Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study

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Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study Philip A Philip, Jill Lacy, Fabienne Portales, Alberto Sobrero, Roberto Pazo-Cid, José L Manzano Mozo, Edward J Kim, Scot Dowden, Ahmed Zakari, Christophe Borg, Eric Terrebonne, Fernando Rivera, Javier Sastre, Venu Bathini, Daniel López-Trabada, Jamil Asselah, Muhammad Wasif Saif, Jack Shiansong Li, Teng Jin Ong, Thomas Nydam, Pascal Hammel

Summary

Background Treatment options for patients with unresectable locally advanced pancreatic cancer are scarce. Results from a subanalysis of the phase 3 MPACT trial in metastatic pancreatic cancer suggested potential activity of nab-paclitaxel plus gemcitabine against locally advanced pancreatic cancer. The objective of this phase 2 trial was to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer. Methods This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy). Patients with Eastern Cooperative Oncology Group performance status of up to 1 underwent six cycles of induction with nab-paclitaxel 125 mg/m² plus gemcitabine 1000 mg/m² (days 1, 8, and 15 of each 28-day cycle). After induction, patients without progressive disease or unacceptable adverse events were eligible to receive continued therapy per investigator’s choice: continued nab-paclitaxel plus gemcitabine, chemoradiation, or surgery. The primary endpoint was time to treatment failure; secondary endpoints were disease control rate, overall response rate, progression-free survival, overall survival, safety, and quality of life. The reported efficacy outcomes were analysed in the intention-to-treat population, and safety outcomes were analysed in the treated population. This trial is registered with ClinicalTrials.gov, NCT02301143, and EudraCT, 2014-001408-23 and is complete. Findings Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study treatment; one patient enrolled but did not receive treatment. 44 (41%) of 107 enrolled patients discontinued induction; the most common reason for discontinuing induction was adverse events (22 [21%] patients). 62 (58%) of 107 enrolled patients completed induction treatment and 47 (44%) patients subsequently received continued treatment per investigator’s choice: 12 (11%) continued nab-paclitaxel plus gemcitabine, 18 (17%) received chemoradiation, and 17 (16%) underwent surgery (seven had R0 resection status, nine had R1). 15 (14%) patients completed induction treatment but did not receive continued treatment. Median time to treatment failure was 9·0 months (90% CI 7·3–10·1); median progression-free survival was 10·9 months (90% CI 9·3–11·6), and median overall survival was 18·8 months (90% CI 15·0–24·0). During induction, 83 patients achieved disease control and the disease control rate was 77·6% (90% CI 70·3–83·5). 36 patients had a best response of partial response; the overall response rate during induction was 33·6% (90% CI 26·6–41·5). The most common treatment-emergent adverse events that were grade 3 or higher in the treated population during induction were neutropenia (35 [33%] of 106 patients), anaemia (12 [11%]), and fatigue (11 [10%]). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths were caused by treatment-related adverse events during the induction phase, and global quality of life was maintained in most patients. Interpretation The data from this trial support the tolerability and activity of nab-paclitaxel plus gemcitabine for locally advanced pancreatic cancer, and a potential to convert unresectable, locally advanced disease to surgically resectable disease. The safety profile was generally consistent with previous findings. Funding Celgene. Copyright © 2020 Elsevier Ltd. All rights reserved.

Introduction The optimal management of locally advanced pancreatic cancer remains an open research question, given the absence of prospective studies of the latest multidrug

chemotherapy regimens in this setting. Upfront systemic chemotherapy is generally recommended for patients with locally advanced pancreatic cancer to control or delay symptoms of tumour progression, prolong survival,

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Lancet Gastroenterol Hepatol 2020 Published Online January 14, 2020 https://doi.org/10.1016/ S2468-1253(19)30327-9 See Online/Comment https://doi.org/10.1016/ S2468-1253(19)30404-2 Department of Oncology, Karmanos Cancer Institute, Wayne State University, Hudson-Webber Cancer Research Center, Detroit, MI, USA (Prof P A Philip MD); Internal Medicine, Yale School of Medicine, New Haven, CT, USA (Prof J Lacy MD); Department of Digestive Oncology, Institut du Cancer de Montpellier, Montpellier, France (F Portales MD); Medical Oncology, IRCCS Ospedale San Martino IST, Genoa, Italy (Prof A Sobrero MD); Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain (R Pazo-Cid MD); Department of Medical Oncology, Hospital Germans Trias i Pujol, Institut Català d’Oncologia Badalona, Barcelona, Spain (Prof J L Manzano Mozo MD); Department of Internal Medicine, UC Davis School of Medicine, University of California Davis, Sacramento, CA, USA (E J Kim MD); Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada (S Dowden MD); Department of Internal Medicine, AdventHealth Cancer Institute, Orlando, FL, USA (A Zakari MD); Department of Medical Oncology, University Hospital of Besançon, Besançon, France (Prof C Borg MD); Department of Gastroenterology, CHU Haut-Lévêque, Pessac, France (E Terrebonne MD); Department of Medical Oncology, Hospital

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Universitario Marqués de Valdecilla, Santander, Spain (F Rivera MD); Department of Medical Oncology, Hospital Clínico San Carlos, Madrid, Spain (J Sastre MD); Division of Hematology/Oncology, UMass Memorial Medical Center, Worcester, MA, USA (V Bathini MD); Department of Medical Oncology, Hôpital Saint Antoine, Paris, France (D López-Trabada MD); Department of Oncology, McGill University Royal Victoria Hospital, Montréal, QC, Canada (J Asselah MD); Medical Oncology, Northwell Health Cancer Institute, Lake Success, NY, USA (M W Saif MD); Celgene Corporation, Summit, NJ, USA (J Shiansong Li PhD, T J Ong MD, T Nydam MD); and Department of Pancreatology, Hôpital Beaujon (AP-HP), Université Denis Diderot-Paris VII, Clichy, France (Prof P Hammel MD) Correspondence to: Prof Philip A Philip, Department of Oncology, Karmanos Cancer Institute, Wayne State University, Hudson-Webber Cancer Research Center, Detroit, MI 48201, USA [email protected]

