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A Review of Recent Real-World Evidence Data in Metastatic Pancreatic Cancer

Web Exclusives - Pancreatic Cancer

Pancreatic cancer is a malignancy that is usually difficult to treat, frequently presents at an advanced stage, and is associated with a high mortality rate. The most common type of pancreatic cancer, pancreatic ductal adenocarcinoma, which accounts for most of pancreatic cancers, begins when abnormal exocrine cells in the pancreas start to multiply rapidly. Pancreatic cancers are relatively uncommon but are associated with high mortality.

In 2019, approximately 57,000 people in the United States are estimated to be diagnosed with pancreatic cancer and 46,000 will die of the disease, making it the fourth most common cause of cancer-related death.1,2 The human toll of pancreatic cancer is further emphasized by the high death rate associated with this disease. Pancreatic cancer accounts for 3.2% of all new cancer cases in the United States, and yet it will cause more than twice the rate (7.5%) of all cancer deaths; moreover, within 5 years of diagnosis, fewer than 1 of 10 patients (9.3%) with pancreatic cancer will still be alive.3

These mortality statistics are largely because of the late-stage presentation of this malignancy.4 Pancreatic cancer is usually asymptomatic at its early stages, and when symptoms become apparent, they are often mistaken for signs of other conditions.2 As a result, more than half (53%) of the patients with pancreatic cancer have distant metastasis at diagnosis compared with only 10% of patients whose disease is confined to the pancreas; therefore, only a minority of patients are candidates for potentially curative surgery.2,3

Even when surgical resection is possible, disease recurrence is common; according to a recent review, pancreatic cancer is associated with “inevitably dismal rates of long-term survival.”4 Adding more gravity to this landscape, the incidence of pancreatic cancer is on the rise.3

The median age at diagnosis of this cancer is 70 years, with a slightly higher incidence rate among men than women, and among African-American patients than other races and ethnicities.3 In addition to age, sex, and race, other risk factors have been identified, including body mass index, periodontal disease, smoking, alcohol consumption, and exposure to chemicals and heavy metals.2

Treatment Landscape

According to the National Comprehensive Cancer Network (NCCN), systemic therapy should be used for all stages of pancreatic cancer, even when surgical resection is possible.2 For the first-line treatment of metastatic disease, the NCCN recommends either a combination of fluorouracil (5-FU), leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) or the combination of gemcitabine plus nab-paclitaxel as preferred category 1 options in patients with good performance status.2 Although FOLFIRINOX is only recommended for patients with an Eastern Cooperative Oncology Group performance status of 0 or 1, gemcitabine may be given to those with a score as high as 2.2 Two notable phase 3 trials, MPACT and PRODIGE,5,6 led to these first-line treatment recommendations.

The MPACT trial, which included 861 patients, showed patients who received gemcitabine with albumin-bound paclitaxel had significantly longer median overall survival than patients who received gemcitabine alone (8.7 months vs 6.6 months, respectively).5 The benefits of adding albumin-bound paclitaxel also included a higher response rate and longer progression-free survival. In all, 4% of patients who received the combination therapy were alive after 3 years compared with no patients in the control arm, thereby supporting the possibility of long-term survival with gemcitabine-based combination regimens.5

The PRODIGE trial, which included 342 patients, compared the efficacy and safety of gemcitabine monotherapy with FOLFIRINOX.6 After a median follow-up of 26.6 months, the median overall survival was significantly longer among patients who received FOLFIRINOX instead of gemcitabine (11.1 months vs 6.8 months, respectively). The median progression-free survival outcomes also supported the superiority of FOLFIRINOX versus gemcitabine monotherapy (6.4 months vs 3.3 months, respectively).6

Although a subsequent meta-analysis concluded FOLFIRINOX was superior to gemcitabine with albumin-bound paclitaxel,7 concerns remained that FOLFIRINOX was associated with toxicities that limited its use and interrupted therapy.8 Therefore, efforts were made to alter FOLFIRINOX, which led to a number of modified FOLFIRINOX regimens that either reduced the doses of the component agents or eliminated the 5-FU bolus.8 A subsequent meta-analysis concluded these modified regimens offered efficacy that compared with the original FOLFIRINOX regimen, but with a more tolerable safety profile.8

A variety of regimens are available as second-line therapy for pancreatic cancer, although the only NCCN category 1 recommendation for patients with metastatic disease is a combination of liposomal irinotecan (nal-IRI) plus 5-FU and leucovorin, which should be prescribed after first-line gemcitabine-based therapy in patients with good performance status.2 The unique component of the nal-IRI regimen is described in greater detail in the next section.

Category 2a NCCN recommendations for second-line and later treatment include FOLFIRINOX or modified FOLFIRINOX; nal-IRI plus 5-FU and leucovorin; irinotecan plus 5-FU and leucovorin (FOLFIRI); leucovorin, 5-FU, and oxaliplatin (FOLFOX); oxaliplatin with 5-FU and leucovorin; capecitabine plus oxaliplatin; capecitabine monotherapy; or continuous infusion 5-FU.2

Liposomal Irinotecan: Mechanism of Action and Efficacy

Irinotecan is an inhibitor of the enzyme topoisomerase 1, which causes single-strand breaks in DNA to relieve torsional strain.9 When topoisomerase 1 is inhibited, single-strand breaks cannot be repaired, leading to double-strand DNA damage and, ultimately, to cell death.9 Technically, irinotecan is a prodrug, and its action results from its active metabolite, SN-38, which is converted from irinotecan by enzymes concentrated in the liver and colon.10

Although conventional irinotecan is effective against pancreatic cancer and therefore is still used as part of the FOLFIRINOX regimen, its use may be limited by toxicity.2,10 Previous successes in oncology by encapsulating agents in carriers (eg, albumin-bound paclitaxel), which can improve safety and efficacy by limiting the degradation and volume of distribution while increasing drug concentrations in tumor tissue, led investigators to develop nal-IRI, which is a liposomal formulation of irinotecan (Figure 1).10-12

Figure 1

This formulation was first validated by preclinical research, which showed nal-IRI outperformed conventional irinotecan via superior pharmacokinetics. Specifically, compared with conventional irinotecan, a 5-fold lower dose of nal-IRI was needed to achieve the same level of the active metabolite SN-38 in tumor tissue, while simultaneously providing greater anticancer activity.10 Subsequent clinical trials, which will be described below, have since added clinical support to these early data.

The US Food and Drug Administration (FDA) approved nal-IRI based on the findings from the phase 3 NAPOLI-1 trial, a global, randomized, open-label study of 417 patients with metastatic pancreatic ductal adenocarcinoma who received gemcitabine-based therapy.13,14 The patients were divided into 1 of 3 groups: 5-FU plus leucovorin (N = 149), nal-IRI monotherapy (N = 151), or nal-IRI plus 5-FU and leucovorin (N = 117).13 Survival analysis showed patients who received the triple combination of nal-IRI plus 5-FU and leucovorin had the best outcomes, with a median overall survival of 6.1 months, compared with 4.2 months for patients who received the combination of 5-FU and leucovorin, and 4.9 months with nal-IRI therapy alone. The most common grade 3 or higher adverse events in the triplet combination group were neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%).13

Recently, an update of this study showed these outcomes were maintained over an extended follow-up; at the 1-year mark, an estimated 26% of patients who received nal-IRI plus 5-FU and leucovorin were still alive compared with 16% of the patients who received 5-FU and leucovorin, which further supports the survival benefit gained by adding nal-IRI to the treatment regimen.15

In 2017, 1 year after the initial NAPOLI-1 results were published, Petrelli and colleagues conducted a retrospective meta-analysis comparing patients with pancreatic cancer who received second-line irinotecan-based therapies versus oxaliplatin-based therapies after first-line gemcitabine-based therapies.16 Using data from 24 studies, the investigators showed the 2 types of therapies had similar survival benefits, with irinotecan-based therapies offering a median overall survival of 5.5 months.16

Regarding nal-IRI specifically, Glassman and colleagues published a retrospective single-center study in 2018 that included 56 patients with advanced metastatic pancreatic cancer who received treatment at Memorial Sloan Kettering Cancer Center.17 Across all patients who received nal-IRI plus 5-FU and leucovorin, the median progression-free survival was 2.9 months and the median overall survival was 5.3 months. For second-line therapy, these times increased to 4.3 months and 8.4 months, respectively. Patients who had not been exposed to irinotecan previously or who did not have disease progression while taking nal-IRI had the best median overall survival outcomes, at 7.7 months and 9 months, respectively.17

When the entire sequence was evaluated, from first-line gemcitabine therapy through second-line nal-IRI–based therapy, the median overall survival across all patients was 23 months. The investigators concluded, “This real-world study supports the findings of NAPOLI-1, demonstrating the safety and efficacy of nal-IRI [plus] 5-FU [and] leucovorin for the treatment of advanced [pancreatic ductal adenocarcinoma] following gemcitabine-based chemotherapy.”17

In 2019, Tossey and colleagues conducted a single-center retrospective analysis comparing FOLFIRI with 5-FU, leucovorin, and nal-IRI.18 The study included 75 patients with locally advanced or metastatic pancreatic cancer, all of whom had received first-line gemcitabine-based therapy. Of the 75 patients, 35 received the nal-IRI regimen and 40 received conventional FOLFIRI. The survival trends favored nal-IRI in progression-free survival (4.1 months vs 3.1 months), overall survival (7.1 months vs 6.7 months), and time to nonresponse to treatment (4.1 months vs 2.2 months). However, no formal testing was conducted, and the study size was relatively small, precluding statistical significance and suggesting the findings should be interpreted with caution.18 It is also noteworthy that unlike the nal-IRI regimen, FOLFIRI has not been tested in a phase 3 setting. Collectively, these factors indicate this study should be considered for hypothesis-generating purposes only.

Although Tossey and colleagues also conducted a financial analysis in the same study and reported that nal-IRI was more expensive than FOLFIRI, these costs were based on observed time to nonresponse to treatment.18 Because time to treatment failure was almost twice as long among patients who received the nal-IRI regimen versus FOLFIRI (4.1 months vs 2.2 months, respectively), the costs of nal-IRI are expected to be comparatively higher. In addition, the costs of several other significant real-world expenses were excluded, including those for inpatient and ambulatory services and the costs of other medications, all of which may fluctuate based on the treatment regimen chosen, as described in greater detail later.18

Review of the Recent Observational Data in Metastatic Pancreatic Cancer

To date, limited observational data have been reported on metastatic pancreatic cancer treatment patterns, patient outcomes, and costs; however, the studies below offer some insight into real-world clinical decisions and the economic factors that influence them.

Sequencing Treatment for Metastatic Pancreatic Cancer

Clinical decisions in cancer care, including the sequence of agents delivered, are guided by a broad array of physician, patient, and contextual factors, such as physician expertise, patient beliefs, and insurance status, respectively.19 A review of decision-making in older adults with cancer identified at least 14 other factors, and as a result of a poor understanding of the possible interactions between them, ultimately concluded that no model exists to sufficiently characterize clinical decision-making in this area.19 Although physicians may turn to guidelines for assistance, the recommendations are not prescriptive.

The most recent NCCN guidelines list 5 first-line and 13 second-line recommended regimens for patients with metastatic pancreatic cancer who have good performance status, and not all of the therapies are approved by the FDA.2,20 All of the above factors explain why optimal treatment selection and sequencing remain unclear.17 In addition to clinical constraints, this lack of clarity may also affect US payers’ ability to make evidence-based treatment management decisions for patients with metastatic pancreatic cancer.

Regarding first-line treatment options for pancreatic cancer, in 2017, Braiteh and colleagues’ retrospective study compared the efficacy of albumin-bound (nab)-paclitaxel plus gemcitabine versus FOLFIRINOX or gemcitabine monotherapy for the first-line treatment of metastatic pancreatic cancer using registry data from a US community setting.21 Patients who received nab-paclitaxel plus gemcitabine had similar time to treatment discontinuation and registry database persistence as those who received treatment with FOLFIRINOX; however, the time to treatment discontinuation and database persistence were significantly longer with nab-paclitaxel plus gemcitabine than with gemcitabine monotherapy (3.4 months vs 2.2 months and 8.6 months vs 5.3 months, respectively). In addition, a higher rate of patients who received FOLFIRINOX or gemcitabine had adverse events of any grade versus patients who received nab-paclitaxel plus gemcitabine.21

Considering these results, the investigators concluded nab-paclitaxel plus gemcitabine is an appropriate first-line therapy for metastatic pancreatic cancer. The investigators also noted these results support earlier findings from the MPACT trial.5,21

In terms of later-line treatment options, a 2019 observational analysis by Kim and colleagues evaluated treatment sequences relevant to nal-IRI.22 The investigators compared patient outcomes with nal-IRI in the third-line setting or later after treatment with 5-FU and gemcitabine-based therapy (N = 121) versus nal-IRI in the second-line setting after gemcitabine-based first-line therapy (N = 129). Data analysis revealed the median overall survival times were longer when patients received nal-IRI in the second-line setting instead of the third-line setting (6.3 months vs 4.1 months, respectively; Figure 2),22 which suggests patients may benefit more from second-line nal-IRI therapy in this treatment setting.

Figure 2

As noted earlier, the real-world median overall survival time with the second-line use of nal-IRI (6.3 months) echoed the overall survival in the phase 3 NAPOLI-1 trial (6.2 months) and in the retrospective study by Glassman and colleagues (8.4 months).15,17,22 Consistency in the clinical and observational outcomes data lends further support for the NCCN’s recommendation for the use of nal-IRI in the second-line treatment setting.

Economic Considerations: Accounting for the US Payer Perspective

Most patients who are diagnosed with pancreatic cancer are older than age 65 years, so the majority of patients receiving systemic treatment for metastatic pancreatic cancer in the United States are eligible for Medicare, which means Medicare data can offer useful insight into real-world clinical outcomes and economic statistics.3

In 2019, Muldoon and colleagues reviewed more than 30,000 Medicare fee-for-service beneficiaries who were diagnosed with metastatic pancreatic cancer between 2013 and 2017, including treatment patterns, costs, and survival rates, based on line of therapy and chemotherapy regimen.23 As anticipated, therapy duration and 90-day survival rates decreased by line of therapy. However, the 90-day survival rate decreased only modestly across the lines of treatment, from 79% with first-line treatment to 73% with third-line treatment. When analyzing the average line of therapy cost by therapy, the cost varied by regimen from less than $15,000 to more than $30,000. As shown in Figure 3, the average line of therapy cost by regimen was comparable for FOLFIRINOX, nal-IRI, and gemcitabine plus nab-paclitaxel.23

Figure 3

Further claims-based analyses by Muldoon and colleagues showed that the use of nal-IRI as a second-line therapy was similar in total cost of care to first-line therapies and is budget neutral.24 The mean total Medicare Part A and Part B costs (excluding professional costs) totaled $32,447 for first-line nab-paclitaxel plus gemcitabine and $33,628 for first-line FOLFIRINOX, which were similar to the cost of nal-IRI ($35,010) in the second-line setting. As expected, the 90-day survival rates for second- and third-line treatment with nal-IRI were lower than with first-line gemcitabine and FOLFIRINOX, but the differences were modest.24

In another recent analysis of Medicare fee-for-service claims from 2019, Pelizzari and colleagues showed that nal-IRI had slightly higher total costs when used as a second-line treatment versus third-line treatment ($41,600 vs $36,810, respectively), but these costs were comparable with first-line FOLFIRINOX and nab-paclitaxel plus gemcitabine.25 Even in the presence of disease progression, the 90-day survival rates with second- and third-line nal-IRI treatment (74% and 71%, respectively) were similar to the rates with first-line gemcitabine-based regimens.

From medical and economic perspectives, these findings lend support to the NCCN category 1 sequence recommendation that patients with metastatic pancreatic cancer and good performance status should receive first-line treatment with nab-paclitaxel plus gemcitabine, followed by second-line treatment with nal-IRI plus 5-FU and leucovorin.2

Drivers of Incremental Medical Costs in Metastatic Pancreatic Cancer

Recently, Herrera-Restrepo and colleagues estimated the budget impact of adding nal-IRI to treatment in patients with disease progression after receiving gemcitabine-based therapy in the first, second, and third lines of therapy.26 The analysis was conducted from a US commercial payer perspective and was designed according to the Academy of Managed Care Pharmacy and International Society for Pharmacoeconomics and Outcomes Research best modeling practice recommendations.

Epidemiologic inputs reflecting the US population of patients with metastatic pancreatic cancer were applied to a hypothetical plan population of 1 million members to calculate the number of patients who were eligible for treatment with nal-IRI.26 The base-case market share included the most frequently prescribed treatment options, as shown in Table 1. Data on treatment cost and duration are shown in Table 2. The treatment costs were derived from a commercially available database (ie, Medi-Span Price Rx), and the administration costs were taken from the 2018 Medicare Physician and Laboratory Fee schedules.26

Table 1

Table 2

The adverse event rates and related costs were calculated for each regimen, and prophylactic granulocyte colony-stimulating factor (G-CSF) use rates and costs were also factored into the modeled calculations for each regimen.26 The base-case calculations were made based on a 100% commercial plan with 1 million members, and with an increasing nal-IRI treatment uptake of 1.4% with first-line treatment, 21.5% with second-line treatment, and 40.2% with third-line treatment relative to the current utilization. Although a modest incremental budget impact was associated with the addition of nal-IRI to the plan’s formulary, this was offset by savings in drug administration, the cost of G-CSF, adverse-event management, and patient monitoring costs, which ultimately rendered the net budget impact neutral (Figure 4).26

Figure 4

The study by Herrera-Restrepo and colleagues highlights the importance of looking beyond drug costs alone when reviewing cost-of-care comparisons. Ancillary costs related to drug choice, such as for the management of drug-specific adverse events, can have sizable impacts on budget, so these factors must also be considered.27 In this context, Hirsch and colleagues performed a claims-based analysis to determine the costs of 3 of the most common adverse events among patients who are receiving FDA-approved NCCN category 1 recommended treatments, which include neutropenia, anemia, and thrombocytopenia.27 The data were drawn from the Medicare fee-for-service population, and the treatments were categorized by treatment regimen and line of therapy. For first-line treatment regimens, the researchers observed statistically significant incremental costs associated with anemia ($3080-$3924), neutropenia ($1610-$2503), and thrombocytopenia ($2678-$3721).

For patients receiving second-line treatment with nal-IRI, only anemia was associated with a statistically significant incremental cost ($3257). In the same treatment group, the incremental costs associated with neutropenia were not statistically different from zero. There were not enough cases of thrombocytopenia to generate a relevant estimate.27

Looking further into the potential monthly cost offsets of NCCN category 1 treatment options for metastatic disease, Muldoon and colleagues reported for first-line treatment options, Medicare Part A inpatient costs were similar across the first-line regimens, ranging from $2721 to $3303, whereas Medicare Part B drug costs, excluding chemotherapy, were highest for FOLFIRINOX ($3881), followed by nab-paclitaxel plus gemcitabine ($1155), and then gemcitabine alone ($827).28 For patients receiving nal-IRI in the second- or third-line setting, even with disease progression, the Part A inpatient costs were lower than the first-line inpatient costs, whereas the Part B drug costs, excluding chemotherapy, were comparable with the costs incurred with first-line therapies.28

These findings suggest ancillary costs may be reduced by following an NCCN category 1 recommendation for sequence of nab-paclitaxel plus gemcitabine, followed by nal-IRI. It should also be noted that various treatment regimens have different adverse-event profiles, but the costs associated with these adverse events have not been well-characterized.

Conclusion

The incidence of pancreatic cancer is on the rise in the United States. In most cases, patients are diagnosed with advanced-stage disease, which means they will have a very poor prognosis; in fact, only 1 of 10 patients diagnosed with pancreatic cancer will be alive within 5 years. Because most patients are not eligible for surgery, chemotherapy remains the mainstay of treatment. Among the chemotherapy options, the NCCN has 3 preferred category 1 treatment choices for patients with good performance status: gemcitabine plus nab-paclitaxel or FOLFIRINOX for first-line treatment, and a combination of nal-IRI, 5-FU, and leucovorin for second-line treatment after gemcitabine-based therapy.

In clinical trials and in observational studies, the nal-IRI combination has demonstrated a survival advantage over treatment with 5-FU and leucovorin alone. Furthermore, nal-IRI has shown 90-day survival rates are similar to first-line treatment options when the drug is used as second-line treatment for metastatic pancreatic cancer. In addition, patients who received second-line treatment with nal-IRI after receiving first-line treatment with gemcitabine have better overall survival than patients who received nal-IRI as third-line treatment or later.

Claims-based analyses have shown nal-IRI as second-line treatment is associated with similar total costs as FOLFIRINOX and nab-paclitaxel plus gemcitabine when used as first-line therapy. Finally, budget impact modeling indicates patients who receive nal-IRI have lower rates of neutropenia and anemia than patients who receive other treatments. Although the treatment costs are higher, these costs are offset by reduced supportive care costs and reduced treatment utilization resulting from fewer adverse events. Therefore, nal-IRI incurs a negligible payer budget impact from a US payer perspective.

The collective evidence discussed here indicates that nal-IRI represents a high-value second-line treatment option for patients with metastatic pancreatic cancer.

 

References

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  28. Muldoon LD, Hirsch J, Dieguez G, Cockrum P. Monthly Parts A and B costs by service and line of therapy for FDA-approved/NCCN Category 1 treatments for patients with metastatic pancreatic cancer. J Clin Oncol. 2019;37(15_suppl). Abstract e18365.
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