State of the Art for Metastatic Pancreatic Cancer Treatment: Where Are We Now?

First-line Therapies

One of the most important years in the history of metastatic PDAC treatment is 1997, because then, chemotherapy with gemcitabine became the standard of care demonstrating clinical benefit and a moderate improvement in survival in comparison to 5-fluorouracile (5-FU) (5). Another turning point in the treatment of metastatic PDAC arrived with the evidence that the FOLFIRINOX regimen had a better efficacy than gemcitabine alone. The overall survival (OS) was 11.1 months in the FOLFIRINOX group and 6.8 months in the gemcitabine group (hazard ratio (HR) for death, 0.57; 95% confidence interval(CI)=0.45-0.73; p<0.001) (6, 7). Though, because of the higher rate of toxicity, it remains a treatment indicated for fit patients with good performance status.

There is no direct comparison between the FOLFIRINOX and the gemcitabine-nab-paclitaxel regimen. It has been shown that the last combination is better than gemcitabine alone in metastatic PDAC patients (7, 8). The median OS was 8.5 months for the addition of nab-paclitaxel to gemcitabine and 6.7 months in the gemcitabine-alone group. Due to better toxicity profile, the regimen with gemcitabine and nab-paclitaxel is suitable even for patients with low Eastern Cooperative Oncology Group (ECOG) performance status (Table I).

Second-line Therapies

Second-line therapy of metastatic PDAC has to be considered in the terms of risks and benefits for the patient. The choice of chemotherapy (CT) regimen depends on patient's performance status (PS) and on prior treatment (7).

In patients with good PS and a good respond to first line CT, the available options are the “wait & see” approach or the consideration of surgical resection of the residual disease, if possible. In patients with progression of disease at the first line CT and good PS, the available options include chemoradiation, with capecitabine or 5-FU, or stereotactic body radiation therapy (SBRT) if not previously given and if the primary site is the sole site of progression or CT. The CT regimens depend on prior CT: in patients previously treated with gemcitabine-based therapy, second line CT might include FOLFIRINOX schedule (5-FU/folinic acid/oxaliplatin/irinotecan), FOLFOX schedule (5-FU/folinic acid/oxaliplatin) or FOLFIRI schedule (5-FU/folinic acid/irinotecan). In patients treated with first-line fluoropyrimidine-based therapy, gemcitabine and albumin-bound paclitaxel is the favourite schedule for patients with good PS, even if some regulatory prescription difficulties exist for nab-paclitaxel as second line treatment. In patients with poor PS, single agent CT schedule with gemcitabine, capecitabine or 5-FU are preferred. In patients with BRCA1/2 gene mutation, 5-FU can be combined with platinum salts (in particular carboplatinum) as second-line CT. In patients with PS of 3/4, with significant comorbidities and a very short life expectancy, palliative and supportive care and a symptomatic treatment are the only therapies to be considered (9). The use of new drugs, alone or combined with standard CT, should be tested in clinical trials to find new therapeutic strategies for patient with PDAC.

However, even after resection with curative intent, the prognosis of the majority of PDAC patients remains poor. Extensive clinical trials using targeted therapies are needed to find new approaches to improve the response rate of patients with PDAC.

EGFR-inhibitors

The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase (TK) receptor. After its activation through ligand binding, it can regulate several downstream signaling pathways which regulate cell proliferation, survival, and apoptosis. Activation of EGFR is a significant event in PDAC development. KRAS is an effector molecule responsible for signal transduction from ligand-bound EGFR to the nucleus. In fact, ERK pathway activation promotes tumor transformation after an initial K-RAS mutation (10).

Two classes of EGFR inhibitors have been developed for anticancer treatment: tyrosine-kinase inhibitors (gefitinib, erlotinib) and EGFR monoclonal antibodies (cetuximab, panitumumab). Erlotinib in combination with gemcitabine as first-line treatment for non-resectable PDAC showed small benefit in OS of PDAC patients (11). EGFR tissue status was not associated with patients' outcome (12). Further, the combination of cetuximab and gemcitabine has been investigated in a phase III trial (13). No significant difference was seen between the two arms in median survival (6.3 months for the combination with gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine monotherapy arm; HR=1.06, p=0.23) (Table II) (13).

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Figure 1.

Inhibition of EGFR and VEGF in PDAC. The EGFR is a transmembrane tyrosin kinase receptor. After its activation through ligand binding, it can regulate several downstream signaling pathways which regulate cell proliferation, survival, and apoptosis. Two classes of EGFR inhibitors have been developed for anticancer treatment: tyrosine-kinase inhibitors (e.g. erlotinib) and EGFR monoclonal antibodies (e.g. cetuximab). MEK-inhibitors and anti-HER agents have been studied in monotherapy or combinations, as described in detail in the text. The VEGF is an important factor involved in angiogenesis. Bevacizumab is an anti-human VEGF monoclonal antibody, regorafenib, foretinib and sunitinib are multiple kinase inhibitor suppressing vascular endothelial growth factor receptor.

Over 90% of PDAC patients harbor somatic mutations in K-RAS. This genetic alteration leads to MAPK effector activation that are responsible for resistance to anti- EGFR therapies (14). To overcome this resistance mechanism, the addition of erlotinib to MEK-inhibitor (selumetinib) has been investigated in a phase II clinical trial (15). Poteet et al. have investigated a combination of EGFR inhibitors (cetuximab, gefitinib) with trametinib (MEK-inhibitor) and concluded that this combination could present a novel effective treatment for PDAC (16). Moreover, the authors found possible predictors of sensitivity to EGFR-inhibitors (mesothelin and TGF-α) (17).

HER2 amplification was found in 2-29% of patients with PDAC (6). The anti-HER2 therapeutic approach has also been investigated in PDAC patients. In a phase II trial, 17 PDAC patients with HER2 overexpression (IHC3+ or IHC2+ with HER2 gene amplification) were treated with capecitabine combined with trastuzumab (18). Unfortunately, this treatment did not prolong survival of patients compared to standard chemotherapy. The role of novel anti-HER agents in PDAC remains to be explored. The possibilities of EGFR pathway inhibition are shown in Figure 1.

VEGF Inhibitors

It's well known that angiogenesis is a crucial process through which cancer can grow and spread to other organs. Many studies have investigated angiogenesis in order to understand its role as a target in the therapy for cancer. Vascular endothelial growth factor (VEGF) is an important factor involved in angiogenesis and it has been shown that it is overexpressed in over 90% of patients with PDAC (19). Bevacizumab is an anti-human VEGF monoclonal antibody with an anti-tumor activity. A phase III trial of the Cancer and Leukemia Group B (CALGB 80303) explored the effect of the combination of bevacizumab with gemcitabine versus gemcitabine alone in advanced PDAC and produced disappointing results, because there was not improvement in survival (20). In another phase II trial, Astsaturov et al. investigated the effects of the combination of bevacizumab with docetaxel in patients previously treated for metastatic pancreatic adenocarcinoma, and showed that bevacizumab showed no benefit in gemcitabine-refractory metastatic PDAC (21). Regorafenib, which is an oral multi-kinase inhibitor that has also antiangiogenic activity, is currently under investigation because of its action as an anti-VEGF. Therefore, in an ongoing phase II trial (NCT02080260), regorafenib is administered in metastatic PDAC patients who progressed after prior chemotherapy with gemcitabine and progression-free survival (PFS) is evaluated. Regorafenib is being also evaluated in combination with gemcitabine (NCT02383433) in metastatic PDAC in a phase II ongoing trial trying to assess PFS, recurrence rate (RR) and OS. A novel drug combination with anti-angiogenic activity, TL-118 is tested in an ongoing phase II trial in combination with gemcitabine to treat metastatic PDAC and efficacy, safety and tolerability is evaluated. The administration of TL-118 seems to have encouraging results in PFS in clinical practice (22). Foretinib is another multiple kinase inhibitor suppressing vascular endothelial growth factor receptor-2 (VEGFR-2) which has demonstrated ability to inhibit tumor growth in vivo (23). Sunitinib is a tyrosine kinase inhibitor which has improved PFS in the maintenance setting in metastatic pancreatic cancer (hazard ratio (HR) 0.51 (95% confidence interval (CI)=0.29-0.89), p-value<0.01). (9) Ziv-aflibercept is a recombinant fusion protein which blocks VEGF-A, VEGF-B and P1GF. A phase III trial showed that the drug didn't improve OS in pancreatic cancer when compared to gemcitabine alone (Table III) (24). The possibilities of VEGF pathway inhibition are shown in Figure 1.

It seems that specific therapy targeting only VEGF will not enter clinical practice. Additional studies are needed to understand the molecular pathways in PDAC. The inhibition of multiple targets could lead to more encouraging results.

Immunotherapy

Despite therapeutic success of immunotherapy in some advanced solid tumors, similar results have not been obtained with PDAC patients. In fact, PDAC is known to be a poorly antigenic tumor and consequently not immunogenic (25). However, many studies have shown that the human immune system can develop a response to PDAC (26, 27). It is assumed that the tumor environment might have a leading role in escaping immune surveillance (25). On this basis, many ongoing trials evaluate immunotherapy alone or in combination with other agents.

A phase II trial evaluated ipilimumab, a human monoclonal antibody that inhibits CTLA-4 in order to develop a T-cell activation, in patients with advanced PDAC. There was a delayed response only in one patient, suggesting no evident improvement. One of the most recent antibodies is anti-PD-L1. Blocking PD-L1 from its interaction with PD-1 facilitates immune response to tumor. Furthermore, it has been shown that TGF-β up-regulates PD-L1 gene transcription (28). An ongoing phase IB/II single-arm study (NCT03451773) evaluates the effect of an investigational drug (M7824) with a dual activity against TGF-beta signaling and PD-L1 inhibition in patients previously treated for PDAC. GVAX is a granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine (25). In a phase II trial GVAX was administered in sixty PDAC resected patients in combination with chemoradiation. The median disease-free survival (DFS) was 17.3 months (95%CI=14.6-22.8), showing no significant difference in OS when compared to the historical controls treated with adjuvant chemoradiation therapy alone (29). Many trials investigate the efficacy of antibody with immunogenic activity in combination with standard chemotherapy. A phase Ib trial evaluating the administration of gemcitabine with escalating doses of CTLA-4 inhibitor (Tramelimumab) showed OS 7.4 months (95%CI=5.8-9.4 months) (30). Another phase I trial compared the effect of a CCR2 inhibitor (PF-04136309), an antagonist of the chemokine receptor to FOLFIRINOX in the first arm, with that of FOLFIRINOX alone in the second arm. The results showed that the combination was safe and tolerable and furthermore, the CCR2 inhibitor was able to reduce tumor associated macrophages (Table IV) (31).

Understanding the complexity of PDAC environment may lead to more effective and more personalized therapy and most of all it could help to overcome the poor immunogenicity of PDAC.

PARP-inhibitors

The importance of genes implicated in DNA damage response or repair pathways in tumor development has been highlighted by the discovery of an increased susceptibility to breast and ovarian cancer in patients harboring germline mutations in BRCA1 and BRCA2 genes. The presence of BRCA1 and BRCA2 mutations increase also the risk of PDAC (32, 33). In order to maintain genomic integrity, cells deploy several mechanisms that detect and repair DNA lesions. Among them, poly(ADP-ribose) polymerase-1 (PARP1) is a family of enzymes that plays import role in DNA damage repair (32). PARP-inhibitors (PARPi), such as olaparib and niraparib have already been approved and are being used in the treatment of the breast and the ovarian cancer with BRCA mutations. As small percentage of PDAC patients harbors BRCA1/2 mutations, there is a rationale of using PARPi as anticancer agents also in PDAC (11). Kaufman et al. treated patients with different tumor types (including PDAC) associated with germline BRCA1/2 mutations with olaparib. The results were challenging, supporting the hypothesis that targeting this mutation is effective regardless of the organ of origin, including PDAC (34-35). Lowery et al. have evaluated the efficacy of veliparib, another PARPi, in patients with germline BRCA or PALB2 mutations who were pretreated for PDAC. The mOS was 3.1 months and the PFS pf 1.7 months (36) Moreover, rucaparib has also been investigated in a phase II single-arm study as single-agent in PDAC patients with BRCA mutations (both somatic and germline), as summarized in Table V (37). Other clinical trials are ongoing to evaluate the efficacy of PARPi in untreated patients with PDAC. Very recently, results from the phase III POLO trial have been presented at the American Society of Clinical Oncology's (ASCO's) 2019 annual meeting. 154 metastatic PDAC patients with germline BRCA mutations were treated with olaparib after platinum-based chemotherapy. PFS were doubled (3.8 vs. 7.4 months), though data for OS were not available. Moreover, the proportion of PDAC patients who had not progressed after two years was increased from 9.6% to 22.1% (38).

Other Approaches

The most common altered genes and pathways include K-RAS, cell cycle and TGF-β pathway. Moreover, even if less common, alterations in DNA repair, WNT signaling, chromatin, RNA processing and Notch signaling have been studied and targeted in several clinical trials. K-RAS mutations are found in 90% of PDAC, CDKN2A mutations in 63%, SMAD4 in 33% and TP53 in 26% (1-4, 7). Most of these mutations or altered signaling pathways have been targeted in clinical trials by stem cell inhibitors, CDK4/6 inhibitors, insulin-like growth factor inhibitors, tropomyosin receptor kinase inhibitors, and STK11 pathway inhibitors. Moreover, exploring the efficacy of drugs targeting stroma, macrophages or metabolism is an interesting approach for PDAC treatment (1-4, 7).

Recently, TGF-β inhibitors have been investigated in clinical trials with promising results. The TGF-β pathway is altered in 14% of PDAC patients (1-4, 7). Alteration of this pathway results in phosphorylation of SMAD proteins which are often mutated in PDAC and subsequently affects cell differentiation, tumor migration and invasion (1-4, 7). Galunisertinib contrasts the three ligands of TGF-β and its efficacy has already been investigated as monotherapy or in combination with other agents (gemcitabine, durvalumab). The combination with the immune checkpoint inhibitor PD-L1 seems to be interesting, as it has been shown that TGF-β up-regulates PD-L1 gene transcription (1-4, 7).