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Developed under the direction and sponsorship of Ipsen Biopharmaceuticals
Metastatic pancreatic cancer is a difficult-to-treat cancer associated with poor outcomes. Moreover, it is known to cause challenging symptoms, which are oftentimes compounded by treatment. As more therapeutic options become available, oncologists can start to consider survival outcomes and the tolerability profile when making treatment recommendations.
Until recently, first-line options for patients with metastatic pancreatic adenocarcinoma (mPDAC) were limited to the following therapies: (1) gemcitabine plus nab-paclitaxel (GEM+Nab-P) and (2) fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). In February 2024, the U.S. Food and Drug Administration approved ONIVYDE® (irinotecan liposome injection), a topoisomerase inhibitor, in combination with oxaliplatin, fluorouracil and leucovorin, for the first-line treatment of adults patients with metastatic pancreatic adenocarcinoma based on results of the Phase 3 NAPOLI 3 trial.
ONIVYDE® (irinotecan liposome injection) is indicated, in combination with oxaliplatin, fluorouracil, and leucovorin, for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma. ONIVYDE is indicated, in combination with fluorouracil and leucovorin, for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy. Limitations of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic pancreatic adenocarcinoma. WARNING: SEVERE NEUTROPENIA AND SEVERE DIARRHEA Neutropenia
Diarrhea
|
"We are excited by the FDA-approval to have another treatment option for patients with newly diagnosed mPDAC,” said Maen Abdelrahim, MD, PhD, PharmB, Section Chief of Gastrointestinal Medical Oncology, Dr. Mary and Ron Neal Cancer Center, Houston Methodist Hospital. “The liposomal formulation of ONIVYDE encapsulates irinotecan in a lipid bilayer, allowing it to remain in circulation for longer than free irinotecan. When compared with free irinotecan, a pre-clinical study showed higher intratumoral levels of irinotecan and its active metabolite SN-38 can be achieved and sustained.”
The importance of proactive AE management and patient education
The ONIVYDE regimen has demonstrated improvements across key outcome measures like overall survival (OS) and progression-free survival (PFS) compared to the previous standard of care, GEM+Nab-P. It also showed higher numerical overall response rates (ORR) vs. GEM+Nab-P. However, when treating patients, it’s equally critical to consider the impact of treatment on day-to-day life and manageability of adverse events. Diarrhea was the most commonly observed adverse event for all grades in the NAPOLI 3 trial. If left unmanaged, diarrhea can be a serious adverse event, but if proactively managed through nutrition (patients should stop lactose-containing products, eat a low-fat diet and maintain hydration during treatment with ONIVYDE) and/or through administration of anti-diarrhetic (atropine for early-onset diarrhea, or loperamide for late-onset diarrhea), the adverse event may be managed and it may allow a patient to continue treatment.
Direct and ongoing conversation with patients about what to expect from treatment, specifically outlining potential adverse events and proactive ways to manage them, is essential to ensure patients speak up about symptoms as they experience them. In this way, early management of adverse events may potentially help the patient stay on therapy. “Including a discussion of the potential adverse events and toxicity for each treatment option is good clinical practice. We use a patient-centered approach that incorporates the input of the patient and their family for mPDAC treatment and the management of side effects. This approach can help empower the patient and their family to become active members of their cancer care team.”
A study was published in 2024 in Journal of Clinical Oncology, that described the reasons for non-treatment in a real-world cohort of patients with pancreatic cancer. The results showed that even among patients with mPDAC, 43.8% did not receive any cancer-directed treatment. The primary reason to decline treatment was due to patient/family preference even when treatment was recommended by their clinician. This further demonstrates the importance of educating patients about what to expect from treatment to make an informed decision.
NAPOLI 3 Results
NAPOLI 3 demonstrated superior efficacy of the ONIVYDE regimen over GEM+Nab-P as a therapeutic option for treatment-naïve patients with mPDAC. A total of 770 patients from 187 worldwide community and academic centers were randomized to receive either the ONIVYDE regimen (NALIRIFOX; n=383) or GEM+Nab-P (n=387). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and overall response rate (ORR), which were tested in a hierarchical approach if OS was significant.
