Month: December 2019

Overall Survival Benefit with ONIVYDE® and Characteristics of Long Term Survivors in Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that for 2019, about 56,770 people will be diagnosed with Pancreatic cancer and about 45,750 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced Pancreatic cancer has been dismal, with a 5-year survival rate for metastatic Pancreatic cancer of approximately 2%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States around 2020.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

NAPOLI-1 is an open-label, Phase III study in which 417 patients with Gemcitabine-refractory metastatic Pancreatic adenocarcinoma were randomly assigned in a 1:1:1 ratio to receive either ONIVYDE® monotherapy (N=151), ONIVYDE® plus 5-FluoroUracil (N=117) or 5-FU with Leucovorin (N=149). Sixty one percent (61%) of patients had cancer in the head of the Pancreas and 68% had liver metastases. Treatment consisted of ONIVYDE® 120 mg/m2 IV over 90 minutes every 3 weeks in Group A, ONIVYDE® 80 mg/m2 IV given over 90 minutes followed by 5-FU 2400 mg/m2 given over 46 hours and racemic Leucovorin 400 mg/m2 IV given over 30 minutes every 2 weeks in Group B and 5-FU 2000 mg/m2 IV given over 24 hours plus racemic Leucovorin 200 mg/m2 IV given over 30 minutes weekly for 4 weeks followed by 2 weeks of rest in Group C (Control group). Each of the two ONIVYDE® containing groups was compared with the 5FU/Leucovorin control group. Treatment groups were well balanced. The Primary study endpoint was Overall Survival and Secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR). The authors in this publication reported the updated Overall Survival analysis from a longer follow up in the NAPOLI-1 trial, as well as baseline characteristics associated with long term survivors (survival of 1 year or more) in the NAPOLI-1 trial. The authors also provided the updated safety and tolerability data.

The combination of ONIVYDE®, 5-FU and Leucovorin maintained its median OS of 6.2 months compared with 4.2 months with 5-FU and Leucovorin alone, with an unstratified Hazard Ratio of 0.75 (P=0.04), and stratified Hazard Ratio of 0.63 (P=0.002). The estimated one-year survival rates were 26% in the ONIVYDE®, 5-FU and Leucovorin arm versus 16% in the 5-FU and Leucovorin combination control arm. Patient characteristics associated with long term survival in the ONIVYDE®, 5-FU and Leucovorin combination arm included Karnofsky Performance Status of 90 or more, age 65 years or less, lower serum CA19-9 levels, Neutrophil-to-Lymphocyte ratio of 5 or less and no liver metastases. There was again no OS advantage with ONIVYDE® monotherapy, when compared with 5-FU and Leucovorin (4.9 versus 4.2 months). The median PFS was 3.1 months in patients receiving ONIVYDE®, 5-FU and Leucovorin and 1.5 months in those receiving 5-FU and Leucovorin combination alone (HR=0.57; P < 0.0001), and was 2.7 months for ONIVYDE® monotherapy compared with 1.6 months for 5-FU and Leucovorin combination control group. The ORR was significantly higher with ONIVYDE®, 5-FU and Leucovorin combination (17%) compared with 1% for the 5-FU and Leucovorin combination (P < 0.0001) and the Disease Control Rate was also higher with ONIVYDE®, 5-FU and Leucovorin combination (52%) versus 24% for the 5-FU and Leucovorin combination control group. No new safety concerns were detected in the current updated analysis.

The authors concluded that for patients with metastatic Pancreatic adenocarcinoma, a combination of ONIVYDE®, 5-FU and Leucovorin improves Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate, with an acceptable safety profile, and represents a new standard of care following Gemcitabine-based therapy. This updated analysis also identified prognostic markers associated with longer survival. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Wang-Gillam A, Hubner RA, Siveke JT, et al. European Journal of Cancer 2019;108:78-87

Isatuximab Combination Significantly Improves Progression Free Survival in Relapsed/Refractory Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32,110 new cases will be diagnosed in 2019 and 12,960 patients are expected to die of the disease. Multiple Myeloma (MM) in 2019 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity.

CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38 and was approved for use in combination with POMALYST® (Pomalidomide) and Dexamethasone in 2017, for the treatment of patients with multiple myeloma who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

Isatuximab is a CD38-targeting monoclonal antibody, similar to DARZALEX®, but unlike DARZALEX®, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from DARZALEX® could position Isatuximab for use in cases when DARZALEX® fails. Additionally, Isatuximab infusions are less cumbersome.

ICARIA-MM trial is an open-label, randomized, multicentre Phase III study in which 307 adult patients with Relapsed and Refractory multiple myeloma who had received at least two previous lines of treatment, including REVLIMID® and a Proteasome Inhibitor were eligible. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. Patients were randomly assigned 1:1 to receive either Isatuximab along with POMALYST® and low-dose Dexamethasone (N =154) or POMALYST® and low-dose Dexamethasone (N = 153). Treatment consisted of 28-day cycles of Isatuximab 10 mg/kg given IV on days 1, 8, 15, and 22 in the first cycle and days 1 and 15 in subsequent cycles. Both groups received POMALYST® 4 mg orally on days 1 to 21 of each cycle and Dexamethasone 40 mg (20 mg for patients aged 75 years or older) oral or IV on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression or unacceptable toxicity. The Primary endpoint was Progression Free Survival, determined by an Independent Response Committee, and assessed in the intent-to-treat population.

At a median follow-up of 11.6 months, the median PFS was 11.5 months in the Isatuximab group versus 6.5 months in the control group (HR= 0.596; P=0.001). In prespecified subgroup analyses, which included patients with poor prognostic features, and those refractory to REVLIMID®, a Proteasome Inhibitor, or both, the Hazard Ratios were consistently in favor of Isatuximab.(HR=0.58). The most common adverse events of any grade in the Isatuximab vs control groups were infusion reactions (38% versus 0%, of which 3% were Grade 3 or 4), upper respiratory tract infection (28% versus 17%), and diarrhea (26% versus 20%).

It was concluded that the addition of Isatuximab to POMALYST® and Dexamethasone significantly improves Progression Free Survival in patients with Relapsed and Refractory multiple myeloma, and is an important new treatment option for the management of patients who become refractory to REVLIMID® and a Proteasome Inhibitor. Multiple myeloma patients will soon have the opportunity to choose between two equally effective treatment options with various modes of administration. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Attal M, Richardson PG, Rajkumar SV, et al. The Lancet. November 14, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)32556-5