Platinum-based Doublet Chemotherapy Research Articles

Sequential treatment of tyrosine kinase inhibitor and platinum-based doublet chemotherapy on EGFR mutant non-small cell lung cancer: a meta-analysis of randomized controlled clinical trials.

There is debate surrounding which treatment is superior in overall survival (OS) rates in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC); first-line tyrosine kinase inhibitor (TKI) followed by second-line platinum-based doublet chemotherapy (PCT), or the reverse sequence. Cross treatment of first- and second-line TKI and PCT makes it difficult to deduce which sequence (TKI-PCT or PCT-TKI) is better for OS. Using the keywords “lung cancer” and “EGFR” we identified clinical trials within the PubMed database which were published between January 2006 and November 2016. Basic characteristics and OS with hazard ratio and 95% confidence intervals were searched and analyzed. In total, 457 articles were reviewed and nine clinical trials with 1,876 patients were of sufficient quality for further analysis. Fixed effects models were performed to pool the data in this meta-analysis. All nine studies were open-labeled, multicenter, Phase III randomized controlled clinical trials. The pooled hazard ratio was 0.96 (95% confidence interval: 0.84–1.10) for OS between first-line TKI followed by second-line PCT compared to the reverse sequence. No statistically significant heterogeneity (I2=0, P=0.553) nor publication bias (Egger’s P=0.991) was observed among these studies. In conclusion, there was no OS benefit between first-line TKI followed by second-line PCT compared to the reverse sequence in EGFR mutant NSCLC patients. Chemotherapy was still useful and irreplaceable for the treatment of NSCLC, especially for those patients with EGFR unavailable for testing.

Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial

Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and safety of vandetanib 300 mg daily in this patient population. This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0-2. The primary endpoint was the objective response rate. A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35-71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity. Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.

Maintenance Sunitinib following Initial Platinum-Based Combination Chemotherapy in Advanced-Stage IIIB/IV Non–Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study—CALGB 30607 (Alliance)

IntroductionThe aim of this study was to evaluate efficacy of maintenance sunitinib after first-line chemotherapy for stage IIIB/IV NSCLC. MethodsCancer and Leukemia Group B 30607 trial was a randomized, double-blind, placebo-controlled, phase III study that enrolled patients without progression after four cycles of first-line platinum-based doublet chemotherapy with or without bevacizumab. Bevacizumab was allowed only during the four cycles of chemotherapy. Patients were randomized to receive sunitinib, 37.5 mg/d, or placebo and were treated until unacceptable adverse event(s), progression, or death. The primary end point was progression-free survival (PFS). ResultsA total of 210 patients were enrolled, randomized, and included in the intent-to-treat analysis. Ten patients did not receive maintenance therapy (four who received placebo and six who received sunitinib). Grade 3/4 adverse events affecting more than 5% of the patients were fatigue (25%), thrombocytopenia (12%), hypertension (12%), rash (11%), mucositis (11%), neutropenia (7%), and anemia (6%) for sunitinib and none for placebo. There were three grade 5 events in patients receiving sunitinib (one pulmonary hemorrhage, one other pulmonary event, and one death not associated with a Common Terminology Criteria for Adverse Events term) and two grade 5 events in patients receiving placebo (one other pulmonary event and one thromboembolism). Median PFS was 4.3 months for sunitinib and 2.6 months for placebo (hazard ratio = 0.62, 95% confidence interval: 0.47–0.82, p = 0.0006). Median overall survival was 11.7 months for sunitinib versus 12.1 months for placebo (hazard ratio = 0.98, 95% confidence interval: 0.73–1.31, p = 0.89). ConclusionsMaintenance sunitinib was safe and improved PFS as maintenance therapy in stage IIIB/IV NSCLC but had no impact on overall survival. There is no room for future investigations of sunitinib in this setting.

A meta-analysis: Evaluation of safety and efficacy of the epidermal growth factor receptor-tyrosine kinase inhibitor monotherapy versus platinum-based doublets chemotherapy in East Asia.