Research in context Evidence before this study This trial was initiated in 2015 and, at the time, there were no category 1 treatment options for locally advanced pancreatic cancer according to National Comprehensive Cancer Network guidelines, and there was one category 1A recommendation according to European Society for Medical Oncology guidelines. Nab-paclitaxel plus gemcitabine was a category 2A recommendation (based on extrapolation of data from the metastatic setting) according to National Comprehensive Cancer Network guidelines. We used these guidelines as a database search because there were no prospective randomised clinical trial data informing treatment guidelines for locally advanced pancreatic cancer. There are currently two preferred treatment options for patients with metastatic pancreatic cancer and good performance status: nab-paclitaxel plus gemcitabine, and FOLFIRINOX or modified FOLFIRINOX. Each is considered an option in locally advanced pancreatic cancer based on extrapolation of data from the metastatic setting; however, there are currently no prospective data in locally advanced pancreatic cancer for either regimen. An exploratory analysis of the MPACT trial showed a median percentage reduction in the sum of pancreatic tumour diameters at nadir from baseline with nab-paclitaxel plus gemcitabine that was more than 3-fold greater compared with gemcitabine monotherapy, suggesting that the combination might be an effective treatment for locally advanced pancreatic cancer.

and maintain quality of life.1,2 Following systemic therapy, chemoradiation in selected patients could prolong local control,1,3 although its potential benefit remains unclear. Previous randomised trials have provided conflicting information on the survival benefit of chemoradiation versus chemotherapy alone.4,5 Additional studies are underway to further delineate the patient population and radiation therapy modalities that provide definitive survival benefits. Complete surgical resection remains the only curative option for patients with pancreatic cancer,2 but resection rates are low in patients with locally advanced pancreatic cancer, as highlighted by the phase 3 LAP07 trial of induction gemcitabine with or without erlotinib followed by chemotherapy or chemoradiotherapy, in which only 18 (4%) of 442 patients with locally advanced pancreatic cancer underwent resection after receiving systemic therapy with gemcitabine, with or without erlotinib.6 Studies have suggested that resection rates could improve in some patients with locally advanced pancreatic cancer with the use of more intensive chemotherapy regimens.7–10 A systematic literature review of studies investigating FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) as first-line treatment for locally advanced pancreatic cancer revealed an average resection rate of 28% (range 0–43%) across 12 studies.11 2

In this trial (LAPACT), we aimed to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer. Added value of this study To our knowledge, the LAPACT trial is the first prospective study to evaluate the safety and activity of nab-paclitaxel plus gemcitabine specifically in patients with locally advanced pancreatic cancer. The primary endpoint of time to treatment failure with nab-paclitaxel plus gemcitabine induction followed by the investigator’s choice of therapy met the protocolspecified target of at least 6·6 months. A proportion of patients also became resectable during induction therapy. No new safety signals were identified. Findings from this study validate nab-paclitaxel plus gemcitabine as an active regimen for treating locally advanced pancreatic cancer, as previously suggested by data from the MPACT trial. Implications of all the available evidence The LAPACT trial showed encouraging antitumour activity and survival data with nab-paclitaxel plus gemcitabine induction. These findings support nab-paclitaxel plus gemcitabine as a chemotherapy regimen of choice for induction, and as a backbone regimen for investigation of novel, targeted agents. Data from the LAPACT trial could strengthen the recommendation for nab-paclitaxel plus gemcitabine in treating patients with locally advanced pancreatic cancer.

The National Comprehensive Cancer Network currently lists nab-paclitaxel (paclitaxel formulated as albuminbound particles) plus gemcitabine as a preferred category 2A recommendation for the treatment of locally advanced pancreatic cancer, based on extrapolation of data from the phase 3 MPACT trial in the metastatic setting.2 Clinical evidence of efficacy and safety specifically in patients with locally advanced pancreatic cancer is needed to strengthen this recommendation. The MPACT trial showed superior efficacy of first-line nab-paclitaxel plus gemcitabine versus gemcitabine monotherapy in metastatic pancreatic cancer across all endpoints.12,13 The most common (grade ≥3) adverse events in MPACT were neutropenia, leukopenia, fatigue, and peripheral neuropathy. An exploratory analysis of the MPACT trial showed a median percentage reduction in the sum of pancreatic tumour diameters at nadir from baseline with nab-paclitaxel plus gemcitabine that was more than 3-fold greater compared with gemcitabine monotherapy, suggesting that the combination might be an effective treatment for locally advanced pancreatic cancer.14 For this phase 2 trial, we assessed the efficacy and safety of six cycles of induction nab-paclitaxel plus gemcitabine in patients with newly diagnosed locally advanced pancreatic cancer. Patients who completed induction therapy without evidence of progressive disease or unacceptable adverse events were eligible to

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receive continued nab-paclitaxel plus gemcitabine, protocol-defined chemoradiation, or surgical resection, per the investigator’s choice.

nab-paclitaxel, gemcitabine, or any of their excipients. Full inclusion and exclusion criteria are listed in the trial protocol.

Methods

Procedures

This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy) and is complete. The study was approved by the institutional review board or ethics committee at each participating centre (appendix pp 1–3) and was conducted in accordance with the International Conference on Harmonisation Guideline E6 require­ ments for Good Clinical Practice and general ethical principles outlined in the Declaration of Helsinki. All patients provided written informed consent before participation. The trial protocol is available in the appendix (pp 13–86). Eligible patients were aged at least 18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of up to 1. Patients were required to have histologically or cytologically confirmed pancreatic adenocarcinoma (pancreatic tumours of endocrine or mixed origin were not allowed). Criteria for unresectable status were defined by the guidelines from the Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus conference on resectable and borderlineresectable pancreatic cancer.15 Specifically, unresectable status was defined by occlusion, thrombosis, or encasement of the superior mesenteric vein or portal vein extending several cms; tumour abutment above 180° or thrombosis of the superior mesenteric artery; abutment or encasement of the celiac axis; or unresectable lymph node involvement. Radiographic criteria (CT or MRI scans) or exploration were used to define tumours as unresectable. Patients were required to have no evidence of distant metastases as defined by CT or MRI scans of the chest, abdomen, and pelvis. Patients could not have received previous anticancer therapies for pancreatic carcinoma. Patients were required to have adequate haematological, hepatic, and renal function (including an absolute neutrophil count ≥1500 cells per µL, haemoglobin concentration ≥9 g/dL, serum albumin concentration >3 g/dL, and bilirubin concentration ≤1·5 times the upper limit of normal). Patients with peripheral sensory neuropathy that was above grade 1, or with any other malignancy in the 5 years before enrolment (with the exception of adequately treated in situ carcinoma of the prostate [Gleason score ≤7], cervical cancer, uterine cancer, or non-melanomatous skin cancer) were excluded. Patients with active infections (bacterial, viral, or fungal) requiring systemic therapy, known infection with hepatitis B or C, or a history of HIV infection (or receiving immunosuppressive or myelo­ suppressive medications) were excluded, and so were patients with a history of allergy or hypersensitivity to

