Twenty-Two Years of Phase III Trials for Patients With Advanced Non–Small-Cell Lung Cancer: Sobering Results

PURPOSE: To determine the changes in clinical trials and outcomes of patients with advanced-stage non–small-cell lung cancer (NSCLC) treated on phase III randomized trials initiated in North America from 1973 to 1994. PATIENTS AND METHODS: Phase III trials for patients with advanced-stage NSCLC were identified through a search of the National Cancer Institute’s Cancer Therapy Evaluation Program database from 1973 to 1994, contact with Cooperative Groups, and by literature search of MEDLINE. Patients with advanced NSCLC treated during a similar time interval were also examined in the SEER database. Trends were tested in the number of trials, in the number and sex of patients entered on the trials, and in survival over time. RESULTS: Thirty-three phase III trials were initiated between 1973 and 1994. Twenty-four trials (73%) were initiated within the first half of this period (1973 to 1983) and accounted for 5,359 (64%) of the 8,434 eligible patients. The median number of patients treated per arm of the trials rose from 77 (1973 to 1983) to 121 (1984 to 1994) (P < .001). Five trials (15%) showed a statistically significant difference in survival between treatment arms, with a median prolongation of the median survival of 2 months (range, 0.7 to 2.7 months). CONCLUSION: Analysis of past trials in North America shows that the prolongation in median survival between two arms of a randomized study was rarely in excess of 2 months. Techniques for improved use of patient resources and appropriate trial design for phase III randomized therapeutic trials with patients with advanced NSCLC need to be developed.

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Phase III trials in patients with advanced stage non-small cell lung cancer: The experience in North America from 1973–1994

Lung Cancer ◽

10.1016/s0169-5002(00)80062-8 ◽

2000 ◽

Vol 29 (1) ◽

pp. 20-21

Author(s):

O.S Breathnach ◽

B Freidlin ◽

B Conley ◽

M.R Green ◽

D.J Johnson ◽

...

Keyword(s):

Lung Cancer ◽

North America ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Phase Iii ◽

Advanced Stage ◽

Small Cell Lung ◽

Phase Iii Trials

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Shifting Patterns in the Interpretation of Phase III Clinical Trial Outcomes in Advanced Non–Small-Cell Lung Cancer: The Bar Is Dropping

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.7804 ◽

2014 ◽

Vol 32 (14) ◽

pp. 1407-1411 ◽

Cited By ~ 31

Author(s):

Adrian G. Sacher ◽

Lisa W. Le ◽

Natasha B. Leighl

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Advanced Nsclc ◽

Statistical Significance ◽

Small Cell ◽

Phase Iii ◽

Small Cell Lung ◽

End Point ◽

Phase Iii Trials ◽

Over Time

Purpose Despite multiple trials of new agents in advanced non–small-cell lung cancer (NSCLC), outcomes remain poor. This study explores how the design and interpretation of randomized trials in advanced NSCLC has changed over time. Methods Phase III randomized controlled trials of systemic therapy for advanced NSCLC between 1980 and 2010 were identified, and their primary end point, outcome, statistical significance, and conclusions were recorded. Results Of 245 trials identified, 203 were eligible for study inclusion. Although overall survival remains the most common primary end point of phase III trials, more trials from the last decade have used progression-free survival instead (none in 1980 to 1990, 13% in 2001 to 2010; P = .002). The percentage of trials meeting their primary statistical end points remained stable over time; however, the percentage of trials reporting a positive outcome without meeting that end point increased (30% in 1980 to 1990, 53% in 2001 to 2010; P < .001). A trend toward decreasing magnitude of survival gain in positive trials was seen over time (3.9 months in 1980 to 1990, 2.5 months in 2001 to 2010; P = .11), with a concomitant increase in the sample size of clinical trials over the same time period (median: 152 patients in 1980 to 1990, 413 in 2001 to 2010; P < .001). Only studies predating 1990 reported negative results as a result of insufficient magnitude of survival benefit despite statistical significance. Conclusion A significant shift has occurred over the past three decades in the design and interpretation of phase III trials in advanced NSCLC. The use of survival as the primary measure of benefit is declining, as is the magnitude of benefit deemed clinically relevant.

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Reporting Trends of Outcome Measures in Phase II and Phase III Trials Conducted in Advanced-Stage Non-small-cell Lung Cancer

Lung ◽

10.1007/s00408-013-9479-z ◽

2013 ◽

Vol 191 (4) ◽

pp. 313-319 ◽

Cited By ~ 6

Author(s):

Saurav Ghimire ◽

Eunjung Kyung ◽

Eunyoung Kim

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Outcome Measures ◽

Phase Ii ◽

Cell Lung Cancer ◽

Small Cell ◽

Phase Iii ◽

Advanced Stage ◽

Small Cell Lung ◽

Phase Iii Trials

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Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.20.01605 ◽

2021 ◽

Vol 39 (7) ◽

pp. 723-733

Author(s):

Hossein Borghaei ◽

Scott Gettinger ◽

Everett E. Vokes ◽

Laura Q. M. Chow ◽

Marco Angelo Burgio ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Advanced Nsclc ◽

Small Cell ◽

Phase Iii ◽

Small Cell Lung ◽

Phase Iii Trials ◽

Previously Treated

PURPOSE Immunotherapy has revolutionized the treatment of advanced non–small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials. METHODS Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated. RESULTS After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3–5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs. CONCLUSION At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.

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Faculty Opinions recommendation of Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120004.586903 ◽

2008 ◽

Author(s):

Daniel Vorobiof ◽

Keo Tabane

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Phase Iii ◽

Advanced Stage ◽

Small Cell Lung ◽

Phase Iii Study

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Immunotherapy in non-metastatic non-small cell lung cancer: Can the benefits of stage IV therapy be translated into earlier stages?

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835918772810 ◽

2018 ◽

Vol 10 ◽

pp. 175883591877281 ◽

Cited By ~ 7

Author(s):

Griet Deslypere ◽

Dorothée Gullentops ◽

Els Wauters ◽

Johan Vansteenkiste

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Advanced Nsclc ◽

Stage Iv ◽

Small Cell ◽

Stage I ◽

Phase Iii ◽

Small Cell Lung ◽

Anaplastic Lymphoma

Over the last decade, several steps forward in the treatment of patients with stage IV non-small cell lung cancer (NCSLC) were made. Examples are the use of pemetrexed, pemetrexed maintenance therapy, or bevacizumab for patients with nonsquamous NSCLC. A big leap forward was the use of tyrosine kinase inhibitors in patients selected on the basis of an activating oncogene, such as epidermal growth factor receptor ( EGFR) activating mutations or anaplastic lymphoma kinase ( ALK) translocations. However, all of these achievements could not be translated into survival benefits when studied in randomized controlled trials in patients with nonmetastatic NSCLC. Aside from chemotherapy and targeted therapy, immunotherapy has become the third pillar in the treatment armamentarium of advanced NSCLC. Antigen-specific immunotherapy (cancer vaccination) has been disappointing in large phase III clinical trials in stages I–III NSCLC. Based on the recent breakthroughs with immune checkpoint inhibitor immunotherapy in metastatic NSCLC, much hope currently rests on the use of this approach in patients with stage I–III NSCLC as well. Here we give a brief overview of how most new therapeutic approaches for advanced NSCLC failed in other stages, and then elaborate on the role of immunotherapy in patients with stage I–III NSCLC.

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Twenty Years of Phase III Trials for Patients With Extensive-Stage Small-Cell Lung Cancer: Perceptible Progress

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.6.1794 ◽

1999 ◽

Vol 17 (6) ◽

pp. 1794-1794 ◽

Cited By ~ 244

Author(s):

John P. Chute ◽

Timothy Chen ◽

Ellen Feigal ◽

Richard Simon ◽

Bruce E. Johnson

Keyword(s):

Lung Cancer ◽

Survival Time ◽

Median Survival ◽

Small Cell ◽

Phase Iii ◽

Seer Database ◽

Small Cell Lung ◽

Phase Iii Trials ◽

Extensive Stage ◽

Over Time

PURPOSE: All cooperative group studies performed in North America for patients with extensive-stage small-cell lung cancer (SCLC) were evaluated to determine the pattern of the clinical trials and the outcome of patients over the past 20 years. PATIENTS AND METHODS: Phase III trials for patients with extensive-stage SCLC were identified through a search of the National Cancer Institute Cancer Therapy Evaluation Program database from 1972 to 1993. Patients with extensive-stage SCLC treated during a similar time interval listed in the Surveillance, Epidemiology, and End Results (SEER) database were also examined. Trends were tested in the number of trials over time, the number and sex of patients entered onto the trials, and the survival time of patients treated over time. RESULTS: Twenty-one phase III trials for patients with extensive-stage SCLC were initiated between 1972 and1990. The median of the median survival times of patients treated on the control arms of the phase III trials initiated between 1972 and 1981 was 7.0 months; for those patients enrolled onto control arms between 1982 and 1990, the median survival time was 8.9 months (P = .001). Analysis of the SEER database of patients with extensive-stage SCLC over the same time period shows a similar 2-month prolongation in median survival time. CONCLUSION: Analysis of 21 phase III trials initiated in North America and the SEER database from 1972 to 1994 demonstrates that there has been a modest improvement in the survival time of patients with extensive-stage SCLC.

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Randomized Phase III Study of Gemcitabine-Cisplatin Versus Etoposide-Cisplatin in the Treatment of Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.1.12 ◽

1999 ◽

Vol 17 (1) ◽

pp. 12-12 ◽

Cited By ~ 334

Author(s):

Felipe Cardenal ◽

M. Paz López-Cabrerizo ◽

Antonio Antón ◽

Vicente Alberola ◽

Bartomeu Massuti ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Disease Progression ◽

Cell Lung Cancer ◽

Advanced Nsclc ◽

Response Rate ◽

Small Cell ◽

Phase Iii ◽

Small Cell Lung ◽

Grade 3

PURPOSE: We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non–small-cell lung cancer (NSCLC). The primary end point of the comparison was response rate. PATIENTS AND METHODS: A total of 135 chemotherapy-naive patients with advanced NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 intravenously (IV) days 1 and 8 or etoposide 100 mg/m2 IV days 1 to 3 along with cisplatin 100 mg/m2 IV day 1. Both treatments were administered in 21-day cycles. One hundred thirty-three patients were included in the intent-to-treat analysis of response. RESULTS: The response rate (externally validated) for patients given gemcitabine-cisplatin was superior to that for patients given etoposide-cisplatin (40.6% v 21.9%; P = .02). This superior response rate was associated with a significant delay in time to disease progression (6.9 months v 4.3 months; P = .01) without an impairment in quality of life (QOL). There was no statistically significant difference in survival time between both arms (8.7 months for gemcitabine-cisplatin v 7.2 months for etoposide-cisplatin; P = .18). The overall toxicity profile for both combinations of drugs was similar. Nausea and vomiting were reported more frequently in the gemcitabine arm than in the etoposide arm. However, the difference was not significant. Gemcitabine-cisplatin produced less grade 3 alopecia (13% v 51%) and less grade 4 neutropenia (28% v 56% ) but more grade 3 and 4 thrombocytopenia (56% v 13%) than did etoposide-cisplatin. However, there were no thrombocytopenia-related complications in the gemcitabine arm. CONCLUSION: Compared with etoposide-cisplatin, gemcitabine-cisplatin provides a significantly higher response rate and a delay in disease progression without impairing QOL in patients with advanced NSCLC.

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Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non–Small-Cell Lung Cancer Previously Treated With Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2004.08.163 ◽

2004 ◽

Vol 22 (9) ◽

pp. 1589-1597 ◽

Cited By ~ 1768

Author(s):

Nasser Hanna ◽

Frances A. Shepherd ◽

Frank V. Fossella ◽

Jose R. Pereira ◽

Filippo De Marinis ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Advanced Nsclc ◽

Performance Status ◽

Small Cell ◽

Phase Iii ◽

Second Line ◽

Small Cell Lung ◽

Previously Treated

Purpose To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non—small-cell lung cancer (NSCLC) previously treated with chemotherapy. Patients and Methods Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m2 intravenously (IV) day 1 with vitamin B12, folic acid, and dexamethasone or docetaxel 75 mg/m2 IV day 1 with dexamethasone every 21 days. The primary end point was overall survival. Results Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P = .105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P < .001), febrile neutropenia (12.7% v 1.9%; P < .001), neutropenia with infections (3.3% v 0.0%; P = .004), hospitalizations for neutropenic fever (13.4% v 1.5%; P < .001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P = .092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P < .001) and all grade alopecia (37.7% v 6.4%; P < .001) compared with patients receiving pemetrexed. Conclusion Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.

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