Treatment Of Advanced Non-squamous Non-small Cell Lung Cancer Research Articles

A lack of association between BMI and chemoimmunotherapy efficacy in advanced non-small cell lung cancer: Secondary analysis of the IMpower150 and IMpower130 clinical trials

BackgroundMultiple studies have indicated that patients with high body mass index (BMI) may have favourable survival outcomes following treatment with an immune checkpoint inhibitor (ICI). However, this evidence is limited by several factors, notably the minimal evidence from randomised controlled trials (RCTs), the use of categorised BMI with inconsistent cut point definitions, and minimal investigation of contemporary combination ICI therapy. Moreover, whether overweight and obese patients gain a larger benefit from contemporary frontline chemoimmunotherapy in non-small cell lung cancer (NSCLC) is unclear.MethodsThis secondary analysis pooled individual patient data from the intention-to-treat population of the IMpower130 and IMpower150 RCTs comparing chemoimmunotherapy versus chemotherapy. Co-primary outcomes were overall survival (OS) and progression-free survival (PFS). The potentially non-linear relationship between BMI and chemoimmunotherapy treatment effect was evaluated using Multivariable Fractional Polynomial Interaction (MFPI). As a sensitivity analysis, chemoimmunotherapy treatment effect (chemoimmunotherapy versus chemotherapy) on survival was also estimated for each BMI subgroup defined by World Health Organisation classification. Exploratory analyses in the respective chemoimmunotherapy and chemotherapy cohort were undertaken to examine the survival outcomes among BMI subgroups.ResultsA total of 1282 patients were included. From the MFPI analysis, BMI was not significantly associated with chemoimmunotherapy treatment effect with respect to either OS (p = 0.71) or PFS (p = 0.35). This was supported by the sensitivity analyses that demonstrated no significant treatment effect improvement in OS/PFS among overweight or obese patients compared to normal weight patients (OS: normal BMI HR = 0.74 95% CI 0.59–0.93, overweight HR = 0.78 95% CI 0.61–1.01, obese HR = 0.84 95% CI 0.59–1.20). Exploratory analyses further highlighted that survival outcomes were not significantly different across BMI subgroups in either the chemoimmunotherapy therapy cohort (Median OS: normal BMI 19.9 months, overweight 17.9 months, and obese 19.5 months, p = 0.7) or the chemotherapy cohort (Median OS: normal 14.1 months, overweight 15.9 months, and obese 16.7 months, p = 0.7).ConclusionThere was no association between high BMI (overweight or obese individuals) and enhanced chemoimmunotherapy treatment benefit in front-line treatment of advanced non-squamous NSCLC. This contrasts with previous publications that showed a superior treatment benefit in overweight and obese patients treated with immunotherapy given without chemotherapy.

A cost-effectiveness analysis of first-line toripalimab plus chemotherapy in advanced nonsquamous non-small cell lung cancer in China

ABSTRACT Background This study compares first-line toripalimab with chemotherapy for advanced nonsquamous non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Research design and methods A three-state Markov model was established to compare the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) of first-line toripalimab plus chemotherapy versus chemotherapy. Clinical outcomes data were acquired from the CHOICE-01 clinical trials. Costs and utilities were gathered from regional databases or published publications. One-way sensitivity and probability sensitivity analyses were used to investigate the stability of the model parameters. Results First-line toripalimab treatment for advanced nonsquamous NSCLC resulted in an incremental cost of $16,214.03 and added 0.77 QALYs compared to chemotherapy, which had an ICER of $21,057.18 per QALY gained. The ICER was substantially lower than the willingness to pay (WTP) threshold in China, which was $37,663.26 per QALY. The toripalimab cycle used was shown to have the greatest impact on the ICERs, according to sensitivity analysis, although none of the factors significantly affected the model’s outcomes Conclusions Toripalimab plus chemotherapy is likely to be a cost-effective option compared with chemotherapy alone for patients with advanced nonsquamous NSCLC from the perspective of the Chinese healthcare system.

Tislelizumab plus chemotherapy is more cost-effective than chemotherapy alone as first-line therapy for advanced non-squamous non-small cell lung cancer.