Results of the study showed that the median OS was 11.1 months (95% confidence interval (CI) (10.0, 12.1)) in the ONIVYDE group and 9.2 months (95% CI (8.3, 10.6)) in the GEM+Nab-P group (hazard ratio (HR) 0.84 [95% CI 0.71–0.99]; p=0.0403; Table 1 and Figure 1). The median PFS was 7.4 months (95% CI (6.0, 7.7)) in the ONIVYDE group and 5.6 months (95% CI (5.3, 5.8)) in the GEM+Nab-P group (HR 0.70 [95% CI 0.59–0.85]; p=0.0001; Table 1). The ORR was 41.8% (36.8%-46.9%; 95% CI) for the ONIVYDE group versus 36.2% (31.4%-41.2%; 95% CI) for patients treated with GEM+Nab-P group (Table 1).
It should be noted that serious adverse reactions occurred in 54% of patients who received ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin. ONIVYDE has black box warnings for severe neutropenia and severe diarrhea: ONIVYDE should be withheld when the absolute neutrophil count is below 1500/mm3 or when neutropenic fever is present. In addition, ONIVYDE should be withheld with grade 2-4 diarrhea. Do not administer to patients with obstructive bowel disease.
The impact of the first-line ONIVYDE regimen
“Typically, fewer than 15% of our patients present with resectable disease; most have advanced or regional disease with a very low rate of 5-year survival. The meaningful clinical improvements in OS and PFS with the ONIVYDE regimen over the currently approved GEM+Nab-P regimen adds an exciting option for treating first-line mPDAC, helping to provide more time for our patients. And, by educating patients about what to expect from treatment, we can help them feel empowered to speak up and raise concerns.”
Table 1. Efficacy Results of All Randomized Patients in NAPOLI 3
| NALIRIFOX* (N=383) | Gem+NabP (N=387) |
Overall Survival | ||
Number of Deaths, n (%) | 259 (68) | 285 (74) |
Median Overall Survival (months) | 11.1 | 9.2 |
(95% CI) | (10.0, 12.1) | (8.3, 10.6) |
Hazard Ratio (95% CI) * | 0.84 (0.71, 0.99) | |
p-value † | 0.0403 | |
Progression-Free Survival | ||
Death or Progression, n (%) | 249 (65) | 259 (67) |
Median Progression-Free Survival (months) | 7.4 | 5.6 |
(95% CI) | (6.0, 7.7) | (5.3, 5.8) |
Hazard Ratio (95% CI) * | 0.70 (0.59, 0.85) | |
P-value † | 0.0001 | |
Objective Response Rate # | ||
ORR (95% CI) | 41.8 (36.8, 46.9) | 36.2 (31.4, 41.2) |
CR, n (%) | 1 (0.3) | 1 (0.3) |
PR, n (%) | 159 (41.5) | 139 (35.9) |
* NALIRIFOX= ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin; Gem+NabP=gemcitabine+nab-paclitaxel; CI=confidence interval
** Based on the stratified Cox proportional hazard model; stratified by ECOG PS (0 vs. 1), region (North America vs. East Asia vs. Rest of the world), and liver metastases (yes vs. no) per interaction web response system
† Based on stratified log-rank test.
# ORR result was not statistically significant.
IMPORTANT SAFETY INFORMATION AND INDICATIONS
WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA See full prescribing information for complete boxed warning Neutropenia
Diarrhea
|
CONTRAINDICATIONS
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction or anaphylaxis to ONIVYDE or irinotecan HCl.
WARNINGS AND PRECAUTIONS
Severe Neutropenia: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 neutropenia occurred in 26% of patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) and fatal neutropenic fever in 0.3% of patients. In NAPOLI 3, the incidence of Grade 3 or 4 neutropenia was similar among Asian patients [6 of 20 (30%)] compared to White patients [76 of 289 (26%)]. Neutropenic fever/neutropenic sepsis was reported in 5% of Asian patients (1 of 20) compared to 2.3% of White patients (7 of 306). In NAPOLI-1, Grade 3 and 4 neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin (ONIVYDE/FU/LV). Neutropenic sepsis occurred in 3% and fatal neutropenic sepsis in 0.8%. In NAPOLI-1, the incidence of Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients.
Monitor complete blood cell counts on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below 1500/mm3 or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm3 or above. Reduce ONIVYDE dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles.
Severe Diarrhea: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 diarrhea (early-onset [within 24 hours of chemotherapy] and late-onset [more than 24 hours following chemotherapy]) occurred in 20% receiving NALIRIFOX. In NAPOLI-1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 late-onset diarrhea was 9% in patients receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 early-onset diarrhea was 3% in patients receiving ONIVYDE/FU/LV.
To reduce the risk of severe diarrhea, patients should stop lactose-containing products, eat a low-fat diet, and maintain hydration during treatment with ONIVYDE. Withhold ONIVYDE for Grade 2-4 diarrhea. Local institutional guidelines should be followed for the treatment of diarrhea that does not improve within 48 hours and may include the addition of diphenoxylate hydrochloride plus atropine sulfate or octreotide. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose.
