Considerations for Second-Line Therapy of Non-Small Cell Lung Cancer
TL;DR: A better understanding of prognostic factors in the first-line setting may allow clinicians to better select patients for second-line therapy, and lead to better-designed second- line trials.
Abstract: For patients with advanced non-small cell lung cancer and a good functional status, platinum-based first-line chemotherapy improves quality of life, reduces diseaserelated symptoms, and improves survival. The addition of bevacizumab to carboplatin and paclitaxel in the first-line setting has been shown to produce a higher response rate and longer progression-free survival and overall survival times than with carboplatin and paclitaxel. Despite these therapies, all patients inevitably experience disease progression. There are currently three agents approved for treating patients who progress after one prior regimen: docetaxel, pemetrexed, and erlotinib. Erlotinib is also indicated for patients who progress after two prior regimens. These agents appear to have similar efficacies in terms of response and overall survival, but have significantly different
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Aix-Marseille University1, Genentech2, Samsung Medical Center3, Seconda Università degli Studi di Napoli4, Wayne State University5, Pontifícia Universidade Católica do Rio Grande do Sul6, University of California, Los Angeles7, European Institute of Oncology8, Istanbul University9, Seoul National University Bundang Hospital10, University of California, Davis11
TL;DR: Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations, and overall survival improvement was similar in patients with squamous non-squamous lung cancer.
3,496 citations
TL;DR: Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitABine and cascplatin alone group and stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01].
Abstract: Summary Background Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m 2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m 2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Findings Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4–12·6]) vs 9·9 months [8·9–11·1]; stratified hazard ratio 0·84 [95% CI 0·74–0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [ Interpretation Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Funding Eli Lilly and Company.
393 citations
TL;DR: Reinforcement learning has tremendous potential in clinical research because it can select actions that improve outcomes by taking into account delayed effects even when the relationship between actions and outcomes is not fully known.
Abstract: There has been significant recent research activity in developing therapies that are tailored to each individual. Finding such therapies in treatment settings involving multiple decision times is a major challenge. In this dissertation, we develop reinforcement learning trials for discovering these optimal regimens for life-threatening diseases such as cancer. A temporal-difference learning method called Q-learning is utilized which involves learning an optimal policy from a single training set of finite longitudinal patient trajectories. Approximating the Q-function with time-indexed parameters can be achieved by using support vector regression or extremely randomized trees. Within this framework, we demonstrate that the procedure can extract optimal strategies directly from clinical data without relying on the identification of any accurate mathematical models, unlike approaches based on adaptive design. We show that reinforcement learning has tremendous potential in clinical research because it can select actions that improve outcomes by taking into account delayed effects even when the relationship between actions and outcomes is not fully known.
To support our claims, the methodology's practical utility is firstly illustrated in a virtual simulated clinical trial. We then apply this general strategy with significant refinements to studying and discovering optimal treatments for advanced metastatic stage IIIB/IV non-small cell lung cancer (NSCLC). In addition to the complexity of the NSCLC problem of selecting optimal compounds for first and second-line treatments based on prognostic factors, another primary scientific goal is to determine the optimal time to initiate second-line therapy, either immediately or delayed after induction therapy, yielding the longest overall survival time. We show that reinforcement learning not only successfully identifies optimal strategies for two lines of treatment from clinical data, but also reliably selects the best initial time for second-line therapy while taking into account heterogeneities of NSCLC across patients.
257 citations
Cites background from "Considerations for Second-Line Ther..."
...Some patients who maintain a good performance status and tolerate therapy without significant toxicities will receive third-line therapy [3]....
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TL;DR: YM155 exhibited modest single-agent activity in patients with refractory, advanced NSCLC and a favorable safety/tolerability profile was reported.
Abstract: Purpose To evaluate the antitumor activity and safety of YM155, a novel, small-molecule suppressor of survivin, as single-agent therapy in patients with previously treated, advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIb/IV NSCLC who had experienced treatment failure during one or two prior chemotherapy regimens (at least one of which was platinum based) received YM155 as a continuous intravenous infusion (4.8 mg/m2/d) over 168 hours followed by observation for 14 days in 21-day treatment cycles. The primary end point was objective tumor response rate (ORR). Secondary end points included duration of stable disease (SD), progression-free survival (PFS), overall survival (OS), safety and pharmacokinetic profiles, and pharmacodynamic evaluations. Results Thirty-seven patients received YM155. Two patients achieved a confirmed partial response, with an ORR of 5.4% (95% CI, 0.7% to 18.2%). An additional 14 patients (37.8%) achieved SD resulting in a disease control rat...
232 citations
Heidelberg University1, Maastricht University Medical Centre2, Kindai University3, Aberdeen Royal Infirmary4, University Hospital of Lausanne5, Guangdong General Hospital6, Oslo University Hospital7, Hebron University8, University of Leicester9, Ludwig Maximilian University of Munich10, Université Paris-Saclay11, Medical University of Białystok12, Claude Bernard University Lyon 113, University of Turin14, Netherlands Cancer Institute15, Athens State University16, Ghent University17, University of Sydney18, National Taiwan University19, University of Chicago20
TL;DR: It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments, and the preclinical evidence for combining these treatments is examined.
176 citations
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TL;DR: While the absolute number of cancer deaths decreased for the second consecutive year in the United States, much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years.
Abstract: Each year, the American Cancer Society (ACS) estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics This report considers incidence data through 2003 and mortality data through 2004 Incidence and death rates are age-standardized to the 2000 US standard million population A total of 1,444,920 new cancer cases and 559,650 deaths for cancers are projected to occur in the United States in 2007 Notable trends in cancer incidence and mortality rates include stabilization of the age-standardized, delay-adjusted incidence rates for all cancers combined in men from 1995 through 2003; a continuing increase in the incidence rate by 03% per year in women; and a 136% total decrease in age-standardized cancer death rates among men and women combined between 1991 and 2004 This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends While the absolute number of cancer deaths decreased for the second consecutive year in the United States (by more than 3,000 from 2003 to 2004) and much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population
7,446 citations
TL;DR: The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths.
Abstract: bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P = 0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage. Conclusions The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non–small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.)
5,584 citations
TL;DR: Elotinib can prolong survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy, and five percent of patients discontinued erlot inib because of toxic effects.
Abstract: Patients with stage IIIB or IV non–small-cell lung cancer, with performance status from 0 to 3, were eligible if they had received one or two prior chemotherapy regimens. The patients were stratified according to center, performance status, response to prior chemotherapy, number of prior regimens, and prior platinum-based therapy and were randomly assigned in a 2:1 ratio to receive oral erlotinib, at a dose of 150 mg daily, or placebo. results The median age of the 731 patients who underwent randomization was 61.4 years; 49 percent had received two prior chemotherapy regimens, and 93 percent had received platinum-based chemotherapy. The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group (P<0.001); the median duration of the response was 7.9 months and 3.7 months, respectively. Progression-free survival was 2.2 months and 1.8 months, respectively (hazard ratio, 0.61, adjusted for stratification categories; P<0.001). Overall survival was 6.7 months and 4.7 months, respectively (hazard ratio, 0.70; P<0.001), in favor of erlotinib. Five percent of patients discontinued erlotinib because of toxic effects. conclusions Erlotinib can prolong survival in patients with non–small-cell lung cancer after firstline or second-line chemotherapy.
5,157 citations
TL;DR: None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.
Abstract: Background We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non–small-cell lung cancer. Methods A total of 1207 patients with advanced non–small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. Results The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin...
4,781 citations
01 Jan 2002
TL;DR: The response rate for all 1155 eligible pa-tients was 19 percent, with a median survival of 79 months (95 percent confidence interval, 73 to 85), a1-year survival rate of 33 percent, and a 2-year surviv-al rate of 11 percent.
Abstract: The response rate for all 1155 eligible pa-tients was 19 percent, with a median survival of 79months (95 percent confidence interval, 73 to 85), a1-year survival rate of 33 percent (95 percent confi-dence interval, 30 to 36 percent), and a 2-year surviv-al rate of 11 percent (95 percent confidence interval,8 to 12 percent) The response rate and survival didnot differ significantly between patients assigned toreceive cisplatin and paclitaxel and those assigned toreceive any of the three experimental regimens Treat-ment with cisplatin and gemcitabine was associatedwith a significantly longer time to the progression ofdisease than was treatment with cisplatin and pacli-taxel but was more likely to cause grade 3, 4, or 5 re-nal toxicity (in 9 percent of patients, vs 3 percent ofthose treated with cisplatin plus paclitaxel) Patientswith a performance status of 2 had a significantlylower rate of survival than did those with a perform-ance status of 0 or 1
3,839 citations