The trial evaluated an induction phase of six cycles of nabpaclitaxel 125 mg/m² by intravenous infusion over approximately 30–45 mins, followed by gemcitabine 1000 mg/m² intravenous infusion over approximately 30 mins on days 1, 8, and 15 of each 28-day cycle (as was previously established in the metastatic setting)12,16 in patients with locally advanced pancreatic cancer. Up to two dose reductions for nab-paclitaxel (to 100 mg/m² and 75 mg/m²) and gemcitabine (to 800 mg/m² and 600 mg/m²) were allowed. After six cycles of nab-paclitaxel plus gemcitabine, patients without disease progression or unacceptable toxicity were eligible to receive continued treatment with nab-paclitaxel plus gemcitabine, chemo­ radiation therapy (concurrent use of capecitabine or gemcitabine with radiation according to institutional practice), or surgical resection per the investigator’s choice (appendix p 9). Patients received treatment until disease progression or unacceptable toxicity. Surgical inter­vention before completion of six cycles of nab-paclitaxel plus gemcitabine was permitted if a patient had a major response to therapy; these patients were considered as having completed the induction phase. Additional nonprotocol-defined anticancer therapy was not allowed; however, supportive care (including, but not limited to, haematopoietic growth factors, antiemetics, analgesics, and antibiotics) was permitted. During induction, patients were assessed by CT or MRI scans at baseline and then every 56 days (+ 7 or – 3 days) and at the 28-day follow-up visit (after the last treatment). During receipt of the investigator’s choice of therapy, scans were done every 56 days (+ 7 or – 3 days) and at the 28-day follow-up visit (after last dose of chemotherapy or chemoradiation) or after surgery (28 days post-surgery). All patients were to have CT or MRI scans until documented disease progression, withdrawal of consent from active participation in the study, loss to follow-up, death, or start of a non-protocol-defined anticancer therapy, whichever came first. Additionally, patients were followed for overall survival and post-study anticancer therapies approximately every 90 days by phone or review of medical records until death, withdrawal of consent, or loss to follow-up. Evaluations were done at the investigative sites, and response was measured by the investigator according to version 1.1 of the Response Evaluation Criteria In Solid Tumours. Resection status (R0, R1, or R2) was graded according to institutional guidelines. Safety data were reviewed on an ongoing basis throughout the study by the study medical monitor and drug safety physician. Patients who discontinued treatment had a safety follow-up visit 28 days after treatment discontinuation. Patients who were going to receive chemoradiation or undergo surgery had a safety

Study design and participants

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See Online for appendix

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107 patients enrolled 1 did not receive treatment 106 received induction 44 discontinued induction 62 completed induction 15 did not receive investigator’s choice of treatment

44 discontinued 22 adverse events 8 progressive disease 4 physician decision 3 patient withdrawal 2 protocol violation 2 symptomatic deterioration 1 death 1 non-adherence 1 other 10 progressive disease 5 progressive disease only 5 progressive disease followed by additional therapy

47 received investigator’s choice of therapy 12 received nab-paclitaxel and gemcitabine 18 received chemoradiation 17 underwent surgery*

4 non-protocol therapy 3 before progressive disease 1 with no progressive disease† 1 progression-free survival follow-up ongoing (no progressive disease and no non-protocol therapy)

Figure 1: Trial profile *All decisions made before completion of six cycles of induction. †Patient deceased.

Intention-totreat population (n=107)

Patients who completed induction therapy and received therapy per investigator’s choice (n=47) Continued nab-paclitaxel plus gemcitabine (n=12)

Chemoradiation (n=18)

Surgery (n=17)

65·0 (60·0–72·0)

64·5 (58·0–69·0)

68·0 (58·0–71·0)

Age (years) Median

65·0 (60·0–72·0)

<65

44 (41%)

5 (42%)

9 (50%)

8 (47%)

65–75

50 (47%)

6 (50%)

9 (50%)

9 (53%)

>75

13 (12%)

1 (8%)

0

0

Sex Female

59 (55%)

6 (50%)

8 (44%)

10 (59%)

Male

48 (45%)

6 (50%)

10 (56%)

7 (41%) 13 (77%)

ECOG performance status 0

50 (47%)

6 (50%)

10 (56%)

1

57 (53%)

6 (50%)

8 (44%)

Median albumin concentration (g/L)

39·0 (35·7–41·5)

39·5 (36·0–42·0)

40·9 (39·0–44·0)

4 (24%) 39·0 (34·0–42·0)

CA19-9 concentration (U/mL) N Median

101 243·3 (38·4–989·9)

Sum of longest diameters of pancreatic tumour (mm)

44·0 (31·0–53·0)

12

15

17

66·8 (39·7–192·1)

568·6 (49·8–1060·8)

55·7 (10·0–250·0)

46·4 (37·0–73·0)

41·0 (34·0–50·0)

41·0 (30·0–44·0)

Neutrophil-to-lymphocyte ratio ≤5

91/105 (87%)

8 (67%)

17 (94%)

15 (88%)

>5

14/105 (13%)

4 (33%)

1 (6%)

2 (12%)

Data are median (IQR) or n (%), unless otherwise specified. ECOG=Eastern Cooperative Oncology Group. CA19-9=serum carbohydrate antigen 19-9.

Table 1: Baseline characteristics of the study population

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visit before treatment and at 28 days after discon­tinuation of chemoradiation or 28 days after surgery. Adverse events were coded using Medical Dictionary for Regulatory Activities version 20.0 and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Laboratory assessments included clinical chemistry panels (at screening, day 1 of each treatment cycle, and at the 28-day follow-up visit; weekly during treatment and at follow-up for patients who received chemo­ radiation; 28 days post-surgery for patients who underwent surgery), complete blood counts (at screen­ing, days 1, 8, and 15 of each treatment cycle, and at the 28-day follow-up visit; weekly during treatment and at follow-up for patients who received chemoradiation; 28 days postsurgery for patients who underwent surgery), and serum carbohydrate antigen 19–9 (CA19–9; concen­ trations collected at the time of every CT or MRI scan).

