On October 21, 2018 Loxo Oncology, Inc. (Nasdaq: LOXO), a biopharmaceutical company developing highly selective medicines for patients with genomically defined cancers, and Bayer AG, Germany, reported updated clinical data for larotrectinib, an investigational oral, selective, and CNS-active TRK inhibitor, in adult and pediatric patients with TRK fusion cancers (Press release, Loxo Oncology, OCT 21, 2018, View Source [SID1234529995]). The update included approximately one year of additional follow-up for the 55 patients described in the larotrectinib New England Journal of Medicine publication from February 2018. In addition, the update included data for an additional 67 patients who were subsequently enrolled across the larotrectinib development program. As of a data cut-off date of July 30, 2018, median duration of response (DOR) had not been reached in either dataset. These data are being presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress.

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"It is exciting to see larotrectinib deliver durable responses to patients in these studies with TRK fusion cancer, regardless of age, tumor site of origin, or CNS involvement," said Ulrik Lassen, M.D., Ph.D., Department of Oncology, Rigshospitalet, Copenhagen. "The sixty-seven new patients have nearly the same overall response rate as the first fifty-five, and duration of response has actually improved with longer patient follow-up. It is interesting to note that once again, depth of response, indicated by a complete response or deep partial response, is a good predictor of duration of response. Additionally, we observed a safety profile with larotrectinib that is conducive to such chronic therapy. The larotrectinib experience provides strong clinical evidence supporting the development of single-purpose drugs against oncogenic driver targets, and underscores the importance of tumor genomic profiling capable of identifying NTRK gene fusions alongside other activating alterations."

Loxo Oncology and Bayer are engaged in a collaboration for the development and commercialization of larotrectinib. The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) submitted by Loxo Oncology, and granted Priority Review for larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. The FDA has set a target action date of November 26, 2018, under the Prescription Drug User Fee Act (PDUFA). Bayer has submitted a Marketing Authorization Application (MAA) in the European Union (EU) and additional filings in other markets are underway.

Key Data Presented

The ESMO (Free ESMO Whitepaper) presentation included additional follow-up for the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancers treated across Loxo Oncology’s Phase 1 adult trial, Phase 2 trial (NAVIGATE), and Phase 1/2 pediatric trial (SCOUT). These patients were the subject of the New England Journal of Medicine publication from February 2018, and constitute the primary analysis population supporting larotrectinib’s NDA filing. The presentation also included data for the 67 TRK fusion patients subsequently enrolled. Presented data were based on a July 30, 2018 data cut-off date, providing approximately one year of additional follow up for the primary analysis population.

The datasets adhered to the intent to treat (ITT) principle and included patients with RECIST-evaluable disease enrolled to the three clinical trials, regardless of prior therapy or tumor tissue diagnostic method used to establish their TRK fusion diagnosis. In the ESMO (Free ESMO Whitepaper) presentation, response evaluations were based on investigator assessment.

The 122-patient integrated dataset included both adult and pediatric patients, who ranged in age from one month to 80 years and carried 24 unique TRK fusion-positive tumor diagnoses. Tumor types included 10 distinct soft tissue sarcomas, salivary gland, infantile fibrosarcoma, thyroid, lung, melanoma, colon, gastrointestinal stromal tumor (GIST), breast, bone sarcoma, cholangiocarcinoma, carcinoma of unknown primary, congenital mesoblastic nephroma, appendiceal, and pancreas cancers.

In the primary dataset, the overall response rate (ORR) was 80% (44/55) (95% CI: 67-90%), with a 62% partial response rate and an 18% complete response rate. In the supplementary dataset, the ORR was 81% (44/54) (95% CI: 69-91%), with a 65% partial response rate and a 17% complete response rate. Across both datasets, the ORR was 81% (88/109) (95% CI: 72-88%), with a 63% partial response rate and 17% complete response rate. The ORR analyses for the supplementary and integrated datasets included nine patients with unconfirmed partial responses awaiting confirmatory response assessments, but did not include 13 patients who were awaiting an initial response assessment and continuing on study.