Tislelizumab is a programmed cell death protein-1 (PD-1) inhibitor. Tislelizumab plus chemotherapy as first-line option for advanced non-squamous non-small cell lung cancer (NSCLC), compared with chemotherapy alone, resulted in significantly prolonged survival outcomes; however, evidence regarding its relative efficacy and cost is lacking. We aimed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy compared with that of chemotherapy alone, from the health care perspective in China. A partitioned survival model (PSM) was used for this study. The survival data were obtained from the RATIONALE 304 trial. Cost-effectiveness was defined as incremental cost-effectiveness ratio (ICER) less than the willingness to pay (WTP) threshold. Incremental net health benefits (INHB), incremental net monetary benefits (INMB), and subgroup analyses were also assessed. Sensitivity analyses were further established to assess the model stability. Compared with chemotherapy alone, tislelizumab plus chemotherapy increased by 0.64 quality-adjusted life-years (QALYs) and 1.48 life-years, and yielded an increase of $16,631 in cost per patient. The INMB and INHB were $7,510 and 0.20 QALYs at a WTP threshold of $38,017/QALY, respectively. The ICER was $26,162/QALY. The outcomes were most sensitive to the HR of OS for tislelizumab plus chemotherapy arm. The probability of tislelizumab plus chemotherapy being considered cost-effective was 87.66% and >50% in most of the subgroups at the WTP threshold of $38,017/QALY. At the WTP threshold of $86,376/QALY, the probability achieved 99.81%. Furthermore, the probability of tislelizumab plus chemotherapy being considered cost-effective in subgroups of patients with liver metastases and PD-L1 expression ≥50% were 90.61 and 94.35%, respectively. Tislelizumab plus chemotherapy is likely to be cost-effective as a first-line treatment for advanced non-squamous NSCLC in China.

Cost-Utility Analysis of Camrelizumab Plus Chemotherapy Versus Chemotherapy Alone as a First-Line Treatment for Advanced Nonsquamous Non-Small Cell Lung Cancer in China.

PurposeTo evaluate the cost utility of camrelizumab plus standard chemotherapy versus standard chemotherapy alone as a first-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC) from the perspective of the Chinese health care system and to provide a reference for health decision-making.MethodsA Markov model consisting of three health states was designed to evaluate the cost utility of these two treatment regimens for NSCLC patients with the incremental cost-effectiveness ratio (ICER) as the primary output indicator. Clinical data were derived from a published phase III clinical trial (CameL; ClinicalTrials.gov; NCT03134872). One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the model uncertainty.ResultsBase case analysis showed that the ICER of camrelizumab plus chemotherapy compared with chemotherapy alone was $43,275.43 per QALY. It was higher than the willingness-to-pay (WTP) threshold of $31,510.57 per QALY in China, which has a standard of three times the GDP per capita recommended by the WHO. One-way sensitivity analysis showed that the utility value of PFS had the greatest influence on the results, and the other sensitive parameters were the cost of subsequent second-line therapy in the two group, the pemetrexed price, the cost of adverse event management and the utility value of PD. The probability sensitivity analysis showed that the probabilities of the cost-effectiveness of camrelizumab plus standard chemotherapy were 27.1%, 66.7% and 88.0% when the WTP values were $40,000, $50,000 and $60,000 per QALY, respectively.ConclusionsTaking three times the GDP per capita in China as the WTP threshold, the camrelizumab plus standard chemotherapy regimen does not have a cost-effectiveness advantage compared with the standard chemotherapy regimen alone as a first-line treatment for advanced NSCLC.

Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-021 with reference bevacizumab