Interstitial Lung Disease (ILD): Irinotecan HCl can cause severe and fatal ILD. Patients with risk factors should be closely monitored for respiratory symptoms before and during ONIVYDE therapy. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.
Severe Hypersensitivity Reaction: Irinotecan, including ONIVYDE, can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.
Embryo-Fetal Toxicity: ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 7 months after the last dose of ONIVYDE treatment.
ADVERSE REACTIONS FOR NALIRIFOX
- The most common adverse reactions (≥20%) of NALIRIFOX were diarrhea (72%), fatigue (62%), nausea (59%), vomiting (40%), decreased appetite (37%), abdominal pain (35%), mucosal inflammation (28%), constipation (25%), and weight decreased (22%).
- Permanent discontinuation of ONIVYDE due to an adverse reaction occurred in 17% of patients. Adverse reactions that resulted in permanent discontinuation of ONIVYDE in ≥1% of patients included neutropenia, thrombocytopenia, diarrhea, fatigue, infections, and cerebrovascular accident.
- Dosage reduction of ONIVYDE due to an adverse reaction occurred in 52% of patients. Adverse reactions that required dosage reduction in ≥1% of patients included anemia, decreased appetite, diarrhea, fatigue, febrile neutropenia, hypokalemia, liver function test abnormalities, nausea, mucosal inflammation, neutropenia, peripheral neuropathy, vomiting, thrombocytopenia, and weight decreased.
- Dosage interruptions of ONIVYDE due to an adverse reaction occurred in 1.9% of patients. Adverse reactions which required dosage interruption in ≥0.5% of patients included hypersensitivity and infusion-related reaction.
- The most common laboratory abnormalities (≥10% Grade 3 or 4) were decreased neutrophils (26%), decreased potassium (22%), decreased lymphocytes (11%), and decreased hemoglobin (10%).
ADVERSE REACTIONS FOR ONIVYDE/FU/LV
- The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%).
- Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis.
- Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia.
- ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.
- The most common severe laboratory abnormalities (≥10% Grade 3 or 4) were lymphopenia and neutropenia.
Postmarketing Experience: Immune system disorders: Hypersensitivity (including anaphylactic reaction and angioedema).
DRUG INTERACTIONS
- Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE.
- Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy.
USE IN SPECIFIC POPULATIONS
- Pregnancy and Reproductive Potential: See WARNINGS & PRECAUTIONS. Advise males with female partners of reproductive potential to use condoms during and for 4 months after the last dose of ONIVYDE treatment.
- Lactation: Advise nursing women not to breastfeed during and for 1 month after the last dose of ONIVYDE treatment.
To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information, including BOXED WARNING, for ONIVYDE.
ONIVYDE is a registered trademark of Ipsen Biopharm Ltd.
©2024 Ipsen Biopharmaceuticals, Inc. All rights reserved. August 2024 ONV-US-005210
Developed under the direction and sponsorship of Ipsen Biopharmaceuticals
Metastatic pancreatic cancer is a difficult-to-treat cancer associated with poor outcomes. Moreover, it is known to cause challenging symptoms, which are oftentimes compounded by treatment. As more therapeutic options become available, oncologists can start to consider survival outcomes and the tolerability profile when making treatment recommendations.
Until recently, first-line options for patients with metastatic pancreatic adenocarcinoma (mPDAC) were limited to the following therapies: (1) gemcitabine plus nab-paclitaxel (GEM+Nab-P) and (2) fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). In February 2024, the U.S. Food and Drug Administration approved ONIVYDE® (irinotecan liposome injection), a topoisomerase inhibitor, in combination with oxaliplatin, fluorouracil and leucovorin, for the first-line treatment of adults patients with metastatic pancreatic adenocarcinoma based on results of the Phase 3 NAPOLI 3 trial.
ONIVYDE® (irinotecan liposome injection) is indicated, in combination with oxaliplatin, fluorouracil, and leucovorin, for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma. ONIVYDE is indicated, in combination with fluorouracil and leucovorin, for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy. Limitations of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic pancreatic adenocarcinoma. WARNING: SEVERE NEUTROPENIA AND SEVERE DIARRHEA Neutropenia
Diarrhea
|
"We are excited by the FDA-approval to have another treatment option for patients with newly diagnosed mPDAC,” said Maen Abdelrahim, MD, PhD, PharmB, Section Chief of Gastrointestinal Medical Oncology, Dr. Mary and Ron Neal Cancer Center, Houston Methodist Hospital. “The liposomal formulation of ONIVYDE encapsulates irinotecan in a lipid bilayer, allowing it to remain in circulation for longer than free irinotecan. When compared with free irinotecan, a pre-clinical study showed higher intratumoral levels of irinotecan and its active metabolite SN-38 can be achieved and sustained.”
