Update on recent key publications in lung oncology: picking up speed

IntroductionAs incidence rates for lung cancer are still very high and lung cancer remains the most deadly cancer since the turn of the millennium, efforts have been made to find new approaches in cancer research. This systematic review highlights how therapeutic options were extended and how the development of new drugs has picked up speed during the last 20 years.MethodsA systematic search was performed in PubMed, Cochrane Library and the European Union Trial Register and 443 records were identified. Our inclusion criteria constituted completed phase I, II and III studies investigating drugs approved by the European Medicines Agency (EMA). Overall, 127 articles were analysed.ResultsDuring the 5 year interval from 2015 to 2020, significantly more drugs were approved after phase III, and occasionally after phase II, trials than between 2000 and 2005 (p=0.002). Furthermore, there was a significant time difference (p=0.00001) indicating an increasingly briefer time interval between the publication of phase I and phase III results in the last few years.DiscussionDue to novel therapeutic approaches, numerous new drugs in lung oncology were approved. This has improved symptoms and prognoses in patients with advanced lung cancer. However, faster approval could make it difficult to scrutinise new options regarding safety and efficacy with sufficient diligence.

Download Full-text

Preapproval and postapproval evidence on drugs for multiple sclerosis

Neurology ◽

10.1212/wnl.0000000000005561 ◽

2018 ◽

Vol 90 (21) ◽

pp. 964-973 ◽

Cited By ~ 8

Author(s):

Chiara Gerardi ◽

Vittorio Bertele' ◽

Silvia Rossi ◽

Silvio Garattini ◽

Rita Banzi

Keyword(s):

Multiple Sclerosis ◽

Clinical Effectiveness ◽

Dimethyl Fumarate ◽

New Drugs ◽

Cochrane Library ◽

European Medicines Agency ◽

The European Union ◽

Disability Progression ◽

Disease Modifying Drugs ◽

Approved Drugs

ObjectiveTo review the evidence supporting the European Union marketing authorization of drugs for multiple sclerosis (MS) and assess how far postmarketing research addresses information gaps at the time of approval.MethodsThrough its database, we identified drugs approved by the European Medicines Agency and gathered data on pivotal trials from the European Public Assessment Reports and corresponding publications. We searched Medline, Embase, Cochrane Library, and trial registries for postmarketing randomized controlled trials testing the drugs identified in any form of the disease.ResultsSince approval of interferon and glatiramer up to 2017, the Agency has examined 10 drugs for the treatment of MS, and 8 were included in this study: alemtuzumab, daclizumab, dimethyl fumarate, fampridine, fingolimod, peginterferon-β-1a, natalizumab, and teriflunomide. We analyzed 16 pivotal trials enrolling almost 16,000 participants. Eleven compared new drugs to placebo, 5 to interferon-β-1a. Annualized relapse rate was the primary outcome in two-thirds and coprimary with disability progression in the 2 studies of alemtuzumab. Of the 52 postmarketing trials, 24 reported final results and 28 were ongoing, terminated, or completed but no results were available. None directly compared the approved drugs, thus leaving their respective therapeutic values unknown. Data on the prevention of disease progression were scarce: none of the disease-modifying drugs showed any effect on disability progression.ConclusionThe lack of comparative evidence and data on clinical effectiveness hamper the assessment of therapeutic value and place in therapy of drugs approved for MS.

Download Full-text

Gefitinib in Combination With Paclitaxel and Carboplatin in Advanced Non–Small-Cell Lung Cancer: A Phase III Trial—INTACT 2

Journal of Clinical Oncology ◽

10.1200/jco.2004.07.215 ◽

2004 ◽

Vol 22 (5) ◽

pp. 785-794 ◽

Cited By ~ 1268

Author(s):

Roy S. Herbst ◽

Giuseppe Giaccone ◽

Joan H. Schiller ◽

Ronald B. Natale ◽

Vincent Miller ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Phase I ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Phase Iii ◽

Biologic Agent ◽

Small Cell Lung ◽

Phase Ii Trials

Purpose Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non–small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC. Patients and Methods Patients received paclitaxel 225 mg/m2 and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P = .64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received ≥ 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect. Conclusion Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.

Download Full-text

A Network Comparison on Safety Profiling of Immune Checkpoint Inhibitors in Advanced Lung Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.760737 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yi-Dan Yan ◽

Jiu-Jie Cui ◽

Jie Fu ◽

Ying-Jie Su ◽

Xiao-Yu Chen ◽

...