BackgroundBCD-021 is a bevacizumab biosimilar which was shown to be equivalent to reference bevacizumab in a wide panel of physicochemical studies as well as preclinical studies in vitro and in vivo. International multicenter phase III clinical trial was conducted to compare efficacy and safety of BCD-021 and reference bevacizumab in combination with paclitaxel and carboplatin in a first-line treatment of inoperable or advanced non-squamous non-small-cell lung cancer (NSCLC).MethodsPatients with no previous treatment for advanced non-squamous NSCLC were randomly assigned 3:2 to BCD-021 or reference bevacizumab and were treated with bevacizumab + paclitaxel + carboplatin. Therapy continued for 6 cycles (every 3 weeks), until progression of the disease or unbearable toxicity. The primary study endpoint was the overall response rate. The study goal was to prove the equivalent efficacy of BCD-021 and reference bevacizumab. Equivalence margins for 95% CI for the difference in the overall response rates were set at [-18%; 18%], for 90% CI for the ratio of overall response rate were set at [67%; 150%].ResultsIn total 357 patients were enrolled in the study, 212 in the BCD-021 group and 145 in the reference bevacizumab group. The ORR was 34.63% in the BCD-022 group and 33.82% in the reference bevacizumab group. Limits of 95% CI for the difference in overall response rates between the groups were [-9.47%; 11.09%]. Limits of 90% CI for the ratio of overall response rate between the groups were [79.6%; 131.73%]. For both approaches CI lied within predetermined equivalence margins. Profile of adverse events (AEs) was similar between the groups (any AEs were reported in 86.89% of patients in BCD-021 group and 89.05% of patients in reference group). No unexpected adverse reactions were reported throughout the study. No statistically significant differences regarding anti-drug antibody occurrence rate was found between BCD-022 (n=4; 1.96%) and comparator (n=5; 3.65%). Both drug products showed low occurrence rate and short life of anti-bevacizumab antibodies. Pharmacokinetics assessment after 1st and 6th study drug injection also demonstrated equivalent PK parameters by all outcome measures.ConclusionsThus, the results of this study demonstrated therapeutic equivalence of bevacizumab biosimilar BCD-021 and referent bevacizumab drug.Trial registrationThe trial was registered with ClinicalTrials.gov (Study Number NCT01763645, date of registration 09/01/2013).

Efficacy and safety of adding bevacizumab biosimilar or original drug to platinum-based chemotherapy as first-line treatment in patients with advanced NSCLC: a systematic review and meta-analysis.

Introduction:The role of bevacizumab combined with paclitaxel and carboplatin in the first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC) has been supported by a large number of data. However, whether bevacizumab biosimilars have the same efficacy and safety as the original drug is still controversial. This meta-analysis was designed to evaluate whether bevacizumab biosimilars have the same clinical efficacy and safety as the original drug in patients with advanced non-squamous NSCLC.Methods:Electronic databases (PubMed, Embase, Cochrane, CNKI, Wanfang, and VIP) and the ClinicalTrail.gov website were extensively searched using relevant search criteria. We included phase III randomized controlled trials (RCTs) to compare the efficacy and safety of marketed biosimilars and Avastin in the first-line treatment of patients with advanced NSCLC. The risk of bias of the included studies was assessed using the RoB 2 assessment scale, and the RevMan 5.4 statistical software was used for meta-analysis.Results:A total of 6360 patients were included in 11 RCTs. There was no statistical difference between the experimental group and the control group in terms of effectiveness [objective response rate (at week 18), disease control rate (at week 18), median duration of response, median progression-free survival, median overall survival (OS), and OS after 12 months]. In terms of safety [treatment-emergent adverse events (grade ⩾3) and treatment-related adverse events (grade ⩾3)], there was also no significant difference between biosimilars and Avastin.Conclusions:The efficacy and safety of bevacizumab biosimilars in the treatment of advanced non-squamous NSCLC are highly similar to those of the original drug combined with paclitaxel and carboplatin, respectively.

Maintenance treatment of combination with bevacizumab vs single agent for advanced non-squamous non-small cell lung cancer: A systematic review and meta-analysis.

