Patient Reviews Using Folfox Chemotherapy for Pancreatic Cancer

• Journal List
• BMC Cancer
• v.twenty; 2020
• PMC7346629

BMC Cancer. 2020; 20: 633.

Meta-analysis examining overall survival in patients with pancreatic cancer treated with 2d-line 5-fluorouracil and oxaliplatin-based therapy after declining first-line gemcitabine-containing therapy: effect of operation status and comparing with other regimens

Zev A. Wainberg, ¹ Kynan Feeney,² Myung Ah Lee,ⁱⁱⁱ Andrés Muñoz,⁴ Antonio Cubillo Gracián,^{5, 6} Sara Lonardi,⁷ Baek-Yeol Ryoo,⁸ Annie Hung,⁹ Yong Lin,^ten Johanna Bendell,^eleven and J. Randolph Hecht^one

Zev A. Wainberg

^oneSection of Medicine, Sectionalization of Hematology/Oncology, David Geffen School of Medicine, Academy of California Los Angeles, Los Angeles, CA United states of america

Kynan Feeney

²Notre Matriarch University, Fremantle and Edith Cowan University Joondalup, Perth, Australia

Myung Ah Lee

³Catholic University of Korea, Seoul, Due south Korea

Andrés Muñoz

⁴Hospital General Universitario Gregorio Marañón, Madrid, Kingdom of spain

Antonio Cubillo Gracián

^fiveHM Universitario Sanchinarro, Centro Integral Oncológico Clara Campal HM-CIOCC, Madrid, Espana

^viDepartamento de Ciencias Médicas Clínicas Universidad San Pablo CEU, Madrid, Spain

Sara Lonardi

⁷Istituto Oncologico Veneto – IRCCS, Padova, Italy

Baek-Yeol Ryoo

⁸Asan Medical Center, University of Ulsan Higher of Medicine, Seoul, South korea

Annie Hung

⁹ARMO Biosciences, a wholly owned subsidiary of Eli Lilly and Company, Redwood Metropolis, CA U.s.a.

Yong Lin

¹⁰Eli Lilly and Company, Indianapolis, IN USA

Johanna Bendell

^elevenSarah Cannon Research Plant/Tennessee Oncology, Nashville, TN United states

J. Randolph Hecht

¹Department of Medicine, Division of Hematology/Oncology, David Geffen Schoolhouse of Medicine, University of California Los Angeles, Los Angeles, CA USA

Received 2020 Feb 20; Accustomed 2020 Jun 25.

Data Availability Argument

All data generated or analyzed during this study are bachelor from the publications cited in the reference listing.

Abstract

Background

Pancreatic cancer has a poor prognosis and few choices of therapy. For patients with acceptable performance status, FOLFIRINOX or gemcitabine plus nab-paclitaxel are preferred first-line handling. 5-Fluorouracil (5-FU)–based therapy (e.thousand. FOLFIRI, OFF, or FOLFOX) are often used in patients who previously received gemcitabine-based regimens. A systematic review was conducted of the safety and efficacy of FOLFOX for metastatic pancreatic cancer following prior gemcitabine-based therapy. A Bayesian fixed-event meta-analysis with adjustment of patient operation status (PS) was conducted to evaluate overall survival (OS) and compare outcomes with nanoliposomal irinotecan combination therapy.

Methods

PubMed.gov, FDA.gov, ClinicalTrials.gov, congress abstracts, Cochrane.org library, and EMBASE database searches were conducted to identify randomized controlled trials of advanced/metastatic disease, prior gemcitabine-based therapy, and 2d-line treatment with v-FU and oxaliplatin. The database search dates were Jan ane, 1990–June thirty, 2019. Endpoints were Bone and severe treatment-related agin events (TRAEs). Trial-level PS scores were standardized by converting Karnofsky grade scores to Eastern Cooperative Oncology Group (ECOG) Form, and overall written report-weighted PS was calculated based on weighted boilerplate of all patients.

Results

Of 282 studies identified, 11 randomized controlled trials (Due north = 454) were included in the meta-analysis. Baseline weighted PS scores predicted Os in 10 of the 11 studies, and calculated PS scores of 1.0 were associated with a median OS of 6.three months (95% posterior interval, five.iv–7.four). Later adjusting for baseline PS, FOLFOX had a like treatment event profile (median OS, range 2.6–six.seven months) as five-FU/leucovorin plus nanoliposomal irinotecan therapy (median Os, 6.one months; 95% confidence interval 4.8–viii.9). Neutropenia and fatigue were the most unremarkably reported Grade 3–iv TRAEs associated with FOLFOX.

Conclusions

Baseline PS is a strong prognostic factor when interpreting the efficacy of 5-FU and oxaliplatin-based therapy of pancreatic cancer later progression on first-line gemcitabine-based regimens. When baseline PS is considered, FOLFOX has a similar treatment effect as 5-FU and nanoliposomal irinotecan therapy and a comparable rubber profile. These findings suggest that 5-FU and oxaliplatin-based therapies remain an acceptable and alternative second-line treatment selection for patients with pancreatic cancer and adequate PS (e.g. ECOG 0–i) following gemcitabine handling.

Keywords: Pancreatic cancer, Metastatic, Performance condition, FOLFOX, Meta-analysis

Background

Pancreatic cancer is the seventh leading cause of global cancer expiry [1] and the third most common cause of cancer-related expiry in the U.s. [2]. It is usually diagnosed at an avant-garde stage, and 80–ninety% of patients with pancreatic cancer have unresectable tumors. For patients with metastatic disease, the five-year survival charge per unit is less than ten% [three]. The National Comprehensive Cancer Network (NCCN) 2019 guidelines recommend chemotherapy with FOLFIRINOX [iv] or gemcitabine plus nab-paclitaxel [5] as preferred options for patients with an acceptable baseline performance status (Eastern Cooperative Oncology Group performance condition [ECOG PS] score of 0–1) [6]. Prison cell-democratic mechanisms of resistance to chemotherapy, yet, further limit therapeutic options, and there have been multiple negative randomized trials in the adjuvant and beginning-line setting [7]. Immunotherapies explored then far have not demonstrated improved benefits over chemotherapy perhaps because tumor cells are nonimmunogenic in nature and are characterized by poor antigenicity [8]. Only 1% of patients with pancreatic cancer have tumors with high levels of microsatellite instability (MSI-H) or mismatch repair deficiencies (dMMR) and are considered to be candidates for checkpoint inhibitors [9, 10]. Furthermore, in the small minority of patients with pancreatic cancer who have germline BRCA mutations (4–7%), progression-free survival (PFS) following poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor therapy was not influenced by prior response to platinum-based therapy [eleven].

In full general, most guidelines recommend the use of gemcitabine as monotherapy or equally office of a combination therapy regimen for patients previously treated with FOLFIRINOX or other fluoropyrimidine-based therapy [half dozen]. For patients previously treated with gemcitabine-based regimens, v-FU–based therapy including FOLFIRI, OFF, and FOLFOX has been recommended [half-dozen]. Recently, the Food and Drug Administration (FDA) approved nanoliposomal irinotecan in combination with 5-FU and leucovorin as second-line therapy after previous gemcitabine-based therapy (NAPOLI-i) [12]. Based on the findings from the NAPOLI-1 study, updated guidelines recommend the use of nanoliposomal irinotecan with fluorouracil and leucovorin in patients with metastatic pancreatic cancer later prior gemcitabine-based therapy [xiii]. In the NAPOLI-one written report, the median overall survival (OS) was six.1 months (95% confidence interval [CI] 4.eight–8.ix) for the combination of nanoliposomal irinotecan/v-FU/leucovorin compared with 4.two months (95% CI 3.iii–five.iii) for 5-FU/leucovorin alone with a hazard ratio of 0.67 (95% CI 0.49–0.92; P = .012) in patients with Karnofsky PS scores of 70 and above [12]. Survival benefits of this regimen were numerically similar to historically 5-FU–based therapy. For example, the stage III CONKO-003 trial of OFF demonstrated a median OS of v.9 months [14]. More than recently, a randomized stage II trial of mFOLFOX reported a median OS of 6.7 months in patients previously treated with gemcitabine [15], and despite not coming together its primary endpoint, the phase 3 PANCREOX report of mFOLFOX demonstrated a median OS of vi.1 months [16].

In the by, many prognostic factors accept been identified and considered, such as hemoglobin level, tumor brunt, liver metastases, venous thromboembolism, baseline expression of B7H1 or B7H4, and baseline CA19–9 [17–23]. Ane of the most meaning prognostic factors is baseline ECOG PS. For example, one small, single-arm, stage Ii accomplice study demonstrated a median Os for 2d-line FOLFOX with a median survival of 4.three months. When patients were stratified past baseline ECOG PS, the median OS was 5.9 months for patients with adequate PS (i.eastward., ECOG PS scores, 0–1) and 2.6 months for those with ECOG PS scores ≥ii [24]. In this paper, we performed a systematic review to better characterize the prophylactic and efficacy of FOLFOX treatment for patients with metastatic pancreatic cancer following prior gemcitabine-based therapy. A Bayesian meta-analysis with adjustment of patient PS was conducted to evaluate the median Os and cross-compare with nanoliposomal irinotecan combination therapy.

Methods

Literature search

Studies were identified from searches conducted in PubMed.gov, FDA.gov, ClinicalTrials.gov, abstracts from individual congress proceedings, the Cochrane.org library, and the EMBASE database between January one, 1990 and June 30, 2019. The search terms used were "pancreatic cancer", "gemcitabine", "FOLFOX", 5-fluorouracil", "oxaliplatin", and "leucovorin".

Inclusion and exclusion criteria

Trials meeting the following criteria were included in the meta-analysis: 1) patients with locally avant-garde and metastatic disease, two) patients who received prior gemcitabine-containing treatment, 3) second-line treatment regimens included 5-FU and oxaliplatin, and 4) reported data included median OS, severe (Grades 3–iv) handling-related adverse events (TRAEs), based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [25]. Trials meeting the following criteria were excluded from the meta-analysis: one) patients who received prior handling with five-FU and oxaliplatin for locally advanced or metastatic pancreatic cancer, 2) patients who received an oral fluoropyrimidine, or irinotecan, capecitabine, or cisplatin equally 2nd-line treatment, and iii) patient PS was not reported.

Data collection and assay

Two reviewers independently evaluated the literature identified from the database searches. For studies reported in dissimilar publications, the most recent report was retained, and the other version was excluded. The data extracted from each written report included author names, publication yr, number of patients, number of survival events, median Bone, and severe adverse events. Whatsoever discrepancies in written report eligibility or data extraction were reconciled. Studies were excluded if the total text of the publication was not available or if PS or median Os data were not reported.

Statistical analyses

The primary endpoint and secondary endpoints were median Os and astringent TRAEs for patients who received FOLFOX or 5-FU/oxaliplatin–based therapy following prior gemcitabine–based regimens for metastatic pancreatic cancer. Adapted PS was included in the meta-analysis model as follows. To standardize the trial-level PS, Karnofsky grade was converted to ECOG Grade according to Oken et al. [26], and the overall written report-weighted PS was calculated based on the weighted average. For example, ECOG 0–1 was converted to numerical value 1, and ECOG ii, 3, and 4 were converted to numerical values 2, 3, and iv, respectively. For a study with due west _i% of the patients had ECOG 0–ane and due west _two% with ECOG ii. The weighted trial performance was calculated as: 1× westward ₁% + two× w _two%. A Bayesian stock-still-effect meta-analysis was performed for the median Bone with weighted trial PS as a predictor. A noninformative prior was used to establish the relationship betwixt log transformation of median Os and PS. The noninformative prior was assumed for the related parameters. The posterior median of OS and 95% posterior interval (PI) were summarized for patients with ECOG PS ≤1. For rubber, Form iii/4 clinically relevant toxicities that were reported in ≥ten% of patients in whatsoever trial were pooled together to evaluate the toxicity of the treatment regimen. To exist conservative, trials that did not study a specific adverse outcome were removed from the group of evaluable patients. All analyses were performed in R 3.five.0.

Results

Written report selection

The CONSORT flow chart that illustrates study identification and selection for the meta-analysis is shown in Fig.1. Of 282 studies identified in the database searches, eleven were called for meta-analysis [14–16, 24, 27–33], and 242 studies were excluded. In total, 454 patients with pancreatic cancer were included in this meta-analysis. The 11 selected studies evaluated 5-FU and oxaliplatin-based regimens, including OFF, FOLFOX, and modified FOLFOX (mFOLFOX6, mFOLFOX4) (Table1).

Table 1

Summary of 5-FU and oxaliplatin-based therapy as 2d-line therapy

Treatment	Author/twelvemonth	Northward	Weighted PS	Original PS	Prior surgery (%)	Deaths	Median Bone (m)	ORR (%)
OFF	Pelzer 2009 [28]	37	i.five	KS: Median: 70, range: [60, 90]	43	33	v.1	half-dozen
OFF	Pelzer 2011 [27]	23	ane.3	KS: Median: lxxx, range: [seventy, 100]	NR	18	four.8	0
OFF	Oettle 2014 [14]	76	1.2	KS: (ninety–100) (53.9%), 70–80 (46.1%)	45	73	five.ix	17
5-FU/OXA-based	Tsavaris 2005 [29]	30	1.7	KS: (lxxx–100) (33.4%), 70–l (66.7%)	NR	20	5.seven	23
FOLFOX	Gebbia 2007 [xxx]	42	i.4	ECOG: one (62%), 2 (38%)	ix	38	6.7	14
FOLFOX	Yoo 2009 [31]	30	1.0	ECOG: 0–1 (97%)	32	25	3.viii	seven
FOLFOX	Zaanan 2014 [24]	12	one.0	ECOG: 0–i (100%)	0	10	5.9	0
FOLFOX	Zaanan 2014 [24]	12	two.v	ECOG: 2–3 (100%)	0	12	2.six	0
FOLFOX	Gill 2016 [16]	54	1.ane	ECOG: 0–one (89%), 2 (11%)	NR	47	vi.one	13
FOLFOX	Berk 2012 [32]	46	1.2	ECOG: 0–1 (78%), 2 (22%)	NR	33.6	6.ii	17
OFF	El-Hadaad 2013 [33]	thirty	1.2	ECOG: 0–one (83.4%), 2 (16%)	NR	29	5.i	7
FOLFOX	Chung 2017 [xv]	62	1.0	ECOG: 0–ane (100%)	NR	53	6.7	xi

Abbreviations: five-FU 5-fluorouracil, ECOG Eastern Cooperative Oncology Group, FOLFOX leucovorin/5-fluorouracil/oxaliplatin, chiliad months, KS Karnofsky status, NR not reported, OFF oxaliplatin/five-fluorouracil/leucovorin, ORR overall response rate, OS overall survival, OXA oxaliplatin, PS performance score

Patient population

In the 454 evaluable patients, the reported PS ranged from Karnofsky performance index scores of threescore–100 and ECOG PS scale scores of 0–iii (Table ​ 1). Of 11 studies, five reported the surgical histories of the patient sample. Rates of prior surgery were eight% [34], ix% [xxx], 32% [31], 43% [28], and 45% [14]. The median Os ranged from 2.6 months to half dozen.7 months, and the overall response rate ranged from 0 to 23% (Table ​ one).

Overall survival

Baseline weighted PS scores predicted OS in 10 of the xi studies (Fig.ii). Results from one study were identified as an outlier, with a median OS of approximately iv months in patients with a baseline weighted PS score of 1.0 [31]. Likely the variability was considering of a long menstruation of time betwixt the determination of gemcitabine-based therapy to FOLFOX treatment (median xv weeks, range 7.0–32.vi weeks). To maintain integrity of the assay, the outlier was non removed from the model. Based on the Bayesian meta-analysis with the adjustment of baseline PS, for 5-FU and oxaliplatin-based therapy (Fig.three), the median OS was 6.two months (95% PI five.four–7.1). For the analysis of FOLFOX therapy (Fig.iv), the median Bone was 6.iii months (95% PI 5.4–7.4).

Association between median overall survival (OS) and patient functioning condition

Overall survival (Os) meta-analysis of 5-fluorouracil (5-FU) and oxaliplatin (OXA)-based therapy

Overall survival (OS) meta-assay of FOLFOX

Safety of FOLFOX

The clinically relevant Form 3–four TRAEs for the selected studies were pooled, and the results are summarized in Table2. The most commonly reported Grade iii–4 TRAEs associated with FOLFOX therapy were neutropenia (21.5%) and fatigue (11.vii%). Other Class 3–4 TRAEs occurring in > 10% in any trial were neurotoxicity (v.3%), thrombocytopenia (four.nine%), anemia (4.5%), diarrhea (iv.2%), and vomiting (four.one%).

Table two

Summary of safety for five-FU and oxaliplatin-based therapy

Treatment	Writer/year	N	Grade three–four clinically relevant toxicities > 10% in whatever trial
			Diarrhea	Neutropenia	Anemia	Neurotoxicity	Fatiguea	Vomiting	Thrombocytopenia
OFF	Pelzer 2009 [28]	37	viii.1	NR	NR	10.eight	NR	13.5	0
OFF	Pelzer 2011 [27]	23	8.vii	NR	NR	NR	NR	NR	NR
OFF	Oettle 2014 [14]	76	one.3	NR	iii.nine	NR	NR	1.3	1.iii
5-FU/OXA-based	Tsavaris 2005 [29]	30	14.ii	NR	three.2	iv.ii	0	0	iii.2
FOLFOX	Gebbia 2007 [30]	42	NR	17	xiv	12	NR	NR	7
FOLFOX	Yoo 2009 [31]	30	0	20	3	0	14	10	3
FOLFOX	Zaanan 2014 [24]	27	0	7.4	vii.4	7.iv	14.eight	0	11.1
FOLFOX	Gill 2016 [16]	49	2	32.7	2	4.1	fourteen.2	4.1	8.2
FOLFOX	Berk 2012 [32]	46	ii	22	0	NR	NR	2	7
OFF	El-Hadaad 2013 [33]	xxx	3.3	23.2	vi.6	half-dozen.6	NR	3.3	6.6
FOLFOX	Chung 2017 [xv]	62	half-dozen.five	NR	3.2	0	12.9	4.8	NR
Evaluable patients for each AE, n			410	224	392	307	198	387	367
Weighted average (%)			4.2	21.5	four.5	5.3	xi.7	4.ane	4.nine

Word

The prognosis of pancreatic cancer remains dismal, and the master first-line treatments for patients with metastatic disease are gemcitabine-based combinations and FOLFIRINOX. For patients previously treated with gemcitabine, second-line 5-FU–based therapy including FOLFIRI, FOLFOX, and OFF have been recommended [six]. In randomized trials, oxaliplatin–based regimens in the 2nd-line setting, such as CONKO-003 and PANCREOX, have had alien efficacy results [35]. In the CONKO-003 trial, the OFF regimen was superior to FF (leucovorin and v-FU) with a median Bone of 5.9 vs. iii.3 months, respectively [xiv]. On the other hand, the PANCREOX written report compared a different oxaliplatin, 5-FU, and leucovorin-containing regimen (mFOLFOX6) with 5-FU/LV, with a median OS of vi.1 vs. 9.nine months, respectively [16]. While mFOLFOX6 produced results consistent with prior studies of oxaliplatin and five-FU combinations, the 5-FU/LV command arm demonstrated surprisingly prolonged survival. One gene that may take contributed to these findings was an imbalance in several baseline characteristics. For example, the median time from diagnosis of advanced disease to treatment was longer in the mFOLFOX6 arm compared with the five-FU/LV arm (7.9 vs. 5.7 months, respectively), and a college proportion of patients in the mFOLFOX6 arm than in the 5-FU/LV arm had baseline ECOG PS scores of ii (11.one% vs. 5.vii%). Additionally, fewer patients in the mFOLFOX6 arm than the 5-FU/LV arm received post-discontinuation therapy (seven% vs. 23%, respectively). It is important to remember that these are relatively pocket-sized studies of fewer than 200 patients each, and comparisons are fraught because of inherent methodologic differences.

The systematic literature review and meta-analysis reported here was conducted in an try to overcome the variability induced past small sample sizes. In addition, after adjusting for PS, the meta-assay of five-FU and oxaliplatin-based therapy (e.g., FOLFOX) demonstrated a numerically like handling effect (median Os range 2.half dozen–6.7 months; Table ​ i) compared with 5-FU/LV plus nanoliposomal irinotecan combination therapy in the NAPOLI-1 trial (median Bone 6.ane months; 95% CI 4.8–8.9) (Table3) [12]. For patients with ECOG PS of 0 or ane, the median OS was 6.ii months (95% PI 5.4–seven.1) for patients who received the oxaliplatin, 5-FU, and LV regimen. In add-on, for the subset meta-assay of FOLFOX therapy (Fig. ​ iv), the median OS demonstrated consequent results with median OS of 6.three months (95% PI v.4–7.4). The nigh usually reported Grade 3–4 TRAEs associated with FOLFOX therapy were neutropenia (21.five%) and fatigue (11.seven%). Other Grade 3–4 TRAEs occurring in > ten% in any trial were neurotoxicity (5.iii%), thrombocytopenia (4.9%), anemia (4.5%), diarrhea (4.2%), and vomiting (4.one%) (Table ​ two). Based on an indirect comparing, this adverse event profile was similar to the findings of the NAPOLI-i trial (Tablefour).

Tabular array 3

Baseline and efficacy contour for nanoliposomal irinotecan-based therapy from NAPOLI-1 [12]

Characteristicsa	Results
N	117
Karnofsky performance 100–lxxx	91%
Lines of prior therapy: 0/ane/2+ (%)	13/53/34
Prior therapy: Gemcitabine mono/combination/v-FU-based (%)	45/55/43
Median Os (95% CI)	6.1 months (four.8–eight.nine)

Table 4

Safety contour for nanoliposomal irinotecan-based therapy [12]

Form iii–iv AEs	Nanoliposomal irinotecan-based therapy (%)	5-FU and OXA-based therapy weighted average (%) [range]
Diarrhea	13	4.2 [0, 14.ii]
Airsickness	11	4.1 [0, 13.five]
Fatigue	14	11.7 [0, fourteen.viii]
Neutropenia	27	21.v [7.four, 32.7]
Anemia	9	four.five [0, 14]
Hypokalemia	iii	NR
Neurotoxicity	NR	v.iii [0, 12]
Thrombocytopenia	NR	4.ix [0, 11.ane]

Abbreviations: 5-FU 5-fluorouracil, AE adverse event, NR non recorded, OXA oxaliplatin

These analyses are not without limitations. Our ability to adjust survival outcomes for other potential prognostic factors was hindered because nosotros did not have admission to the full study datasets. For example, prior surgery, levels of the CA-19-9 antigen, baseline hemoglobin levels, BRCA1 or BRCA2 mutation status, or the time from diagnosis to the initiation of treatment were not always reported. In addition, the cross-trial comparison between the meta-analysis of the FOLFOX treatment regimen and the results from NAPOLI-i are indirect and must be interpreted with caution.

Conclusions

In this meta-assay, nosotros confirmed that baseline PS is a stiff prognostic factor when interpreting the efficacy of 5-FU and oxaliplatin-based therapy after progression of pancreatic cancer with starting time-line gemcitabine-containing therapies. After adjusting for patient PS, the meta-assay of 5-FU and oxaliplatin-based therapy (eastward.yard., FOLFOX) shows a numerically similar treatment effect as 5-FU and nanoliposomal irinotecan therapy in the NAPOLI-1 trial. In addition, the adverse event profile is also comparable between the two handling regimens. The findings from our analyses suggest that the combination of 5-FU and oxaliplatin-based therapies remains an acceptable and culling 2d-line treatment option for patients with pancreatic cancer and adequate PS (east.k., ECOG 0/i) who have received gemcitabine-based therapies.

Acknowledgements

The authors thank David Ferry and Sujata Rao for their thoughtful review of the manuscript. Medical writing assistance was provided by Emerge Laden of ProScribe Medical Affairs – Envision Pharma Group, and was funded past Eli Lilly and Visitor. ProScribe Medical Affairs' services complied with international guidelines for Good Publication Practice (GPP3).

Abbreviations

CI	Conviction interval
CTCAE	Mutual Terminology Criteria for Adverse Events
dMMR	Mismatch repair deficiencies
ECOG	Eastern Cooperative Oncology Group
FDA	Food and Drug Administration
5-FU	5-fluorouracil
MSI-H	High level of microsatellite instability
NCCN	National Comprehensive Cancer Network
OS	Overall survival
PARP	Poly(adenosine diphosphate–ribose) polymerase
PFS	Progression-gratuitous survival
PI	Posterior interval
PS	Performance status
TRAE	Handling-related adverse event

Authors' contributions

ZAW, B-YR, M-AL, AH, and YL participated in the meta-assay methodology and design; YL and AH screened identified literature and conducted data extraction and statistical assay. ZAW, KF, M-AL, AM, ACG, SL, B-Year, AH, YL, JB and JRH were involved in the interpretation of the data. YL wrote the manuscript. ZAW, KF, M-AL, AM, ACG, SL, B-YR, AH, YL, JB and JRH contributed to improving the manuscript and read and canonical the version of the manuscript to be published. All authors accept responsibility for appropriate content.

Funding

Eli Lilly and Visitor was involved in the study design, data collection, data assay, and preparation of the manuscript.

Availability of data and materials

All data generated or analyzed during this study are bachelor from the publications cited in the reference list.

Ethics blessing and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

ZAW has received research funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Ipsen, and Merck, and has served as a consultant and on advisory panels for Bayer, Eli Lilly and Company, Daiichi Sankyo, EMD Serono, Five Prime, Ipsen, Macrogenics, Merck, Molecular Templates, and Novartis. AM has received enquiry funding from Leo Pharma and Sanofi; has served every bit a consultant and on advisory panels for Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, Leo Pharma, Pfizer, and Sanofi; has participated in speaker bureaus for Bayer, Eli Lilly and Company, MSD, Rovi, and Servier; has received reimbursements for travel, accommodations, and expenses from Celgene and Roche; and holds patents, royalties, and other intellectual property (risk assessment model in venous thromboembolism in patients with cancer). SL has received research funding from Amgen and Merck Serono; has served equally a consultant and on advisory panels for Amgen, Eli Lilly and Company, Merck Serono, and Servier; and has participated in speaker bureaus for Bristol-Myers Squibb, Eli Lilly and Company, Merck Serono, Roche, and Servier. JB's institution has received inquiry funding from AbbVie, Acerta Pharma, ADC, Agios, Amgen, Apexigen, Arch Oncology, Arcus Biosciences, ARMO, Assortment, Arrys, AstraZeneca, Bayer, Bellicum, Blueprint, Boehringer Ingelheim, Boston Biomedical, Bristol-Myers Squibb, Calithera, Celgene, Celldex, CytomX, Daiichi Sankyo, Effector, Eisai, Eli Lilly and Company, EMD Serono, Evelo, 5 Prime, FORMA, Forty Vii, Genentech/Roche, Gilead, Gossamer Bio, GSK, Harpoon, ImClone, Incyte, Innate, Ipsen, Jacobio, Koltan, LEAP, Macrogenics, Marshall Edwards, MedImmune, Merck, Merrimack, Mersana, Merus, Millennium, Nektar, Novartis, Novocare, OncoGenex, OncoMed, Onyx, Pfizer, Pieris, Prelude Oncology, Rgenix, Sanofi, Seattle Genetics, Shattuck Labs, Sierra, SynDevRx, Takeda, Tarveda, Tracon, Tyrogenex, Taiho, TempestTx, TG Therapeutics, Unum Therapeutics, and Vyriad; has served every bit a consultant and on advisory panels for Agios, Amgen, Apexigen, Arch Oncology, ARMO, Array, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Continuum Clinical, Cyteir, Daiichi Sankyo, Eli Lilly and Visitor, Five Prime number, FORMA, Genentech/Roche, Gilead, GSK, Incyte, Innate, Ipsen, Janssen, LEAP, MacroGenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular Partners, Novartis, OncoGenex, OncoMed, Phoenix Bio, Prelude Therapeutics, Sanofi, Seattle Genetics, Taiho, Tanabe Research Laboratories, TD2 (Translational Drug Evolution), TG Therapeutics, Tizona, Tolero, and Torque; and has received reimbursements for food, drink, and travel from ARMO, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, FORMA, Genentech/Roche, Gilead, Ipsen, MedImmune, Merck, Novartis, OncoMed, OncoGenex, and Taiho. JRH received grants, personal fees, and non-financial back up from ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the written report.

AH and YL are employees of Eli Lilly and Visitor, and YL acknowledges stock/equity ownership in Eli Lilly and Company. KF, Thou-AL, ACG, and B-YR have no competing interests to declare.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346629/

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