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تعداد آیتم قابل مشاهده باقیمانده : -13 مورد

Second- and later-line systemic therapy for metastatic exocrine pancreatic cancer

Second- and later-line systemic therapy for metastatic exocrine pancreatic cancer
Authors:
Richard M Goldberg, MD
Harshabad Singh, MBBS
Dana B Cardin, MD, MSCI
Section Editors:
Kenneth K Tanabe, MD
Rachna T Shroff, MD, MS, FASCO
Deputy Editor:
Sonali M Shah, MD
Literature review current through: Apr 2025. | This topic last updated: Feb 07, 2025.

INTRODUCTION — 

For patients with locally advanced unresectable or metastatic exocrine pancreatic cancer, systemic therapy can reduce tumor burden, improve disease-related symptoms, and prolong overall survival (OS). The goals of systemic therapy are palliative and not curative.

This topic will review second- and later-line systemic therapy for patients with metastatic exocrine pancreatic cancer who progress on initial systemic therapy. Initial systemic therapy and supportive care for metastatic exocrine pancreatic cancer are discussed separately.

●(See "Initial systemic therapy for metastatic exocrine pancreatic cancer".)

●(See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer".)

●(See "Endoscopic ultrasound-guided celiac plexus interventions for pain related to pancreatic disease".)

PRETREATMENT EVALUATION — 

For patients with metastatic pancreatic exocrine cancer, the initial pretreatment evaluation includes imaging studies, laboratory testing, including assessing for both germline and somatic (tumor) molecular alterations that influence the selection of therapy, and supportive care. Further details are discussed separately. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'Pretreatment evaluation'.)

The decision to pursue second-line systemic therapy is individualized and often based on the patient's performance status (PS), comorbidities, and response to prior therapies as well as their goals of care, preferences, and support systems. Patients who are ineligible for (or decide to forego) further systemic therapy may be offered best supportive care. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer".)

For patients who choose to pursue second-line therapy, clinical factors influencing the choice of therapy include the regimen used for first-line therapy, Eastern Cooperative Oncology group (ECOG) PS (table 1), patient comorbidities, and the presence or absence of actionable molecular alterations. Clinical trial enrollment is encouraged, where available.

ACTIONABLE MOLECULAR ALTERATIONS

KRAS G12C-mutated tumors — The KRAS gene is one of the most frequently mutated genes in pancreatic cancer. The KRAS G12C substitution comprises 1 to 2 percent of all RAS mutations [1,2]. (See "Molecular pathogenesis of exocrine pancreatic cancer", section on 'KRAS'.)

For patients with metastatic pancreatic cancer whose tumors test positive for a KRAS G12C mutation, we offer initial treatment with chemotherapy using the same approach as those without an actionable molecular alteration. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'KRAS G12C positive-tumors'.)

For those who progress on initial chemotherapy, we suggest second-line therapy with the KRAS G12C inhibitor adagrasib rather than further chemotherapy. We prefer adagrasib because, in our clinical experience, it appears to be a more potent inhibitor than sotorasib. However, sotorasib is also an acceptable option as these agents have not been directly compared in clinical trials.

Adagrasib — Adagrasib, a specific inhibitor of KRAS G12C, is an effective treatment option for patients with metastatic KRAS G12C-positive pancreatic adenocarcinoma who progress on prior systemic therapy.

In a phase II basket trial (KRYSTAL-1), 64 patients with advanced, heavily pretreated tumors of various histologies with KRAS G12C mutations were treated with adagrasib. At a median follow-up of 17 months, among the 21 patients with pancreatic adenocarcinoma, objective responses were seen in seven patients (objective response rate [ORR] of 33 percent) [3]. Median progression-free survival (PFS) and overall survival (OS) were five and eight months, respectively.

Sotorasib — Sotorasib, a specific inhibitor of KRAS G12C, is effective in patients with metastatic KRAS G12C-mutated pancreatic adenocarcinoma who progress on prior systemic therapy.

In a phase I/II trial (CodeBreak 100), sotorasib was evaluated in an expanded cohort of 38 patients with metastatic KRAS G12C mutation-positive pancreatic ductal adenocarcinoma who had previously received systemic therapy [4,5]. At a median follow-up of 17 months, objective responses were seen in eight patients (21 percent), all of which were partial responses; the disease control rate was 84 percent [5]. Median treatment duration was approximately 18 weeks. Median PFS and OS were four and seven months, respectively. The grade ≥3 toxicity rate was 16 percent, including diarrhea and fatigue (5 percent each). Other grade ≥3 toxicities included abdominal pain, increases in alanine transaminase (ALT) or aspartate transaminase (AST), pleural effusion, and pulmonary embolism. (See "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation", section on 'Sotorasib' and "Hepatotoxicity of molecularly targeted agents for cancer therapy", section on 'Sotorasib' and "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Sotorasib'.)

Other agents — Other agents, such as divarasib [6] and glecirasib [7] have been evaluated in clinical trials that included patients with KRAS G12C mutation-positive pancreatic cancer. The use of these drugs remains investigational in this population.

BRCA1/2 or PALB2 pathogenic variants — Patients with metastatic pancreatic adenocarcinoma and a germline or somatic pathogenic variant in the core homologous repair deficiency (HRD) genes BRCA1/2 or PALB2 are initially treated with platinum-based chemotherapy, such as FOLFIRINOX or gemcitabine plus cisplatin, followed by maintenance therapy with a poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib or rucaparib. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'BRCA1/2 or PALB2 pathogenic variants'.)

