Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Jassem, 2008

Type of study: RCT, phase III

Setting and country:
45 institutions, worldwide

Funding and conflicts of interest:
Funding: Eli Lilly & Co

Conflicts of interest:
Employment: Shengyan Hong: Eli Lilly & Co; Johannes Blatter: Eli Lilly & Co; Susumu Adachi: Eli Lilly & Co Leadership: N/A Consultant:

Axel Hanauske: Eli Lilly & Co; Christian Manegold: Eli Lilly & Co Stock:

Shengyan Hong: Eli Lilly & Co; Johannes Blatter: Eli Lilly & Co; Susumu

Adachi: Eli Lilly & Co
Honoraria: Rodryg Ramlau: Eli Lilly & Co (C);

Armando Santoro: Eli Lilly & Co (C); Christian Manegold: Eli Lilly & Co

Research Funds: Christian Manegold: Funds, Eli Lilly & Co
Testimony:

Christian Manegold: Eli Lilly & Co
Other: N/A

Inclusion criteria:

- patients ≥18 years old

- histologically diagnosed advanced malignant pleural mesothelioma

- one prior systemic chemotherapy regimen (excluding pemetrexed) for advanced or metastatic disease

- unidimensionally and/or bidimensionally measurable disease
- Karnofsky performance score ≥70

- adequate bone marrow reserve (absolute neutrophil count ≥1.5 x 10⁹/L, platelets ≥100 x 10⁹/L and hemoglobin ≥9 g/dL)
- creatinine clearance ≥45 mL/min, calculated by the modified Cockcroft and Gault lean body mass formula
- estimated life expectancy ≥8 weeks
- Prior radiation to less than 25% of the bone marrow and pleurodesis were allowed if completed ≥14 days before study

Exclusion criteria:

- not reported

N total at baseline:

Intervention: 123

Control: 120

Important prognostic factors:

age median(range):

I: 60 (32-78)

C: 61 (33-79)

Sex:

I: 78.0% M

C: 77.5% M

Disease stage
IA, Ab, II / III / IV%

I:10.6/27.6/61.8%

C: 11.7/30.0/58.3%

Histology:
I: 73.2% epithelial
C: 71.2% epithelial

Respons prior chemotherapy:

Complete response / partial response / stable disease / progressive disease:

I: 1.6/18.7/40.7/31.7%

C: 2.5/20.88/41.7/30%

Groups comparable at baseline?

Yes; Both arms had a similar mean interval from date of progression after

prior chemotherapy to date of random assignment to this study (P+BSC arm: 2.1 months; BSC arm: 2.0 months).

Pemetrexed + best supportive care (P+BSC)

Pemetrexed (Alimta; Eli Lilly & Co, Indianapolis, IN) 500 mg/m2 was

administered to patients on the PBSC arm as a 10-minute intravenous

infusion on day 1 of a 3-week cycle. Treatment continued for eight cycles

unless PD occurred or the investigator or patient decided to discontinue treatment. Additional cycles were allowed if the patient had shown clinical

benefit.

P+BSC patients were administered oral folic acid (350 to 1,000 µg daily), beginning 1 to 2 weeks before the first pemetrexed dose until 3 weeks after the final dose. Vitamin B12 (1,000 µg intramuscular injection) was administered

1 to 2 weeks before the first pemetrexed dose and every 9 weeks thereafter until 3 weeks after the final dose. Dexamethasone (4 mg or equivalent) was administered orally twice daily, beginning the day before and ending the day after each pemetrexed dose.
Pemetrexed doses were delayed if neutrophils or platelets decreased to

less than baseline levels. Dose modifications occurred for neutrophil levels of

less than 0.5 x 10⁹/L and platelet levels of 50 to 100 x 10⁹/L (25% reduction)

or platelet levels of less than 50 x 10⁹/L (50% reduction). Treatment was

delayed for grade 3 or 4 nonhematologic toxicities (except grade 3 transaminase

elevation, nausea, or vomiting) or calculated creatinine clearance of less

than 45 mL/min. When nonhematologic toxicities resolved, doses were resumed

at 25% reduction. Dose re-escalation was not allowed. Any patient

requiring a third dose reduction or treatment interruption ≥ 42 days had

treatment discontinued. Patients on the P+BSC arm could receive granulocyte

colony-stimulating factors for neutrophil levels less than 0.5 x 10⁹/L,

neutropenic fever, or neutropenic infection. Leucovorin could be administered

for grade 4 leukopenia or neutropenia lasting≥3 days, grade 4 thrombocytopenia,

grade 3 thrombocytopenia with associated bleeding, or grade 3

or 4 mucositis.

