Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma

Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a lethal disease with a median survival duration of less than 1 year [1‐4]. While two combination regimens, FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) and nab-paclitaxel/gemcitabine are used as standard therapies, the median survival associated with these regimens is less than a year, hence the need to seek other novel therapeutic approaches [5]. Progress in basic and translational immunology has confirmed the importance of controlling the immune system in cancer progression and in its treatment, and has renewed an interest in immune-based therapy for various cancers, including PDAC.

The main cellular components contributing to the immunosuppressive microenvironment include myeloid-derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), mast cells, and T-regulatory cells (Tregs) [6, 7]. MDSCs comprise a heterogeneous population of immature cells of myeloid lineage that are considered to be key in orchestrating the suppressive tumor microenvironment. MDSC prevalence is increased in the peripheral blood and in the tumor microenvironment of patients with solid tumors, including PDAC [8]. In solid tumors, the number of circulating MDSCs significantly correlates with clinical state and metastatic tumor burden [9] and, in mice, reduction of MDSCs by inhibition [10] or deletion [11, 12] of factors that promote MDSC expansion has been shown to improve antitumor immune response [10], reduce primary and metastatic tumor progression [11], and abolish the tumor-promoting activity of MDSCs [11]. The pharmacologic modulation of MDSCs and prevention of their appearance or infiltration in solid tumors represent potential novel and innovative therapeutic strategies in cancer [10, 13‐18].

In murine models of pancreatic cancer, it has been shown that MDSCs are upregulated in the tumor-bearing host, promote tumor growth, and suppress antitumor immunity [8]. The chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) signaling axis contributes to tumor progression through CCR2-mediated MDSC recruitment and/or accumulation [19‐21]. PF-04136309, an orally administered CCR2 inhibitor, could block CCR2-mediated signal transduction, chemotaxis, and CCL2 binding in human monocytes and human whole blood. In addition, tumor-bearing wild-type mice treated with a CCR2 inhibitor demonstrated a significant decrease in liver metastasis compared with vehicle or gemcitabine-only treated mice [8]. These results suggest that CCR2 is a promising therapeutic target in PDAC, a condition associated with a marked upregulation of MDSCs in the tumor microenvironment in both mouse models and patients.

Previously, a phase Ib study demonstrated the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX significantly increased the proportion of patients achieving partial response (PR) compared to that anticipated with FOLFIRINOX alone [22]. The study also demonstrated the clinical activity of PF-04136309 correlated with an accumulation of CCR2+ inflammatory monocytes (IM) in the bone marrow, reduced levels of IM in peripheral blood, and decreased TAM in tumors. These encouraging results prompted the current study, which assessed the efficacy, safety, and tolerability, as well as the pharmacokinetics (PK) and pharmacodynamics, of PF-04136309 combined with nab-paclitaxel/gemcitabine in patients with mPDAC.

mPDAC is a lethal disease with poor 5-year survival and is projected to be the second leading cause of cancer death by 2020 in the United States [23, 24]. Although both FOLFIRINOX and gemcitabine combined with nab-paclitaxel improve patient survival and disease response compared with single-agent gemcitabine, there is an immunosuppressive tumor microenvironment directed in part by the CCL2/CCR2 axis. Since the degree of therapeutic resistance with metastatic spread affects the lethality of aggressive cancers, understanding and targeting the mechanisms that are responsible for chemoresistance is critical to improving therapeutic outcomes. Immunologic targeting, in particular, is considered a key to effective treatment of this refractory disease [25, 26].

In a prior phase II study, patients with previously untreated advanced pancreatic cancer dosed with 125 mg/m² nab-paclitaxel plus 1000 mg/m² gemcitabine on days 1, 8, and 15 every 28 days reported grade ≥ 3 TEAEs of neutropenia, leukopenia, thrombocytopenia, and anemia [27], with a median progression-free survival and overall survival of 7.9 months and 12.2 months, respectively. In the current study, we observed similar grade ≥ 3 hematologic TEAEs (except thrombocytopenia) with PF-04136309 500 mg BID in combination with nab-paclitaxel/gemcitabine and following the same dosing and treatment schedule as the previously reported phase II study [27].