Median duration of response (DOR) had not been reached in either the primary dataset or supplementary dataset, with median follow-up of 17.6 months and 7.4 months, respectively. In the primary dataset, Kaplan-Meier landmark analyses improved since the July 2017 data cut-off date. At 6 months, 88% of responses were ongoing (83% based on the July 2017 data cut-off date). At 12 months, 75% of responses were ongoing (71% based on the July 2017 data cut-off date). Kaplan-Meier landmark analyses of the supplementary dataset were highly concordant with the primary dataset. At 6 months, 93% of responses were ongoing and at 12 months, 81% of responses were ongoing. Across the integrated dataset, as of the July 2018 data cut-off date, 84% of responding patients remained on treatment or had undergone surgery with curative intent. Of 8 TRK fusion patients treated in the Phase 1 trial, 6 remained in response and on therapy at 22, 30, 33, 34, 37, and 41 months of follow up. With median follow-up for progression-free survival (PFS) of 19.6 months in the primary dataset, median PFS had been reached, at 28.3 months (95% CI: 9.9 months – Not estimable). This estimate is not statistically stable due to a low number of progression events, as evidenced by the wide confidence interval.

The safety data presented at ESMO (Free ESMO Whitepaper) encompassed the entire larotrectinib safety database in cancer patients (n=207), which includes 70 patients without a TRK fusion diagnosis. Larotrectinib was well tolerated, with the majority of adverse events recorded as grade 1 or 2. No treatment-related grade 3 or 4 adverse events occurred in more than 5% of patients. Eleven patients (9%) required larotrectinib dose reductions. In all cases, patients whose doses were reduced maintained their best response at the lower dose. One patient (<1%) discontinued larotrectinib due to an adverse event.

The ESMO (Free ESMO Whitepaper) presentation will be available online at View Source

Larotrectinib Program Update

As of September 30, 2018, the larotrectinib program had treated 179 patients with TRK fusion cancer, which includes the 122 patients reported at ESMO (Free ESMO Whitepaper), an additional 15 treated since the ESMO (Free ESMO Whitepaper) data cut-off date, 24 treated under expanded access protocols, and 18 who had either non-measurable disease or primary central nervous system tumors. By comparison, the program had treated 133 patients with TRK fusion cancer as of March 31, 2018 and 98 as of September 30, 2017.

About Larotrectinib
Larotrectinib is an oral, selective, and CNS-active investigational tropomyosin receptor kinase (TRK) inhibitor in clinical development for the treatment of patients with cancers that harbor a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In clinical trials, larotrectinib demonstrated anti-tumor activity in patients with tumors harboring NTRK gene fusions, regardless of patient age or tumor type. In an analysis of 55 RECIST-evaluable adult and pediatric patients with NTRK gene fusions, using a July 17, 2017 data cutoff, larotrectinib demonstrated a 75 percent centrally-assessed confirmed overall response rate (ORR) and an 80 percent investigator-assessed confirmed ORR, across many different types of solid tumors. The majority (93 percent) of all adverse events were grade 1 or 2.

Larotrectinib has been granted Priority Review, Breakthrough Therapy Designation, Rare Pediatric Disease Designation and Orphan Drug Designation by the U.S. FDA.

In November 2017, Loxo Oncology and Bayer entered into an exclusive global collaboration for the development and commercialization of larotrectinib and LOXO-195, a next-generation TRK inhibitor. Bayer and Loxo Oncology are jointly developing the two products with Loxo Oncology leading the ongoing clinical studies as well as the filing in the U.S., and Bayer leading ex-U.S. regulatory activities and worldwide commercial activities. In the U.S., Loxo Oncology and Bayer will co-promote the products.

For additional information about the larotrectinib clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123 or visit www.loxooncologytrials.com/trk-trials.

About TRK Fusion Cancer
TRK fusion cancer occurs when a neurotrophic tyrosine receptor kinase (NTRK) gene fuses with another unrelated gene, producing an altered tropomyosin receptor kinase (TRK) protein. The altered protein, or TRK fusion protein, is constantly active, triggering a permanent signal cascade. These proteins become the primary driver of the spread and growth of tumors in patients with TRK fusion cancer. TRK fusion cancer is not limited to certain types of cells or tissues and can occur in any part of the body. NTRK gene fusions occur in various adult and pediatric solid tumors with varying prevalence, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, GIST, infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas. Only sensitive and specific tests can reliably detect TRK fusion cancer. Next-generation sequencing (NGS) can provide a comprehensive view of genomic alterations across a large number of genes. Fluorescence in situ hybridization (FISH) can also be used to test for TRK fusion cancer, and immunohistochemistry (IHC) can be used to detect the presence of TRK protein.