There were no restrictions as to type or timing of poststudy treatment.

Best supportive care (BSC)

Patients on the BSC-arm received treatment administered with the intent

to maximize quality of life without a specific antineoplastic regimen. This

included antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood

transfusions, nutritional support, and focal external-beam radiation for

control of pain, cough, dyspnea, or hemoptysis. BSC excluded surgery, immunotherapy,

anticancer hormonal therapy, systemic chemotherapy, and radiotherapy

(except palliative).

There were no restrictions as to type or timing of poststudy treatment.

Length of follow-up:

Patients were assessed at 3-week intervals and remained on study for 24 weeks (corresponding to eight cycles)

unless progressive disease (PD) or early discontinuation occurred. Postdiscontinuation

assessments occurred every 6 weeks until PD and then

every 90 days until death.

 
median follow-up time for survival: 14.5 months

Loss-to-follow-up:

Twenty-three P+BSC patients completed eight or more cycles, and six BSC patients remained on study for eight or more cycle equivalents (24 weeks).

Discontinued treatment:

Incomplete outcome data:

None (not reported)

Outcome measures and effect size (include 95%CI and p-value if available):

Overall survival

Median overall survival time:

P+BSC: 8.5 months (95%CI: 6.2-10.5 months)
BSC: 9.7 months (95%CI: 8.4-10.9 months)
p=0.7434
HR=0.95 (95%CI: 0.71-1.27)

Quality of life

There was no statistically significant difference between the arms in mean change from baseline among any of the lung cancer symptom scale questions. As a result of higher patient dropout on the BSC arm, an insufficient number of patients had four consecutive average symptom burden index scores required to

assess this quality-of-life parameter.

Adverse events/safety

- No treatment related deaths occurred on either arm

- Three P+BSC patients discontinued treatment, including two patients as a result of treatment-related adverse events (Grade 1 and grade 2 decrease in creatinine clearance).
- statistical significance not reported

Significantly more BSC patients (51.7%)

than P+BSC patients (28.5%) received postdiscontinuation chemotherapy

(P =.0002). The percentage of BSC patients who received

pemetrexed after discontinuing from study treatment was also much

higher (18.3% v 3.3%, respectively; P =.0001). Furthermore, BSC

patients received postdiscontinuation chemotherapy significantly earlier

than P+BSC patients (median time to initiation, 4.3 v 15.7

months, respectively; log-rank P=.0001).

powercalculation presumed that 120 patients per group were needed to detect 2 months improvement in median overall survival.

Kindler 2012

Type of study:

RCT

Setting and country:

Multicentre,

USA

Funding and conflicts of interest:
Funding: National Cancer Institute

Grants
Conflicts of interest:
Employment or Leadership Position: None Consultant or Advisory

Role: Hedy L. Kindler, Genentech/Roche (C); David R. Gandara,

Genentech/Roche (C); Lee M. Krug, Genentech (C); James P. Stevenson,

Genentech (C), Eli Lilly (C); Pasi A. Ja¨nne, Genentech/Roche (C); David

I. Quinn, Genentech (C); Marianna N. Koczywas, Genentech (C), Eli

Lilly (C); Julie R. Brahmer, Genentech (C); Kathy S. Albain, Genentech/

Roche (C); Walter M. Stadler, Genentech (C); Everett E. Vokes,

Genentech (C) Stock Ownership: None Honoraria: James P. Stevenson,

Genentech, Eli Lilly; Marianna N. Koczywas, Genentech, Eli Lilly; Julie R.

Brahmer, Genentech; Nicholas J. Vogelzang, Genentech/Roche, Eli Lilly

Research Funding: Hedy L. Kindler, Genentech, Eli Lilly; David R.