Outcomes The primary efficacy endpoint was time to treatment failure, defined as the time after the first dose of study therapy until treatment failure. Treatment failure was defined as discontinuation of study therapy because of disease progression (assessed by the investigator), death by any cause, or the start of a non-protocol-defined anticancer therapy. Patients who did not progress, die, or start a new non-protocol-defined anticancer therapy were censored on the last date of tumour assessment. Secondary efficacy endpoints were disease control rate after six cycles of nab-paclitaxel plus gemcitabine based on best response during induction (ie, a complete response, partial response, or stable disease, with stable disease required for ≥16 or ≥24 weeks, as well as a landmark analysis at month 6 excluding tumour assess­ments after

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A Patients not experiencing treatment failure (%)

100

Role of the funding source The protocol was designed by the first author (PAP) in collaboration with Celgene. Celgene monitored the study and provided nab-paclitaxel to all study sites. Data were collected by the study investigators and analysed by a

60 40 20 0

6

9

12

15

18

21

24

27

30

70 (2)

52 (2)

29 (2)

21 (2)

14 (4)

9 (6)

5 (7)

2 (10)

0 (12)

3

Number at risk 107 (0) 95 (2) (number censored)

B 100

Statistical analysis

Median 10·9 months (90% CI 9·3–11·6)

80 60 40 20 0

0

6

9

12

15

85 (2)

68 (2)

44 (2)

33 (2)

3

Number at risk 107 (0) 97 (2) (number censored)

18

21

24

27

24 (4) 15 (10) 10 (12) 4 (17)

30 0 (21)

C 100

Overall survival (%)

The primary (time to treatment failure) and secondary (progression-free survival and overall survival) efficacy endpoints were summarised using the standard KaplanMeier method, with medians and two-sided 90% CIs using the method of Brookmeyer and Crowley.17 No formal statistical testing was done for time to treatment failure. The null hypothesis for the primary endpoint was a median of up to 5·1 months, and the alternative hypo­ thesis was a median of more than 5·1 months (5·1 months was the median time to treatment failure observed with nab-paclitaxel plus gemcitabine in the phase 3 MPACT trial).12 A total sample size of 100 patients allowed 80% power to detect a 30% increase in the median time to treatment failure from 5·1 to 6·6 months. The sample size was calculated assuming a one-sided α of 0·05, that patients would be enrolling for 24 months, and that each patient would be followed for a minimum of 1 year; 110 patients were to be enrolled (assuming a 10% dropout rate). Efficacy analyses were done in the intention-to-treat and per-protocol populations. The intention-to-treat pop­ ulation included all patients enrolled in the study, and the per-protocol population included all patients enrolled in the study who received at least one dose of nabpaclitaxel and gemcitabine, fulfilled the study enrolment criteria, and did not have any relevant major protocol deviations. The treated population, which included all patients who received at least one dose of nab-paclitaxel or gemcitabine, was used for all safety analyses. All statistical analyses were done with SAS (version 9.2 or higher). This trial is registered with ClinicalTrials.gov, NCT02301143, and EudraCT, 2014-001408-23.

Median 9·0 months (90% CI 7·3–10·1)

80

0

Progression-free survival (%)

non-protocol-defined anticancer therapy or surgery), over­ all response rate (ie, a complete or partial response) during induction, progression-free survival, overall survival, and differences in quality-of-life out­ comes from baseline during and after treatment with nab-paclitaxel plus gemcitabine. Quality-of-life out­ comes were assessed using the European Organisation for Research and Treat­ ment of Cancer quality-of-life questionnaires QLQ-C30 and QLQ-PAN26. Quality-of-life data were reported as the mean change in global health status/quality of life scale during the induction chemo­therapy phase. Post-hoc analyses examined the rate and quality of surgical resection (R0 or R1) and changes from baseline in serum CA19-9 concentrations. Safety endpoints were the incidences of treatment-emergent adverse events, serious adverse events, laboratory abnormalities, and other safety parameters.

Median 18·8 months (90% CI 15·0–24·0)

80 60 40 20 0

0

3

6

9

12

15

18

21

24

27

30

33

Time (months) Number at risk 107 (0) 101 (2) 96 (2) 86 (3) 76 (3) 59 (4) 53 (4) 37 (15) 26 (23) 14 (29) 1 (39) 0 (40) (number censored)

Figure 2: Time to treatment failure (A), progression-free survival (B), and overall survival (C) in the intention-to-treat population

biostatistician (JSL), who is employed by Celgene. Data were interpreted all authors and by Celgene. The first draft of the manuscript was written by PAP in collab­ oration with the study investigators, clinical researchers (TJO and TN), and a biostatistician (JSL) employed by Celgene. PAP made the decision to submit the manu­ script for publication, which was agreed on by all authors. All authors had access to raw data. PAP had full access to all the data in the study and had final responsibility to submit for publication.

Results Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study

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100 0

Maximum change from baseline (%)

80 60 40 20 0 –20 –40 –60 –80 –100

0

5

10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 Patients (n=101)

Figure 3: Best percentage change from baseline in the sum of longest target lesion diameters during the nab-paclitaxel plus gemcitabine induction phase Lesion diameters were assessed by the study investigators. During induction, 45 (44·6%) of 101 evaluable patients achieved a reduction in the sum of longest diameters of at least 30% from baseline (red dotted line).

Intention-to-treat population (n=107) Best response during induction phase Complete response

0

Partial response

36 (34%)

All stable disease

60 (56%)

Stable disease ≥16 weeks

47 (44%)

Stable disease ≥24 weeks

35 (33%)

Progressive disease

5 (5%)

Not evaluable

1 (1%)

No post-baseline assessment

5 (5%)

Best response at landmark analysis Complete response

0

Partial response

29 (27%)

Stable disease

36 (34%)

Response was measured by the investigator according to the Response Evaluation Criteria In Solid Tumours version 1.1 and excluded tumour assessments after non-protocol-defined anticancer therapy or surgery.

