ONIVYDE® (irinotecan liposome injection) Efficacy Results

ONIVYDE + 5-FU/LV EXTENDED OVERALL SURVIVAL (OS)

PROVEN TO EXTEND OS BY APPROXIMATELY 2 MONTHS IN NAPOLI-1 PRIMARY ANALYSIS^1*

ONIVYDE + 5-FU/LV increased OS by approximately 2 months compared with 5-FU/LV alone, in the NAPOLI-1 primary analysis¹

In an exploratory analysis, 1-year probability of survival was 24% with ONIVYDE + 5-FU/LV and 17% with 5-FU/LV^14,15

Limitations: This should not be interpreted as a treatment difference between arms at 1 year due to potential bias and no formal statistical protection for false positive findings

_{*NAPOLI-1 was a global, phase 3, randomized, open-label, multicenter trial in patients (N=417) with metastatic adenocarcinoma of the pancreas whose disease had progressed following gemcitabine-based therapy. Patients were initially randomized to receive ONIVYDE (100 mg/m² every 3 weeks) or 5-FU/LV. After 63 patients were enrolled, a third arm, ONIVYDE (70 mg/m² every 2 weeks) + 5-FU/LV, was added. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint, median OS, was assessed with 2 pair-wise comparisons: ONIVYDE (n=151) vs 5-FU/LV (n=149) and ONIVYDE + 5-FU/LV (n=117) vs 5-FU/LV (n=119, post-protocol amendment). There was no improvement in OS for ONIVYDE vs 5-FU/LV (HR=1.00, p=0.97 [2-sided log-rank]).^1,7}

_{†ONIVYDE monotherapy had no effect on OS.}

_{HR=hazard ratio; CI=confidence interval; 5-FU=fluorouracil; LV=leucovorin.}

More about the phase 3 trial, NAPOLI-1

Final analysis of NAPOLI-1

For the final post-hoc analysis of NAPOLI-1, follow-up data were analyzed after additional efficacy events were recorded. The primary analysis included 313 OS events as of February 14, 2014; the final analysis included 382 OS events as of November 16, 2015.¹⁴

Read the final analysis paper

The final analysis of NAPOLI-1 included an exploratory, post-hoc analysis of a long-term (≥1 year) survivor subgroup, which showed a ≥1-year survival of 25% with ONIVYDE + 5‑FU/LV vs 13% with 5‑FU/LV alone.¹⁴

Limitations: The exploratory, post-hoc analysis of NAPOLI-1 was not prespecified and was not powered for statistical significance, so its results should be interpreted with caution.

In the exploratory, post-hoc analysis, baseline characteristics of patients in the ONIVYDE + 5-FU/LV arm who survived ≥1 year were more likely to be: Karnofsky performance status ≥90, age ≤65 years, CA 19‑9 levels <59x the upper limit of normal, neutrophil-to-lymphocyte ratio ≤5, no liver metastases.^1,14

See Phase 3 NAPOLI-1 Study Design

FIGHT ON WITH DOUBLED PROGRESSION-FREE SURVIVAL (PFS)

DOUBLED PFS VS 5-FU/LV ALONE^1,7*

ONIVYDE + 5-FU/LV doubled PFS compared with 5-FU/LV alone, in the NAPOLI-1 primary analysis¹(PFS as a secondary endpoint)

In an exploratory analysis, 1-year probability of survival was 24% with ONIVYDE + 5-FU/LV and 17% with 5-FU/LV^14,15

Limitations: This should not be interpreted as a treatment difference between arms at 1 year due to potential bias and no formal statistical protection for false positive findings

_{HR=hazard ratio; CI=confidence interval; 5-FU=fluorouracil; LV=leucovorin.}

Confirmed objective response rate (ORR) in NAPOLI-1

ONIVYDE + 5-FU/LV demonstrated a confirmed ORR of 7.7% (9/117) and 5-FU/LV demonstrated a confirmed ORR of 0.8% (1/119)^1†

_{NAPOLI-1 was a global, phase 3, randomized, open-label, multicenter trial in patients (N=417) with metastatic adenocarcinoma of the pancreas whose disease had progressed following gemcitabine-based therapy. Patients were initially randomized to receive ONIVYDE (100 mg/m² every 3 weeks) or 5-FU/LV. After 63 patients were enrolled, a third arm, ONIVYDE (70 mg/m² every 2 weeks) + 5-FU/LV, was added. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was median OS. Additional efficacy endpoints were PFS and ORR.^1,7}

^†_{Investigator assessment per RECIST v1.1.⁷}

_{RECIST=response evaluation criteria in solid tumors.}

_{HR=hazard ratio; CI=confidence interval; 5- FU=fluorouracil; LV=leucovorin}

IMPORTANT SAFETY INFORMATION & INDICATION

WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA

Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with 5-FU and LV. Withhold ONIVYDE for absolute neutrophil count below 1500/mm³ or neutropenic fever. Monitor blood cell counts periodically during treatment
Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity

INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATION

ONIVYDE^® (irinotecan liposome injection) is indicated, in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

CONTRAINDICATION

ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl

WARNINGS AND PRECAUTIONS

Severe Neutropenia: See Boxed WARNING. In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian (18/33 [55%]) vs White patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients
Severe Diarrhea: See Boxed WARNING. Severe and life-threatening late-onset (onset >24 hours after chemotherapy [9%]) and early-onset diarrhea (onset ≤24 hours after chemotherapy [3%], sometimes with other symptoms of cholinergic reaction) were observed
Interstitial Lung Disease (ILD): Irinotecan HCl can cause severe and fatal ILD. 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 Reactions: Irinotecan HCl 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 females of reproductive potential to use effective contraception during and for 1 month after ONIVYDE treatment

ADVERSE REACTIONS

The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%)
The most common Grade 3/4 adverse reactions (≥10%) were diarrhea (13%), fatigue/asthenia (21%), and vomiting (11%)
Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/5-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/5-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/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia
The most common laboratory abnormalities (≥20%) were anemia (97%), lymphopenia (81%), neutropenia (52%), increased ALT (51%), hypoalbuminemia (43%), thrombocytopenia (41%), hypomagnesemia (35%), hypokalemia (32%), hypocalcemia (32%), hypophosphatemia (29%), and hyponatremia (27%)

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 ONIVYDE treatment
Lactation: Advise nursing women not to breastfeed during and for 1 month after ONIVYDE treatment

Please see full Prescribing Information, including Boxed WARNING.

References: 1. ONIVYDE [package insert]. Basking Ridge, NJ. Ipsen Biopharmaceuticals, Inc.; 2017. 2. Ipsen data on file: IQVIA medical claims post-gemcitabine usage analysis, June 2018-May 2019. 3. Ipsen data on file. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma V.2.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed July 12, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org. 5. Sohal DPS, Kennedy EB, Khorana A, et al. Metastatic Pancreatic Cancer ASCO Clinical Practice Guideline Update. J Clin Oncol. 2018;36(24):2545-2556. 6. Deeb A, Haque S-U, Olowokure O. Pulmonary metastases in pancreatic cancer, is there a survival influence? J Gastrointest Oncol. 2015;6(3):E48-E51. 7. Data on file #1. Basking Ridge, NJ. Ipsen Biopharmaceuticals, Inc.; 2015. 8. Wang-Gillam A, Li C-P, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387:545-557. 9. Zhang H. Onivyde for the therapy of multiple solid tumors. OncoTargets Ther. 2016;9:3001-3007. 10. Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24(33):5313-5327. 11. Columbia University Irving Medical Center. The Pancreas Center. Lab tests. https://columbiasurgery.org/pancreas/lab-tests. Accessed January 29, 2020. 12. NIH. National Cancer Institute. Pancreatic cancer treatment (adult) (PDQ®)-health professional version. https://www.cancer.gov/types/pancreatic/hp/pancreatic-treatment-pdq. Accessed November 27, 2019. 13. Ducreux M, Cuhna AS, Caramella C, et al; on behalf of ESMO Guidelines Committee. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5):v56-v68. 14. Wang-Gillam A, Huber RA, Siveke JT, et al. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019;108:78-87. 15. Data on file #3. Basking Ridge, NJ. Ipsen Biopharmaceuticals, Inc.; 2015.