For patients who progress on platinum-based chemotherapy with or without maintenance therapy with a PARP inhibitor, there are limited data for the optimal treatment approach. Clinical trial enrollment is encouraged, where available. For those who are not eligible for or decline clinical trials, we evaluate and treat for other actionable molecular alterations. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'Actionable molecular alterations'.)

If no actionable molecular alterations are identified, we treat using the same approach to second-line therapy in patients who lack an actionable molecular alteration, which depends upon the initial chemotherapy regimen received. (See 'No actionable molecular alterations' below.)

For patients who progress on platinum-based chemotherapy alone, we do not typically offer second-line therapy with a PARP inhibitor due to limited efficacy [8-13]. As an example, in a phase II trial of 19 patients with previously treated pancreatic cancer and germline or somatic pathogenic variants in BRCA1/2, rucaparib demonstrated an ORR of 16 percent. None of the patients with disease progression on prior platinum-based chemotherapy demonstrated an ORR [12].

Non-core HRD pathogenic variants — Patients with metastatic pancreatic cancer and pathogenic variants (either germline or somatic) in homologous repair deficiency (HRD) genes other than the core genes (BRCA1/2 or PALB2), such as ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 are initially treated with platinum-based therapy, such as dose-modified FOLFIRINOX (table 2), FOLFOX (table 3), and NALIRIFOX. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'Non-core HRD pathogenic variants'.)

For such patients who progress on these regimens, we evaluate and treat for other actionable molecular alterations. If no actionable alterations are identified, we treat using the same approach to second-line therapy in patients who lack an actionable molecular alteration, which depends upon the initial chemotherapy regimen received. (See 'No actionable molecular alterations' below.)

We do not offer second-line therapy with PARP inhibitors due to lack of regulatory approval and limited data in those with non-core HRD pathogenic variants [14].

MSI-H/dMMR tumors — For patients with metastatic pancreatic cancer that is mismatch repair deficient (dMMR)/microsatellite-instability high (MSI-H), we offer initial treatment with immunotherapy, such as pembrolizumab or nivolumab plus ipilimumab. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'MSI-H/dMMR tumors'.)

For those who progress on initial treatment with immunotherapy, the optimal approach to second-line therapy is not established. Clinical trial enrollment is encouraged, where available. For those who are not eligible for or decline clinical trials, we evaluate for other actionable molecular alterations. If none are identified, we offer chemotherapy with the same regimens used to treat systemic-therapy naïve patients who lack an actionable molecular alteration. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer".)

For those who progress on initial systemic therapy but did not previously receive immunotherapy, we offer second-line therapy with either pembrolizumab (table 4), dostarlimab, or nivolumab plus ipilimumab, given the durable treatment responses seen with these agents.

Pembrolizumab — Pembrolizumab (table 4) was evaluated in a phase II trial (KEYNOTE-158) of 351 patients with advanced, treatment-refractory dMMR/MSI-H solid tumors, including 22 patients with pancreatic cancer [15,16]. At a median follow-up of 38 months, objective responses were seen in four patients (18 percent), one of which was complete. The median duration of response was not reached (range 8 to 24 months or longer).

Further data on the efficacy of pembrolizumab in advanced dMMR/MSI-H tumors are discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Pembrolizumab'.)

Dostarlimab — Dostarlimab has been evaluated in clinical trials of advanced, treatment-refractory dMMR/MSI advanced solid tumors, including pancreatic cancer. Further details are discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Dostarlimab'.)

Nivolumab plus ipilimumab — Nivolumab plus ipilimumab is an option for patients with dMMR/MSI-H metastatic pancreatic cancer, good Eastern Cooperative Oncology group (ECOG) performance status (PS; 0 to 1) (table 1), and minimal comorbidities who have not previously received immunotherapy. Data are discussed separately. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'Nivolumab plus ipilimumab'.)

TRK fusion-positive cancers — For patients with metastatic pancreatic cancer whose tumors test positive for a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, we offer initial therapy with a tropomyosin receptor kinase (TRK) inhibitor. Options include larotrectinib, entrectinib, and repotrectinib. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'TRK fusion-positive tumors' and "TRK fusion-positive cancers and TRK inhibitor therapy".)

Patients who progress on initial treatment with a TRK inhibitor should undergo repeat molecular profiling to assess for resistance mutations. This information may help determine the appropriate management strategy, which may include standard systemic therapy for metastatic pancreatic cancer. Further details are discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'TRK inhibitor resistance' and "Initial systemic therapy for metastatic exocrine pancreatic cancer".)

RET fusion-positive tumors — For patients with metastatic pancreatic cancer whose tumors test positive for a rearranged during transfection (RET) gene fusion, we offer initial therapy with selpercatinib. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'RET fusion-positive tumors'.)

For those who progress on selpercatinib, the optimal approach to second-line therapy is not established. Clinical trial enrollment is encouraged, where available. For those who are not eligible for or decline clinical trials, we evaluate for other actionable molecular alterations. If none are identified, we offer chemotherapy with the same regimens used to treat systemic-therapy naïve patients who lack an actionable molecular alteration. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer".)