Table 2: Best response during induction phase and at landmark analysis

treatment; one patient enrolled but did not receive treatment for reasons unrelated to the study (figure 1). Selected baseline characteristics of the intention-to-treat population and those who received therapy per investigator’s choice are reported in table 1. The median age was 65 years (IQR 60·0–72·0), 59 (55%) of 107 enrolled patients were female, and the proportions of patients with ECOG performance status 0 and 1 were approximately equal. Numerical differences in patient populations receiving therapy per investigator’s choice were apparent for ECOG performance status, baseline CA19-9 concentration, and neutrophil-to-lymphocyte ratio. The median follow-up time for overall survival was 25·4 months (95% CI 22·4–27·2). 6

62 (58%) of 107 patients completed the nab-paclitaxel plus gemcitabine induction phase, while 44 (41%) patients discontinued treatment (figure 1). The main reasons for discontinuing the induction phase were adverse events (22 [21%] patients; appendix p 4) and progressive disease (eight [8%]). Among those who discontinued the induction phase, the most frequent follow-up treatment was chemotherapy (most commonly gemcitabine; appendix p 5). 17 (16%) patients discon­ tinued the induction phase before entering cycle three, and the primary reason for discontinuation was adverse events (nine [53%] of 17 patients). After the induction phase, 49 (46%) of 107 patients were designated to enter the continued treatment phase per investigator’s choice, and 47 (44%) received treatment (figure 1). 15 (14%) patients who completed the induction phase did not receive continued therapy: ten (9%) had progressive disease (five of whom received a new treatment after progressive disease), four (4%) received a new non-protocol-defined treatment (either before progressive disease, or no progressive disease was reported), and one (1%) had progression-free survival during ongoing follow-up (figure 1). Among the 47 patients who received continued treatment per investigator’s choice, 12 (26%) continued nab-paclitaxel plus gemcitabine and 18 (38%) received chemoradiation. Of the 12 patients who continued treatment with nabpaclitaxel plus gemcitabine, nine subsequently discon­ tinued treatment. All patients who received chemoradiation completed treatment. 20 patients were considered for surgery (all decisions were made before completion of the six cycles of induction). 17 (36%) of 47 patients who received continued treatment entered this phase for surgery (16 completed surgery [seven had R0 and nine had R1]; appendix p 6). Two patients were considered for surgery after completing induction treatment, but they did not undergo surgery because one had disease progression and one was unsuitable based on an assessment by the gastrointestinal surgeon. These two patients did not enter the continued treatment phase. Two other patients were unresectable at the point of surgery; one entered the nabpaclitaxel plus gemcitabine group per investigator’s choice and was counted only in this group in the continued treatment phase. Additionally, 11 patients had surgery with the aim of resection in the survival follow-up period (five of whom received chemoradiation before surgery). Therefore, overall during the study, 27 patients had surgery with the aim of resection. In the intention-to-treat population, median time to treatment failure was 9·0 months (90% CI 7·3–10·1; figure 2A). Median progression-free survival, according to investigator assessment, was 10·9 months (90% CI 9·3–11·6; figure 2B). Median overall survival was 18·8 months (90% CI 15·0–24·0; figure 2C). 74 (73%) of 101 evaluable patients with a baseline and at least one post-baseline assessment had a reduction in tumour burden during the treatment period (figure 3).

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The median best percentage change from baseline in the sum of longest target lesion diameters was a reduction of 20·0% (IQR –40·9 to 0·0). Best responses to treatment during the induction phase are shown in table 2. 36 (34%) patients had a best response of partial response during induction; the overall response rate during induction was 33·6% (90% CI 26·6–41·5). When using a definition of stable disease of at least 16 weeks, 83 patients achieved disease control during induction and the disease control rate was 77·6% (90% CI 70·3–83·5; table 2). Setting the requirement for stable disease to at least 24 weeks resulted in an inductionphase disease control rate of 66·4% (90% CI 58·5–73·4). In a landmark analysis at month 6 (after completion of six cycles of induction therapy), the disease control rate (excluding tumour assessments after non-protocoldefined anticancer therapy or surgery) was 60·7% (90% CI 52·8–68·2; table 2). Serum CA19-9 concentrations decreased in most patients during induction (appendix pp 10–11). Specifically, among the 92 patients with a baseline and at least one post-baseline assessment, serum CA19-9 concentrations decreased by at least 50% in 68 (74%) patients and by at least 70% in 51 (55%) patients. In the treated population of 106 patients, median treatment duration was 21 weeks (IQR 13–24). The median number of cycles received was five (IQR 3–6; appendix p 7), which was inclusive of patients who had surgery before completing six cycles. The median percentage of planned dose received (ie, relative dose intensity) was 84·2% (IQR 72·2–100·0) for nab-paclitaxel 125 mg/m² and 82·2% (IQR 71·4–100·0) for gemcitabine 1000 mg/m². The percentages of patients who had at least one nab-paclitaxel dose reduction (67 [63%] patients) or gemcitabine dose reduction (66 [62%]) were similar; all dose reductions were due to adverse events (two patients had additional reasons; appendix p 7). During induction, 105 (99%) of 106 patients in the treated population had at least one treatment-emergent adverse event and 85 (80%) had a treatment-emergent adverse event that was grade 3 or higher (table 3; grade 1–2 treatment-emergent adverse events are summarised in appendix p 8). The most frequent (≥10% incidence) treatment-emergent adverse events that were grade 3 or higher were neutropenia (35 [33%] patients), anaemia (12 [11%]), and fatigue (11 [10%]). Four (4%) patients had febrile neutropenia that was grade 3 or higher and five (5%) had peripheral neuropathy that was grade 3 or higher. 38 (36%) patients had at least one serious adverse event (33 [31%] grade ≥3). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths due to treatment-related adverse events occurred during induction. Of the 99 patients evaluable for quality of life at baseline, 42 (43%) were evaluable at cycle six. On day 1 of

Patients with ≥1 treatment-emergent adverse event

Grade 3

Grade 4

Grade 5

63 (59%)

20 (19%)

2 (2%)

General disorders and administration site conditions Fatigue

11 (10%)

0

0

Peripheral oedema

1 (1%)

0

0

Pyrexia

1 (1%)

