Efficacy and safety profile of nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic cancer treated to disease progression: a subanalysis from a phase 3 trial (MPACT)

Worldwide pancreatic cancer mortality and incidence rates are nearly equal [1]. In the United States and Europe, pancreatic cancer is the fourth leading cause of cancer-related mortality, with a 5-year survival rate of 7 % to 8 % among patients with all disease stages [2‐4]. Surgical resection offers the only curative treatment for pancreatic cancer; however, only 15 % to 20 % of patients are candidates for surgery at diagnosis [5]. Even when an R0 resection is achieved, many patients will relapse within 2 years, and it is likely that distant micrometastases have already been established in the ≈ 15 % to 20 % of patients believed to be surgery candidates [6, 7]. According to the Surveillance, Epidemiology, and End Results Program, 52 % of patients with pancreatic cancer are diagnosed with metastatic disease, which portends a 2.6 % 5-year survival rate [4].

At the metastatic stage, the goals of treatment are to palliate symptoms and prolong survival [7]. Since the phase 3 trial nearly 20 years ago [8] that led to the approval of gemcitabine (Gem), numerous phase 3 trials of Gem combination regimens have failed to demonstrate a clinically and statistically significant survival benefit compared with Gem monotherapy in patients with metastatic pancreatic cancer [9‐16]. Recently, 2 regimens, FOLFIRINOX (folinic acid + 5-fluorouracil [5-FU] + irinotecan + oxaliplatin) and nab-paclitaxel (nab-P) + Gem, demonstrated significantly longer survival compared with Gem alone [17‐19]. The phase 3 MPACT trial (ClinicalTrials.gov NCT00844649) demonstrated superior efficacy of nab-P + Gem compared with Gem alone for all trial endpoints, including the primary endpoint, overall survival (OS; median, 8.7 vs 6.6 months; hazard ratio [HR], 0.72; P < 0.001) in patients with metastatic pancreatic cancer and Karnofsky performance status ≥ 70 [18, 19]. In the MPACT trial, grade ≥ 3 adverse events (AEs) were effectively managed by dose reductions and delays.

Although results from the phase 3 PRODIGE and MPACT trials were encouraging [17, 19], the regimens are not recommended for all patients with metastatic pancreatic cancer. A retrospective analysis found that 75 % of real-world patients with metastatic pancreatic cancer did not meet the PRODIGE trial inclusion criteria, with performance status, age, and elevated bilirubin levels being the main reasons for ineligibility [20]. The inclusion criteria of the MPACT trial [18] allowed for nab-P + Gem to be administered to a wider range of patients, including older patients or those with poorer performance status. Because nab-P + Gem has now become the most commonly used first-line chemotherapy option for patients with metastatic pancreatic cancer in the United States [21], it is important to better understand how to achieve the optimal benefit with this regimen. Per protocol, patients in MPACT were treated until progressive disease (PD) or unacceptable toxicity. The current exploratory analysis investigated characteristics and outcomes of patients who were treated until PD as assessed by radiological imaging.

This subanalysis provides evidence that the nab-P + Gem combination is an active first-line treatment option with significant clinical efficacy for patients with metastatic pancreatic cancer because the majority of patients were treated until PD, which was associated with longer survival compared with the ITT population. Treatment until PD allowed better efficacy (as assessed by OS and disease control), likely due to the longer treatment duration and greater treatment exposure these patients received compared with those in the ITT population [18]. In addition, more than half of the patients who were treated to PD received a subsequent therapy, indicating that nab-P + Gem was also a feasible first-line option on which a treatment plan can be built. Conversely, ≈ 20 % of patients in the study discontinued treatment due to AEs in the absence of PD, which limited their treatment exposure and potential efficacy benefit.

A detailed examination revealed interesting differences in the relationships of reason for discontinuation, treatment exposure, and efficacy between the 2 treatment arms. Among patients who received nab-P + Gem, there was greater efficacy in terms of OS, PFS, and ORR between patients treated until PD vs the ITT population. Conversely, although there was a survival benefit in the Gem-alone arm between patients treated until PD vs the ITT population, the difference in PFS and ORR between the 2 cohorts was modest. The difference in treatment duration between patients treated until PD and the overall treated population was numerically longer for those who received nab-P + Gem compared with Gem alone (1.4 vs 0.8 months). The cumulative Gem dose in the PD cohort was 14 % and 11 % higher than that in the overall treated population for the nab-P + Gem and Gem-alone arms, respectively; however, the cumulative nab-P dose was 22 % higher for the PD cohort than the overall treated cohort for the combination arm (Table 3). These data raise the intriguing but speculative question of whether exposure to nab-P vs Gem imparts a greater relative treatment benefit.

Adverse events associated with chemotherapy are routinely managed by dose modification. A post hoc analysis of patients who underwent dose reductions or delays in the MPACT trial demonstrated that OS was significantly longer for those with vs without dose modifications [22]. Thus, mitigating AEs associated with nab-P + Gem through dose modification is not detrimental to treatment efficacy. The present analysis reveals that patients who were treated until PD had more dose reductions and delays compared with those in the ITT population, which suggests that effective treatment management may have allowed them to continue to receive and benefit from therapy.

The most common reasons for discontinuation due to AEs in the combination arm were peripheral neuropathy, fatigue, and thrombocytopenia. Rates of grade 3 peripheral neuropathy were relatively similar among patients treated to PD or AEs and the overall treated population, as were rates of grade 2 peripheral neuropathy. Management of peripheral neuropathy is accomplished by pausing treatment or reducing the treatment dose. Interestingly, in the MPACT trial, OS was significantly longer among patients who developed grade 3 peripheral neuropathy vs those who did not develop peripheral neuropathy [23]. Furthermore, dose modification was frequently used for patients who developed grade 3 peripheral neuropathy (≥1 dose delay [80 %] and/or reduction [41 %]). This approach for the management of peripheral neuropathy led to longer treatment duration, and ultimately, greater treatment exposure, which likely influenced survival outcomes. Collectively, these results underscore the importance of AE management through dose modification.

Analysis of treatment effect by ORR is a direct measurement of antitumour activity and, unlike OS, which can be confounded by subsequent therapies, improvements in ORR can be directly attributed to the ongoing treatment [24]. Progression-free survival encompasses time to disease progression or death [24] and represents an important aspect of palliative treatment pancreatic cancer. Patients treated to AEs in the absence of PD still experienced treatment benefit, as evidenced by ORR and PFS analyses, which suggests that management of AEs before the need for discontinuation may have prolonged treatment and potentially increased survival. The shorter OS in patients treated to AEs is likely due to the shorter treatment duration and infrequent use of subsequent therapies among patients in this cohort. It also remains unanswered whether any of these patients could have resumed therapy outside of a protocol requirement, in which strict rules apply for AE management and treatment discontinuation.

Historically, treatment beyond first line has been an option for a subset of patients with metastatic pancreatic cancer [25, 26]. Several randomized phase 2 clinical trials have explored second-line chemotherapy use in patients with metastatic pancreatic cancer [27‐30]. Patients enrolled in these trials were all previously treated with Gem or Gem-based regimens, and efficacy results were modest. The current analysis, although not specifically designed to test this hypothesis, shows that, in the treatment-to-PD cohort, OS was numerically longer among patients who received a subsequent therapy compared with those who did not, regardless of treatment arm. The longest OS was achieved by those who received first-line nab-P + Gem followed by a subsequent therapy. A hypothetical explanation might be that first-line treatment with nab-P + Gem reduced tumor burden, which decreased cancer-related symptoms and ultimately allowed greater use of second-line therapies. These types of comparisons must be interpreted cautiously given the possibility of differences in patient characteristics, such as performance status, at the end of first-line treatment. However, > 50 % of patients who were treated to PD were able to receive subsequent therapy, which supports the suitability of nab-P + Gem as a first-line treatment for metastatic pancreatic cancer.

The results presented herein emphasize that first-line treatment with nab-P + Gem can be optimized for maximum treatment benefit. As revealed by previous subanalyses of the MPACT trial, effective AE management (ie, by treatment delay or dose reduction) allows for longer treatment duration, which, in turn, increases treatment exposure [22, 23]. Therefore, physicians should pay close attention to and promptly address AEs, when possible, to allow treatment to PD. This MPACT subanalysis reveals that most patients treated to PD were able to achieve adequate treatment exposure while managing AEs, which translated to improved disease control and longer survival.