The importance of proactive AE management and patient education
The ONIVYDE regimen has demonstrated improvements across key outcome measures like overall survival (OS) and progression-free survival (PFS) compared to the previous standard of care, GEM+Nab-P. It also showed higher numerical overall response rates (ORR) vs. GEM+Nab-P. However, when treating patients, it’s equally critical to consider the impact of treatment on day-to-day life and manageability of adverse events. Diarrhea was the most commonly observed adverse event for all grades in the NAPOLI 3 trial. If left unmanaged, diarrhea can be a serious adverse event, but if proactively managed through nutrition (patients should stop lactose-containing products, eat a low-fat diet and maintain hydration during treatment with ONIVYDE) and/or through administration of anti-diarrhetic (atropine for early-onset diarrhea, or loperamide for late-onset diarrhea), the adverse event may be managed and it may allow a patient to continue treatment.
Direct and ongoing conversation with patients about what to expect from treatment, specifically outlining potential adverse events and proactive ways to manage them, is essential to ensure patients speak up about symptoms as they experience them. In this way, early management of adverse events may potentially help the patient stay on therapy. “Including a discussion of the potential adverse events and toxicity for each treatment option is good clinical practice. We use a patient-centered approach that incorporates the input of the patient and their family for mPDAC treatment and the management of side effects. This approach can help empower the patient and their family to become active members of their cancer care team.”
A study was published in 2024 in Journal of Clinical Oncology, that described the reasons for non-treatment in a real-world cohort of patients with pancreatic cancer. The results showed that even among patients with mPDAC, 43.8% did not receive any cancer-directed treatment. The primary reason to decline treatment was due to patient/family preference even when treatment was recommended by their clinician. This further demonstrates the importance of educating patients about what to expect from treatment to make an informed decision.
NAPOLI 3 Results
NAPOLI 3 demonstrated superior efficacy of the ONIVYDE regimen over GEM+Nab-P as a therapeutic option for treatment-naïve patients with mPDAC. A total of 770 patients from 187 worldwide community and academic centers were randomized to receive either the ONIVYDE regimen (NALIRIFOX; n=383) or GEM+Nab-P (n=387). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and overall response rate (ORR), which were tested in a hierarchical approach if OS was significant.
Results of the study showed that the median OS was 11.1 months (95% confidence interval (CI) (10.0, 12.1)) in the ONIVYDE group and 9.2 months (95% CI (8.3, 10.6)) in the GEM+Nab-P group (hazard ratio (HR) 0.84 [95% CI 0.71–0.99]; p=0.0403; Table 1 and Figure 1). The median PFS was 7.4 months (95% CI (6.0, 7.7)) in the ONIVYDE group and 5.6 months (95% CI (5.3, 5.8)) in the GEM+Nab-P group (HR 0.70 [95% CI 0.59–0.85]; p=0.0001; Table 1). The ORR was 41.8% (36.8%-46.9%; 95% CI) for the ONIVYDE group versus 36.2% (31.4%-41.2%; 95% CI) for patients treated with GEM+Nab-P group (Table 1).
It should be noted that serious adverse reactions occurred in 54% of patients who received ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin. ONIVYDE has black box warnings for severe neutropenia and severe diarrhea: ONIVYDE should be withheld when the absolute neutrophil count is below 1500/mm3 or when neutropenic fever is present. In addition, ONIVYDE should be withheld with grade 2-4 diarrhea. Do not administer to patients with obstructive bowel disease.
The impact of the first-line ONIVYDE regimen
“Typically, fewer than 15% of our patients present with resectable disease; most have advanced or regional disease with a very low rate of 5-year survival. The meaningful clinical improvements in OS and PFS with the ONIVYDE regimen over the currently approved GEM+Nab-P regimen adds an exciting option for treating first-line mPDAC, helping to provide more time for our patients. And, by educating patients about what to expect from treatment, we can help them feel empowered to speak up and raise concerns.”