Several clinical trials have shown that advanced nonsmall cell lung cancer (NSCLC) patients can benefit from treatment with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy than receiving platinum-based doublets chemotherapy in the first-line treatment of advanced NSCLC; the objective of this study was to evaluate whether patients could be treated with EGFR-TKI for advanced NSCLC in the first-line setting. A literature search was conducted on the Cochrane Controlled Trials Register Databases, MEDLINE, EMBASE, Web of Science databases, and Chinese Biomedical Literature Database without exclusion of material published in any language. We performed a meta-analysis of five randomized studies that compared EGFR-TKI with platinum-based doublets chemotherapy for the patients of advanced NSCLC in the first-line setting. The primary end-point was the progression-free survival (PFS) of each treatment arm. The secondary end-points were overall survival (OS), objective response rate (ORR), adverse effects, and quality of life (qol). Five randomized controlled trials totaling 2080 patients were included in the review. Meta-analysis results are as follows: There were statistically significant differences in overall PFS (hazard ratio [HR] =0.47; 95% confidence interval [CI]: [0.27, 0.83], P = 0.009) and the PFS of the EGFR-M + subgroup (HR = 0.29; 95% CI: [0.17-0.51], P < 0.0001). Compared with patients receiving the platinum-based doublets chemotherapy group, there were no statistically significant differences between the two groups with regard to overall OS (HR = 0.92; 95% CI: [0.80-1.06], P = 0.25). Compared with the platinum-based doublets chemotherapy, EGFR-TKI significantly prolonged PFS, increased ORR, improved qol, not significantly increased the nonhematologic toxicity and at the same time decreased the nonhematologic toxicity but not significantly increased the transaminase toxicity for advanced NSCLC patients in East Asia. Although there is convincing evidence to confirm the results mentioned herein, they still need to be confirmed by large-sample trials.

OA23.01 Anti-EGFR Monoclonal Antibodies plus Chemotherapy in the First-Line Treatment of Advanced NSCLC: A Meta-Analysis

Monoclonal Antibodies (mAbs) against the Epidermal Growth Factor Receptor (EGFR) in association with platinum-based doublet chemotherapy have emerged as a potential first-line treatment option for advanced non-small cell lung cancer (NSCLC). This study was conducted to systematically review available data and evaluate the efficacy and toxicity of anti-EGFR mAbs plus chemotherapy vs chemotherapy alone for advanced NSCLC. We carried out a search on network databases and oncology conference abstracts for studies between 1990 and January 2016. Only prospective randomized clinical trials were included. Primary endpoints were overall survival (OS) and toxicity frequency. Secondary endpoints were progression-free survival (PFS) and overall response rate (ORR). Subgroup analysis was performed assessing histological subtypes, EGFR protein expression by immunohistochemistry (IHC), EGFR gene copy number by fluorescence in-situ hybridization (FISH), EGFR mutation status, and smoking status. Seven studies (2 with necitumumab and 5 with cetuximab) were included with 5,057 patients. Compared to chemotherapy alone, significant benefits were demonstrated by the addition of anti-EGFR mAb to chemotherapy in OS (HR 0.90; 95%CI 0.84-0.95), PFS (HR 0.93; 95%CI 0.87-0.98), and ORR (OR 1.27; 95%CI 1.06-1.51). In subgroup analyses, the association of anti-EGFR mAb was associated with improved OS among patients with squamous histology (HR 0.84; 95%CI 0.76-0.92), tumours with high EGFR expression by IHC (HR 0.83; 95%CI 0.70-0.98), and smokers (HR 0.87; 95%CI 0.79-0.96). Patients with squamous histology and high EGFR expression by IHC achieved the highest benefit with the association (HR 0.71; 95%CI 0.59-0.86). The OS with the association also seemed to be higher in EGFR FISH negative and in EGFR wild-type tumours, but without statistical significance. Chemotherapy plus anti-EGFR mAb caused more grade 3 or worse adverse events (OR 1.73; 95%CI 1.50-2.00), remarkedly these known to be associated with anti-EGFR therapy, such as acne-like rash (OR 34.13; 95%CI 16.40-71.00) and hypomagnesemia (OR 6.23; 95%CI 3.04-12.77). Anti-EGFR therapy plus platinum-based doublet chemotherapy as first-line treatment demonstrated significant efficacy benefits with acceptable toxicity for advanced NSCLC. This benefit is more expressive among squamous histology with high EGFR expression. EGFR protein expression by IHC seems to be a predictive marker for survival in the association group. Further research is needed to corroborate these findings.

P2.02-060 SBRT and Sequential Chemotherapy for Stage IIA to IIIA Non-Small Cell Lung Cancer - A Phase I Dose Escalation Study