For those who progress on initial systemic therapy but did not previously receive selpercatinib, we offer second-line therapy with selpercatinib given the durable responses seen with this agent. In a phase I/II basket trial (LIBRETTO-001), 45 patients with a variety of RET fusion-positive treatment-refractory solid tumor histologies were treated with selpercatinib [17]. In the entire cohort, at a median follow-up of 15 months, the ORR was 44 percent, and the median duration of response was 25 months. Among the 11 patients with advanced pancreatic cancer, partial responses were seen in six patients (54 percent); the median duration of response was not reached. The most common grade ≥3 toxicities were hypertension and transaminase elevation.

Selpercatinib has accelerated approval from the US Food and Drug Administration (FDA) for the treatment of adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options [18].

BRAF V600E mutant tumors — For patients with metastatic pancreatic cancer whose tumors test positive for a BRAF V600E mutation, we offer initial treatment with chemotherapy using the same approach as those without an actionable molecular alteration. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'BRAF V600E positive-tumors'.)

For those who progress on initial systemic therapy, we suggest second-line therapy with dabrafenib plus trametinib rather than chemotherapy. This BRAF plus MEK inhibitor combination has an acceptable toxicity profile and can be administered orally for patient convenience. However, efficacy is modest in BRAF V600E mutant pancreatic cancer (stable disease as best response in one patient in the NCI-MATCH Trial) [19]. This approach is also mainly extrapolated from a phase II trial (ROAR) of BRAF V600E mutant metastatic biliary tract cancers [20]. (See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma", section on 'BRAF V600E-mutated cancers' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

Dabrafenib plus trametinib has accelerated approval from the FDA for patients with any unresectable or metastatic solid tumor with a BRAF V600E mutation who have progressed on prior therapy and have no satisfactory alternative treatment options [18].

NRG1 fusion-positive tumors — For patients with neuregulin 1 (NRG1) fusion-positive tumors, we offer initial treatment with chemotherapy using the same approach as those without an actionable molecular alteration. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'No actionable molecular alterations'.)

For those who progress on initial systemic therapy, we suggest second-line therapy with zenocutuzumab rather than chemotherapy. NRG1 gene fusions are rare oncogenic mutations that are detected in less than 1 percent of a variety of solid tumors. The resulting NRG1 fusion proteins bind to human epidermal growth factor 2 (HER2) and create heterodimerization of the HER2/HER3 proteins. The HER2/HER heterodimerization subsequently triggers downstream signaling that leads to increased tumor growth. Zenocutuzumab is a bispecific immunoglobulin G subclass 1 (IgG1) antibody that targets HER2/HER3 dimerization and NRG1 protein binding.

In an open-label phase II basket trial (eNRGy) that included 36 patients with advanced or metastatic NRG1 fusion-positive pancreatic adenocarcinoma who progressed on prior systemic therapy (either FOLFIRINOX, gemcitabine plus taxane-based therapy, or both), responses were seen in 15 patients (ORR of 42 percent) [21]. The median duration of response was seven months (ranging from 2 to 21 months). The grade ≥3 toxicity rate was 7 percent including anemia, nausea, diarrhea, vomiting, abdominal pain, and elevated AST or ALT (1 percent or less for each). Other toxicities of concern with zenocutuzumab include infusion-related reactions, interstitial lung disease, and left ventricular dysfunction. (See "Infusion reactions to systemic chemotherapy" and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)

Based on these data, the FDA granted accelerated approval for zenocutuzumab in adult patients with advanced unresectable or metastatic pancreatic adenocarcinoma harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy [18].

HER2-positive tumors — For patients with human epidermal growth factor 2 (HER2)-positive metastatic pancreatic cancer, we offer initial- and second-line systemic therapy using the same approach as those without an actionable molecular alteration. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'No actionable molecular alterations' and 'No actionable molecular alterations' below.)

For patients with HER2-positive (immunohistochemistry [IHC] 3+) tumors who progress on multiple lines of systemic therapy and have no other satisfactory treatments available, fam-trastuzumab deruxtecan is an option for later-line therapy. However, patients should be cautioned that data are limited in pancreatic cancer and that this drug carries a risk of interstitial lung disease. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Fam-trastuzumab deruxtecan'.)

In an open-label phase II trial (DESTINY-PanTumor02), 267 patients with HER2-expressing (IHC 3+ or 2+) solid tumors of various histologies who had received at least one prior systemic therapy or lacked alternative therapies were treated with trastuzumab deruxtecan [22]. At a median follow-up of 13 months, in the entire cohort, the ORR was 37 percent, with responses among all tumor histologies. Among the subset of 25 patients with pancreatic cancer, objective responses were seen in one patient. In addition, the ORRs were higher for those with IHC 3+ disease than IHC 2+ disease (56 versus 35 percent). Similar results were also seen in another phase II trial (DESTINY-PanTumor01) [23].

Based on the data from DESTINY-PanTumor02, the FDA granted accelerated approval to fam-trastuzumab deruxtecan for patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options [18].

NO ACTIONABLE MOLECULAR ALTERATIONS — 

Patients with metastatic pancreatic cancer who lack actionable molecular alterations are typically treated with initial chemotherapy. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'No actionable molecular alterations'.)

For those who progress on initial chemotherapy, selection of second- and later-line therapy is based upon which regimen was used for initial therapy as well as the patient's Eastern Cooperative Oncology Group (ECOG) performance status (PS) (table 1) and biliary function. Patients should generally be treated with agents not previously used as part of initial systemic therapy.

