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MM-398 improved outcomes in metastatic pancreatic cancer
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The addition of the novel agent MM-398 to second-line 5-FU/leucovorin extended survival in patients with metastatic pancreatic cancer, according to an expanded analysis of the phase 3 NAPOLI-1 trial presented at the Gastrointestinal Cancer Symposium.
MM-398 (Merrimack Pharmaceuticals), which received fast track designation from the FDA based on its activity in this combination, is a nanotherapeutic derivative of the chemotherapy drug irinotecan. In this form, in which it is encapsulated in a lipid sphere, the agent can circulate longer than standard irinotecan.
In the open-label NAPOLI-1 trial, Li-Tzong Chen, MD, PhD, of director, investigator and attending physician at the National Institute of Cancer Research at National Health Research Institutes in Taiwan, and colleagues enrolled 417 patients from 76 sites in 14 countries. All patients had metastatic pancreatic cancer and had undergone prior treatment with gemcitabine-based therapy.
Researchers randomly assigned patients 1:1:1 to one of three arms. In Arm A, patients received MM-398 120 mg/m2 intravenously for 90 minutes every 3 weeks. In Arm B, patients received 5-FU at 2,000 mg/m2 for 24 hours plus racemic leucovorin 200 mg/m2 for 30 minutes every 4 weeks, followed by 2 weeks rest. In Arm C, patients received MM-398 80 mg/m2 intravenously for 90 minutes, followed by 5-FU 2,400 mg/m2 for 46 hours and racemic leucovorin 400 mg/m2 for 30 minutes every 2 weeks.
OS served as the primary endpoint.
Analysis of the per-protocol population — which included all patients who received at least 80% of the target dose in the first 6 weeks — showed those who received MM-398 plus 5-FU and leucovorin demonstrated median OS of 8.9 months (range, 6.4-10.5), whereas those who received 5-FU and leucovorin alone demonstrated median OS of 5.1 months (range 4.0-7.2 months). Researchers calculated an HR of 0.47 (95% CI, 0.29-0.77) in favor of the MM-398 combination.
Results showed MM-398 monotherapy did not confer a statistically significant OS advantage compared with 5-FU and leucovorin.
Subgroup analyses showed the addition of MM-398 to 5-FU and leucovorin was associated with improved OS among patients stratified by stage at diagnosis, number of previous therapies, time since last prior therapy and other pretreatment characteristics.
In the intent-to-treat population, which included all randomized patients, those assigned MM-398 plus 5-FU and leucovorin demonstrated longer median OS than those who received 5-FU and leucovorin alone (6.1 months vs. 4.2 months; HR=0.57; 95% CI, 0.41-0.8). Patients assigned the combination also demonstrated significant improvements in PFS (3.1 months vs. 1.5 months; P=.0001) and overall response rate (16% vs. 1%; P<.001).
A higher percentage of patients assigned the MM-398 regimen demonstrated a ≥50% reduction in CA 19-9 levels (36% vs. 12%; P=.0009).
The most frequent grade ≥3 adverse events reported in MM-398–treated patients in the NAPOLI-1 trial were neutropenia, fatigue, diarrhea and vomiting.
For more information:
Chen LT. Abstract #234. Presented at: 2015 Gastrointestinal Cancers Symposium; Jan. 15-17, 2015; San Francisco.
Disclosure: See the full study for a full list of financial disclosures.
Perspective
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David P. Ryan, MD
Approximately 40,000 people each year die of pancreatic cancer in the United States. Since the mid-1990s, single-agent gemcitabine has been the standard first-line regimen for patients with advanced pancreatic cancer. Multiple clinical trials evaluated camptothecins — including irinotecan — with gemcitabine in the first-line setting and failed to show an improvement in OS. The CONKO-003 study (Oettle H, et al. J Clin Oncol. 2014:doi:10.1200/JCO.2013.53.6995) evaluated a regimen of 5-FU and oxaliplatin compared with 5-FU in patients who progressed on gemcitabine therapy, and it demonstrated an improvement in OS in the oxaliplatin arm (5.9 vs. 3.3 months).Because this study was not a registration study, second-line chemotherapy remains an open question as to whether it should consist of single-agent fluoropyrimidine or combination therapy. At the Massachusetts General Hospital Cancer Center and many other institutions, a regimen consisting of 5-FU and oxaliplatin — usually FOLFOX — became the standard second-line treatment for patients with advanced pancreatic cancer.
In this setting, investigators evaluated the novel liposomal encapsulated irinotecan, MM-398, in a phase 3 trial designed to compare 5-FU/leucovorin with 5-FU/leucovorin plus MM-398 or MM-398 alone. In their updated analysis, presented at the Gastrointestinal Cancers Symposium, the investigators showed a 1.9-month improvement in OS for the combination of MM-398 and 5-FU/LV compared with 5-FU/LV alone. Of note, there was no improvement in OS among patients who received MM-398 alone.
Recently, two multi-chemotherapy regimens (gemcitabine/nab-paclitaxel and FOLFIRINOX) administered in the first-line setting for patients with pancreatic cancer have demonstrated improvement in OS. Therefore, the results of the MM-398 study raise at least three important questions.
First, can the combination of 5-FU and camptothecins be synergistic? It is interesting that this is now the second study to demonstrate improvement in OS with the combination of a fluoropyrimidine and a camptothecin in pancreatic cancer. We had abandoned camptothecins in this disease due to several negative clinical trials when combining them with gemcitabine.
Second, will patients who have received multi-agent first-line chemotherapy receive the same benefit with the combination of 5-FU and MM-398 in the second-line setting? It is doubtful that patients who have already received 5-FU and irinotecan with the FOLFIRINOX regimen will experience the same benefit in the second-line setting from MM-398 and 5-FU/LV. Is this a safe assumption, and can we make the same statement for patients who have received gemcitabine/nab-paclitaxel? Both of these questions will need to be evaluated in randomized studies.
Lastly, will the FDA, European and Asian authorities approve MM-398 for use in the gemcitabine-refractory setting? The answer to this question will depend upon how these groups view the second-line setting of pancreatic cancer, and whether the nontraditional regimen of 5-FU and leucovorin was the community standard in this setting. It seems reasonable to assume that MM-398 will have similar effects with the other more popularly used regimens of 5-FU/LV.
MM-398 is an exciting new formulation of irinotecan that appears to have significant benefits for patients with pancreatic cancers. It also may be useful in other irinotecan-sensitive tumors and clinical trials will need to explore these areas as well as further define its role in pancreatic cancer.
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