Gandara, Genentech/Roche, Eli Lilly; Lee M. Krug, Eli Lilly; James P.

Stevenson, Genentech, Eli Lilly; Kathy S. Albain, Eli Lilly; Nicholas J.

Vogelzang, Genentech/Roche, Eli Lilly; Walter M. Stadler, Genentech

Expert Testimony: None Other Remuneration: None

Inclusion criteria:

- histologically or cytologically confirmed malignant mesothelioma not amenable to curative intent surgery
- International mesothelioma Interest Group stage II or greater was required for patients with pleural malignant mesothelioma
- an Eastern Cooperative Oncology Group performance status of 0 to 1
- age greater than 18 years
- life expectancy of more than 3 months
- adequate bone marrow function (leukocytes ≥ 3000/µL, granulocytes ≥ 1500/µL, and platelets ≥ 100000/µL)
- adequate renal function (creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 60 mL/min and urine protein <1 + or < 1500 mg/d: per 24 hours)
- adequate hepatic function (total bilirubin within normal institutional limits and AST and ALT ≤ 2.5 x upper limit of normal)
- adequate coagulation function (prothrombin time international normalized ratio ≤ 1.5)
- prior radiation was allowed if completed more than 4 weeks prior and there was measurable disease outside the radiation port.

Exclusion criteria:

- prior systemic cytotoxic chemotherapy (prior intrapleural cytotoxic agents were allowed)
- nonhealing wound
- major surgery within 6 weeks
- bleeding diathesis
- pulmonary embolus
- deep venous thrombosis
- clinically significant cardiac, peripheral vascular or CNS disease
- currently active second malignancy
- uncontrolled intercurrent illness
- computed tomography scan documentation of invasion of adjacent organs

N total at baseline:

Intervention: 57

Control:58
baseline scores calculated without drop outs included

Important prognostic factors:

For example

age ± SD:

I: 62.4 ± 9.0

C 62.6 ± 12.1:

Sex:

I: 73.6% M

C: 83.6% M

Primary site of disease:
I: 92.5% pleural

C: 90.9% pleural

Histology:
I: 73.6% epithelioid

C: 67.3% epithelioid

Groups comparable at baseline?
Although the random assignment was stratified by histology and

PS, in 39 patients, the information provided at random assignment

was incorrect. Twenty-six of the discrepancies in PS were a result of a

systematic error in which a Karnofsky performance score of 90 was

mapped into an ECOGPS of 1 rather than 0. The data in Table 1 show

the correct classifications determined on audit and rereview. The

consequence of these errors is that the guaranteed balance of the

treatment arms with respect to these factors was lost; however, the validity

of the random assignment is not affected.

Gemcitabine 1,250 mg/m2 was given intravenously on days 1 and 8 of a

21-day cycle, followed by cisplatin 75 mg/m2 intravenously on day 1, for six

cycles. Bevacizumab 15mg/kg was administered intravenously after

cisplatin on day 1 of each cycle. Bevacizumab or placebo was continued every

21 days until disease progression, unacceptable adverse events, or patient

withdrawal of consent.

A cycle was not started until the absolute neutrophil count (ANC) was more than 1.5x10⁹/L and the platelet

count was more than 100x10⁹/L.

Gemcitabine 1,250 mg/m2 was given intravenously on days 1 and 8 of a

21-day cycle, followed by cisplatin 75 mg/m2 intravenously on day 1, for six

cycles. Placebo was administered intravenously after

cisplatin on day 1 of each cycle. Placebo was continued every

21 days until disease progression, unacceptable adverse events, or patient

withdrawal of consent

A cycle was not started until the absolute neutrophil count (ANC) was more than 1.5x10⁹/L and the platelet

count was more than 100x10⁹/L.

Length of follow-up:

Until progression disease or death

Loss-to-follow-up:

Intervention:

N=4 (7%)

Reasons:
- protocol violations (n=2)
- ineligible (n=1)
- did not receive treatment (n=1)

Control:

N=3 (5%)

Reasons:
- protocol violation (n=1)

- did not receive treatment (n=1)

Incomplete outcome data:

None (not reported)

Outcome measures and effect size (include 95%CI and p-value if available):

Overall survival:
median overall survival:
I: 15.6 months (95%CI: 10.6 -18.7 months)
C: 14.7 months (95% CI: 10.3 - 20.0 months)
HR: 1.04 (95%CI: 0.68-1.59)
p=0.87 (unadjusted)
p= 0.91 (adjusted for progressive disease and histology)

Quality of life:
not reported

Adverse events/safety

There were no

statistically significant differences in the rates of grade 3 or greater

toxicity between treatment groups.

A sample size of 106

patients (53 per arm) provided 90% power to detect a hazard ratio (HR) of

1.75, using a one-sided

Zalcman 2016

Type of study:

RCT

Setting and country:

Multicentre, France

Funding and conflicts of interest:
Funding: This study was funded by the Intergroupe Francophone de Cancérologie

Thoracique (IFCT). This study was supported by funds from the French

Ministry of Health (Programme Hospitalier de Recherche Clinique,

2007), the French League against Cancer funding for IFCT,

research subventions for biomarker correlative studies from

F Hoff mann-La Roche to IFCT, and funds from Caen University

Hospital (Apricus Biosciences 2013), Canceropole North-West (2013),

and the Normandy League against Cancer (2014) to GZ.
Conflicts of interest:GZ participated in advisory boards for Roche, Eli Lilly, Bristol-Myers

Squibb, Clovis Oncology, AstraZeneca, Boehringer Ingelheim, and Pfizer,

all outside the submitted work, and received a research grant from Roche.

OM participated in advisory boards for Roche and Boehringer Ingelheim

outside the submitted work. JMaz has received grants from Roche outside

the submitted work. RC reports personal fees and non-financial support

from Roche, Eli Lilly, and Bristol-Myers Squibb; personal fees from

Boehringer Ingelheim and AstraZeneca; and non-financial support from

Amgen, all outside the submitted work. AS reports grants from Roche

during the conduct of this study. He was an advisory board member for

Merck Sharp & Dohme, Bristol-Myers Squibb, Seattle Genetics, Roche,

and AstraZeneca; received research grants from Amgen, Teva, and Roche;

received travel grants from Boehringer Ingelheim; and had investigators in

clinical trials in his department for Celgene, Merck Sharp & Dohme,

AstraZeneca, MedImmune, Verastem, Pierre Fabre, Clovis, Roche,

GlaxoSmithKline, Atex, Lilly, and BI, all outside the submitted work. VG

reports personal fees from Eli Lilly and Roche outside the submitted work.

DM-S reports personal fees from Roche, Eli Lilly, Pfizer, Novartis,

AstraZeneca, Clovis, Amgen, and Boehringer Ingelheim, all outside the

submitted work. LG reports grants, personal fees, and non-financial

support from Roche; personal fees and non-financial support from Eli Lilly

and AstraZeneca; and personal fees from Bristol-Myers Squibb and

Boehringer Ingelheim, all outside the submitted work. CA-V reports

personal fees from Roche and Eli Lilly during the conduct of this study and

personal fees from Amgen, Boehringer Ingelheim, Sismex-Inostics,

AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, and Clovis, all outside

the submitted work. BM reports grants and personal fees from Roche

during the conduct of this study, grants from and being a board member

of Lilly, grants and personal fees from Bristol-Myers Squibb and

AstraZeneca, and personal fees from Chugai, all outside the submitted

work. All other authors declare no competing interests.

Inclusion criteria:

- aged 18-75 years
- histologically proven malignant pleural mesothelioma with pleural biopsies

- ECOG performance status of 0-2
- at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT
- life expectancy of longer than 12 weeks
-prophylactic radiation treatment of all tracts (3x7 Gy) before chemotherapy and within 28 days after pleural biopsy was mandatory
- adequate haemotological, liver and renal function (creatinine clearance of ≥60 mL/min)
- coagulation international normalised ratio of less than or equal to 1.5
- prothrombin time of less than or equal to 1.5 times the upper limit of normal within 7 days before enrolment were needed

Exclusion criteria:

- previous chemotherapy
- substantial cardiovascular comorbidity
- amenable to curative surgery
- presence of central nervous system metastases
- use of antiaggregant treatments (aspirin ≥ 325 mg per day, clopidogrel, ticlopidine, of dipyridamole)
- anti-vitamin K drugs at a curative dose
- treatment with low-molecular-weight heparin at a curative dose (anticoagulants at a preventive dose were allowed)
- treatment with non-steroidal anti-inflammatory drugs
- uncontrolled hypertension, haemoptysis and major surgery (including thoracotomy) within 28 days before enrolment
- those with a history of inherited bleeding, diathesis, or coagulopathy
- recent myocardial infarction or cerebrovascular accident (<6 months before date of diagnosis)
- uncontrolled ischaemic cardiopathy (unstable angina)
- congestive heart failure
- severe uncontrolled cardiac arrhythmia or history of abdominal fistula or gastrointestinal perforation withing 6 months of enrollment

N total at baseline:

Intervention: 223

Control:225

Important prognostic factors:

For example

Median age (IQR):

I:65.7 (61.5-70.0)

C: 65.5 (60.8-70.3)

Sex:

I:75 % M

C: 76% M

Histology:
I: 80% epithelioid

C: 81% epithelioid

Groups comparable at baseline?

yes

Describe intervention (treatment/procedure/test):

Patients received intravenously 500 mg/m² pemetrexed

(day 1) plus 75 mg/m² cisplatin plus

15 mg/kg bevacizumab in 21 day cycles for up

to six cycles. The

PCB group allowed maintenance bevacizumab after the

six cycles until disease progression or toxic effects

Describe control (treatment/procedure/test):
Patients received intravenously 500 mg/m² pemetrexed

(day 1) plus 75 mg/m² cisplatin in 21 day cycles for up

to six cycles

Length of follow-up:

Median follow-up was

39·4 months (25·5–54·8), with no difference between the

two groups.

Loss-to-follow-up:

None (not reported)

Incomplete outcome data:

None (not reported)

Outcome measures and effect size (include 95%CI and p-value if available):

Overall survival:
median
I: 18.8 months (95% CI: 15.9 – 22.6)
C: 16.1 months (95%CI: 14.0 – 17.9)
adjusted HR: 0.77 (95% CI: 0.62-0.95)
(adjustment for minimisation variables: histology, performance status score, study centre, smoking status)

p=0.0167

Quality of Life

9 weeks: QoL questionnaire C30
I: n=121
C: n=131

9 weeks: Lung Cancer Symptom Score-Meso:
I: n=159

C: n=151

Adverse events/safety

We included all randomised patients in the intention-to treat

population in which we did the efficacy analyses. We

included patients who received at least one cycle of study

treatment in the safety population (safety analysis). The

phase 3 part needed 445 patients (including those from

the phase 2 part) and 385 deaths over 48 months, with a

24 month follow-up (80% power; two-sided α=0·05;

appendix). Patients enrolled in the phase 2 part

contributed in the phase 3 part without inflating the α

risk because of the hierarchical nature of the phase 2

and 3 hypotheses, also known as closed tests.20 We based

this sample size on a primary outcome of median OS

increasing from roughly 13 months to 17·3 months—ie, a

33% improvement—with addition of bevacizumab

(hazard ratio (HR) 0·75).

Role of the funding source

Bevacizumab was provided by Roche (France). Intergroupe

Francophone de Cancérologie Thoracique (IFCT) collected

and interpreted data. IFCT investigators and staff had a

role in study design and data analysis. IFCT had no role in

writing of the report. The corresponding author had full

access to all the data in the study and had final

responsibility for the decision to submit the publication.

Study reference

(first author, publication year)

Describe method of randomisation

Bias due to inadequate concealment of allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?

(unlikely/likely/unclear)

Bias due to loss to follow-up?

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?

(unlikely/likely/unclear)

Jassem, 2008

centralized randomization system

Unlikely

Likely

Likely

Unclear

Unlikely

Unlikely

Unlikely

Kindler, 2012

Random number generator, using method of permuted blocks (size 6) within each stratum

Unlikely

Unlikely

Unclear

Unclear

Unlikely

Unlikely

Likely

Zalcman, 2016

Computer randomisation using a minimisation method and stratification

Unlikely

Likely

Likely

Likely

Likely

For quality of life, % of improved patients was reported instead of quality of life scores

Unlikely

Unlikely