Good PS, no hyperbilirubinemia

Prior FOLFIRINOX — For patients who progress on initial therapy with FOLFIRINOX and have an ECOG performance status (PS) of 0 to 1 (table 1), total bilirubin level of less than 1.5 times the upper limit of normal (ULN), and a good comorbidity profile (table 5), we suggest second-line therapy with gemcitabine plus nabpaclitaxel (table 6) rather than other systemic agents. Appropriate alternatives include single-agent gemcitabine (table 7) and gemcitabine plus erlotinib.

Gemcitabine plus nabpaclitaxel — For patients who progress on FOLFIRINOX, gemcitabine plus nabpaclitaxel (table 6) is an effective option for second-line therapy based on observational studies [24-26] and clinical trials [27-29]. Data are as follows:

●In a retrospective study, 427 patients with advanced pancreatic cancer previously treated with FOLFIRINOX received either gemcitabine plus nabpaclitaxel or gemcitabine alone [25]. There were imbalances in the groups that might have favored better outcomes with gemcitabine alone (eg, the group receiving combined therapy had more patients presenting with metastatic disease, more than two metastatic sites, and more peritoneal metastases). Despite these imbalances, combination therapy was associated with improved disease control rate (56 versus 32 percent), progression-free survival (PFS; median 3.5 versus 2.3 months), and overall survival (OS; median 7.1 versus 4.7 months). Gemcitabine plus abraxane was associated with more treatment-related toxicity (grade ≥3 in 44 versus 29 percent), especially hematologic and neuropathy.

●In a randomized phase II trial (QUILT-3.010) of 78 patients with advanced pancreatic cancer who progressed on FOLFIRINOX, the combination of NPC-1C, an antibody directed against MUC5AC, and gemcitabine plus nabpaclitaxel resulted in similar OS (median 5 versus 6.6 months), PFS (median 3.4 versus 2.7 months), and objective response rate (ORR; 3 percent for each) compared with gemcitabine plus nabpaclitaxel alone [28]. Although this trial did not demonstrate any additional benefit with adding NPC-1C to gemcitabine plus nabpaclitaxel, it established the benchmark PFS and OS outcomes for gemcitabine plus nabpaclitaxel as second-line therapy following initial therapy with FOLFIRINOX. Similar outcomes for gemcitabine plus nabpaclitaxel were seen in the control arm of another randomized trial (Trybeca-1) [29].

Gemcitabine — Gemcitabine (table 7) has also been evaluated as second-line therapy in patients with metastatic pancreatic cancer who progress on FOLFIRINOX. In observational studies, gemcitabine results in ORRs of 8 to 11 percent, disease control rates ranging from 26 to 40 percent, median PFS of two to three months, and median OS of four to five months [25,30-33]. In a randomized trial of patients with metastatic pancreatic adenocarcinoma who progressed on FOLFIRINOX, second-line therapy with single-agent gemcitabine demonstrated similar OS relative to gemcitabine plus paclitaxel and caused less toxicity [34].

Gemcitabine plus erlotinib — The use of gemcitabine plus erlotinib as second-line therapy is extrapolated from studies in patients with systemic-therapy naïve disease. Although a randomized trial demonstrated an OS benefit for the addition of erlotinib to gemcitabine, the absolute magnitude of the OS benefit was modest and caused more toxicity [35]. Further details are discussed separately. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'Less-preferred regimens'.)

Prior gemcitabine plus nabpaclitaxel — For patients who progress on initial therapy with gemcitabine plus nabpaclitaxel and have an ECOG PS of 0 to 1, total bilirubin of less than 1.5 times the ULN, and a good comorbidity profile (table 5), we suggest second-line therapy with either FOLFIRI (table 8) or fluorouracil (FU) plus leucovorin (LV) and liposomal irinotecan rather than other systemic agents. In a phase III trial, FU plus LV and liposomal irinotecan improved OS with an acceptable toxicity profile [36]. However, FOLFIRI is similarly effective as second-line therapy in this setting, based on data from separate randomized trials [37] and in our clinical experience. In addition, the two regimens have not been directly compared in randomized trials to determine whether liposomal irinotecan is superior to conventional irinotecan in this setting. (See 'Fluorouracil, leucovorin, and liposomal irinotecan' below.)

Fluorouracil, leucovorin, and liposomal irinotecan — In an open-label phase III trial (NAPOLI-1), 417 patients with locally advanced or metastatic pancreatic cancer who were previously treated with gemcitabine-based therapy were randomly assigned to either liposomal irinotecan plus FU and LV; liposomal irinotecan alone; or FU plus LV alone [36]. Relative to FU plus LV alone, liposomal irinotecan plus FU and LV improved OS (median OS 6.1 versus 4.2 months, hazard ratio [HR] 0.67, 95% CI 0.49-0.92), PFS (median PFS 3.1 versus 1.5 months, HR 0.56, 95% CI 0.41-0.75), and ORRs (16 versus 1 percent). Common grade ≥3 toxicities with combination therapy included neutropenia (27 percent), fatigue (14 percent), diarrhea (13 percent), vomiting (11 percent), nausea (8 percent), asthenia (8 percent), and abdominal pain (7 percent).