Stereotactic Body Radiation Therapy (SBRT) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC) due to excellent local control and survival outcomes. Its role in larger tumors is undefined, and patients with inoperable locally advanced NSCLC patients are treated with conventionally fractionated radiation therapy and chemotherapy. Our phase I dose escalation trial evaluates the maximum tolerated dose (MTD) of SBRT in patients with stage IIA to IIIA NSCLC involving a larger primary tumor and/or hilar involvement. Patients with inoperable stage IIA to IIIA (T2b-T4N0M0 and TanyN1M0) NSCLC fit for SBRT and sequential chemotherapy were eligible. SBRT dose escalation levels in a classic 3+3 design were 40Gy, 50Gy, and 60Gy in 5 fractions, delivered every other day. Platinum-based doublet chemotherapy was initiated 6 to 8 weeks after SBRT. The primary endpoint was the MTD based on SBRT-related acute (<3 months) ≥ grade 4 or persistent ≥ grade 3 toxicities (per Common Terminology Criteria for Adverse Events [CTCAE] v4.03). Patient reported outcomes were assessed using the NCI PRO-CTCAE questionnaire. Nine patients were enrolled, three at the 40 Gy and six at the 50 Gy dose level. All patients received SBRT to the prescribed dose. Two patients receiving 50 Gy were no longer eligible for chemotherapy after SBRT. Median follow-up time was 6.3 months (range: 2.5 - 28.9). At the 40 Gy dose level, there was one patient with late (≥3 months post-SBRT) grade 3 pneumonia and one with late grade 3 bronchial obstruction. The dose was escalated to 50 Gy. At the 50 Gy dose level, two patients experienced persistent grade 3 radiation pneumonitis. One patient also had acute grade 4 respiratory insufficiency and contralateral pneumothorax. In the expanded 50 Gy cohort, one patient experienced persistent grade 3 nausea, vomiting, and abdominal pain, and another developed grade 3 chest wall pain. Therefore 50 Gy was determined to be the MTD. On PRO-CTCAE questionnaires patients most frequently reported fatigue (75%), dyspnea (50%), cough (38%), and pain (38%) as interfering “quite a bit” or “very much” with their daily activities. We determined that 50 Gy in five fractions followed by sequential chemotherapy is the MTD for SBRT in patients with stage IIA to IIIA NSCLC. Long-term outcomes and larger trials will be needed to assess whether SBRT results in superior local control and survival compared to conventional chemoradiation. Made possible by the generous support of the DallePezze Foundation.

Comparison study of quality of life in advanced lung cancer patients on tyrosine kinase inhibitor and platinum doublet chemotherapy.

Lung cancer is most common cause of cancer death in the world. Most of the patient are diagnosed in the late stages and receive only palliative treatment. The main objective of the palliative chemotherapy is to improve survival as well as the quality of life (QOL). QOL is the most neglected dimension of cancer care in developing countries like India. Palliative chemotherapeutic agent which has minimum toxicity and prolongs the survival of metastatic cancer patients is the need of the day. In this study, 43 metastatic adenocarcinoma of lung patients of South Indian origin were enrolled. Twenty patients out of this 43 were epidermal growth factor receptor (EGFR) mutation positive and were started on tyrosine kinase inhibitor (TKI). Rest 23 patients were EGFR mutation negative and were started on various platinum-based doublet chemotherapy. QOL was measured using Cancer Institute QOL Questionnaire version 2 at the beginning of therapy and at the end of 3 months. Our study showed that metastatic lung cancer patients had average QOL at presentation. The QOL in patients on TKI improved compared to those on platinum doublet chemotherapy during the second assessment, but this improvement was statistically not significant. In this study, the metastatic lung cancer patients had an average QOL during initial presentation. Patients on TKI had a trend toward better QOL after 3 months of treatment compared to platinum doublet chemotherapy.

MA08.06 Impact of Depth of Response (DpR) on Survival in Patients with Advanced NSCLC Treated with First-Line Chemotherapy

DpR, defined as maximum tumor shrinkage, has emerged as a potential predictor for long-term treatment outcome across multiple tumors, including NSCLC treated with immunotherapy or targeted therapy. This exploratory analysis evaluated whether DpR correlated with survival in patients with advanced NSCLC treated with platinum-doublet chemotherapy in a phase III randomized clinical trial. Patients received first-line nab-paclitaxel 100 mg/m2 weekly or paclitaxel 200 mg/m2 q3w, both + carboplatin AUC 6 q3w. The current analysis evaluated DpR as best percent change from baseline in total target lesion length during treatment. For patients with tumor shrinkage, data were grouped into quartiles based on maximum percent shrinkage from baseline (Q1: > 0%-≤ 25%; Q2: > 25%-≤ 50%; Q3: > 50%-≤ 75%, Q4: > 75%) and compared with data from patients with no change or tumor growth (NC/G). Tumor measurement by independent review (baseline and postbaseline) was evaluable in 959 patients pooled across treatments. The median (Figure) and 1-year OS increased with each quartile vs NC/G (NC/G: 4.8 months and 17%; Q1: 10.4 months and 44%; Q2: 14.5 months and 62%; Q3: 19.3 months and 71%; Q4: 23.5 months and 70%) with HRs for OS vs NC/G of 0.42 for Q1 (95% CI, 0.33-0.53; P < 0.0001), 0.28 for Q2 (0.22-0.36; P < 0.0001), 0.23 for Q3 (0.16-0.31; P < 0.0001), and 0.19 for Q4 (0.11-0.33; P < 0.0001), respectively. Similar findings were observed for all quartiles vs NC/G for age (≥ 70 and < 70 years) and histology (squamous and nonsquamous) in subset analyses (P < 0.05 for all comparisons). DpR was associated with increased OS in patients with advanced NSCLC receiving first-line platinum-based doublet chemotherapy, regardless of age or histology. These findings underscore the importance of evaluating quality of treatment response in this patient population.