Table 1. Efficacy Results of All Randomized Patients in NAPOLI 3
| NALIRIFOX* (N=383) | Gem+NabP (N=387) |
Overall Survival | ||
Number of Deaths, n (%) | 259 (68) | 285 (74) |
Median Overall Survival (months) | 11.1 | 9.2 |
(95% CI) | (10.0, 12.1) | (8.3, 10.6) |
Hazard Ratio (95% CI) * | 0.84 (0.71, 0.99) | |
p-value † | 0.0403 | |
Progression-Free Survival | ||
Death or Progression, n (%) | 249 (65) | 259 (67) |
Median Progression-Free Survival (months) | 7.4 | 5.6 |
(95% CI) | (6.0, 7.7) | (5.3, 5.8) |
Hazard Ratio (95% CI) * | 0.70 (0.59, 0.85) | |
P-value † | 0.0001 | |
Objective Response Rate # | ||
ORR (95% CI) | 41.8 (36.8, 46.9) | 36.2 (31.4, 41.2) |
CR, n (%) | 1 (0.3) | 1 (0.3) |
PR, n (%) | 159 (41.5) | 139 (35.9) |
* NALIRIFOX= ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin; Gem+NabP=gemcitabine+nab-paclitaxel; CI=confidence interval
** Based on the stratified Cox proportional hazard model; stratified by ECOG PS (0 vs. 1), region (North America vs. East Asia vs. Rest of the world), and liver metastases (yes vs. no) per interaction web response system
† Based on stratified log-rank test.
# ORR result was not statistically significant.
IMPORTANT SAFETY INFORMATION AND INDICATIONS
WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA See full prescribing information for complete boxed warning Neutropenia
Diarrhea
|
CONTRAINDICATIONS
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction or anaphylaxis to ONIVYDE or irinotecan HCl.
WARNINGS AND PRECAUTIONS
Severe Neutropenia: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 neutropenia occurred in 26% of patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) and fatal neutropenic fever in 0.3% of patients. In NAPOLI 3, the incidence of Grade 3 or 4 neutropenia was similar among Asian patients [6 of 20 (30%)] compared to White patients [76 of 289 (26%)]. Neutropenic fever/neutropenic sepsis was reported in 5% of Asian patients (1 of 20) compared to 2.3% of White patients (7 of 306). In NAPOLI-1, Grade 3 and 4 neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin (ONIVYDE/FU/LV). Neutropenic sepsis occurred in 3% and fatal neutropenic sepsis in 0.8%. In NAPOLI-1, the incidence of Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients.
Monitor complete blood cell counts on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below 1500/mm3 or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm3 or above. Reduce ONIVYDE dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles.
Severe Diarrhea: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 diarrhea (early-onset [within 24 hours of chemotherapy] and late-onset [more than 24 hours following chemotherapy]) occurred in 20% receiving NALIRIFOX. In NAPOLI-1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 late-onset diarrhea was 9% in patients receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 early-onset diarrhea was 3% in patients receiving ONIVYDE/FU/LV.
To reduce the risk of severe diarrhea, patients should stop lactose-containing products, eat a low-fat diet, and maintain hydration during treatment with ONIVYDE. Withhold ONIVYDE for Grade 2-4 diarrhea. Local institutional guidelines should be followed for the treatment of diarrhea that does not improve within 48 hours and may include the addition of diphenoxylate hydrochloride plus atropine sulfate or octreotide. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose.
Interstitial Lung Disease (ILD): Irinotecan HCl can cause severe and fatal ILD. Patients with risk factors should be closely monitored for respiratory symptoms before and during ONIVYDE therapy. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.
Severe Hypersensitivity Reaction: Irinotecan, including ONIVYDE, can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.
Embryo-Fetal Toxicity: ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 7 months after the last dose of ONIVYDE treatment.
ADVERSE REACTIONS FOR NALIRIFOX
- The most common adverse reactions (≥20%) of NALIRIFOX were diarrhea (72%), fatigue (62%), nausea (59%), vomiting (40%), decreased appetite (37%), abdominal pain (35%), mucosal inflammation (28%), constipation (25%), and weight decreased (22%).
- Permanent discontinuation of ONIVYDE due to an adverse reaction occurred in 17% of patients. Adverse reactions that resulted in permanent discontinuation of ONIVYDE in ≥1% of patients included neutropenia, thrombocytopenia, diarrhea, fatigue, infections, and cerebrovascular accident.
- Dosage reduction of ONIVYDE due to an adverse reaction occurred in 52% of patients. Adverse reactions that required dosage reduction in ≥1% of patients included anemia, decreased appetite, diarrhea, fatigue, febrile neutropenia, hypokalemia, liver function test abnormalities, nausea, mucosal inflammation, neutropenia, peripheral neuropathy, vomiting, thrombocytopenia, and weight decreased.