Of note, liposomal irinotecan monotherapy did not demonstrate superior PFS or OS over FU plus LV, and caused more severe toxicity compared with combination therapy, suggesting that liposomal irinotecan should only be used in combination with FU plus LV.

Based on these results, liposomal irinotecan, in combination with FU and LV, is approved by the US Food and Drug Administration (FDA) for patients with metastatic pancreatic cancer following prior administration of a gemcitabine-based regimen [18].

FOLFIRI — FOLFIRI (table 8) has shown acceptable activity in patients with pancreatic cancer refractory to gemcitabine-based therapy, with median OS of five to seven months and median PFS of two to three months [37-40]. In a randomized phase II trial (SWOG S1513) of 123 patients with treatment-refractory metastatic pancreatic cancer (over 90 percent of whom had received initial therapy with gemcitabine plus nabpaclitaxel), veliparib (a polymerase [PARP] inhibitor) plus modified FOLFIRI demonstrated similar OS (median 5.4 versus 6.5 months) and PFS (median 2.1 versus 2.9 months) relative to FOLFIRI alone [37]. Although this trial did not demonstrate any additional benefit with combining veliparib with FOLFIRI, it established the benchmark PFS and OS outcomes for FOLFIRI as second-line therapy following progression on gemcitabine plus nabpaclitaxel.

There are limited randomized trials directly comparing FOLFIRI with FU plus oxaliplatin-based regimens in this setting. A randomized phase II trial conducted in 61 patients with gemcitabine-refractory pancreatic cancer suggested similar OS between modified FOLFIRI and FOLFOX [41]. By contrast, a meta-analysis of five randomized trials evaluated the addition of oxaliplatin or various irinotecan formulations to a fluoropyrimidine in patients with metastatic pancreatic cancer who progressed on a first-line gemcitabine-based regimen [36,42-46]. In this meta-analysis, the addition of irinotecan to a fluoropyrimidine significantly improved both PFS (HR 0.64) and OS (HR 0.7), whereas the addition of oxaliplatin to a fluoropyrimidine modestly improved PFS (HR 0.81) but not OS (HR 1.03) [46].

Other regimens — For patients who progress on gemcitabine plus nabpaclitaxel, other second-line treatment options include modified FOLFIRINOX, FOLFOX, and CAPOX.

modified FOLFIRINOX — For patients who progress on gemcitabine-based therapy, second-line therapy with modified FOLFIRINOX (table 2) is an option for the rare patients with good ECOG PS (0 to 1), minimal tumor-related symptoms, and minimal toxicity from prior systemic therapy [47,48].

In a phase III trial (MPACA-3) of 80 patients with metastatic pancreatic cancer who progressed on gemcitabine-based therapy, second-line therapy with modified FOLFIRINOX improved OS (median nine versus five months, HR 0.4, 95% CI 0.2-0.7) and PFS (median five versus two months, HR 0.4, 95% CI 0.2-0.6) relative to S-1 [48]. Grade 3 to 4 toxicity rates were higher with FOLFIRINOX (56 versus 17 percent). Limitations of this study include the use of S-1 as the control arm, which is not widely available for use outside of countries in Asia.

FOLFOX — Modified FOLFOX-6 (table 3) is an option for second-line therapy in patients with metastatic pancreatic cancer who progress on gemcitabine plus nabpaclitaxel, regardless of serum total bilirubin level, although it did not confer an OS benefit over FU plus LV alone in a randomized trial [44].

In patients with gemcitabine-refractory disease, data from observational studies and phase II trials suggested efficacy for FOLFOX [40,49-53]. However, in an open-label phase III trial (PANCREOX) of 108 patients with advanced pancreatic cancer previously treated with gemcitabine, second-line therapy with modified FOLFOX-6 demonstrated similar PFS (median three months for each) and inferior OS (median 6 versus 10 months) compared with FU plus LV alone [44]. In other randomized trials (SWOG S1115 and SEQUOIA) where FOLFOX was the control arm, similar outcomes were seen for median OS (range six to seven months) and median PFS (two months) [54,55].

CAPOX — Capecitabine plus oxaliplatin is modestly active in gemcitabine-refractory metastatic pancreatic cancer [49,51,56]. In a prospective study, 85 patients with advanced pancreatic cancer who progressed on gemcitabine-based chemotherapy were treated with either FOLFOX or CAPOX. In those treated with CAPOX, the partial response and stable disease rates were 18 and 41 percent, whereas in those treated with FOLFOX, the partial response and stable disease rates were 17 and 26 percent, respectively [49]. In a phase II trial of 39 patients with gemcitabine-refractory pancreatic cancer, objective responses were seen in one patient (2 percent) and stable disease in 10 patients (26 percent) [56].

Prior NALIRIFOX — For patients who progress on initial therapy with NALIRIFOX and have an ECOG PS of 0 to 1 (table 1), total bilirubin level of less than 1.5 times the ULN, and a good comorbidity profile (table 5), there are limited data for the optimal treatment approach. Clinical trial enrollment is encouraged. For those who are ineligible for or decline clinical trials, we offer the same approach to second-line therapy as patients who progress on FOLFIRINOX. (See 'Prior FOLFIRINOX' above.)

ECOG PS 2, no hyperbilirubinemia — For patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, total bilirubin less than 1.5 times ULN, and a good comorbidity profile (table 5), we offer initial therapy with gemcitabine plus nabpaclitaxel. Alternative options for initial therapy include FOLFOX, CAPOX, and FOLFIRI. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'ECOG PS of 2, no hyperbilirubinemia'.)

