**4. 2020: current first-line options for the treatment of metastatic and or unresectable adenocarcinoma of the pancreas and their historical development**

Based on the knowledge from preclinical assays and clinical studies that had showed synergist activity of irinotecan, oxaliplatin and 5-FU combination, a phase 1 trial assessed a regimen that combined 5-FU, leucovorin. Irinotecan and oxaliplatin [20]. This trial included 34 patients with different malignancies, 6 of them with pancreatic advanced cancer. Among pancreatic cancer patients one partial response and one complete response were achieved. For all the patients treated main grade 3–4 toxicities included 78% neutropenia (12% febrile neutropenia), 41% asthenia, 37% peripheral neuropathy, 27% diarrhea and 24% nausea and vomiting, 6% thrombocytopenia and 5% anemia. 51% of the patients required granulocyte colony stimulating factor (G-CSF).

FOLFIRINOX regimen (oxaliplatin 85 mg/m<sup>2</sup> + Irinotecan 180 mg/ m2 + Leucovorin 400 mg/m2 + 5-FU 400 mg/m2 in bolus and 5-FU 2400 mg/m2 in 46 hours in continuous infusion) every 2 weeks was evaluated in a phase 2 French clinical trial that included 46 patients with advanced or metastatic pancreatic adenocarcinoma that had not received previous treatment (chemotherapy, radiotherapy or chemoradiation), with ages between 18 and 70 years, performance status 0–1, adequate bone marrow function, total bilirubin not superior than 1.5 times the upper normal level (UNL), AST – ALT and alkaline phosphatases <3 ULN (5 < ULN in patients with liver metastasis) and an adequate renal function were some of the selection criteria [21]. Patients with brain or leptomeningeal disease were excluded. Primary end point of the trial was response rate end according to former WHO criteria; secondary end points included safety, quality of life and clinical benefit assessment. Treatment was given until progression of disease or unacceptable toxicity for up to 6 months of chemotherapy in case of benefit. According to protocol atropine was allowed to be administered to diminish the risk of severe cholinergic syndrome in patients that presented it in a previous cycle. Antiemetic prophylaxis treatment was permitted at investigator's discretion. Loperamide was allowed for patients with delayed diarrhea and oral fluroquinolones in case that diarrhea lasted more than 2 days. After cycle 1 of treatment G-CSFs were also allowed to be used in case of need. The median of age of patients was 56 years, 65% were male and 76% stage IV B, doses reductions were indicated in the 14% of the total of cycles for all the patients. Most of delays for new cycles were due to hematological toxicities. By investigators assessment and after a median follow up of 33 months, the overall response rate was 26% (all partial responses) and 39% of patients achieved stable disease, the median duration of response was 10.4 months, PFS was 5.6 months, median OS was 10.2 months (9.5 months for metastatic patients and 15.7 months for locally advanced disease), 1-year survival was 43%. Grade 3–4 neutropenia occurred in the 52% of patients but only 4% of febrile neutropenia was reported, 8% of treated patients need hospitalization due to diarrhea, grade 3 and 4 vomiting was 20 and 17%, grade 3 and 4 asthenia was 20 and 21%, grade 2 and 3 peripheral neuropathy was 13 and 15% respectively and 7 patients were discontinued of treatment for this last toxicity. Concerning quality of life 18% of patients reported worsening and 37% reported improvement in quality of life.

By those days, the standard of care for advanced PC gemcitabine was compared head to head against FOLFIRINOX regimen in a first line of treatment, multicenter phase 2–3 clinical trial designed by the same French group [22]. About 342 patients were randomized in a 1:1 ratio to receive either FOLFIRINOX every 2 weeks at the same doses than in the phase 2 trial or gemcitabine that was given intravenously 1000 mg/m2 weekly during 7 weeks and 1 week off, then 1000 mg/m2 weekly

during 3 weeks and 1 week of rest. Main inclusion criteria were age 18 years or older, histologically or cytologically confirmed adenocarcinoma of the pancreas, measurable disease, ECOG 0–1 and adequate hepatic, renal and bone marrow function. Exclusion criteria included but were not limited to an age older than 76 years, previous radiotherapy for measurable lesions, brain metastases and others.