Background:When the patients of advanced non-squamous non-small cell lung cancer (NSCLC) have achieved remission by induction therapy, it is controversial that combination with bevacizumab is used as maintenance therapy. Pemetrexed is a classic drug for maintenance therapy, is bevacizumab the superiority to pemetrexed is also unclear. This meta-analysis aims to evaluate the effectiveness and safety of advanced non-squamous NSCLC in the maintenance treatment.Method:From the establishment as of December 6, 2020, PubMed, Embase, and Cochrane electronic databases were searched and the American Society of Clinical Oncology, European Society of Medical Oncology, and National Comprehensive Cancer Network databases in the past 10 years. The application of combination with bevacizumab, pemetrexed was studied in clinical trials of maintenance treatment for advanced NSCLC. The extracted data include progression-free survival (PFS), overall survival (OS), and grade 3–4 adverse events (AE).Results:Seven clinical trials we screened, 6 were phase III RCTs, and a cohort trial, including 3298 patients. Compared with bevacizumab and pemetrexed, PFS of combination with bevacizumab was significantly improved (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.65–0.77, P < .00001), but OS was not improved (HR = 0.93, 95% CI = 0.85–1.01, P = .10). Compared with bevacizumab and pemetrexed, no significant difference of PFS (HR = 0.87, 95% CI = 0.69–1.09, P = .21), and OS (HR = 0.87, 95% CI = 0.72–1.05, P = .15) was found. A higher incidence of grade 3–4 AE occurred in combination with bevacizumab (odds ratio = 1.63, 95% CI = 1.35–1.97, P < .00001).Conclusions:PFS was significantly improved in patients with advanced non-squamous NSCLC who use bevacizumab combination with single-agent as maintenance treatment, but it does not translate into the advantages of OS; compared with bevacizumab, no PFS and OS benefits were found. A higher incidence of grade 3–4 AE occurred in combination with bevacizumab than pemetrexed and bevacizumab.

Does Pemetrexed Work in Targetable, Nonsquamous Non-Small-Cell Lung Cancer? A Narrative Review.

Simple SummaryThe chemotherapy agent pemetrexed is currently considered in combination with other therapies for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) in patients negative for gene mutations/rearrangements. The aim of this review was to highlight data from clinical studies with pemetrexed in patients with advanced nonsquamous NSCLC positive for gene mutations/rearrangements. The results of the review suggest that pemetrexed could be a treatment option in patients with advanced nonsquamous NSCLC positive for certain gene mutations/rearrangements.Pemetrexed is currently mainly considered for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) negative for gene mutations/rearrangements (wild-type disease (WTD)). This narrative review aimed to highlight the role of pemetrexed in the treatment of onco-driven nonsquamous advanced NSCLC by reviewing published clinical studies. For epidermal growth factor receptor (EGFR) mutations, patient survival following first-line pemetrexed–platinum was longer than for WTD. Later-line pemetrexed-based treatment after tyrosine kinase inhibitor (TKI) failure provided greater benefits than non-pemetrexed regimens. First- and later-line pemetrexed-based therapy also provided survival benefits in patients with anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearrangements. In patients with rearranged during transfection (RET) proto-oncogene rearrangements, survival with pemetrexed was similar to that in ALK- and ROS1-positive patients and longer than that in patients with Kirsten rat sarcoma (KRAS) virus proto-oncogene mutations or WTD, although the available studies were limited. For Erb-b2 receptor tyrosine kinase 2 (ERRB2) mutations, first-line pemetrexed showed outcomes similar to those for EGFR and KRAS alterations. Data on pemetrexed in patients with KRAS mutations or MNNG HOS-transforming (MET) expression were limited. Pemetrexed could be an option for first- and second-line treatment for TKI failure in nonsquamous advanced NSCLC with select targetable driver mutations.

Prospective Feasibility Study of Amrubicin and Bevacizumab Therapy for Patients With Previously Treated Advanced NSCLC.

The efficacy of the combination of amrubicin and bevacizumab against advanced non small-cell lung cancer (NSCLC), as a second or third-line treatment, was evaluated. Amrubicin was administered for 3 days to patients with previously treated advanced NSCLC, whereas bevacizumab was administered on day 1 of each cycle; this regimen was repeated every 3 weeks. Among the 16 patients, an overall response rate of 12.5% (for two patients) was achieved, and the overall disease control rate was 93.7%. Progression free survival and overall survival were 8.5 and 16.6 months, respectively. Grade 3 or 4 haematological toxicities were leukopenia, neutropenia, and febrile neutropenia. Grade 3 proteinuria and infection were the non haematological adverse events. The combination of amrubicin and bevacizumab is a promising regimen in the second or third-line treatment for advanced non-squamous NSCLC; however, physicians must recognise the risk of proteinuria related with this regimen.

P1.04-78 Efficacy of Checkpoint Inhibitors in Combination with Chemotherapy for First-Line Treatment of Advanced Non-Squamous NSCLC

Checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab, or atezolizumab) have created a fundamental paradigm shift in the management of non-small cell lung cancer (NSCLC). In recent years, many randomized clinical trials (RCT) have combined different checkpoint inhibitors with various standard chemotherapy regimens as first-line treatment of advanced non-squamous NSCLC. In general, these trials have included patients across different levels of PD-L-1 expression. The purpose of our study is to consolidate the efficacy of checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced non- squamous NSCLC. We systematically conducted a comprehensive literature search using PUBMED, MEDLINE, EMBASE databases and meeting abstracts from inception through March 2019. RCTs of first-line chemotherapy ± immunotherapy in patients with advanced non-squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. A total of 3228 patients with advanced non-squamous NSCLC from 6 RCTs (Keynote – 021,189, IMpower – 130, 132, 150, and Lynch et al.) and a subgroup of another RCT (Checkmate-227) were included. The study arm used standard chemotherapy regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab while control arm used only standard chemotherapy regimens. The randomization ratio was 2:1 in IMpower-130 and Keynote-189 studies and 1:1 in other studies. The I2statistic for heterogeneity was 15, suggesting some heterogeneity among RCTs. The pooled HR for PFS was statistically significant at 0.61 (95% CI: 0.55-0.67; P <0.00001), and the pooled HR for OS was noted at 0.78 (95% CI: 0.65- 0.94; P = 0.01).The PFS benefit was observed in all PD-L1 categories, including PD-L1 negative/ tumor proportion score (TPS) of less than 1% cohort (HR, 0.67; 95% CI: 0.53- 0.84; P = 0.0005), PD-L1 low/ TPS ≥1-49% cohort (HR, 0.62; 95% CI: 0.52- 0.74; P <0.00001) and PD-L1 high/ TPS ≥50% cohort (HR, 0.42; 95% CI: 0.33- 0.52; P <0.00001). Our study showed that first-line checkpoint inhibitors in combination with chemotherapy significantly improved PFS and OS compared to standard chemotherapy in patients with advanced non-squamous NSCLC and the PFS benefit was consistent regardless of PD-L1 expression.

Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced nonsquamous non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

125 Background: RCTs have tested the role of adding immunotherapy to standard therapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in the first-line setting. We conducted a systematic review and meta-analysis of RCTs to assess the efficacy and toxicity of adding immunotherapy in this patient population. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line standard therapy +/- immunotherapy in patients with advanced non-squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥grade 3). Heterogeneity was assessed with Cochrane Q-statistic. Random effects were used due to significant heterogeneity among studies. Results: Three phase 2 &amp; 3 RCTs (Keynote – 021,189 and IMpower – 150) including 1431 patients with advanced non-squamous NSCLC patients were included in the analysis. Keynote 021 &amp; 189 trials did not allow patients with EGFR or ALK mutations, while IMpower 150 trial allowed EGFR or ALK mutations. The study arm used standard regimens in combination with pembrolizumab or atezolizumab while control arm used only standard regimens. The pooled HR for PFS was 0.57 (95% CI: 0.5-0.65; P=0.00001), the pooled HR for OS was 0.61 (95% CI: 0.43-0.87; P=0.006), and the pooled RR for ORR was 1.83 (95 CI: 1.13-2.95; P=0.01). The pooled RRs for all-grade AEs and high-grade AEs were 1 (95% CI: 0.99-1.02; P=0.48) and 1.11 (95% CI: 0.97-1.28; P=0.14), respectively. Conclusions: Pooled data showed significant improvement in PFS, OS &amp; ORR with chemo-immunotherapy compared to the standard treatment regimen for the first-line treatment of advanced non-squamous NSCLC. There was no increase in the risk of all-grade and high-grade AEs.

A Trial-Based Cost-Effectiveness Analysis of Bevacizumab and Chemotherapy Versus Chemotherapy Alone for Advanced Nonsquamous Non–Small-Cell Lung Cancer in China