For such patients who progress on initial systemic therapy, we opt for a regimen not previously received for second-line therapy:

●Prior gemcitabine plus nabpaclitaxel – For patients who were initially treated with gemcitabine plus nabpaclitaxel, we offer second-line therapy with either FOLFIRI (table 8) or FU plus LV and liposomal irinotecan. (See 'FOLFIRI' above and 'Fluorouracil, leucovorin, and liposomal irinotecan' above.)

●Prior fluoropyrimidine-based therapy – For patients who were initially treated with FOLFOX, CAPOX, or FOLFIRI, we suggest second-line therapy with gemcitabine plus nabpaclitaxel (table 6) rather than other systemic agents. (See 'Gemcitabine plus nabpaclitaxel' above.)

These combination regimens may be administered with proactive adjustments to drug dosing and schedules to minimize toxicity. For example, gemcitabine plus nabpaclitaxel may be administered every other week whereas for FU-based combination regimens, the bolus FU may be omitted to reduce toxicity [57].

For patients who are unable to tolerate combination therapy, we have a low threshold to convert to single-agent therapy. Such options, if not previously received, include gemcitabine [58] (table 7), a fluoropyrimidine (eg, FU plus LV (table 9) or capecitabine [59]), and paclitaxel [60].

ECOG PS 0 to 2 and hyperbilirubinemia — For patients with metastatic pancreatic cancer and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2 and total serum bilirubin 1.5 times the ULN or greater, preferred options for second-line therapy are FOLFOX and FU plus LV, if not previously received for initial therapy. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'ECOG PS 0 to 2 with hyperbilirubinemia'.)

For example, second-line therapy with either FOLFOX or FU may be appropriate for fit patients who were initially treated with a regimen that did not contain a fluoropyrimidine (eg, gemcitabine plus nabpaclitaxel) in the setting of adequate serum bilirubin levels but subsequently develop tumor-related hyperbilirubinemia not amenable to mechanical interventions. (See 'FOLFOX' above.)

For those with a persistently elevated serum total bilirubin level who progress on fluoropyrimidine-containing regimens, there are limited options for second-line therapy. Agents that are commonly used, such as liposomal irinotecan, irinotecan, and gemcitabine, are generally not offered to patients with hyperbilirubinemia since they are mainly eliminated by the liver. Patients should be evaluated for alternate therapies, clinical trials, or best supportive care. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer".)

POOR PS AND/OR SIGNIFICANT COMORBIDITIES — 

Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 to 4 and/or poorly controlled comorbid conditions should be offered supportive care, regardless of the presence or absence of an actionable molecular alteration. Systemic therapy should only be offered on an individualized, case-by-case basis. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer".)

SPECIAL POPULATIONS

Acinar cell cancers — Patients with metastatic acinar cell carcinoma typically receive initial therapy with an oxaliplatin-based regimen such as FOLFOX or FOLFIRINOX. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'Acinar cell carcinoma'.)

For those who progress on these regimens, there are limited data for the optimal approach to second- and later-line therapy. For such patients, we offer second-line therapy with gemcitabine plus nabpaclitaxel, extrapolating from data in pancreatic ductal adenocarcinoma. (See 'Gemcitabine plus nabpaclitaxel' above.)

Other options that have been evaluated in metastatic acinar cell carcinoma include gemcitabine plus oxaliplatin [61-63], gemcitabine plus cisplatin [63], gemcitabine plus docetaxel and capecitabine [63], FOLFIRI [64], and cisplatin plus irinotecan [63].

Patients may also undergo testing for potentially actionable molecular alterations, although data for the frequency of such alterations are limited [65,66].

ASSESSING TREATMENT RESPONSE — 

Patients receiving second-line systemic therapy should be periodically evaluated using imaging studies and serum tumor markers, if initially elevated. Further details are discussed separately. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'Assessing treatment response'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pancreatic cancer".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Pancreatic cancer (The Basics)")

●Beyond the Basics topic (see "Patient education: Pancreatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Second- and later-line systemic therapy for metastatic exocrine pancreatic cancer – Second- and later-line systemic therapy for metastatic exocrine pancreatic cancer will be reviewed here. Systemic therapy can reduce tumor burden, improve disease-related symptoms, and prolong overall survival (OS). The goals of systemic therapy are palliative and not curative. Enrollment in clinical trials is encouraged, where available. Patients who are ineligible for (or decide to forego) further systemic therapy may be offered best supportive care. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer".)

An overview of initial systemic therapy for metastatic exocrine pancreatic cancer is discussed separately. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer".)

●Tumors with actionable molecular alterations

•KRAS G12C mutation-positive tumors – For patients with a KRAS G12C mutation-positive tumor who progress on initial chemotherapy, we suggest second-line therapy with the KRAS G12C inhibitor adagrasib (Grade 2C), but sotorasib is also an acceptable option. (See 'KRAS G12C-mutated tumors' above.)

•BRAF V600E mutation-positive tumors – For patients with BRAF V600E mutation-positive tumors who progress on initial chemotherapy, we suggest second-line therapy with dabrafenib plus trametinib rather than chemotherapy (Grade 2C). (See 'BRAF V600E mutant tumors' above.)