Keyword(s):

Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Sensitivity Analyses ◽

Advanced Lung Cancer ◽

Cochrane Library ◽

Public Attention ◽

Grade 3

BackgroundImmune checkpoint inhibitors (ICIs) have become one of the standard treatment options for advanced lung cancer. However, adverse events (AEs), particularly immune–related AEs (irAEs), caused by these drugs have aroused public attention. The current network meta-analysis (NMA) aimed to compare the risk of AEs across different ICI–based regimens in patients with advanced lung cancer.MethodsWe systematically searched the PubMed, EMBASE, and Cochrane Library databases (from inception to 19 April 2021) for relevant randomized controlled trials (RCTs) that compared two or more treatments, with at least one ICI administered to patients with advanced lung cancer. The primary outcomes were treatment–related AEs and irAEs, including grade 1–5 and grade 3–5. The secondary outcomes were grade 1–5 and grade 3–5 irAEs in specific organs. Both pairwise and network meta-analyses were conducted for chemotherapy, ICI monotherapy, ICI monotherapy + chemotherapy, dual ICIs therapy, and dual ICIs + chemotherapy for all safety outcomes. Node–splitting analyses were performed to test inconsistencies in network. Sensitivity analyses were adopted by restricting phase III RCTs and studies that enrolled patients with non–small cell lung cancer.ResultsOverall, 38 RCTs involving 22,178 patients with advanced lung cancer were enrolled. Both pooled incidence and NMA indicated that treatments containing chemotherapy increased the risk of treatment–related AEs when compared with ICI-based regimens without chemotherapy. As for grade 1–5 irAEs, dual ICIs + chemotherapy was associated with the highest risk of irAEs (probability in ranking first: 50.5%), followed by dual-ICI therapy (probability in ranking second: 47.2%), ICI monotherapy (probability in ranking third: 80.0%), ICI monotherapy + chemotherapy (probability in ranking fourth: 98.0%), and finally chemotherapy (probability in ranking fifth: 100.0%). In grade 3–5 irAEs, subtle differences were observed; when ranked from least safe to safest, the trend was dual ICIs therapy (60.4%), dual ICIs + chemotherapy (42.5%), ICI monotherapy (76.3%), ICI monotherapy + chemotherapy (95.0%), and chemotherapy (100.0%). Furthermore, detailed comparisons between ICI–based options provided irAE profiles based on specific organ/system and severity.ConclusionsIn consideration of overall immune–related safety profiles, ICI monotherapy + chemotherapy might be a better choice among ICI–based treatments for advanced lung cancer. The safety profiles of ICI–based treatments are various by specific irAEs and their severity.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42021268650

Download Full-text

Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.8406 ◽

2006 ◽

Vol 24 (1) ◽

pp. 136-140 ◽

Cited By ~ 20

Author(s):

Andrew J. Vickers ◽

Joyce Kuo ◽

Barrie R. Cassileth

Keyword(s):

Clinical Trials ◽

Phase I ◽

Cancer Patients ◽

Phase Ii ◽

Dose Finding ◽

Phase Iii ◽

High Dose ◽

Free Text ◽

Phase Ii Trials ◽

Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

Download Full-text

Large fraction radiotherapy plus misonidazole for treatment of advanced lung cancer: report of a phase I/II trial

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/0360-3016(82)90532-6 ◽

1982 ◽

Vol 8 (2) ◽

pp. 303-308 ◽

Cited By ~ 17

Author(s):

Joseph R Simpson ◽

Carlos A Perez ◽

Theodore L Phillips ◽

Joseph P Concannon ◽

Richard J Carella

Keyword(s):

Lung Cancer ◽

Phase I ◽

Large Fraction ◽

Advanced Lung Cancer

Download Full-text

Phase III double-blind study comparing the efficacy and safety of proposed biosimilar MYL-1402O and reference bevacizumab in stage IV non-small-cell lung cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211045845 ◽

2021 ◽

Vol 13 ◽

pp. 175883592110458

Author(s):

Mark A. Socinski ◽

Cornelius F. Waller ◽

Tazeen Idris ◽

Igor Bondarenko ◽

Alexander Luft ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Events ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Phase Iii ◽