The first-line bevacizumab plus chemotherapy resulted in a clinical efficacy for Chinese patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). Some economic analyses have carried out various methods to evaluate the cost-effectiveness of bevacizumab as the first-line treatment for NSCLC in other countries. Our objective was to assess the cost-effectiveness of bevacizumab plus chemotherapy compared with chemotherapy alone for the first-line treatment of advanced nonsquamous NSCLC. A Markov model was applied from the perspective of the Chinese health care system to assess cost-effectiveness. It was based on the clinical trial BEYOND that compared bevacizumab plus carboplatin/paclitaxel (B+CP) with placebo plus carboplatin and paclitaxel (PI+CP) for advanced nonsquamous NSCLC. Ten-year quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. One-way sensitivity analysis and probabilistic sensitivity analyses (PSA) were performed. QALYs were 1.17 years in the B+CP group and 0.83 years in the PI+CP group, resulting in a difference of 0.34 years. The ICER was $130,937.09/QALY, which was far beyond the willing-to-pay threshold of $24,314/QALY. At a threshold of $130,584/QALY, addition of bevacizumab had a 50% probability of being cost-effective. Bevacizumab is not cost-effective when combined with chemotherapy for patients with advanced nonsquamous NSCLC based on the Chinese health care system, resulting in a less demand in the Chinese market.

Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057

BackgroundNivolumab, a programmed death-1 inhibitor, prolonged overall survival and had a favourable safety profile versus docetaxel in previously treated patients with advanced non-squamous non-small cell lung cancer (NSCLC) in the phase III CheckMate 057 trial. AimTo evaluate health-related quality of life (HRQoL) using patient-reported outcomes. MethodsDisease-related symptoms and general health status were assessed using two validated patient-reported instruments, the Lung Cancer Symptom Scale (LCSS) and the European Quality of Life Five Dimensions (EQ-5D), respectively. The proportion of patients with disease-related symptom improvement at 12 weeks on the LCSS average symptom burden index (ASBI) was a secondary end-point. LCSS 3-item global index (3-IGI), EQ-5D utility index and EQ-5D visual analogue scale (VAS) scores were also determined. Mixed-effects model repeated measures (MMRM) and time to first deterioration analyses assessed longitudinal changes. ResultsMean baseline LCSS ASBI scores were similar in both arms. By week 12, rates of disease-related improvement (95% confidence interval) were similar between nivolumab (17.8% [13.6–22.7]) and docetaxel (19.7% [15.2–24.7]); however, numerical differences in LCSS ASBI mean change from baseline favoured nivolumab. Subsequently, LCSS ASBI scores improved with nivolumab and worsened with docetaxel, with statistically significant between-arm differences at weeks 12, 24, 30 and 42. HRQoL improvements with nivolumab versus docetaxel were also supported by the LCSS 3-IGI, EQ-5D VAS and MMRM analysis. Time to first HRQoL deterioration was longer with nivolumab than with docetaxel. ConclusionNivolumab improved disease-related symptoms and overall health status versus docetaxel for second-line treatment of advanced non-squamous NSCLC. Clinical trial registrationNCT01673867.

Treatment patterns and cost-effectiveness of first line treatment of advanced non-squamous non-small cell lung cancer in Medicare patients

Aim: To assess the cost-effectiveness of first-line pemetrexed/platinum and other commonly administered regimens in a representative US elderly population with advanced non-squamous non-small cell lung cancer (NSCLC).Materials and methods: This study utilized the Surveillance Epidemiology and End Results (SEER) cancer registry linked to Medicare claims records. The study population included all SEER-Medicare patients diagnosed in 2008–2009 with advanced non-squamous NSCLC (stages IIIB–IV) as their only primary cancer and who started chemotherapy within 90 days of diagnosis. The study evaluated the four most commonly observed first-line regimens: paclitaxel/carboplatin, platinum monotherapy, pemetrexed/platinum, and paclitaxel/carboplatin/bevacizumab. Overall survival and total healthcare cost comparisons as well as incremental cost-effectiveness ratios (ICERs) were calculated for pemetrexed/platinum vs each of the other three. Unstratified analyses and analyses stratified by initial disease stage were conducted.Results: The final study population consisted of 2,461 patients. Greater administrative censorship of pemetrexed recipients at the end of the study period disproportionately reduced the observed mean survival for pemetrexed/platinum recipients. The disease stage-stratified ICER analysis found that the pemetrexed/platinum incurred total Medicare costs of $536,424 and $283,560 per observed additional year of life relative to platinum monotherapy and paclitaxel/carboplatin, respectively. The pemetrexed/platinum vs triplet comparator analysis indicated that pemetrexed/platinum was associated with considerably lower total Medicare costs, with no appreciable survival difference.Limitations: Limitations included differential censorship of the study regimen recipients and differential administration of radiotherapy.Conclusions: Pemetrexed/platinum yielded either improved survival at increased cost or similar survival at reduced cost relative to comparator regimens in the treatment of advanced non-squamous NSCLC. Limitations in the study methodology suggest that the observed pemetrexed survival benefit was likely conservative.