•Neuregulin 1 (NRG1) fusion-positive tumors – For patients with an NRG1 fusion-positive tumor who progress on initial chemotherapy, we suggest second-line therapy with zenocutuzumab rather than chemotherapy (Grade 2C). (See 'NRG1 fusion-positive tumors' above.)

•HER2-positive tumors – For patients with human epidermal growth factor 2 (HER2)-positive (immunohistochemistry [IHC] 3+) tumors who progress on multiple lines of systemic therapy and have no other satisfactory treatments available, fam-trastuzumab deruxtecan is an option for later-line therapy. (See 'HER2-positive tumors' above.)

•Other molecular alterations – For patients with all other actionable alterations who progress on initial systemic therapy, we evaluate and treat for alternative actionable molecular alterations. If no other actionable molecular alterations are identified, we offer chemotherapy using the same approach as those whose tumors lack an actionable molecular alteration and depending on whether they received prior chemotherapy.

-BRCA1/2 or PALB2 pathogenic variants – (See 'BRCA1/2 or PALB2 pathogenic variants' above.)

-Non-core homologous repair deficiency (HRD) pathogenic variants – (See 'Non-core HRD pathogenic variants' above.)

-Mismatch repair deficient (dMMR)/microsatellite-instability high (MSI-H tumors) – (See 'MSI-H/dMMR tumors' above.)

-Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors – (See 'TRK fusion-positive cancers' above.)

-Rearranged during transfection (RET) fusion-positive tumors – (See 'RET fusion-positive tumors' above.)

●No actionable molecular alterations – For patients whose tumors lack actionable molecular alterations and progress on initial chemotherapy, selection of second- and later-line therapy is based upon which regimen was used for initial therapy as well as the patient's Eastern Cooperative Oncology Group (ECOG) performance status (PS) (table 1) and biliary function. Patients should generally be treated with agents not previously used as part of initial systemic therapy. (See 'No actionable molecular alterations' above.)

•Good ECOG PS, no hyperbilirubinemia – For patients with an ECOG PS of 0 to 1 (table 1), total bilirubin level of less than 1.5 times the upper limit of normal (ULN), and a good comorbidity profile (table 5), our approach to second-line therapy is as follows:

-Prior FOLFIRINOX or NALIRIFOX – For patients who progress on initial therapy with FOLFIRINOX or NALIRIFOX, we suggest second-line therapy with gemcitabine plus nabpaclitaxel (table 6) rather than other systemic agents (Grade 2C). Appropriate alternatives include single-agent gemcitabine (table 7) and gemcitabine plus erlotinib. (See 'Prior FOLFIRINOX' above and 'Prior NALIRIFOX' above.)

-Prior gemcitabine plus nabpaclitaxel – For patients who progress on initial therapy with gemcitabine plus nabpaclitaxel, we suggest second-line therapy with either FOLFIRI (table 8) or fluorouracil (FU) plus leucovorin (LV) and liposomal irinotecan rather than other systemic agents (Grade 2C). (See 'Prior gemcitabine plus nabpaclitaxel' above.)

•ECOG PS of 2, no hyperbilirubinemia – For patients with an ECOG PS of 2, total bilirubin less than 1.5 times ULN, and a good comorbidity profile (table 5) who progress on initial chemotherapy, we opt for a regimen not previously received. (See 'ECOG PS 2, no hyperbilirubinemia' above.)

-Prior gemcitabine plus nabpaclitaxel – For patients who were initially treated with gemcitabine plus nabpaclitaxel, we offer second-line therapy with either FOLFIRI (table 8) or FU plus LV and liposomal irinotecan. (See 'FOLFIRI' above and 'Fluorouracil, leucovorin, and liposomal irinotecan' above.)

-Prior fluoropyrimidine-based regimen – For patients who were initially treated with FOLFOX, CAPOX, or FOLFIRI, we suggest second-line therapy with gemcitabine plus nabpaclitaxel (table 6) rather than other systemic agents (Grade 2C). (See 'Gemcitabine plus nabpaclitaxel' above.)

These combination regimens may be administered with proactive adjustments to drug dosing and schedules to minimize toxicity. For patients who are unable to tolerate combination therapy, we have a low threshold to convert to single-agent therapy not previously received such as gemcitabine, a fluoropyrimidine, and paclitaxel.

•ECOG PS 0 to 2 and hyperbilirubinemia – For patients with ECOG PS 0 to 2 and total serum bilirubin 1.5 times the ULN or greater, preferred options for second-line therapy are FOLFOX and FU plus LV, if not previously received. (See 'ECOG PS 0 to 2 and hyperbilirubinemia' above.)

•Poor PS and/or significant comorbidities – Patients with an ECOG PS of 3 to 4 and/or poorly controlled comorbid conditions should be offered supportive care, regardless of the presence or absence of an actionable molecular alteration. Systemic therapy should only be offered on an individualized, case-by-case basis. (See 'Poor PS and/or significant comorbidities' above.)

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Topic 127094 Version 23.0

References

1 : KRAS mutation in pancreatic cancer.

2 : Translational advances in pancreatic ductal adenocarcinoma therapy.

3 : Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation.

4 : KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.

5 : Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer.

6 : Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation.

7 : Preliminary activity and safety results of KRAS G12C inhibitor glecirasib (JAB-21822) in patients with pancreatic cancer and other solid tumors.

