scholarly journals Neoadjuvant immunotherapy for non-small cell lung cancer: right drugs, right patient, right time?

2021 ◽  
Vol 9 (6) ◽  
pp. e002248
Author(s):  
Elizabeth Ahern ◽  
Ben J Solomon ◽  
Rina Hui ◽  
Nick Pavlakis ◽  
Ken O'Byrne ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Phase Iii ◽  
Direct Selection ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
The Right

Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC; the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.

scholarly journals Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Sarah-Louise Ryan ◽  
Keyur A. Dave ◽  
Sam Beard ◽  
Martina Gyimesi ◽  
Matthew McTaggart ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cellular Response ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Learning Approaches ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Novel Biomarkers

Platinum-based chemotherapy remains the cornerstone of treatment for most people with non-small cell lung cancer (NSCLC), either as adjuvant therapy in combination with a second cytotoxic agent or in combination with immunotherapy. Resistance to therapy, either in the form of primary refractory disease or evolutionary resistance, remains a significant issue in the treatment of NSCLC. Hence, predictive biomarkers and novel combinational strategies are required to improve the effectiveness and durability of treatment response 6for people with NSCLC. The aim of this study was to identify novel biomarkers and/or druggable proteins from deregulated protein networks within non-oncogene driven disease that are involved in the cellular response to cisplatin. Following exposure of NSCLC cells to cisplatin, in vitro quantitative mass spectrometry was applied to identify altered protein response networks. A total of 65 proteins were significantly deregulated following cisplatin exposure. These proteins were assessed to determine if they are druggable targets using novel machine learning approaches and to identify whether these proteins might serve as prognosticators of platinum therapy. Our data demonstrate novel candidates and drug-like molecules warranting further investigation to improve response to platinum agents in NSCLC.

Randomized Phase III Trial of Docetaxel Versus Vinorelbine or Ifosfamide in Patients With Advanced Non–Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy Regimens

2000 ◽  
Vol 18 (12) ◽  
pp. 2354-2362 ◽  
Author(s):  
Frank V. Fossella ◽  
Russell DeVore ◽  
Ronald N. Kerr ◽  
Jeffrey Crawford ◽  
Ronald R. Natale ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Phase Iii ◽  
Control Treatment ◽  
Rank Test ◽  
Small Cell Lung ◽  
Phase Iii Trial ◽  
Platinum Based Chemotherapy

PURPOSE: To confirm the promising phase II results of docetaxel monotherapy, this phase III trial was conducted of chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC) who had previously failed platinum-containing chemotherapy. PATIENTS AND METHODS: A total of 373 patients were randomized to receive either docetaxel 100 mg/m2 (D100) or 75 mg/m2 (D75) versus a control regimen of vinorelbine or ifosfamide (V/I). The three treatment groups were well-balanced for key patient characteristics. RESULTS: Overall response rates were 10.8% with D100 and 6.7% with D75, each significantly higher than the 0.8% response with V/I (P = .001 and P = .036, respectively). Patients who received docetaxel had a longer time to progression (P = .046, by log-rank test) and a greater progression-free survival at 26 weeks (P = .005, by χ2 test). Although overall survival was not significantly different between the three groups, the 1-year survival was significantly greater with D75 than with the control treatment (32% v 19%; P = .025, by χ2 test). Prior exposure to paclitaxel did not decrease the likelihood of response to docetaxel, nor did it impact survival. There was a trend toward greater efficacy in patients whose disease was platinum-resistant rather than platinum-refractory and in patients with performance status of 0 or 1 versus 2. Toxicity was greatest with D100, but the D75 arm was well-tolerated. CONCLUSION: This first randomized trial in this setting demonstrates that D75 every 3 weeks can offer clinically meaningful benefit to patients with advanced NSCLC whose disease has relapsed or progressed after platinum-based chemotherapy.

Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Gemcitabine/Cisplatin Alone or With Sorafenib for the First-Line Treatment of Advanced, Nonsquamous Non–Small-Cell Lung Cancer

2012 ◽  
Vol 30 (25) ◽  
pp. 3084-3092 ◽  
Author(s):  
Luis G. Paz-Ares ◽  
Bonne Biesma ◽  
David Heigener ◽  
Joachim von Pawel ◽  
Timothy Eisen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
First Line ◽  
Escape Trial ◽  
End Point

Purpose This trial evaluated the efficacy and safety of sorafenib plus gemcitabine/cisplatin in chemotherapy-naive patients with unresectable stage IIIB to IV nonsquamous non–small-cell lung cancer (NSCLC). Patients and Methods Between February 2007 and March 2009, 904 patients were randomly assigned to daily sorafenib (400 mg twice a day) or matching placebo plus gemcitabine (1,250 mg/m2 per day on days 1 and 8) and cisplatin (75 mg/m2 on day 1) for up to six 21-day cycles. Because of safety findings from the Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC (ESCAPE) trial, patients with squamous cell histology were withdrawn from the trial in February 2008 and excluded from analysis. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS) and time-to-progression (TTP). Results The primary analysis population consisted of 772 patients (sorafenib, 385; placebo, 387); the two groups had similar demographic and baseline characteristics. Median OS was similar in the sorafenib and placebo groups (12.4 v 12.5 months; hazard ratio [HR], 0.98; P = .401). By investigator assessment, sorafenib improved median PFS (6.0 v 5.5 months; HR, 0.83; P = .008) and TTP (6.1 v 5.5 months; HR, 0.73; P < .001). Grade 3 to 4 drug-related adverse events more than two-fold higher in the sorafenib group included hand-foot skin reaction (8.6% v 0.3%), fatigue (7.3% v 3.6%), rash (5.7% v 0.5%), and hypertension (4.2% v 1.8%). No unexpected toxicities were observed. Conclusion This study did not meet its primary end point of improved OS when sorafenib was added to first-line gemcitabine/cisplatin in patients with advanced nonsquamous NSCLC. Identification of predictive biomarkers is warranted in future trials of sorafenib.

Small Cell Lung Cancer: Advances in Diagnosis and Management

2020 ◽  
Vol 41 (03) ◽  
pp. 435-446
Author(s):  
Ayushi F. Chauhan ◽  
Stephen V. Liu
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Standards Of Care ◽  
Small Cell Lung ◽  
Early Stage Disease ◽  
Platinum Based Chemotherapy ◽  
Thoracic Radiation

AbstractSmall cell lung cancer (SCLC) is an aggressive subtype of lung cancer characterized by rapid growth and early spread. It is a highly lethal disease that typically is diagnosed at a late stage. Surgery plays a very small role in this cancer, and management typically involves chemotherapy, delivered with thoracic radiation in early-stage disease. Platinum-based chemotherapy is initially very effective, inducing rapid and often deep responses. These responses, though, are transient, and upon relapse, SCLC is highly refractory to therapy. Immunotherapy has shown promise in delivering meaningful, durable responses and the addition of immunotherapy to first-line chemotherapy has led to the first improvements in survival in decades. Still, the disease remains difficult to manage. Incorporating radiation therapy at specific points in patient management may improve disease control. The development of predictive biomarkers and novel targeted therapies will hopefully improve options for patients in the near future. This review focuses on the current standards of care and future directions.

Randomized Phase III Placebo-Controlled Trial of Carboplatin and Paclitaxel With or Without the Vascular Disrupting Agent Vadimezan (ASA404) in Advanced Non–Small-Cell Lung Cancer

2011 ◽  
Vol 29 (22) ◽  
pp. 2965-2971 ◽  
Author(s):  
Primo N. Lara ◽  
Jean-Yves Douillard ◽  
Kazuhiko Nakagawa ◽  
Joachim von Pawel ◽  
Mark J. McKeage ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Controlled Trial ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Vascular Disrupting Agent ◽  
Platinum Based Chemotherapy ◽  
Vascular Disrupting

Purpose This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 (vadimezan), when combined with first-line platinum-based chemotherapy, improves survival in patients with advanced non–small-cell lung cancer (NSCLC) versus chemotherapy alone. Patients and Methods Patients with advanced stage IIIB or IV NSCLC, stratified by sex and tumor histology, were randomly assigned 1:1 to paclitaxel (200 mg/m2) and carboplatin (area under the curve, 6.0) with or without ASA404 (1,800 mg m2), given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results One thousand two hundred ninety-nine patients were randomly assigned. The trial was stopped for futility at interim analysis. At final analysis, there was no difference in OS seen between ASA404 (n = 649) and placebo (n = 650) arms: median OS was 13.4 and 12.7 months respectively (hazard ratio [HR], 1.01; 95% CI, 0.85 to 1.19; P = .535). Similarly, no OS difference was seen in the histologic (squamous or nonsquamous) and sex (male or female) strata. Median PFS was 5.5 months in both arms (HR, 1.04; P = .727), while ORR was 25% in both arms (P = 1.0). Overall rate of adverse events (AEs) was comparable between the ASA404 and placebo arms. Grade 4 neutropenia (27% v 19%) and infusion site pain (10% v 0.5%) were reported more frequently in the ASA404 arm. Conclusion The addition of ASA404 to carboplatin and paclitaxel, although generally well tolerated, failed to improve frontline efficacy in advanced NSCLC.