In addition to those hematologic TEAEs, we observed three patients with grade 3 pneumonitis, one patient with grade 4 hypoxia, and one patient with grade 5 pneumonia among the 21 patients in the current study. The patient with grade 5 pneumonia received PF-04136309 500 mg BID in cycle 1 through day 16, and was hospitalized due to pneumonia 6 days later. It is important to note that both nab-paclitaxel and gemcitabine have a known association with pulmonary toxicity, mainly pneumonitis, both alone and in combination (synergistically). An observed rate of pneumonitis in patients treated with gemcitabine was approximately 1% and was elevated up to 4% when combined with nab-paclitaxel [3], leading to a high level of morbidity. Furthermore, advanced-stage disease, smoking, and alcohol consumption, and possibly underlying lung disease, can be potential risk factors of gemcitabine-related pneumonitis [28]. Infections, in particular, are frequent complications in patients with malignancies. Although relevant laboratory information was not available, bone-marrow suppression, as a predisposing factor for infection as well as dyspnea and pneumonitis, is a common side effect of nab-paclitaxel and gemcitabine. The patient with grade 5 pneumonia was a smoker and thus had an additional predisposing factor for respiratory tract infections. Nevertheless, we observed a relatively high incidence (24%) of pulmonary toxicity in this study, whereas no pulmonary events have been reported in patients administered PF-04136309 as a single agent in non-oncology studies (N = 178: 76 healthy volunteers and 102 patients) and in 39 patients with advanced PDAC treated with PF-04136309 in combination with FOLFIRINOX [22]. Some of the pulmonary toxicity observed in this study may have been caused by the combination between PF-04136309 and gemcitabine with nab-paclitaxel.

Multiple measures may need to be undertaken in order to further understand these pulmonary events. The clinical outcome would likely depend on the particular macrophage populations involved (immune regulatory vs. pro-immune) and characteristics of the local tissue environment, since the mechanism of action of PF-04136309 is the inhibition of the trafficking of IMs from the bone marrow to the tumor, resulting in the depletion of TAMs from tumor microenvironment, enhancing antitumor immunity [22]. On the other hand, depletion of macrophages from healthy tissues could theoretically increase the probability of autoimmune-mediated inflammation or, alternatively, the probability of infection, potentially elevating the risk of gemcitabine-related pneumonitis. Further validation by a larger study is necessary to clarify mechanisms of pulmonary toxicity, which may be caused by the combination of nab-paclitaxel, gemcitabine, and PF-04136309.

Previous phase II and III studies in patients with PDAC demonstrated that a regimen of nab-paclitaxel plus gemcitabine had tolerable adverse effects with antitumor activity [27] and improved patients’ survival and response rate [3] compared with gemcitabine alone. PF-04136398 in combination with FOLFIRINOX was shown to be well-tolerated and demonstrated clinical activity in patients with borderline resectable and locally advanced pancreatic cancer [22]. In the present study, although the efficacy of PF-04136309 in combination with nab-paclitaxel/gemcitabine could not be evaluated adequately in a small patient population, based on all 21 patients, an ORR of 23.8% was observed; the ORR for the 500 mg BID treatment group (n = 17) was 29.4%.

The hypothesized mechanism of action of PF-04136309 is the inhibition of CCL2-induced trafficking of IM from the bone marrow to the tumor. Three components of this proof of mechanism are the depletion of TAM from the tumor, a decrease of CD14 + CCR2+ IM in the peripheral blood, and the accumulation of CD14 + CCR2+ IM in bone marrow. Although we observed a drop of CD14 + CCR2+ IM in peripheral blood, a decrease of CCR2+ TAM in the tumor was only observed for two patients and is inadequate to support a definitive conclusion about this component of the mechanism of action. Further, an accumulation of CCR2 + CD14+ IM in the bone marrow did not take place at week 6 post dose compared with baseline, unlike a previous study examining the combination of PF-04136309 with FOLFIRINOX [22]. The lack of accumulation of IM in the bone marrow can be explained in part by the previous observation that gemcitabine treatment resulted in persistence of IM in the peripheral blood of patients [8], thus possibly counterbalancing the effect of PF-04136309 with regard to IM maintenance in the bone marrow.

A recent study that analyzed patient samples and mice with established orthotopic tumors demonstrated that patients with non-metastatic PDAC administered a CCR2 inhibitor showed a compensatory influx of C-X-C motif chemokine receptor 2 [CXCR2] + tumor-associated neutrophils (TAN), an increase that correlates with poor prognosis in PDAC [29]. Targeting CCR2+ TAM and CXCR2+ TAN in combination caused influx of both CD8+ and CD4+ T cells in the tumor microenvironment, improving antitumor immunity and reducing tumor burden [29]. In the present study, one patient who received PF-04136309 had an increase in programmed cell death protein 1 (PD-1) + CD4+ and PD-1 + CD8+ cells in the tumor biopsy sample (data not shown), suggesting PF-04136309 also modulated PD-1 immune checkpoint in mPDAC. These results imply CCR2 inhibition reprogrammed the immunosuppressive tumor microenvironment and that tumor-induced immune plasticity in response to treatment with CCR inhibitors may be responsible for therapeutic resistance.

Although our data are limited by the nonrandomized design and small sample size, some clinical activity was observed with the combination of PF-04136309 and nab-paclitaxel/gemcitabine; nonetheless the combination had a safety profile that raises concern for synergistic pulmonary toxicity in patients with mPDAC. Inhibition of CCR2 by treatment with PF-04136309 in the presence of nab-paclitaxel/gemcitabine resulted in a drop of IM in peripheral blood and tumor, but unexpectedly did not accumulate IM in the bone marrow, possibly due to compensatory activity by gemcitabine.