0

0

Asthenia

9 (8%)

0

0

Chills

1 (1%)

0

0

Influenza-like illness

1 (1%)

0

0

Malaise

1 (1%)

0

0

General physical health deterioration

1 (1%)

0

0

Death

0

0

1 (1%)

Generalised oedema

1 (1%)

0

0

Diarrhoea

4 (4%)

0

0

Nausea

1 (1%)

0

0

Vomiting

3 (3%)

0

0

Abdominal pain

2 (2%)

0

0

Stomatitis

1 (1%)

0

0

Abdominal distension

1 (1%)

0

0

Gastric obstruction

1 (1%)

0

0

Pancreatitis

1 (1%)

0

0

Peripheral sensory neuropathy

4 (4%)

0

0

Peripheral neuropathy

0

1 (1%)

0

Presyncope

1 (1%)

0

0

Syncope

1 (1%)

0

0

Decreased appetite

2 (2%)

0

0

Hypokalaemia

5 (5%)

0

0

Hyperglycaemia

6 (6%)

0

0

Dehydration

2 (2%)

0

0

Hyperkalaemia

1 (1%)

0

0

Hypoglycaemia

1 (1%)

0

0

Hypovolaemia

1 (1%)

0

0

Lactic acidosis

1 (1%)

0

0

Metabolic acidosis

1 (1%)

0

0

Alopecia

2 (2%)

0

0

Drug eruption

1 (1%)

0

0

Gastrointestinal disorders

Nervous system disorders

Metabolism and nutrition disorders

Skin and subcutaneous tissue disorders

Blood and lymphatic system disorders Anaemia

12 (11%)

Neutropenia

24 (23%)

0 11 (10%)

0 0

Thrombocytopenia

4 (4%)

0

0

Leukopenia

5 (5%)

0

0

Lymphopenia

4 (4%)

0

0

Febrile neutropenia

3 (3%)

1 (1%)

0

Leukocytosis

2 (2%)

0

0

4 (4%)

0

0

3 (3%)

0

0

0

Investigations Platelet count decreased Neutrophil count decreased Alanine aminotransferase increased

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10 (9%) 6 (6%)

(Table 3 continues on next page)

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Grade 3

Grade 4

Grade 5

(Continued from previous page) Aspartate aminotransferase increased

2 (2%)

0

0

Blood alkaline phosphatase increased

4 (4%)

0

0

White blood cell count decreased

3 (3%)

0

0

Gamma-glutamyltransferase increased

2 (2%)

1 (1%)

0

Blood bilirubin increased

1 (1%)

1 (1%)

0

Blood creatinine increased

0

1 (1%)

0

Transaminases increased

1 (1%)

0

0

Pulmonary embolism

2 (2%)

1 (1%)

0

Pneumonitis

1 (1%)

0

0

Respiratory, thoracic, and mediastinal disorders

Infections and infestations Pneumonia

5 (5%)

1 (1%)

0

Cellulitis

1 (1%)

0

0

Liver abscess

1 (1%)

0

0

Lung infection

1 (1%)

0

0

Neutropenic sepsis

0

2 (2%)

0

Sepsis

0

2 (2%)

0

Clostridium difficile colitis

1 (1%)

0

0

Diverticulitis

1 (1%)

0

0

Escherichia coli sepsis

1 (1%)

0

0

Escherichia coli gastroenteritis

1 (1%)

0

0

Pancreas infection

1 (1%)

0

0

Parainfluenza virus infection

1 (1%)

0

0

Back pain

2 (2%)

0

0

Bone pain

1 (1%)

0

0

Hypotension

2 (2%)

0

0

Hypertension

2 (2%)

0

0

Superficial thrombophlebitis

1 (1%)

0

0

Cholecystitis

1 (1%)

0

0

Hepatocellular injury

1 (1%)

0

0

Bile duct obstruction

1 (1%)

0

0

Acute cholecystitis

0

1 (1%)

0

Hepatic cirrhosis

1 (1%)

0

0

Cholestatic jaundice

1 (1%)

0

0

Liver disorder

1 (1%)

0

0

Atrial fibrillation

2 (2%)

0

0

Acute coronary syndrome

1 (1%)

0

0

Cardiac arrest

0

0

1 (1%)

1 (1%)

0

0

Foot fracture

1 (1%)

0

0

Peripancreatic fluid collection

1 (1%)

0

0

Spinal compression fracture

1 (1%)

0

0

Musculoskeletal and connective tissue disorders

Vascular disorders

Hepatobiliary disorders

Cardiac disorders

Renal and urinary disorders Obstructive uropathy Injury, poisoning, and procedural complications

Table 3: Treatment-emergent adverse events during the induction phase in the treated population (n=106)

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each cycle, patients were asked to rate their overall health and quality of life during the past week. Quality of life remained relatively unchanged during the first two cycles, and a slight reduction was observed after cycle three (appendix p 12). However, by the end of cycle four, patient quality of life had improved; this was maintained through the beginning of cycle six. Overall, patient global health status was maintained through day 1 of cycle six.

Discussion This phase 2 LAPACT trial was designed to establish the role of induction therapy with nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer. 62 (58%) of 107 enrolled patients completed the induction phase. Following induction, 47 (44%) patients underwent further treatment as per investigator’s choice and continued nab-paclitaxel plus gemcitabine (12 [11%] patients), received chemoradiation (18 [17%]), or under­ went surgery (17 [16%]). 11 patients had surgery in the survival follow-up period. The median time to treatment failure (9·0 months) was longer than what was observed with nab-paclitaxel plus gemcitabine in the MPACT trial (5·1 months).12 In the induction phase, the overall response rate was 33·6% (90% CI 26·6–41·5) and the disease control rate (based on stable disease ≥16 weeks) was 77·6% (90% CI 70·3–83·5). The combination of nab-paclitaxel and gemcitabine was generally well tolerated, and safety data gave a safety profile that was consistent with that from the metastatic setting.12 Quality of life was stable or improved during induction and investigator’s choice of treatment. Most patients with locally advanced pancreatic cancer receive systemic chemotherapy to delay tumour progression and palliate disease symptoms.1,3 The MPACT trial12 reported positive findings with nabpaclitaxel plus gemcitabine and the PRODIGE trial18 reported positive findings with FOLFIRINOX in the metastatic setting; however, neither regimen has been prospectively analysed specifically in patients with locally advanced pancreatic cancer. To our knowledge, the LAPACT trial is the first to prospectively investigate the efficacy and safety of nab-paclitaxel plus gemcitabine induction for the treatment of locally advanced pancreatic cancer. In the present study, the primary endpoint of time to treatment failure with nab-paclitaxel plus gemcitabine induction followed by treatment per investigator’s choice was a median of 9·0 months (90% CI 7·3–10·1), which exceeded the protocol-specified target of 6·6 months. Tumour control and response to therapy are important aspects of induction treatment and could affect subsequent treatments. In the phase 2 SCALOP trial19 of patients with locally advanced pancreatic cancer who received induction gemcitabine and capecitabine followed by chemoradiotherapy, the disease control rate (responding or stable disease) was 64·9% after 12 weeks of induction chemotherapy with gemcitabine and