European Medicines Agency ◽

Small Cell Lung ◽

Serious Adverse Events ◽

Double Blind

Purpose: This phase III study compared the efficacy and safety of proposed biosimilar MYL-1402O with reference bevacizumab (BEV), as first-line treatment for patients with stage IV non-squamous non-small-cell lung cancer. Patients and methods: Patients were randomly assigned (1:1) to receive MYL-1402O or bevacizumab with carboplatin-paclitaxel up to 18 weeks (6 cycles), followed by up to 24 weeks (8 cycles) of bevacizumab monotherapy. The primary objective was comparison of overall response rate (ORR), based on independently reviewed best tumor responses as assessed during the first 18 weeks. ORR was analyzed per US Food and Drug Administration (ratio of ORR) and European Medicines Agency (difference in ORRs) requirements for equivalence evaluation. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety, and immunogenicity over a period of 42 weeks, and pharmacokinetics (up to 18 weeks). Results: A total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 [confidence interval (CI) 0.83, 1.12] and the difference in ORR was −1.6 (CI −9.0, 5.9) between treatment arms; CIs were within the predefined equivalence margins. Overall, the incidence of treatment-emergent adverse events and serious adverse events was comparable. Treatment-emergent anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (6.5% versus 4.8% ADA positivity rate in MYL-1402O versus BEV, respectively). The incidence of neutralizing antibody post-baseline was lower in the MYL-1402O arm (0.6%) compared to the bevacizumab arm (2.5%). Conclusions: MYL-1402O is therapeutically equivalent to bevacizumab, based on the ORR analyses, with comparable secondary endpoints. Trial Registry Information EU Clinical Trials Register, Registration # EudraCT no. 2015-005141-32 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-005141-32 Plain language summary Previous studies established bioequivalence of the proposed bevacizumab biosimilar MYL-1402O to reference bevacizumab. In this randomized, double-blind, phase III trial, MYL-1402O ( n = 337) demonstrated comparable efficacy to bevacizumab ( n = 334) in treating advanced non-squamous non-small-cell lung cancer per Food and Drug Administration and European Medicines Agency requirements for equivalence; the ratio of objective response rate (ORR) was 0.96 [90% confidence interval (CI) 0.83, 1.12] and the difference in ORR (MYL-1402O:bevacizumab) was −1.6 (95% CI −9.0, 5.9). Median progression-free survival at 42 weeks was comparable: 7.6 (7.0, 9.5) with MYL-1402O versus 9.0 (7.2, 9.7) months ( p = 0.0906) with bevacizumab, by independent review. Treatment-emergent adverse events leading to death (2.4% vs 1.5%), serious adverse events (17.6% vs 16.7%), and antidrug antibodies (6.5% vs 4.8%), were comparable in the MYL-1402O vs bevacizumab arms, respectively. The incidence of neutralizing antibody post-baseline was lower with MYL-1402O (0.6%) than with bevacizumab (2.5%). These findings confirm therapeutic equivalence of MYL-1402O to bevacizumab, providing opportunities for improving access to bevacizumab.

Download Full-text

A Phase I-II Study of Sequential Infusion VP-16 and Cisplatin Therapy in Advanced Lung Cancer

American Journal of Clinical Oncology ◽

10.1097/00000421-198904000-00005 ◽

1989 ◽

Vol 12 (2) ◽

pp. 114-117 ◽

Cited By ~ 9

Author(s):

J. E. Krook ◽

J. R. Jett ◽

C. Little

Keyword(s):

Lung Cancer ◽

Phase I ◽

Advanced Lung Cancer ◽

Cisplatin Therapy

Download Full-text

Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.6.2150 ◽

1998 ◽

Vol 16 (6) ◽

pp. 2150-2156 ◽

Cited By ~ 166

Author(s):

S Wojtowicz-Praga ◽

J Torri ◽

M Johnson ◽

V Steen ◽

J Marshall ◽

...

Keyword(s):

Lung Cancer ◽

Phase I ◽

Plasma Concentrations ◽

Study Drug ◽

Advanced Lung Cancer ◽

Pharmacokinetic Analysis ◽

Antiinflammatory Drugs ◽

Concurrent Administration ◽

Inflammatory Polyarthritis

PURPOSE This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies. PATIENTS AND METHODS A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied. RESULTS The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment. CONCLUSION Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.

Download Full-text

Prognostic role of the advanced lung cancer inflammation index in cancer patients: a meta-analysis

World Journal of Surgical Oncology ◽

10.1186/s12957-019-1725-2 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 3

Author(s):

Xin Hua ◽

Jing Chen ◽

Ying Wu ◽

Jun Sha ◽

Shuhua Han ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Patients ◽

Cell Lung Cancer ◽

Meta Analysis ◽

Small Cell ◽

Advanced Lung Cancer ◽

Cochrane Library ◽

Small Cell Lung ◽

Cancer Inflammation

Abstract Background Inflammation plays a critical role in the development and progression of cancers. The advanced lung cancer inflammation index (ALI) is thought to be able to reflect systemic inflammation better than current biomarkers. However, the prognostic significance of the ALI in various types of cancer remains unclear. Our meta-analysis aimed to comprehensively investigate the relationship between the ALI and oncologic outcomes to help physicians better assess the prognosis of cancer patients. Methods The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched for relevant studies. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated and pooled from the included studies. Furthermore, a sensitivity analysis was performed to evaluate the reliability of the articles. Finally, Begg’s test, Egger’s test, and the funnel plot were applied to assess the significance of publication bias. Results In total, 1736 patients from nine studies were included in our meta-analysis. The median cutoff value for the ALI was 23.2 (range, 15.5–37.66) in the analyzed studies. The meta-analysis showed that there was a statistically significant relationship between a low ALI and worse overall survival (OS) in various types of cancer (HR = 1.70, 95% CI = 1.41–1.99, P < 0.001). Moreover, results from subgroup meta-analysis showed that the ALI had a significant prognostic value in non-small cell lung cancer, small cell lung cancer, colorectal cancer, head and neck squamous cell carcinoma, and diffuse large B cell lymphoma (P < 0.05 for all). Conclusions These results showed that a low ALI was associated with poor OS in various types of cancer, and the ALI could act as an effective prognostic biomarker in cancer patients.

Download Full-text