint, the pc referral rate, was numerically higher, but statistically similar, for patients in the elcss-ql and standard arms. The hrqol scores over time were not significantly different between the two study arms. Conclusions: The elcss-ql is feasible as a tool for use in routine clinical practice, although no statistically significant effect of its use was demonstrated in our study. Improving access to supportive care through the collection of patient-reported outcomes and hrqol should be an important component of care for patients with advanced lung cancer.

Longitudinal health utilities, symptoms and toxicities in patients with ALK-rearranged lung cancer treated with tyrosine kinase inhibitors: a prospective real-world assessment.

Background: Tyrosine kinase inhibitors (tkis) have dramatically improved the survival of patients with ALK-rearranged (ALK+) non-small-cell lung cancer (nsclc). Clinical trial data can generally compare drugs in a pair-wise fashion. Real-world collection of health utility data, symptoms, and toxicities allows for the direct comparison between multiple tki therapies in the population with ALK+ nsclc. Methods: In a prospective cohort study, outpatients with ALK+ recruited between 2014 and 2018, treated with a variety of tkis, were assessed every 3 months for clinico-demographic, patient-reported symptom and toxicity data and EQ-5D-derived health utility scores (hus). Results: In 499 longitudinal encounters of 76 patients with ALK+ nsclc, each tki had stable longitudinal hus when disease was controlled, even after months to years: the mean overall hus for each tki ranged from 0.805 to 0.858, and longitudinally from 0.774 to 0.912, with higher values associated with second- or third-generation tkis of alectinib, brigatinib, and lorlatinib. Disease progression was associated with a mean hus decrease of 0.065 (95% confidence interval: 0.02 to 0.11). Health utility scores were inversely correlated to multiple symptoms or toxicities: rho values ranged from -0.094 to -0.557. Fewer symptoms and toxicities were associated with the second- and third-generation tkis compared with crizotinib. In multivariable analysis, only stable disease state and baseline Eastern Cooperative Oncology Group performance status were associated with improved hus. Conclusions: There was no significant decrease in hus when patients with ALK+ disease were treated longitudinally with each tki, as long as patients were clinically stable. Alectinib, brigatinib, and lorlatinib had the best toxicity profiles and exhibited high mean hus longitudinally in the real-world setting.

Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors.

BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues.

The role of the epidermal growth factor receptor tyrosine kinase inhibitors as therapy for advanced, metastatic, and recurrent non-small-cell lung cancer: a Canadian national consensus statement.

PURPOSE: To provide consensus recommendations on the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIS) in patients with advanced or meta-static non-small-cell lung cancer (NSCLC). METHODS: Using a systematic literature search, phase II trials, randomized phase III trials, and meta-analyses were identified for inclusion. RESULTS: A total of forty-six trials were included. Clear evidence is available that EGFR-TKIS should not be administered concurrently with platinum-based chemotherapy as first-line therapy in advanced or metastatic nsclc. Evidence is currently insufficient to recommend single-agent EGFR-TKIS as first-line therapy either in unselected populations or in populations selected on the basis of molecular or clinical characteristics. Following failure of platinum-based chemotherapy, the evidence suggests that second-line EGFR-TKIS or second-line chemotherapy result in similar survival. Quality of life and symptom improvement for patients treated with an EGFR-TKI appear better than they do for patients treated with second-line docetaxel. Sequence of therapy may not appear to be important, but if survival is the outcome of interest, the goal should be to optimize the number of patients receiving three lines of therapy. Based on available data, molecular markers and clinical characteristics do not appear to be predictive of a differential survival benefit from an EGFR-TKI and therefore those factors should not be used to select patients for EGFR-TKI therapy. CONCLUSIONS: The EGFR-TKIS represent an additional therapy in the treatment of advanced or metastatic NSCLC. The results of ongoing clinical trials may define the optimal role for these agents and the effectiveness of combinations of these agents with other targeted agents.

Enhancing treatment decision-making: pilot study of a treatment decision aid in stage IV non-small cell lung cancer.

We developed a decision aid (DA) for patients with metastatic non-small cell lung cancer (NSCLC), to better inform patients of their prognosis and treatment options, and facilitate involvement in decision-making. In a pilot study, 20 patients with metastatic NSCLC attending outpatient clinics at a major cancer centre, who had already made a treatment decision, reviewed acceptability of the DA. The median age of the patients was 61 years (range 37-77 years), 35% were male, 20% had a university education, and most (75%) had English as a first language. Most had received chemotherapy, with 65% currently on treatment. Patients were not anxious at baseline and had clear understanding of the goals and toxicity of chemotherapy in advanced NSCLC. After reviewing the DA, patients' anxiety decreased slightly (P=0.04) and knowledge scores improved by 25% (P<0.001). Most improvements in understanding were of prognosis with and without chemotherapy, although patients still believed advanced NSCLC to be curable. Patients rated the DA highly with respect to information clarity, usefulness and were positive about its use in practice, although 40% found the prognostic information slightly upsetting. The DA for advanced NSCLC is feasible, acceptable to patients and improves understanding of advanced NSCLC without increasing patient anxiety.