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capecitabine. In the LAP07 trial,6 269 (60·9%) of 442 patients had controlled disease (complete response plus partial response plus stable disease) after 16 weeks.6 In the current analysis, the disease control rate (based on stable disease ≥16 weeks) during induction was 77·6% (90% CI 70·3–83·5). In the SCALOP trial6 median overall survival was 12·7 months (95% CI 11·0–14·5; all registered patients), and in the LAP07 trial median overall survival was 12·8 months (95% CI 11·8–14·1; overall),6,19 whereas in the current study it was 18·8 months (90% CI 15·0–24·0). A systematic review of studies investigating FOLFIRINOX in patients with locally advanced pancreatic cancer revealed a median overall survival ranging from 10·0 to 32·7 months (with a patient-level median overall survival of 24·2 months);11 however, the contribution of retrospective data is worth mentioning. Furthermore, median overall survival in the three studies that were comprised exclusively of patients with locally advanced pancreatic cancer11 ranged from 21 to 26 months. The design of the studies in the systematic review11 underscores the scarcity of prospective clinical trial data in the local advanced setting—the 13 studies that met eligibility criteria included one prospective non-randomised phase 2 study (with patients with metastatic disease), one prospective cohort study, and 11 retrospective studies. Collectively, these findings support nab-paclitaxel plus gemcitabine as an active regimen for the treatment of locally advanced pancreatic cancer. A recent retrospective study of patients treated with nab-paclitaxel plus gemcitabine or other gemcitabinebased combinations for borderline or locally advanced pancreatic cancer showed that 137 (77%) of 177 patients had at least a 50% reduction in CA19-9 concentrations, and CA19-9 response was found to be an independent prognostic factor.20 In the LAPACT study, serum CA19-9 concentrations decreased in most patients during induction (by ≥50% in 68 [74%] of 92 patients and by ≥70% in 51 [55%] patients). The tolerability profile observed in our study supports the feasibility of nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer. Nabpaclitaxel plus gemcitabine was well tolerated, as evidenced by the induction-phase completion rate of 58% and a median of five treatment cycles per patient. The most common adverse events that were grade 3 or higher during induction were neutropenia and anaemia, a finding that is generally consistent with results of the phase 3 MPACT trial.12 Peripheral neuropathy that was grade 3 or higher was reported in less than 5% of patients, a rate lower than that reported in the MPACT trial.12 Quality of life was generally maintained during the induction phase in patients with locally advanced pancreatic cancer, despite a greater incidence of some (grade ≥3) adverse events with nabpaclitaxel plus gemcitabine versus gemcitabine alone in the MPACT trial.12

Additionally, the induction-phase disease control rate was promising and suggestive of antitumour activity with the regimen. Importantly, although surgical resection is generally rare for patients with unresectable locally advanced pancreatic cancer, and despite all patients in this study being considered unresectable at baseline, 16 (15%) of 107 patients underwent either an R0 or R1 resection following the induction phase, suggesting the potential for conversion of unresectable to resectable tumours in some patients with nab-paclitaxel plus gemcitabine. The LAPACT trial—a global study and one of the largest locally advanced pancreatic cancer trials to date— was, to the best of our knowledge, the first to prospectively evaluate the efficacy and safety of a newer, active systemic chemotherapy regimen specifically in a patient popu­ lation with locally advanced, unresectable disease without evidence of distant metastasis. Thus, these results could strengthen the recommendation of nab-paclitaxel plus gemcitabine for the treatment of locally advanced pancreatic cancer. The use of nab-paclitaxel plus gemcitabine or FOLFIRINOX remains an active question for the treatment of locally advanced disease, with several phase 2 and 3 studies investigating nab-paclitaxel plus gemcitabine or FOLFIRINOX (or derivatives) either alone or as a chemotherapy backbone in combination with therapies such as targeted agents and radiation. There are limitations to the present study and some challenges to treating locally advanced pancreatic cancer in general. The design of this study—single-arm, not randomised—poses challenges in contextualising the outcomes, particularly regarding the survival and conversion to resectability data. The purpose of the study was to establish the role of induction therapy with nabpaclitaxel and gemcitabine in patients with locally advanced pancreatic cancer. The non-randomised design was meant to reproduce the clinical practice of induction chemotherapy followed by the options of chemo­ radiation or, in some cases, surgery. Although the patient population was purely those with locally advanced pancreatic cancer, tumour features used for designating disease as locally advanced were not specifically collected during the trial; such data would have been informative for treatment decisions in clinical practice. Furthermore, no central review of the imaging was done, and eligi­ bility determination was dependent on investigators’ adherence to the protocol criteria for unresectable disease. No central review of images might complicate the interpretation of our findings, particularly among those who underwent surgery. Additionally, although the investigator’s choice of therapy following induction is more reflective of the real-world clinical setting, no criteria were established to guide the choice, and resection status was not defined in the protocol, which might hinder replication of the results in other settings. The investigator’s choice of therapy could have led to some variability in overall survival outcomes and in the absence of reporting survival for each investigator’s