OS was the primary end point of this trial. Secondary end points included PFS, tumor response, safety and quality of life. The median number of cycles was 10 for FOLFIRINOX arm (range 1–47) and 6 for Gemcitabine (range 1–26) (p < 0.001). With a median follow up of 26 months median OS was 11.1 months for FOLFIRINOX arm and 6.8 months for Gemcitabine arm (HR 0.57; p < 0.001). Reported survival rates at 6–12-18 months were 57.6–20.6% and 6% for gemcitabine arm and 75.9, 48.4, 18.6% for FOLFIRINOX arm. According to RECIST criteria there was a 31.6% of responses among the FOLFIRINOX treated patients including 1 complete response but also 38.6% of stable disease as the best response. For the gemcitabine arm it was reported a 41.5% of stable disease and only a 9.4% of partial responses. Median PFS was 6.4 months and 3.3 months for FOLFIRINOX and Gemcitabine arms respectively (HR 0.47; p < 0.001). Patients that received a second line of therapy had a median OS de 4.4 months in each group since new treatment started. Grade 3 and 4 toxicities were more frequent in the FOLFIRINOX arm including neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, peripheral neuropathy and also grade 2 alopecia. ALT elevations were significatively higher among gemcitabine treated patients. 42% of the FOLFIRINOX-treated patients required G-CSF but only 5% of the patients of the gemcitabine arm. At a 6 months period 66% of gemcitabine treated patients and 31% in the FOLFIRINOX arm had a decrease in the scores of quality of life (HR 0.47; p < 0.01). Later reports from the same group remarked about the risk of worsening in quality of life among patients treated with FOLFIRINOX regimen when compared with gemcitabinetreated patients [23].

Based on the results of this French trial, FOLFIRINOX has shown to be superior in terms of OS, PFS and ORR, and it is currently worldwide accepted as a first line option of treatment for patients with advanced PC, however, it is necessary to remember that this regimen was approved in patients younger of 76 years old and it was assessed only in French population.

Some authors have reported their experiences in patients using some modifications of the FOLFIRINOX regimen (known as modified FOLFIRINOX or mFOLFIRINOX). Considering a significant dispersion of results among them, some retrospective analysis and meta- analysis showed similar results in terms of survival but with less toxicity when compared with the results from the pivotal study mentioned above [24]. Avoiding 5-FU bolus and using hematopoietic growth factors also seems to be safe in mFOLFIRINOX regimen when it is used in metastatic pancreatic cancer [25].

Before FOLFIRINOX was recognized as the first option of treatment for advanced disease the standard of treatment was gemcitabine. Gemcitabine has lower efficacy but a better toxicity profile when compared with FOLFIRINOX and it can still be used in the first line of treatment among patients that are not amenable to receive FOLFIRINOX or gemcitabine-nab paclitaxel combination. Nab-paclitaxel is a derivate, solvent-free, albumin bound form of paclitaxel with some relevant advantages over paclitaxel including a significant lower hypersensitivity reactions profile and a shorter infusion time. Its formulation with albumin also allows nab-paclitaxel to reach the tumor microenvironment by using endogenous albumin transport pathways [26]. A glycoprotein that has been related in the carcinogenesis of several solid tumors, SPARC (secreted protein acidic and rich in cysteine), has been found in high levels in the tumor stroma of pancreatic cancer, mainly in

#### *Current Systemic Treatment Options for Metastatic and Unresectable Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.93225*

peritumoral fibroblasts and it has been linked with bad prognosis. In complete resected patients 5-year survival has been reported to be worse among pancreatic cancer patients that express stromal SPARC and it might be considered as a prognostic marker [27]. Tumor stroma's SPARC seems to facilitate that nab-paclitaxel penetrates the tumor microenvironment hypothesizing that this drug may have a significant potential role in the pancreatic cancer control [28].

As earlier mentioned in this chapter, gemcitabine was combined with several other drugs looking to improve survival and quality of life in advanced PC, unfortunately those trials` outcomes were mostly negative. One exception was gemcitabine plus Nab-paclitaxel combination that is currently another recommended first-line treatment option in the metastatic setting of patients harboring adenocarcinoma of the pancreas. Comparing nab-paclitaxel with other chemotherapy agents, there is evidence of synergism in a mouse model when gemcitabine was combined with nab-paclitaxel by reducing cytidine deaminase levels that involves gemcitabine's metabolism [29].

A phase 1–2 clinical trial was conducted to define the maximum tolerated dose (MTD) of gemcitabine plus Nab-paclitaxel combination in previously untreated metastatic PC patients. The regimen was then finally defined as gemcitabine 1000 mg/m<sup>2</sup> plus nab paclitaxel 125 mg/m2 weekly for 3 weeks every 28 days. Reported dose limiting toxicities were mainly neutropenia and sepsis. Outcomes from patients treated with the MTD showed a 1-year survival of 48%, with a median OS of 12.2 months and a response rate of 48%. Interestingly, as part of this trial FDG PET CT response was also assessed and showed that patients with complete metabolic response had a longer overall survival of 20.1 months versus 10.3 months in patients that did not achieve a metabolic complete response (p = 0.01) [30].

Von Hoff et al., following the previous phase 1–2 trial, designed an international multicenter open label phase 3 clinical trial to compare gemcitabine plus nab-paclitaxel combination with gemcitabine alone in patients with advanced PC (MPACT trial) [31]. The study arm used the same doses of gemcitabine and nabpaclitaxel suggested by the previous phase1–2 trial. The control arm, gemcitabine alone was given in a dose of 1000 mg/m2 weekly for 7 weeks in an 8 weeks cycle (defines as protocol as cycle 1) and then 1000 mg/m2 weekly for 3 weeks every 4 weeks. The primary end point was OS and secondary end points included PFS and ORR. Inclusion criteria included patients with a confirmed metastatic adenocarcinoma of the pancreas with measurable disease by RECIST 1.0, Karnofsky score of 70–100, chemotherapy naive (patients that received previous gemcitabine or 5-FU as radiosensitizers were allowed to participate in the trial), adequate renal, bone marrow and liver function as defined by protocol. Patients that had received adjuvant chemotherapy and patients with locally advance disease were excluded. Stratification was according to Karfnofsky score, presence or not of liver metastases and geographical region. Randomization was performed in a 1:1 ratio and the trial included 861 patients (63% from North America, 15% from Eastern Europe, 14% from Australia and 9% from western Europe). 10% of patients were older than 75 years and 8% of patients had ECOG 2. The primary end point of the trial was met, median OS was 8.5 months for the combination arm and 6>7 months for the gemcitabine alone group (HR 0.72; p < 0.001). 1 and 2-year survival were higher for the gemcitabine plus nab-paclitaxel combination arm (35 and 9%) arm when compared with gemcitabine alone (9 and 4%). Patients that underwent a second line of treatment lived longer if they had been treated with the combination treatment (9.4 months for gemcitabine-nab paclitaxel versus 6.8 months for gemcitabine alone, HR 0.68; p < 0.001). PFS, ORR and disease control rate (DCR) were also higher in the combination arm: PFS 5.5 months versus 3.7 months

(HR 0.69, p < 0.001), ORR 23% versus 7% (p < 0.001) and DCR of-16 weeks-orlonger 48% versus 33% respectively (p < 0.001). In addition, patients that had a decrease in basal CA 19–9 of 90% or more irrespective of the treatment arm live longer when compared with patients that reached a decrease of this biomarker lower than 90% (13.5 months versus 8.2 months, HR 0.53; p < 0.001). 15% of patients from gemcitabine arm and 32% of the combination arm received at least 6 months of treatment. Reported grade 3–4 toxicities were higher among gemcitabine-nab paclitaxel arm (neutropenia 38 vs. 27%, leukopenia 31 vs. 16%, fatigue 17 vs. 7%, peripheral neuropathy 17 vs. 1%, diarrhea 6 vs. 1%). Discontinuation of nab paclitaxel due to peripheral neuropathy grade 1–3 was 8% and no grade 4 neuropathy was reported. 3% of patients in the combination arm developed febrile neutropenia and 26% receipted G-CSF versus 1 and 15% for gemcitabine arm respectively. There was a 4% of fatal events in each group but sepsis and pneumonitis related deaths were more frequent among gemcitabine plus nab paclitaxel treated patients.

Un update of the long-term survival of this trial was later published [32]. The median OS for the gemcitabine-nab paclitaxel combination was 8.7 months versus 6.6 months for the gemcitabine arm (HR 0.72; p < 0.001). Patients that lived 3 years or longer was only a 4% and they all had been treated with the combination treatment. Higher CA 19–9 and neutrophil to lymphocyte ratio > 5 were associated with worse survival and there was a trend for more benefit in those poor prognosis subgroups.

The phase 2 multicenter, international, single arm LAPACT trial was addressed to assess the efficacy and safety of gemcitabine plus Nab-paclitaxel combination in patients with locally advanced, unresectable nonmetastatic, previously untreated pancreatic cancer [33]. Primary end point was time to treatment failure (TTF). This study was designed for all the patients to be treated in a "induction phase" with gemcitabine 1000 mg/m2 plus nab-paclitaxel 125 mg/m2 weekly for 3 weeks in a 28 days cycle for a total of 6 cycles. After this induction period, patients without disease progression, by investigator choice, were treated with the same chemotherapy regimen or chemoradiation or surgery (patients with responses before this 6 cycles period could undergo surgery without have to end the complete all preprogrammed chemotherapy treatment). Only ECOG 0–1 patients were allowed to be enrolled. A total of 106 patients were evaluable. Median TTF was 8.6 months and PFS 10.2 months. Main reasons for discontinuing treatment were adverse events (18%) and progressive disease (7%). Grade 3 or higher toxicity reported included 42% neutropenia, 11% anemia, 10% fatigue and 4% of peripheral neuropathy. Respecting to efficacy to treatment 32.7% of patients had a partial response and 57.9% stable disease as the best reported response. 43% of patients continue treatment with gemcitabine plus nab paclitaxel after induction treatment, 16% underwent chemoradiation and 15% of patients underwent surgery (n 16). Of the 16 patients that underwent surgery, 7 patients achieved a R0 resection and 9 patients a R1 resection.