Feasibility study of first-line chemotherapy using Pemetrexed and Bevacizumab for advanced or recurrent nonsquamous non-small cell lung cancer in elderly patients: TORG1015.

BackgroundThe addition of bevacizumab to cytotoxic agents prolongs survival in patients with nonsquamous non-small cell lung cancer (NSCLC). To date, there is no evidence to suggest that treatment with a cytotoxic agent plus bevacizumab is more effective than a cytotoxic agent alone for nonsquamous NSCLC in elderly patients. We conducted a feasibility study of pemetrexed plus bevacizumab as a first-line treatment for advanced or recurrent nonsquamous NSCLC in elderly patients.MethodsMajor eligibility and exclusion criteria included: chemotherapy-naive status; non-fitness for bolus combination chemotherapy; stage III/IV or relapsed nonsquamous NSCLC; age ≥70; performance status 0–1; absence of brain metastasis; and no history of hemoptysis and thoracic irradiation. Pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) were administered intravenously on day 1, and repeated every 3 weeks thereafter. The primary endpoint was safety, and the secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the percentage of patients who completed ≥3 cycles.ResultsFrom October 2010 to April 2012, a total of 12 patients were enrolled. No dose-limiting toxicity or treatment-related deaths were observed. Three patients achieved PR, and the ORR was 25 %. The median PFS and OS were 5.4 months (95 % CI 1.1–8.8 months) and 13.6 months (95 % CI 5.3–15.6 months), respectively. Seven of 12 patients (58 %) received ≥3 cycles.ConclusionsPemetrexed plus bevacizumab in the treatment of elderly patients with nonsquamous NSCLC was well tolerated and shows promise as first-line treatment.Trial registrationUMIN Clinical Trial Registry; UMIN000004263. Registered on 25 September, 2010.

Treatment of Advanced and Metastatic Squamous Non-small Cell Lung Cancer

Lung cancer is a disease with a poor prognosis, and is the leading cause of cancer-related death in Korea as well as the USA. Unlike non-squamous non-small cell lung cancer (NSCLC), squamous NSCLC rarely harbors epidermal growth factor receptor and anaplastic lymphoma kinase mutations for which directed molecular targeted therapies are available. Traditional cytotoxic chemotherapy drugs, including cisplatin, have been approved for use in the treatment of advanced and metastatic squamous NSCLC. The second-generation regimens—gemcitabine, paclitaxel, docetaxel, and vinorelbine with cisplatin—are standard first-line treatments for advanced and metastatic squamous NSCLC. Docetaxel was approved for second-line treatment in 1999. Addition of the anti-angiogenic agent, ramucirumab, to docetaxel showed improved survival in squamous cell NSCLC patients in the second-line setting compared with single-agent docetaxel. The immune checkpoint inhibitor-programmed cell death-1 inhibitor, nivolumab, is currently approved for squamous cell NSCLC. Pembrolizumab also received FDA approval for treatment of NSCLC cases in which tumor tissue is positive for programmed cell death-ligand 1 expression. Keywords: Neoplasm, Squamous cell; Lung neoplasms; Drug therapy; Angiogenesis inhibitors; Immunotherapy 중심 단어: 편평상피세포암; 폐암; 약물 치료; í˜ˆê´€í˜•ì„±ì–µì œì œ; 면역 치료

First-Line Pemetrexed Plus Cisplatin Followed by Gefitinib Maintenance Therapy Versus Gefitinib Monotherapy in East Asian Never-Smoker Patients With Locally Advanced or Metastatic Nonsquamous Non–Small-cell Lung Cancer: Quality of Life Results From a Randomized Phase III Trial