- Dosage interruptions of ONIVYDE due to an adverse reaction occurred in 1.9% of patients. Adverse reactions which required dosage interruption in ≥0.5% of patients included hypersensitivity and infusion-related reaction.
- The most common laboratory abnormalities (≥10% Grade 3 or 4) were decreased neutrophils (26%), decreased potassium (22%), decreased lymphocytes (11%), and decreased hemoglobin (10%).
ADVERSE REACTIONS FOR ONIVYDE/FU/LV
- The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%).
- Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis.
- Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia.
- ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.
- The most common severe laboratory abnormalities (≥10% Grade 3 or 4) were lymphopenia and neutropenia.
Postmarketing Experience: Immune system disorders: Hypersensitivity (including anaphylactic reaction and angioedema).
DRUG INTERACTIONS
- Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE.
- Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy.
USE IN SPECIFIC POPULATIONS
- Pregnancy and Reproductive Potential: See WARNINGS & PRECAUTIONS. Advise males with female partners of reproductive potential to use condoms during and for 4 months after the last dose of ONIVYDE treatment.
- Lactation: Advise nursing women not to breastfeed during and for 1 month after the last dose of ONIVYDE treatment.
To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information, including BOXED WARNING, for ONIVYDE.
ONIVYDE is a registered trademark of Ipsen Biopharm Ltd.
©2024 Ipsen Biopharmaceuticals, Inc. All rights reserved. August 2024 ONV-US-005210
Developed under the direction and sponsorship of Ipsen Biopharmaceuticals
Metastatic pancreatic cancer is a difficult-to-treat cancer associated with poor outcomes. Moreover, it is known to cause challenging symptoms, which are oftentimes compounded by treatment. As more therapeutic options become available, oncologists can start to consider survival outcomes and the tolerability profile when making treatment recommendations.
Until recently, first-line options for patients with metastatic pancreatic adenocarcinoma (mPDAC) were limited to the following therapies: (1) gemcitabine plus nab-paclitaxel (GEM+Nab-P) and (2) fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). In February 2024, the U.S. Food and Drug Administration approved ONIVYDE® (irinotecan liposome injection), a topoisomerase inhibitor, in combination with oxaliplatin, fluorouracil and leucovorin, for the first-line treatment of adults patients with metastatic pancreatic adenocarcinoma based on results of the Phase 3 NAPOLI 3 trial.
ONIVYDE® (irinotecan liposome injection) is indicated, in combination with oxaliplatin, fluorouracil, and leucovorin, for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma. ONIVYDE is indicated, in combination with fluorouracil and leucovorin, for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy. Limitations of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic pancreatic adenocarcinoma. WARNING: SEVERE NEUTROPENIA AND SEVERE DIARRHEA Neutropenia
Diarrhea
|
"We are excited by the FDA-approval to have another treatment option for patients with newly diagnosed mPDAC,” said Maen Abdelrahim, MD, PhD, PharmB, Section Chief of Gastrointestinal Medical Oncology, Dr. Mary and Ron Neal Cancer Center, Houston Methodist Hospital. “The liposomal formulation of ONIVYDE encapsulates irinotecan in a lipid bilayer, allowing it to remain in circulation for longer than free irinotecan. When compared with free irinotecan, a pre-clinical study showed higher intratumoral levels of irinotecan and its active metabolite SN-38 can be achieved and sustained.”
The importance of proactive AE management and patient education
The ONIVYDE regimen has demonstrated improvements across key outcome measures like overall survival (OS) and progression-free survival (PFS) compared to the previous standard of care, GEM+Nab-P. It also showed higher numerical overall response rates (ORR) vs. GEM+Nab-P. However, when treating patients, it’s equally critical to consider the impact of treatment on day-to-day life and manageability of adverse events. Diarrhea was the most commonly observed adverse event for all grades in the NAPOLI 3 trial. If left unmanaged, diarrhea can be a serious adverse event, but if proactively managed through nutrition (patients should stop lactose-containing products, eat a low-fat diet and maintain hydration during treatment with ONIVYDE) and/or through administration of anti-diarrhetic (atropine for early-onset diarrhea, or loperamide for late-onset diarrhea), the adverse event may be managed and it may allow a patient to continue treatment.
Direct and ongoing conversation with patients about what to expect from treatment, specifically outlining potential adverse events and proactive ways to manage them, is essential to ensure patients speak up about symptoms as they experience them. In this way, early management of adverse events may potentially help the patient stay on therapy. “Including a discussion of the potential adverse events and toxicity for each treatment option is good clinical practice. We use a patient-centered approach that incorporates the input of the patient and their family for mPDAC treatment and the management of side effects. This approach can help empower the patient and their family to become active members of their cancer care team.”
A study was published in 2024 in Journal of Clinical Oncology, that described the reasons for non-treatment in a real-world cohort of patients with pancreatic cancer. The results showed that even among patients with mPDAC, 43.8% did not receive any cancer-directed treatment. The primary reason to decline treatment was due to patient/family preference even when treatment was recommended by their clinician. This further demonstrates the importance of educating patients about what to expect from treatment to make an informed decision.
NAPOLI 3 Results
NAPOLI 3 demonstrated superior efficacy of the ONIVYDE regimen over GEM+Nab-P as a therapeutic option for treatment-naïve patients with mPDAC. A total of 770 patients from 187 worldwide community and academic centers were randomized to receive either the ONIVYDE regimen (NALIRIFOX; n=383) or GEM+Nab-P (n=387). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and overall response rate (ORR), which were tested in a hierarchical approach if OS was significant.
Results of the study showed that the median OS was 11.1 months (95% confidence interval (CI) (10.0, 12.1)) in the ONIVYDE group and 9.2 months (95% CI (8.3, 10.6)) in the GEM+Nab-P group (hazard ratio (HR) 0.84 [95% CI 0.71–0.99]; p=0.0403; Table 1 and Figure 1). The median PFS was 7.4 months (95% CI (6.0, 7.7)) in the ONIVYDE group and 5.6 months (95% CI (5.3, 5.8)) in the GEM+Nab-P group (HR 0.70 [95% CI 0.59–0.85]; p=0.0001; Table 1). The ORR was 41.8% (36.8%-46.9%; 95% CI) for the ONIVYDE group versus 36.2% (31.4%-41.2%; 95% CI) for patients treated with GEM+Nab-P group (Table 1).
It should be noted that serious adverse reactions occurred in 54% of patients who received ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin. ONIVYDE has black box warnings for severe neutropenia and severe diarrhea: ONIVYDE should be withheld when the absolute neutrophil count is below 1500/mm3 or when neutropenic fever is present. In addition, ONIVYDE should be withheld with grade 2-4 diarrhea. Do not administer to patients with obstructive bowel disease.
The impact of the first-line ONIVYDE regimen
“Typically, fewer than 15% of our patients present with resectable disease; most have advanced or regional disease with a very low rate of 5-year survival. The meaningful clinical improvements in OS and PFS with the ONIVYDE regimen over the currently approved GEM+Nab-P regimen adds an exciting option for treating first-line mPDAC, helping to provide more time for our patients. And, by educating patients about what to expect from treatment, we can help them feel empowered to speak up and raise concerns.”
Table 1. Efficacy Results of All Randomized Patients in NAPOLI 3
| NALIRIFOX* (N=383) | Gem+NabP (N=387) |
Overall Survival | ||
Number of Deaths, n (%) | 259 (68) | 285 (74) |
Median Overall Survival (months) | 11.1 | 9.2 |
(95% CI) | (10.0, 12.1) | (8.3, 10.6) |
Hazard Ratio (95% CI) * | 0.84 (0.71, 0.99) | |
p-value † | 0.0403 | |
Progression-Free Survival | ||
Death or Progression, n (%) | 249 (65) | 259 (67) |
Median Progression-Free Survival (months) | 7.4 | 5.6 |
(95% CI) | (6.0, 7.7) | (5.3, 5.8) |
Hazard Ratio (95% CI) * | 0.70 (0.59, 0.85) | |
P-value † | 0.0001 | |
Objective Response Rate # | ||
ORR (95% CI) | 41.8 (36.8, 46.9) | 36.2 (31.4, 41.2) |
CR, n (%) | 1 (0.3) | 1 (0.3) |
PR, n (%) | 159 (41.5) | 139 (35.9) |
* NALIRIFOX= ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin; Gem+NabP=gemcitabine+nab-paclitaxel; CI=confidence interval
** Based on the stratified Cox proportional hazard model; stratified by ECOG PS (0 vs. 1), region (North America vs. East Asia vs. Rest of the world), and liver metastases (yes vs. no) per interaction web response system
† Based on stratified log-rank test.
# ORR result was not statistically significant.
IMPORTANT SAFETY INFORMATION AND INDICATIONS
WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA See full prescribing information for complete boxed warning Neutropenia
Diarrhea
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CONTRAINDICATIONS
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction or anaphylaxis to ONIVYDE or irinotecan HCl.