8 : A case report of a dramatic response to olaparib in a patient with metastatic pancreatic cancer harboring a germline BRCA2 mutation.

9 : An Analysis of Patients with DNA Repair Pathway Mutations Treated with a PARP Inhibitor.

10 : Olaparib (O) in patients (pts) with pancreatic cancer with BRCA1/2 inactivating mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study

11 : Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.

12 : Rucaparib Monotherapy in Patients With Pancreatic Cancer and a Known Deleterious BRCA Mutation.

13 : Talazoparib in Patients With Solid Tumors With BRCA1/2 Mutation: Results From the Targeted Agent and Profiling Utilization Registry Study.

14 : Olaparib Monotherapy for Previously Treated Pancreatic Cancer With DNA Damage Repair Genetic Alterations Other Than Germline BRCA Variants: Findings From 2 Phase 2 Nonrandomized Clinical Trials.

15 : Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.

16 : Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study.

17 : Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial.

18 : Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial.

19 : Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H.

20 : Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.

21 : Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer.

22 : Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial.

23 : Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study.

24 : Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort.

25 : Gemcitabine + Nab-paclitaxel or Gemcitabine alone after FOLFIRINOX failure in patients with metastatic pancreatic adenocarcinoma: a real-world AGEO study.

26 : Gemcitabine/nab-paclitaxel as second-line therapy following FOLFIRINOX in metastatic/advanced pancreatic cancer-retrospective analysis of response.

27 : Second-Line Gemcitabine Plus Nab-Paclitaxel for Patients with Unresectable Advanced Pancreatic Cancer after First-Line FOLFIRINOX Failure.

28 : Effect of a MUC5AC Antibody (NPC-1C) Administered With Second-Line Gemcitabine and Nab-Paclitaxel on the Survival of Patients With Advanced Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial.

29 : Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with advanced pancreatic adenocarcinoma (NCT03665441).

30 : Role of gemcitabine as second-line therapy after progression on FOLFIRINOX in advanced pancreatic cancer: a retrospective analysis.

31 : Gemcitabine as second-line chemotherapy after Folfirinox failure in advanced pancreatic adenocarcinoma: A retrospective study.

32 : Evaluation of gemcitabine efficacy after the FOLFIRINOX regimen in patients with advanced pancreatic adenocarcinoma.

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34 : Gemcitabine and Paclitaxel Versus Gemcitabine Alone After 5-Fluorouracil, Oxaliplatin, and Irinotecan in Metastatic Pancreatic Adenocarcinoma: A Randomized Phase III PRODIGE 65-UCGI 36-GEMPAX UNICANCER Study.

35 : Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.

36 : Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial.

37 : Randomized Phase II Study of PARP Inhibitor ABT-888 (Veliparib) with Modified FOLFIRI versus FOLFIRI as Second-line Treatment of Metastatic Pancreatic Cancer: SWOG S1513.

38 : Irinotecan plus bolus/infusional 5-Fluorouracil and leucovorin in patients with pretreated advanced pancreatic carcinoma: a multicenter experience of the Gruppo Oncologico Italia Meridionale.

39 : FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study.

40 : Three fluoropyrimidine-based regimens in routine clinical practice after nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: An AGEO multicenter study.

41 : A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer.

42 : Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer.

43 : Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial.

44 : PANCREOX: A Randomized Phase III Study of 5-Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy.

45 : Randomised phase II trial of irinotecan plus S-1 in patients with gemcitabine-refractory pancreatic cancer.

46 : Second-line treatment in patients with pancreatic ductal adenocarcinoma: A meta-analysis.

47 : 5-fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma.

48 : Modified FOLFIRINOX versus S-1 as second-line chemotherapy in gemcitabine-failed metastatic pancreatic cancer patients: A randomised controlled trial (MPACA-3).

49 : XELOX vs. FOLFOX4 as second line chemotherapy in advanced pancreatic cancer.

50 : FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study.

51 : Clinical Outcomes of Second-Line Chemotherapy after Progression on Nab-Paclitaxel Plus Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma.

52 : Second-line treatment with oxaliplatin, leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: A phase II study.

53 : Second-line chemotherapy in advanced pancreatic carcinoma: a multicenter survey of the Gruppo Oncologico Italia Meridionale on the activity and safety of the FOLFOX4 regimen in clinical practice.

54 : Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial.

55 : Randomized Phase III Study of FOLFOX Alone or With Pegilodecakin as Second-Line Therapy in Patients With Metastatic Pancreatic Cancer That Progressed After Gemcitabine (SEQUOIA).

56 : Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer.

57 : Omission of 5-Fluorouracil Bolus From Multidrug Regimens for Advanced Gastrointestinal Cancers: A Multicenter Cohort Study.

58 : Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.

59 : Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer.

60 : Paclitaxel as second-line chemotherapy in patients with gemcitabine-refractory pancreatic cancer: a retrospective study.

61 : Pancreatic Acinar Cell Carcinoma.

62 : Systemic Chemotherapy for Advanced Rare Pancreatic Histotype Tumors: A Retrospective Multicenter Analysis.

63 : Acinar cell carcinoma of the pancreas: new genetic and treatment insights into a rare malignancy.

64 : Clinical characteristics and outcomes from an institutional series of acinar cell carcinoma of the pancreas and related tumors.

65 : Whole-exome sequencing of pancreatic neoplasms with acinar differentiation.

66 : Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes.