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landmarks
Pancreatic cancer
New combined-therapy option for metastatic disease
Rachel Goodwin, MD, MSc, FRCPC, Oncologist, The Ottawa Hospital Cancer Centre
TRIAL SUMMARY: Combined nab-paclitaxel
plus gemcitabine provides superior efficacy
vs gemcitabine alone for metastatic PC
In preclinical models of pancreatic cancer (PC), nab-paclitaxel
(nab-P; 130 nm albumin-bound paclitaxel) has demonstrated
both single-agent activity and synergy with gemcitabine (G).
A phase I/II study in metastatic PC (J Clin Oncol 2011:
4548–54) also reported promising efficacy for nab-P + G, warranting a phase III study of nab-P + G vs G alone in this setting.
In this large, international study conducted at 151 community and academic centres, 861 patients with metastatic
PC and a Karnofsky performance status (KPS) ≥70 were
randomized 1:1 to receive nab-P 125 mg/m2 + G 1000
mg/m2 on days 1, 8 and 15 every 4 weeks, or G alone
1000 mg/m2 weekly for 7 weeks followed by 1 week of rest
(cycle 1) and then on days 1, 8 and 15 every 4 weeks (cycle
≥2). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and
overall response rate (ORR) by independent review.
Patients’ median age was 63 years (range 27–88). KPS
was 100 (16%), 90 (44%), 80 (32%) and 70 (7%). Patients
had advanced disease with liver metastases (84%), ≥3 metastatic sites (46%) and Cancer Antigen (CA) 19-9 ≥59 ×
upper limit of normal (ULN) (46%). Nab-P + G was superior to G for all efficacy endpoints: median OS 8.5 vs 6.7
months (HR 0.72; 95% CI 0.617–0.835; p=0.000015);
median PFS 5.5 vs 3.7 months (HR 0.69; 95% CI 0.581–
0.821; p=0.000024); ORR 23% vs 7% (p=1.1 × 10−10) by
Response Evaluation Criteria In Solid Tumors (RECIST)
version 1.0. Metabolic response assessed by positron emission tomography (PET) in 257 patients was 63% for nab-P
+ G vs 38% for G (p=0.000051). CA19-9 response (≥90%
decrease) was 31% for nab-P + G vs 14% for G (p<0.0001).
Grade 3 and worse adverse events (AEs) with nab-P + G vs
G included neutropenia (38% vs 27%), fatigue (17 % vs
7%), diarrhea (6% vs 1%) and febrile neutropenia (3% vs
1%). Grade 3 and higher peripheral neuropathy (PN)
occurred in 17% vs 1% of patients who received nab-P + G
vs G, respectively; for nab-P + G, PN improved to grade ≤1
in a median of 29 days, and 44% of patients resumed nab-P
treatment. Median treatment duration was 3.9 months for
nab-P + G and 2.8 months for G.
The study concluded that nab-P + G was superior to G
across all efficacy endpoints, had an acceptable toxicity profile and is a new standard for treatment of metastatic PC
that could become the backbone for new regimens.
COMMENTARY: Approximately 45,000 people in the
United States and 4,700 in Canada will be diagnosed with
pancreatic cancer in 2013.1,2 The majority will have adenocarcinoma histology and about 80% will present with advanced,
nonoperable disease. Treatments in this setting aim to control disease and treat symptoms using systemic therapies,
radiation and in some cases, palliative surgery. Metastatic
and locally advanced, nonoperable pancreatic cancers have
poor survival rates, with very few patients alive at two years.
New therapies to improve patient longevity are needed.
In the late 1990s, gemcitabine was approved and became
standard of care over single-agent 5-fluorouracil (5-FU),
based on the Burris trial that enrolled 126 previously
untreated patients with locally advanced or metastatic pancreatic cancer.3 Gemcitabine had significantly better clinical
response (24% vs 5%), median OS (5.6 vs 4.4 months) and
one-year survival (18% vs 2%). In 2011, our first-line standard of care for good-performance patients with adequate
liver function changed to FOLFIRINOX (infusional 5-FU,
leucovorin, oxaliplatin and irinotecan) from gemcitabine,
based on the ACCORD 11 trial.4 In this study, 342 patients
with chemotherapy-naive metastatic pancreatic cancer, per-
formance status 0–1, serum total bilirubin <1.5 times the
upper limit of normal were randomly assigned to gemcitabine alone vs FOLFIRINOX. FOLFIRINOX showed
superior objective response rate (32% vs 9%), median PFS
(6.4 vs 3.3 months) and OS (11.1 vs 6.8 months). Importantly, there was no decline in quality of life despite higher
rates of neutropenia, febrile neutropenia, sensory neuropathy,
vomiting, fatigue and diarrhea with FOLFIRINOX.5 How
much irinotecan contributes to the cytotoxicity of FOLFIRINOX is debatable, given the encouraging phase II data
of FOLFOX6 (infusional 5-FU, leucovorin with oxaliplatin).6
Attempts have been made to improve first-line activity of
gemcitabine by combining it with other chemotherapies and
targeted agents; examples include, but are not limited to,
capecitabine and erlotinib. A meta-analysis of two phase III
trials and one phase II trial showed a statistically significant
survival benefit for gemcitabine with capecitabine over
gemcitabine alone (HR 0.86; 95% CI 0.75–0.98).7 The
combination of gemcitabine and erlotinib showed a 2-week
OS improvement compared to gemcitabine alone.8 These
were modest improvements in outcomes at a cost of
increased toxicity.
Von Hoff DD, Ervin TJ, Arena FP. Results of a randomized phase III
trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the
pancreas with PET and CA19-9 correlates. ASCO 2013. J Clin Oncol
2013;31(suppl): Abstract 4005.
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landmarks
MPACT examined the outcomes of another gemcitabine
doublet, nab-P + G, based on preclinical data showing synergy of these 2 agents, single-agent activity and a promising
phase II trial.9 This well-conducted multinational randomized phase III trial found clinically meaningful improvements
in OS (8.5 vs 6.7 months), PFS (5.5 vs 3.7 months) and
ORR (23% vs 7%) with nab-P + G over G. PET and CA
19-9 were found to correlate with survival. As well, in subgroup analysis, patients with poorer performance status,
liver metastatic disease and higher CA 19-9 values seemed
to do better with nab-P + G. The survival data were robust
such that subsequent lines of therapy did not impact conclusions. As expected, there were predictable additional
≥grade 3 AEs in the experimental arm. Unlike in the
FOLFIRINOX trial, however, quality of life data were not
reported so the full impact on patients is unknown. In
In Brief
Already known
• Metastatic and locally advanced, nonoperable
pancreatic cancers have poor overall survival,
with few patients alive at two years.
• Attempts have been made to improve first-line
activity of gemcitabine by combining it with various chemotherapies and targeted agents, resulting
in very modest improvements in outcomes at a cost
of increased toxicity.
What this study showed
• This is the first phase III study showing statistically
and clinically improved overall survival, progression-free survival and overall response rate of the
gemcitabine chemotherapy doublet nab-P + G
over G. Grade 3 and worse adverse events with nab-P
+ G vs G included neutropenia, fatigue, diarrhea,
febrile neutropenia and peripheral neuropathy.
Next steps
• Further research is needed to identify clinical subsets
and molecular markers that predict response to
nab-P + G, as well as to test nab-P + G response
in nonmetastatic patients, such as in the locally
advanced, neoadjuvant and adjuvant settings.
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addition, cost-effectiveness data have yet to be reported.
Despite these limitations, this trial represents another key
milestone in the treatment of metastatic pancreatic cancer.
This is the first phase III study showing clinically meaningful OS data with a gemcitabine chemotherapy combination.
For the first time, we have improved first-line chemotherapy choices over single-agent gemcitabine when treating metastatic pancreatic cancer patients. These include
FOLFIRINOX, presented in 2011, and now nab-P +G,
offering 11.1- and 8.5-month median OS, respectively.
The next step is to identify subgroups and molecular markers
that predict response and help to determine the appropriateness of one regime over the other. While nab-P + G and
FOLFIRINOX had similar patient populations — metastatic
with good performance status and liver function —
nab-P + G allowed patients over the age of 75 years and
had slightly more Eastern Cooperative Oncology Group
(ECOG) performance status 2 patients. Performance of
nab-P + G in the locally advanced, neoadjuvant and adjuvant
settings is unknown. These data are also lacking for
FOLFIRINOX, although a large multinational adjuvant
study is currently underway.
Disclosure
Dr. Goodwin reports no conflict of interest relevant to this article.
References
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin
2013;63:11-30.
2. Canadian Cancer Society. Cancer statistics. Available at www.cancer.ca.
3. Burris HA 3rd, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced
pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403-13.
4. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.
5. Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F et al. Impact of FOLFIRINOX
compared with gemcitabine on quality of life in patients with metastatic
pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial.
J Clin Oncol 2013;31:23-9.
6. Ghosn M, Farhat F, Kattan J et al. FOLFOX-6 combination as the first-line treatment of locally advanced and/or metastatic pancreatic cancer. Am J Clin Oncol
2007;30:15-20.
7. Cunningham D, Chau I, Stocken DD et al. Phase III randomized comparison of
gemcitabine versus gemcitabine plus capecitabine in patients with advanced
pancreatic cancer. J Clin Oncol 2009;27:5513-8.
8. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with
gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial
of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;
25:1960-6.
9. Von Hoff DD, Ramanathan RK, Borad MJ et al. Gemcitabine plus nab-paclitaxel
is an active regimen in patients with advanced pancreatic cancer: a phase I/II
trial. J Clin Oncol 2011;29:4548-54.