WARNINGS AND PRECAUTIONS
Severe Neutropenia: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 neutropenia occurred in 26% of patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) and fatal neutropenic fever in 0.3% of patients. In NAPOLI 3, the incidence of Grade 3 or 4 neutropenia was similar among Asian patients [6 of 20 (30%)] compared to White patients [76 of 289 (26%)]. Neutropenic fever/neutropenic sepsis was reported in 5% of Asian patients (1 of 20) compared to 2.3% of White patients (7 of 306). In NAPOLI-1, Grade 3 and 4 neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin (ONIVYDE/FU/LV). Neutropenic sepsis occurred in 3% and fatal neutropenic sepsis in 0.8%. In NAPOLI-1, the incidence of Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients.
Monitor complete blood cell counts on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below 1500/mm3 or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm3 or above. Reduce ONIVYDE dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles.
Severe Diarrhea: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 diarrhea (early-onset [within 24 hours of chemotherapy] and late-onset [more than 24 hours following chemotherapy]) occurred in 20% receiving NALIRIFOX. In NAPOLI-1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 late-onset diarrhea was 9% in patients receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 early-onset diarrhea was 3% in patients receiving ONIVYDE/FU/LV.
To reduce the risk of severe diarrhea, patients should stop lactose-containing products, eat a low-fat diet, and maintain hydration during treatment with ONIVYDE. Withhold ONIVYDE for Grade 2-4 diarrhea. Local institutional guidelines should be followed for the treatment of diarrhea that does not improve within 48 hours and may include the addition of diphenoxylate hydrochloride plus atropine sulfate or octreotide. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose.
Interstitial Lung Disease (ILD): Irinotecan HCl can cause severe and fatal ILD. Patients with risk factors should be closely monitored for respiratory symptoms before and during ONIVYDE therapy. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.
Severe Hypersensitivity Reaction: Irinotecan, including ONIVYDE, can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.
Embryo-Fetal Toxicity: ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 7 months after the last dose of ONIVYDE treatment.
ADVERSE REACTIONS FOR NALIRIFOX
- The most common adverse reactions (≥20%) of NALIRIFOX were diarrhea (72%), fatigue (62%), nausea (59%), vomiting (40%), decreased appetite (37%), abdominal pain (35%), mucosal inflammation (28%), constipation (25%), and weight decreased (22%).
- Permanent discontinuation of ONIVYDE due to an adverse reaction occurred in 17% of patients. Adverse reactions that resulted in permanent discontinuation of ONIVYDE in ≥1% of patients included neutropenia, thrombocytopenia, diarrhea, fatigue, infections, and cerebrovascular accident.
- Dosage reduction of ONIVYDE due to an adverse reaction occurred in 52% of patients. Adverse reactions that required dosage reduction in ≥1% of patients included anemia, decreased appetite, diarrhea, fatigue, febrile neutropenia, hypokalemia, liver function test abnormalities, nausea, mucosal inflammation, neutropenia, peripheral neuropathy, vomiting, thrombocytopenia, and weight decreased.
- Dosage interruptions of ONIVYDE due to an adverse reaction occurred in 1.9% of patients. Adverse reactions which required dosage interruption in ≥0.5% of patients included hypersensitivity and infusion-related reaction.
- The most common laboratory abnormalities (≥10% Grade 3 or 4) were decreased neutrophils (26%), decreased potassium (22%), decreased lymphocytes (11%), and decreased hemoglobin (10%).
ADVERSE REACTIONS FOR ONIVYDE/FU/LV
- The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%).
- Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis.
- Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia.
- ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.
- The most common severe laboratory abnormalities (≥10% Grade 3 or 4) were lymphopenia and neutropenia.
Postmarketing Experience: Immune system disorders: Hypersensitivity (including anaphylactic reaction and angioedema).
DRUG INTERACTIONS
- Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE.
- Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy.
USE IN SPECIFIC POPULATIONS
- Pregnancy and Reproductive Potential: See WARNINGS & PRECAUTIONS. Advise males with female partners of reproductive potential to use condoms during and for 4 months after the last dose of ONIVYDE treatment.
- Lactation: Advise nursing women not to breastfeed during and for 1 month after the last dose of ONIVYDE treatment.
To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information, including BOXED WARNING, for ONIVYDE.
ONIVYDE is a registered trademark of Ipsen Biopharm Ltd.
©2024 Ipsen Biopharmaceuticals, Inc. All rights reserved. August 2024 ONV-US-005210