BackgroundThe efficacy results from an open-label, randomized, multicenter study found no significant difference in progression-free survival between pemetrexed plus cisplatin followed by maintenance gefitinib (PC/G) and gefitinib monotherapy (G) in patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) and unknown epidermal growth factor receptor (EGFR) mutation status (hazard ratio favored PC/G). The present report describes the quality of life (QoL) results from that trial. Patients and MethodsChemotherapy-naive, East Asian, light ex-smokers or never-smokers with advanced nonsquamous NSCLC and unknown EGFR mutation status (n = 236) were randomly assigned (1:1) to PC/G or G. EGFR mutation status was subsequently determined for 74 patients. The symptoms and QoL were assessed using the Lung Cancer Symptom Scale (LCSS). The time to worsening of symptoms (TWS) was analyzed using the Kaplan-Meier method. ResultsIn the overall population, the TWS was generally longer in the G group (n = 109) than in the PC/G group (n = 109) for the LCSS symptoms classified as treatment-related (loss of appetite, fatigue) and tumor-related (cough, dyspnea, hemoptysis, pain). In the subgroup of patients with wild-type EGFR, the TWS was generally longer in the PC/G group (n = 13) than in the G group (n = 8) for the tumor-related LCSS symptoms. ConclusionIn this study population clinically selected to respond to gefitinib, the LCSS scores were more favorable in the G group than in the PC/G group. Patients with wild-type EGFR tended to show greater improvement in tumor-related LCSS symptoms with chemotherapy than with gefitinib alone. These LCSS outcomes provide further evidence that patients with wild-type EGFR might not benefit from first-line treatment of advanced NSCLC with gefitinib.

Assessment of chemotherapy strategy using bevacizumab for non-squamous non-small cell lung cancer in a real-world setting: A multi-institutional observational study

Abstract Micro-abstract We retrospectively analyzed 162 patients with non-squamous non-small cell lung cancer (NSCLC) who underwent first-line chemotherapy with bevacizumab (BEV); 127 patients without driver oncogenes, 17 patients with EGFR major mutations, 12 patients with ALK rearrangements, 4 patients with EGFR minor mutations and 2 patients with rare types of histology. Background BEV has been approved for treatment of non-squamous NSCLC and is authenticated as one of the key drugs in the treatment of advanced non-squamous NSCLC. Patients and methods We retrospectively analyzed patients with stage IIIB/IV non-squamous NSCLC who underwent chemotherapy with BEV in first-line setting. Results In 162 patients who underwent chemotherapy combined with BEV as first-line treatment, the median overall survival (OS) and progression-free survival (PFS) were 23.5 months and 6.8 months, respectively. The PFS did not differ significantly by the presence of driver oncogenes. In patients without driver oncogenes, more patients who received carboplatin plus pemetrexed with BEV could complete at least 4 cycles of induction therapy and more of these patients proceeded to maintenance therapy than those who received carboplatin plus paclitaxel with BEV, which resulted in better outcome associated with carboplatin plus pemetrexed with BEV. Continuation of BEV beyond first progression did not show any survival benefit. In EGFR mutation-positive patients, the order of BEV-containing regimen and TKI did not influence on OS. None of 18 patients with brain metastases detected at diagnosis developed intracranial hemorrhage. Conclusions PFS of first-line chemotherapy using BEV was not influenced by the existence of driver oncogenes. In patients without driver mutations in real clinical practice, as the first-line partner regimen with BEV, carboplatin plus pemetrexed may be more feasible as compared to carboplatin plus paclitaxel. BEV use beyond first progression did not deliver significant survival benefit. BEV was safe for brain metastases.

Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial

CTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor (EGFR). Patients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m(2)) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data. From February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40-0.75, P < 0.001] as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38-0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49-1.04, P = 0.077). Quality-of-life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43-2.08, P = 0.877). CTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients. NCT00891579.

Meta-Analysis Examining Impact of Age on Pemetrexed (pem) Efficacy for the Treatment of Advanced Nonsquamous (NS) Non-Small Cell Lung Cancer (NSCLC): Metastatic Non-Small Cell Lung Cancer

Elderly patients are often undertreated relative to younger patients in clinical practice. Pem is efficacious as a first-line, second-line, and maintenance treatment for advanced NS NSCLC. Analysis of individual trials in first-line (JMDB) and maintenance (JMEN, PARAMOUNT) settings showed comparable survival (favoring pem over comparators) and toxicity profiles of pem in elderly and nonelderly subgroups. Now, a meta-analysis is presented to give an integrated review of the impact of age on pem efficacy.