This chemotherapy regimen, gemcitabine plus nab-paclitaxel combination, is currently also an option to consider for unresectable patients, with a very low curative option, in tumors that have a real minor chance to undergo a R0 resection, as it has already been already described for FOLFIRINOX and chemoradiation [34, 35].

No phase 3 clinical trial has compared the efficacy of FOLFIRINOX and gemcitabine plus nab-paclitaxel combination, for this reason selection of patients for either treatment must consider the differences between both phase 3 pivotal trials. The phase 2 trial LAPACT also provide us some information for unresectable patients that underwent gemcitabine- nab paclitaxel treatment looking for a neoadjuvant option considering that phase 3 trial MPACT only enrolled metastatic patients. MPACT trial allowed the inclusion of patients older than 75 years (10%)

#### *Current Systemic Treatment Options for Metastatic and Unresectable Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.93225*

and poorer performance status (8% ECOG 2), in the FOLFIRINOX phase 3 trial patients older than 75 years were not allowed and ECOG was limited to <2. Despite that FOLFIRINOX trial was a multicenter only included French sites, however, MPACT included patients from North America, Europe, and Australia.

A systematic meta-analysis aimed to answer if there is superiority of FOLFIRINOX or gemcitabine-nab paclitaxel combination in the first line of treatment for metastatic or advanced PC. Based on 16 retrospective studies that included 2123 gemcitabine plus nab-paclitaxel treated patients and 1690 FOLFIRINOX treated patients, no statistical significantly differences were found in terms of overall risk of death, PFS and RR. Toxicity was in line of the pivotal trials [36]. These results may help to conclude that despite of the numerically superiority in OS of the phase 3 FOLFIRINOX trial when it is compared with MPACT trial, and in the absence of a comparative head to head phase 3 trial for these 2 regimens, clinicians may use any of those according with their experience but also taking account of the medical conditions and biography of each patient to be treated.

BRCA 1–2 mutations have been found between the 5% and 12.8% of pancreatic cancer patients among different patient populations [6]. In a retrospective observational study that analyzed the outcomes in 71 PC patients harboring BRCA 1–2 germline mutations, OS was statistically higher among stage 3–4 patients that were treated with platinum-based chemotherapy when compared with patients that did not use platin compounds as part of their treatment (22 versus 9 months, p = 0.039) [37].

Recently published, the POLO study (Pancreas Cancer Olaparib Ongoing) was a phase 3 multicenter doble blinded in patients with metastatic PC and BRCA1–2 germline mutations that had received at least 16 weeks of a platinum-based palliative chemotherapy and had no disease progression during the treatment, then patients were assigned to receive olaparib (300 mg twice daily) or placebo in a 2:1 ratio [38]. The primary end point of the trial was PFS by a blinded independent central review. 154 patients were randomized (3315 patients screened). 86% of the olaparib group and 81% of the placebo group had been treated with FOLFIRINOX regimen and 2 and 5% with gemcitabine cisplatin combination, respectively. Primary end point, PFS was met showing longer median PFS among patients treated with olaparib versus placebo (7.4 versus 3.8 months, HR 0.53, p = 0.004), however, no benefit in overall survival was found for 18.9 months in olaparib arm and 18.1 months in placebo arm (p = 0.68). 23% of patients olaparib-treated had response (including 2 patients that achieved a complete response) vs. 12% in the placebo arm by blinded independent central review, with a median duration of response of 24.9 versus 3.7 months respectively. Considering that POLO trial resulted in a positive trial achieving to meet its primary end point PFS, FDA in December 2019 got the approval for the use of olaparib for the maintenance treatment of adult patients with germline BRCA-mutated metastatic adenocarcinoma of the pancreas without disease progression on at least 16 weeks of a first-line platinum-based chemotherapy regimen such as FOLFIRINOX and cisplatin-based chemotherapy. This way, olaparib became the first drug to be approved as a maintenance treatment for pancreatic cancer and currently is a new weapon to improve PFS among BRCA-mutated PC patients.