Study of gefitinib maintenance in unselected patients with metastatic primary lung adenocarcinoma: A descriptive study.

Maintenance treatment of patients with advanced nonsmall cell lung cancer (NSCLC) without disease progression after first-line chemotherapy is a subject of ongoing research. The aim of this study was to investigate the efficacy, safety, and tolerability of the epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor, i.e., gefitinib in the maintenance setting irrespective of EGFR status. Patients aged 18 years or older of Indian origin, who had a life expectancy of >12 weeks with histologically or cytologically confirmed Stage IV NSCLC, the WHO performance status of 0-2, and who had completed four to six cycles of first-line platinum-based doublet chemotherapy without disease progression or unacceptable toxic effects were included in the study. The primary endpoint of the study was progression-free survival in the intention-to-treat population. Twenty-five patients with a median age of 55 years (40-68) were included in the study. The median progression-free survival (PFS) for the entire group was 8 months (95% confidence interval [CI] =1.45-14.54) had not reached for EGFR-positive patient, but in the EGFR negative cohort, the PFS was 4.98 months (hazard ratio = 0.092, 95% CI = 3.4-6.5, P = 0.01). The median overall survival (OS) of the study group was 15 months (95% CI = 3.7-26.4), all patients with EGFR positive were alive (100% survival). The median OS for EGFR negative group was about 6.3 months. The major toxicity observed was rash/acne in 15 patients, pruritus in 7 patients, and one patient had Grade 4 pneumonitis. Gefitinib maintenance is safe, well-tolerated therapy, produces significant PFS and OS benefit in EGFR mutation-positive patient. It is definitely not a choice for EGFR negative group. In EGFR unknown group, the role of maintenance still needs to be explored.

MA11.09 Progastrin-Releasing Peptide (ProGRP) to Rule out Progressive Disease in Patients with Small Cell Lung Carcinoma (SCLC)

For patients with SCLC, response to chemotherapy is monitored by computed tomography (CT) scans, which can be costly and inconvenient. A previous study showed that baseline levels (>100 pg/ml) of the tumor marker, ProGRP, were positively correlated with advanced SCLC, and a decline in ProGRP levels during treatment was associated with response.1 However, the best approach to fully exploit ProGRP for monitoring treatment response is still unknown. The objective of this study was to determine if progression could be ruled out solely by combining the changes in ProGRP levels over two chemotherapy cycles. Patients with SCLC receiving first-line platinum-based doublet chemotherapy or a single-agent cytotoxic in any subsequent treatment line were included from six centers in Europe and China. Samples were collected prospectively and ProGRP levels were measured in serum or plasma samples using a fully automated ProGRP assay at baseline and after chemotherapy cycles 1 and 2. Only patients with blood samples taken at these time points and with elevated baseline ProGRP >100 pg/ml were eligible for this analysis. A logistic regression model was calculated to incorporate changes after the first cycle (i.e. from baseline to the end of cycle 1) and in between cycles (i.e. end of cycle 1 to the end of cycle 2). Progression was ascertained with CT scans. A non-progressor was defined as a patient with complete response, partial response, or stable disease, according to the RECIST v1.1 or WHO criteria. Progressors were patients with progressive disease only. Overall, 123 patients (n=108 non-progressors, n=15 progressors) satisfied the eligibility criteria. Median age was 62.0 years (range 36.0–83.0), 56% were male, and 78% reported to be current or past smokers. In this population, a decline in ProGRP from both baseline to cycle 1 and from cycle 1 to cycle 2 was associated with non-progression (AUC 91.5%; 95% CI: 85.3−97.8; sensitivity 100%; specificity 71%). All patients who experienced a >25% relative decline in ProGRP levels after the first chemotherapy cycle, followed by any further decrease (>0%) after the second cycle, were found to be non-progressors. By measuring the change in ProGRP levels at baseline and after each of the two subsequent chemotherapy cycles, we were able to identify patients with non-progressive disease. This might reduce the need for interim CT scans.

First-line therapy outcomes in patients with advanced stage nonsmall cell lung cancer treated at nongovernment tertiary care centrer in India: Experience from a real world practice.

Reports on first line or subsequent treatment and their outcomes for patients with advanced nonsmall cell lung cancer (NSCLC) in India are scarce. The present study is an attempt to understand real world practice scenario of first-line therapy and outcome in advanced stage NSCLC patients. Observational study was conducted at a nongovernment tertiary cancer care center. Totally 83 patients with newly diagnosed advanced NSCLC who were evaluated for further treatment from 2008 onward were included in the study. Best supportive care was the only treatment received in 11/83 patients. Sixty-three patients received platinum-based doublet chemotherapy and nine received epidermal growth factor receptor tyrosine kinase inhibitor (TKI) as first-line therapy. Pemetrexed and platinum was the most common first-line chemotherapy (56%) regimen used. First-line chemotherapy had to be discontinued in these eight patients due to Grade III/IV toxicity. Disease control rate with the first-line chemotherapy was 70% (partial response 38%, stable disease 32%). Median overall survival (OS) was 17 months with OS at 1 and 2 years was 52% and 29.5%, respectively. First-line platinum-based chemotherapy is feasible and does achieve disease control in the majority of patients with advanced NSCLC. Strategies of selection of therapy based on histology and the presence of driver mutations, use of small molecule TKI, maintenance therapy and multiple lines of therapies are being increasingly implemented in clinical practice and thus improving survival of Indian patients of NSCLC.