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choice, the extent of this variability is unknown. Lastly, a general challenge in decision-making for locally advanced pancreatic cancer is the limited accuracy of imaging scans, which could be caused by the dense stroma surrounding pancreatic tumours.21,22 In conclusion, the findings from the LAPACT trial suggest the potential for nab-paclitaxel plus gemcitabine to become a chemotherapy regimen option for induction therapy for locally advanced pancreatic cancer, as well as to serve as a backbone regimen onto which novel, targeted agents could be added. This trial could also provide a better understanding of the natural history of locally advanced pancreatic cancer, in an era in which more efficient systemic therapies and better definitions of locally advanced disease are being investigated. Contributors PAP, TJO, and TN designed the research; PAP, JL, FP, AS, RP-C, JLMM, EJK, SD, AZ, CB, ET, FR, JS, VB, DL-T, JA, MWS, and PH collected data; JSL analysed data; and PAP, JL, FP, AS, RP-C, JLMM, EJK, SD, AZ, CB, ET, FR, JS, VB, DL-T, JA, MWS, JSL, TJO, TN, and PH interpreted data. All authors drafted the manuscript (including relevant intellectual content); gave final approval to be published; agreed to be accountable for all aspects of the work; and ensured that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. Declaration of interests PAP has received research funding from Celgene, Bayer, and Incyte; fees from Celgene for serving on advisory boards; and fees from Bayer, Roche, Sanofi, and Amgen for participation in speakers’ bureaus. JL has received fees from Celgene and AstraZeneca for serving on advisory boards and fees from Navigant Consulting. AS has received speaker fees from Celgene. EJK has received research funding from Celgene, Bristol-Myers Squibb, Astellas, Samumed, Boston Biomedical, Halozyme, EpicentRx, Merck, and Oncomed; fees from Armo for serving on advisory boards; fees from Vicus for consulting; and speaker fees from Guardant Health. AZ has received fees from Amgen and Bayer for participation in speakers’ bureaus. CB has received fees from Roche, Bayer, and Servier for serving on advisory boards. FR has received fees from Celgene for consulting; research funding from Celgene, Amgen, Merck Serono, Roche, Sanofi, Bayer, Lilly, and Merck Sharp & Dohme; and fees from Celgene, Amgen, Merck Serono, Roche, Sanofi, Bayer, Lilly, Servier, and Baxalta for serving on advisory boards. JS has received fees and nonfinancial support from Merck Serono and Ipsen, and honoraria or consulting fees from Celgene, Roche, Lilly, Servier, Shire, Bayer, Merck Sharp & Dohme, Amgen, Bristol-Myers Squibb, and Sanofi. MWS has received research funding from Celgene, Taiho, Pharmacyclics, and NanoCarrier, and fees from Celgene for participation in speakers’ bureaus. JSL and TJO report employment and stock ownership with Celgene. TN reports employment with Celgene. PH has received research funding from AstraZeneca, Celgene, Erytech, and Halozyme, and fees from Amgen, Celgene, Shire, Erytech, and Lilly for serving on advisory boards. All other authors declare no competing interests. For data sharing requests see www.celgeneclinicaldatasharing. com

Data sharing Data requests may be submitted to Celgene and must include a description of the research proposal. Acknowledgments This study was funded by Celgene (Summit, NJ, USA). Writing assistance was provided by Aaron Runkle of MediTech Media, and funded by Celgene. Biostatistical support was provided by Ruiyun Jiang of Celgene. The authors are fully responsible for all content and editorial decisions for this manuscript. References 1 Balaban EP, Mangu PB, Khorana AA, et al. Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016; 34: 2654–68.

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National Comprehensive Cancer Network. NCCN guidelines: pancreatic adenocarcinoma (version 3). 2019. https://www.nccn. org/professionals/physician_gls/pdf/pancreatic.pdf (accessed Sept 9, 2019). Lutz MP, Zalcberg JR, Ducreux M, et al. 3rd St. Gallen EORTC Gastrointestinal Cancer Conference: consensus recommendations on controversial issues in the primary treatment of pancreatic cancer. Eur J Cancer 2017; 79: 41–49. Loehrer PJ Sr, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011; 29: 4105–12. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000–01 FFCD/SFRO study. Ann Oncol 2008; 19: 1592–99. Hammel P, Huguet F, van Laethem JL, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 2016; 315: 1844–53. Stein SM, James ES, Deng Y, et al. Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer. Br J Cancer 2016; 114: 737–43. Hosein PJ, Macintyre J, Kawamura C, et al. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer 2012; 12: 199. Marthey L, Sa-Cunha A, Blanc JF, et al. FOLFIRINOX for locally advanced pancreatic adenocarcinoma: results of an AGEO multicenter prospective observational cohort. Ann Surg Oncol 2015; 22: 295–301. Sadot E, Doussot A, O’Reilly EM, et al. FOLFIRINOX induction therapy for stage 3 pancreatic adenocarcinoma. Ann Surg Oncol 2015; 22: 3512–21. Suker M, Beumer BR, Sadot E, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 2016; 17: 801–10. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691–703. Goldstein D, El-Maraghi RH, Hammel P, et al. Nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst 2015; 107: pii dju413. Kunzmann V, Ramanathan RK, Goldstein D, et al. Tumor reduction in primary and metastatic pancreatic cancer lesions with nab-paclitaxel and gemcitabine: an exploratory analysis from a phase 3 study. Pancreas 2017; 46: 203–08. Vauthey JN, Dixon E. AHPBA/SSO/SSAT Consensus Conference on Resectable and Borderline Resectable Pancreatic Cancer: rationale and overview of the conference. Ann Surg Oncol 2009; 16: 1725–26. Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011; 29: 4548–54. Brookmeyer RC, Crowley JJ. A k-sample median test for censored data. J Am Stat Assoc 1982; 77: 433–40. Conroy T, Desseigne F, Ychou M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817–25. Mukherjee S, Hurt CN, Bridgewater J, et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol 2013; 14: 317–26. Reni M, Zanon S, Balzano G, et al. Selecting patients for resection after primary chemotherapy for non-metastatic pancreatic adenocarcinoma. Ann Oncol 2017; 28: 2786–92. Cassinotto C, Cortade J, Belleannée G, et al. An evaluation of the accuracy of CT when determining resectability of pancreatic head adenocarcinoma after neoadjuvant treatment. Eur J Radiol 2013; 82: 589–93. Evans DB, George B, Tsai S. Non-metastatic pancreatic cancer: resectable, borderline resectable, and locally advanced-definitions of increasing importance for the optimal delivery of multimodality therapy. Ann Surg Oncol 2015; 22: 3409–13.

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