Molecular profiles of predictive biomarkers for platinum-based chemotherapy in Non-Small Cell Lung Cancer (NSCLC)

Meta Gene ◽  
2021 ◽  
pp. 100993
Author(s):  
NiloofarTaleghani Seyedabadi ◽  
Sara YousefZadeh Shoushtari ◽  
Asma Soofi ◽  
Javad Arabpour ◽  
Zinat Shams ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Molecular Profiles

Phase III Trial of Two Versus Four Additional Cycles in Patients Who Are Nonprogressive After Two Cycles of Platinum-Based Chemotherapy in Non–Small-Cell Lung Cancer

2007 ◽  
Vol 25 (33) ◽  
pp. 5233-5239 ◽  
Author(s):  
Joon Oh Park ◽  
Sang-We Kim ◽  
Jin Seok Ahn ◽  
Cheolwon Suh ◽  
Jung Shin Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Survival Rates ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
The Difference ◽  
American Society

PurposeThis trial was conducted to determine the optimal duration of chemotherapy in Korean patients with advanced non–small-cell lung cancer (NSCLC).Patients and MethodsPatients with stages IIIB to IV NSCLC who had not progressed after two cycles of chemotherapy were randomly assigned to receive either four (arm A) or two (arm B) more cycles of third-generation, platinum-doublet treatment.ResultsOf the 452 enrolled patients, 314 were randomly assigned to the groups. One-year survival rates were 59.0% in arm A and 62.4% in arm B, and the difference of 3.4% (95% CI, −8.0 to 4.8) met the predefined criteria for noninferiority. The median time to progression (TTP), however, was 6.2 months (95% CI, 5.7 to 6.7 months) in arm A and 4.6 months (95% CI, 4.4 to 4.8 months) in arm B, the difference of which is statistically significant (P = .001). The frequencies of hematologic and nonhematologic toxicities were similar in the two arms.ConclusionThis study confirms the noninferiority of overall survival with four cycles compared with six cycles of chemotherapy for the first-line treatment of advanced NSCLC and supports the current American Society of Clinical Oncology guidelines. Notably, patients receiving six cycles of chemotherapy compared with four cycles showed a favorable TTP, suggesting that further investigation of the new strategies of maintenance therapy with less toxic agents after three to four cycles of induction chemotherapy might be warranted to improve survival, with consideration of both ethnicity and pharmacogenomic signatures.

scholarly journals A phase III, randomized, double-blind, controlled trial of carboxyamidotriazole plus chemotherapy for the treatment of advanced non-small cell lung cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592096584
Author(s):  
Xiaoyan Si ◽  
Jinwan Wang ◽  
Ying Cheng ◽  
Jianhua Shi ◽  
Liying Cui ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Placebo Group ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Controlled Trial ◽  
Objective Response ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy

Background: Carboxyamidotriazole (CAI), a calcium channel blocker, inhibits tumor cell proliferation, metastasis, and angiogenesis. This trial aimed to determine whether CAI combined with conventional chemotherapy could prolong progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients. Methods: Patients were assigned into groups (3:1 ratio) to receive either chemotherapy + CAI or chemotherapy alone. Cisplatin (25 mg/m2) was administered by intravenous infusion on days 1, 2, and 3, and vinorelbine (25 mg/m2) on days 1 and 8 of each 3-week cycle for four cycles. CAI was administered at 100 mg daily with concomitant chemotherapy; this treatment was continued after chemotherapy was ceased until serious toxicity or disease progression had occurred. PFS was the primary endpoint, and the secondary endpoints were objective response rate (ORR), disease control rate, overall survival (OS), and quality of life. Results: In total, 495 patients were enrolled in the trial: 378 in the chemotherapy + CAI group and 117 in the chemotherapy + placebo group. PFS was significantly greater in the chemotherapy + CAI [median, 134 days; 95% confidence interval (CI) 127–139] than in the chemotherapy + placebo (median, 98 days; 95% CI: 88–125) group, with a hazard ratio of 0.690 (95% CI: 0.539–0.883; p = 0.003). There was no difference in the OS rates of both groups. The ORR was greater in the chemotherapy + CAI group than in the chemotherapy + placebo group (34.6% versus 25.0%, p = 0.042). Adverse events of ⩾grade 3 occurred more frequently in the CAI group [256 (68.1%) versus 64 (55.2%); p = 0.014]. Conclusion: CAI + platinum-based chemotherapy prolonged PFS and could be a useful therapeutic option to treat NSCLC. Clinical Trial Registration: chinadrugtrials.org.cn identifier: CTR20160395

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