P2.06-022 First-Line Durvalumab plus Tremelimumab vs Platinum-Based Chemotherapy for Advanced/Metastatic NSCLC: Phase 3 NEPTUNE Study: Topic: Phase III

Current first-line therapy for advanced EGFR and ALK wild-type NSCLC is associated with poor survival and there remains a significant need for more effective treatments in this population. Blockade of immune checkpoints programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) represents a promising anticancer therapeutic strategy. In preclinical models, targeting both PD-1 and CTLA-4 provides for non-redundant pathway blockade and potential synergy. Durvalumab (MEDI4736) is a selective, high-affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 (IC50 0.1 nM) and CD80 (IC50 0.04 nM). Tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4. A Phase 1b study of durvalumab + tremelimumab demonstrated encouraging clinical activity and a manageable tolerability profile in advanced NSCLC, with activity observed in patients with high and low/no tumor PD-L1 expression (NCT02000947). NEPTUNE (NCT02542293) is a randomised, open-label, multicentre, global, Phase 3 study. Immunotherapy- and chemotherapy-naïve patients with advanced/metastatic EGFR and ALK wild-type NSCLC (with either PD-L1 high expression [≥25% tumor cells staining for PD-L1 at any intensity] or PD-L1 low/negative expression [<25% tumor cells staining for PD-L1 at any intensity] ) will be randomised (1:1) to durvalumab (20 mg/kg i.v. every 4 weeks [q4w] for up to 12 months) + tremelimumab (1 mg/kg i.v. q4w for up to 4 doses); or standard-of-care platinum-based doublet chemotherapy. The primary endpoint is overall survival (OS). Secondary endpoints are progression-free survival (PFS), objective response rate (ORR), duration of response and proportion of patients alive and progression free at 12 months by investigator assessment (RECIST v1.1); time from randomisation to second progression; OS, PFS and ORR in patients with PD-L1 low/negative NSCLC; safety (CTCAE v4.03) and tolerability; pharmacokinetics; and immunogenicity. Exploratory outcomes include potential biomarkers of response to treatment and impact of subsequent anticancer therapies on OS. Recruitment is ongoing. Not-applicable. Not-applicable.

P3.02c-038 First-Line Atezolizumab plus Chemotherapy in Chemotherapy-Naïve Patients with Advanced NSCLC: A Phase III Clinical Program: Topic: IT

First-line treatments for patients with advanced NSCLC include targeted therapies and platinum-based doublet chemotherapy±bevacizumab and/or pemetrexed. Although immunotherapies targeting the PD-L1/PD-1 pathway are available for advanced NSCLC beyond the first line, chemotherapy is a key first-line option for patients, despite poor survival outcomes, highlighting the need for additional treatment options. Atezolizumab, a monoclonal anti–PD-L1 antibody, inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy has been reported with atezolizumab monotherapy in patients with squamous and nonsquamous NSCLC, with a survival benefit observed across all PD-L1 expression levels. Additionally, Phase Ib data showed the potential for chemotherapy to further enhance responses to atezolizumab, with tolerable safety, in patients with NSCLC. Bevacizumab in combination with atezolizumab may enhance efficacy in non-squamous NSCLC by inhibiting VEGF-mediated immunosuppression. Four global, Phase III, randomized, open-label trials are evaluating atezolizumab+platinum-based chemotherapy±bevacizumab in chemotherapy-naive patients with stage IV NSCLC. Eligible patients must have stage IV NSCLC, measurable disease (RECIST v1.1) and ECOG PS 0-1 and be chemotherapy naive. Exclusion criteria include untreated CNS metastases, autoimmune disease and prior exposure to immunotherapy. Patients will be enrolled regardless of PD-L1 expression status. Patients randomized to the experimental arm will receive atezolizumab 1200 mg with standard platinum-based chemotherapy in IMpower130 and 131 and also ±bevacizumab in IMpower150 for four or six 21-day cycles, then maintenance with atezolizumab in IMpower130 and 131 and atezolizumab+bevacizumab in IMpower150. In IMpower132, experimental-arm patients will receive atezolizumab+platinum-based chemotherapy+pemetrexed, then maintenance with atezolizumab+pemetrexed. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include objective response rate and safety. Evaluation of predictive biomarkers associated with efficacy will be performed.Tabled 1TrialIMpower130IMpower131IMpower132IMpower150HistologyNonsquamousSquamousNonsquamousNonsquamousPlanned enrollment(N)65010255681200ExperimentalAtezolizuma+carboplatin+nab-paclitaxelAtezolizuma+carboplatin+paclitaxel or Atezolizumab+carboplatin+nab-paclitaxelAtezolizuma+carboplatinor cisplatin+pemetrexedAtezolizumab+carboplatin+paclitaxel or Atezolizumab+carboplatin+paclitaxel+bevacizumabComparatorCarboplatin+nab-paclitaxelCarboplatin+nab-paclitaxelCarboplatinor cisplatin+pemetrexedCarboplatin+paclitaxel+bevacizumabStratification factorsSexLiver metastasesCentrally assessedPD-L1 expression by IHCSexLiver metastasesCentrally assessedPD-L1 expression by IHCSexECOG PSChemotherapy type (carboplatin vs cisplatin)Smoking statusSexLiver metastasesCentrally assessedPD-L1 expression by IHCIdentifierNCT02367781NCT02367794NCT02657434NCT02366143ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry. Open table in a new tab ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry. Section not applicable. Section not applicable.

PUB039 Role of Pemetrexed and Cisplatin Combination Therapy in Advanced Non Squamous Cell Lung Cancer

NSCLC is the leading cause of cancer death in today’s scenario. Despite significant progress in early stage disease, survival rates for advanced disease remain low. Platinumbased doublet chemotherapy has become the current standard of care for advanced nonsmall cell lung cancer (NSCLC) which has shown modest prolongation of survival and improvement in cancerrelated symptoms. All the patients received [email protected] 500mg/m2 Day 1 and Cisplatin @ 75mg/m2 every 21 days with restaging after 3 and 6 cycles. Overall response rate was the primary end point and PFS as secondary end point. In this retrospective study, 90 patients were analyzed. The patients treated with pemetrexed plus cisplatin had a median age of 58 years and were predominantly men (70) with nonsquamous histology (60), stage IV (52) disease, and a performance status of 0 (40). Response rates were 48%. Median time to progression was 7 months. Median overall survival was 12 months. The 1year survival rate was 52%. Hematologic toxicities observed in the patients were grade 3/4 neutropenia (20%), grade 3 thrombocytopenia (10%), and grade 3 anemia (6%). Ten patients had febrile neutropenia. The combination of pemetrexed and cisplatin was effective and safe and associated with acceptable toxicities and relatively long survival in patienst with advanced NSCLC.

482TiP Global, Phase 3 study of first-line durvalumab (MEDI4736) + tremelimumab vs standard of care platinum-based chemotherapy in advanced/metastatic NSCLC: NEPTUNE

Background There is an urgent need for improved first-line therapy for advanced EGFR and ALK wild-type NSCLC, for which current molecularly targeted therapies are not indicated. Blockade of programmed cell death-1 (PD-1) and cytotoxic T- lymphocyte-associated antigen-4 (CTLA-4) immune checkpoints represents a promising anticancer therapeutic strategy. As PD-1 and CTLA-4 regulate immune responses by different mechanisms, targeting both pathways provides the potential for additive or synergistic effects. Durvalumab is a selective, high-affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 and CD80. Tremelimumab is a selective human IgG2 mAb against CTLA-4. In a Phase 1b study (NCT02000947), durvalumab + tremelimumab demonstrated a manageable tolerability profile in advanced NSCLC, with clinical activity observed both in pts with high levels of tumour PD-L1 expression and in pts with low/no tumour PD-L1 expression. Trial design: NEPTUNE (NCT02542293) is a randomised, open-label, multicentre, global, Phase 3 study assessing durvalumab + tremelimumab vs standard of care in immunotherapy- and chemotherapy-naïvepts with advanced/metastatic EGFR and ALK wild-type NSCLC. Pts with either PD-L1 high expression or PD-L1 low/no expression (≥25% or < 25% of tumour cells with membrane staining, respectively) will be randomised (1:1) to durvalumab (20 mg/kg i.v. q4w for upto12 months) + tremelimumab (1 mg/kg i.v. q4w for up to 4 doses); or platinum-based doublet chemotherapy. Stratification factors are PD-L1 expression level, histology and smoking history. The primary endpoint is overall survival (OS). Secondary endpoints are progression-free survival (PFS), objective response rate (ORR), duration of response and proportion of pts alive and progression free at 12 months by investigator assessment (RECIST v1.1); time to second progression; OS, PFS and ORR in pts with PD-L1 low/negative NSCLC; safety (CTCAE v4.03) and tolerability; pharmacokinetics; and immunogenicity. Exploratory outcomes include potential biomarkers of response to treatment and impact of subsequent anticancer therapies on OS. Recruitment is ongoing. Clinical trial indentification NCT02542293 Legal entity responsible for the study AstraZeneca PLC Funding AstraZeneca Disclosure T. Mok: SB/Grants/Res/Stock/Hono/rEmploy: AZ Roche/Genentech, Pfizer EL BI MSD Amgen Janssen Clovis GSK Novartis BMS PrIME SFJ Roche MSD BioMarin ACEA Vertex BMS geneDecode OncoGenex Celgene Sanomics Merck Serono MSD GSK BMS Aveo & Biodesix CUHK. P. Schmid: Research: Roche, Genentech, AZ, Astellas, Medivation, Novartis, Oncogenex. G. de Castro, Jr: Speakers Bureau: AstraZeneca, MSD, BMS Consultant: Roche, MSD. K. Syrigos: Honoraria: BMS, Novartis, Roche, BI. C. Martin: Speakers Bureau: BMS, BI N. Yamamoto: Grants/ Research Support: Chugai, BI, Ono Pharmaceutical CO Consultant: AZ, Chugai, BI, Ono Pharmaceutical CO Honoraria: AZ, Chugai, BI, MSD, Ono Pharmaceutical Co. O. Arén: Honoraria: BMS. R. Ramlau: Consultant: MSD, Roche, El Lilly, BI Honoraria: MSD, Roche, El Lilly, BI. L. Trani: Employee: AZ. All other authors have declared no conflicts of interest.

Metabolic response assessment with 18F-FDG-PET/CT is superior to modified RECIST for the evaluation of response to platinum-based doublet chemotherapy in malignant pleural mesothelioma

PurposeEfficient monitoring of tumor responsiveness to chemotherapy is essential to mitigate high mortality risks and cytotoxic effects of chemotherapeutics. However, there is no consensus on the most suitable diagnostic technique/parameters for assessing response to chemotherapy in malignant pleural mesothelioma (MPM). We compared the tumor responsiveness of MPM patients as assessed using modified RECIST (mRECIST) criteria and integrated 18F-FDG-PET/CT. MethodsHistologically confirmed MPM patients (N=82) who were treated with three cycles of cisplatin and pemetrexed, or carboplatin and pemetrexed, were included. mRECIST and integrated 18F-FDG-PET/CT were used to evaluate MPM tumor response to chemotherapy. Metabolic non-responders were defined as those with a 25% or greater increase in SUVmax compared with the previous value. Time to progression (TTP) and overall survival (OS) were compared between metabolic-responders and non-responders. ResultsAfter three cycles of chemotherapy, 62(75.6%) of the patients were classified as having SD, 15 (18%) with partial remission (PR), and 5 (6%) with progressive disease (PD), based on mRECIST criteria. The cumulative median OS was 728.0days (95% confidence interval [CI]: 545.9–910.1) and cumulative median TTP was 365.0days (95% CI: 296.9–433.1). For the 82 patients, the disease control rate was 93.9%, whereas the metabolic response rate was only 71.9% (p<0.001). All PD and PR patients were found to be metabolic responders on 18F-FDG-PET/CT; however, among the 62mRECIST SD patients, 18 (29%) were classified as metabolic non-responders. The median TTP for metabolic responders was 13.7 months, while it was 10.0 months for non-responders(p<0.001). Metabolic responders had a trend toward longer OS, although the difference did not reach statistical significance (metabolic responders:33.9 months; non-responders: 21.6 months; p>0.05). ConclusionSeveral mRECIST-confirmed SD MPM patients may be classified as metabolic non-responders on18F-FDGPET/CT. Metabolic response is significantly correlated with the median TTP, suggesting it should be included in the evaluation of the response to chemotherapy in MPM patients classified as mRECIST SD, to identify non-responders.

A potential new therapeutic option for patients with advanced EGFR mutation-positive non-small cell lung cancer in first-line setting.

EGFR mutation-positive non-small cell lung cancer (NSCLC) is a well-defined molecular subtype of lung cancer. We already know data on frequency and characteristics of EGFR mutations among patients with NSCLC and their response to tyrosine kinase inhibitors (TKIs) (1). Actually these small molecules represent the standard first-line treatments for this setting of patients, while platinum-based doublet chemotherapy is the standard first-line treatment for patients with wild type EGFR NSCLC (2).

A prospective, multicenter, phase II clinical study of concurrent chemotherapy and thoracic three-dimensional radiotherapy for stage IV non-small cell lung cancer -Impact of clinical factors on survival (PPRA-RTOG003)

Objective To investigate the impact of clinical factors on survival in patients receiving concurrent chemotherapy and three-dimensional radiotherapy (3DRT) for stage IV non-small cell lung cancer (NSCLC). Methods A total of 203 patients were enrolled in a prospective clincial study from 2008 to 2012, and among these patients, 178 patients were eligible for analysis of clinical factors. All patients were treated with platinum-based doublets chemotherapy, with a median number of chemotherapy cycles of 4(2-6 cycles) and a median dose of 3DRT of 60.3 Gy (36.0-76.5 Gy). The Kaplan-Meier method was used to calculate overall survival (OS) rates, the log-rank test was used to compare survival rates between groups, and the Cox regression model were used for multivariate analysis. Results The 1-, 2-, and 3-year overall survival rates were 56%, 16%, and 10%, respectively, and the median survival time was 13 months (95% CI=11.500-14.500). The univariate analysis showed that platelet count ≤221×109/L, neutrophil count ≤5.2×109/L, white blood cell count<7×109/L, and improvement in Karnofsky Performance Scale (KPS) after treatment significantly prolonged OS (P=0.000, 0.022, 0.003, and 0.029), and metastasis to a single organ and hemoglobin≥120 g/L tended to prolong OS (P=0.058 and 0.075). The multivariate analysis showed that white blood cell count<7×109/L, platelet count ≤221×109/L, and improvement in KPS after treatment were beneficial to OS (all P<0.05). Conclusions White blood cell count and platelet count before treatment and KPS after treatment are prognostic factors for patients with stage IV NSCLC receiving concurrent chemotherapy and 3DRT. Clinical Trial Registry ClinicalTrials.gov, registration number: ChiCTRTNC10001026. Key words: Carcinoma, non-small cell lung/three-dimensional radiotherapy; Carcinoma, non-small cell lung/concurrent chemoradiotherapy; Clinical factors; Prognosis

Metastatic Lung Cancer: Emerging Therapeutic Strategies.

Advanced stage nonsmall cell lung cancer had been treated mainly with platinum-based doublet chemotherapy, and other cytotoxic agents that offered significant survival advantage over best supportive care, until recently. Modest improvements were achieved with the addition of antibodies targeting the vascular endothelial growth factor, and the introduction of maintenance chemotherapy. Improvements in our knowledge of lung cancer biology have shifted the current treatment paradigm from being based on histology to one based on molecular biomarkers. Identification of potentially targetable driver mutations in a subgroup of these patients, pertaining to genes directing cell signaling pathways involved in proliferation and survival, has been the single most influential development in the treatment of lung cancer in the last two decades. Personalized medicine based on driver mutations offers enhanced efficacy at the expense of relatively minimal toxicity burden. Targeting the epidermal growth factor receptor pathway in patients with an activating mutation results in substantial improvement in patient outcome. Similarly, targeting ALK (anaplastic lymphoma kinase) fusion gene with first- and second-generation inhibitors results in improved efficacy over chemotherapy. For certain other mutations such as MET exon 14 and BRAF, promising inhibitory strategies are being investigated. In addition, the recent emergence of immune checkpoint inhibitors to reverse exhaustion of T cells has been a major breakthrough in rapidly changing the therapeutic landscape for lung cancer. This article reviews the role of systemic therapy in advanced stage lung cancer.

1246P - Adjusted indirect comparison using propensity score matching of osimertinib to doublet chemotherapy in patients with EGFRm T790M NSCLC who have progressed after EGFR-TKI

In the absence of randomized data comparing osimertinib to platinum-based doublet chemotherapy (PBDC) in patients (pts) with metastatic epidermal growth factor receptor (EGFRm) T790M non-small cell lung cancer (NSCLC) who have progressed after EGFR-TKI, an adjusted indirect comparison can offer a robust estimate of treatment effect. The IMPRESS study placebo arm (PBDC) (data cut-off [DCO] 2014 May) included a subgroup of pts with the T790M mutation and disease progression following response to EGFR-TKI. Pts had similar demographic and disease characteristics as those in AURA extension (NCT01802632) and AURA2 (NCT02094261) trials of osimertinib (DCO May 2015), and therefore represent a valid comparator to demonstrate differences in outcomes. The efficacy of osimertinib relative to PBDC was assessed using an adjusted indirect comparison of two non-randomized data sets comprising pts with a confirmed T790M mutation (by tissue or plasma ctDNA respectively): AURA (N = 405) and IMPRESS placebo arm (N = 60). A propensity score (PS) approach was used to adjust for differences in baseline demographics and disease characteristics. Baseline characteristics of both groups were compared using statistical tests. The PS model included 22 variables with P < 0.2. Only pts within the PS distributions of both treatment groups were included in the final analyses. To adjust for remaining differences between the groups, PS was incorporated as a covariate in the treatment comparison of osimertinib relative to PBDC for each endpoint. Following estimation of PS for each pt and balancing across the groups (osimertinib N = 287, PBDC N = 51) osimertinib demonstrated: A statistically significant improvement in median progression-free survival (PFS) of 9.7 months vs 5.3 months (HR 0.28, 95% CI 0.19–0.42, P < 0.0001) An improvement in objective response rate (ORR) of 64.6% vs 34.8% (OR 4.76, 95% CI 2.21–10.26, P < 0.001). In this indirect comparison, a statistically significant improvement in PFS and ORR was demonstrated for osimertinib compared to PBDC. AURA3 will provide a randomized comparison of osimertinib and PBDC.