On October 21, 2018 LSK BioPharma (or "LSKB"), a US-based biopharmaceutical firm and Jiangsu Hengrui Medicine, Co., Ltd. (SHA:600276, or "Hengrui"), one of the largest and most innovative fully-integrated biopharmaceutical companies based in China, reported that the companies have entered into a global clinical collaboration in patients with advanced hepatocellular carcinoma (HCC), evaluating the safety and efficacy of LSKB’s rivoceranib, also known as apatinib or Aitan (brand name) in China, a selective and potent VEGFR-2 inhibitor, in combination with Hengrui’s camrelizumab (SHR-1210), a humanized anti-PD-1 monoclonal antibody currently under NDA review in China for classic Hodgkin’s Lymphoma (cHL) (Press release, LSK BioPharma, OCT 21, 2018, View Source [SID1234530127]).

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Under the terms of the clinical collaboration agreement, Hengrui will be responsible for administering the clinical trial with all study costs outside of China shared equally among both parties. LSKB will retain full commercial rights for rivoceranib outside of China and Hengrui will retain full commercial rights for camrelizumab worldwide.

"At diagnosis, hepatocellular carcinoma typically has a dismal prognosis due to a lack of treatment options and the ineffectiveness of standard systemic therapies," said Dr. Sung Chul Kim, LSKB’s President, "we are enthusiastic to work with Hengrui for the potential to help more patients by combining rivoceranib with camrelizumab."

"We are pursuing camrelizumab in about 20 clinical trials in China. There is ample scientific evidence and preliminary clinical data supporting the synergistic effects of camrelizumab when used in combination with apatinib (rivoceranib)," said Dr. Lianshan Zhang, President of Global R&D of Hengrui. "We look forward to partnering with LSKB to build upon the existing preclinical and clinical data and further explore this combination therapy for patients with hepatocellular carcinoma, an area of high unmet medical needs."

"As one of the leading biopharmaceutical companies in China, we are committed to developing innovative medicines to address the urgent clinical needs. Through years of effort, Hengrui has built a robust oncology pipeline, which holds significant potential to benefit cancer patients. We are excited about this collaboration to accelerate the delivery of effective and durable treatment options for patients around the world," said Dr. Piaoyang Sun, Chairman of Hengrui.

Currently, Hengrui is conducting an open-label, single arm multicenter phase 2 study (NCT03463876) to evaluate the efficacy and safety of the combination of camrelizumab and apatinib in patients with advanced HCC in China, where Hengrui has received approval of apatinib monotherapy for advanced gastric cancer. At ASCO (Free ASCO Whitepaper) 2018, it was reported that the objective response rate (ORR) and disease control rate (DCR) were 50.0% and 85.7%, respectively, among 14 evaluated advanced HCC patients treated by camrelizumab in combination with apatinib in an open-label, phase 1 study in China (Xu et al., NCT02942329). In addition, camrelizumab and apatinib combination therapy is also being evaluated by Hengrui for multiple indications including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and gastric cancer (GC) in China.

It is hypothesized that the combination of rivoceranib and camrelizumab may enhance the immune system, aiding the fight against cancer. In addition to the known anti-angiogenic effects of rivoceranib, it may also enhance camrelizumab’s anti-tumor activity by normalizing tumor vasculature and reversing the tumor suppressive immune microenvironment.

About Rivoceranib (Apatinib)
Rivoceranib, also known as apatinib or Aitan (brand name) in China, is the first successful small-molecule angiogenesis inhibitor in gastric cancer. Rivoceranib acts by inhibiting angiogenesis, a critical process in cancer growth and proliferation. Specifically, rivoceranib selectively inhibits VEGFR-2 which mediates the primary pathway for tumor-mediated angiogenesis.

Hengrui, who owns the China rights to rivoceranib, received the approval from China National Medical Products Administration (NMPA, formerly known as CFDA) in 2014 to market the drug under the brand name Aitan in China for advanced gastric cancer. LSKB, which holds the global rights (ex-China), is currently conducting a global (12 countries including US, Japan, Korea, Italy, Germany, and Russia) phase 3 clinical trial of rivoceranib in advanced or metastatic gastric cancer patients. Rivoceranib (apatinib) is currently listed in 220 clinical studies on www.clinicaltrials.gov with over 20,000 patients enrolled or planned to be enrolled in numerous cancers including GC, colorectal cancer (CRC), HCC, NSCLC, esophageal cancer, thyroid cancer, mesothelioma, and neuroendocrine tumors. It has also shown potential to significantly improve outcomes in combination with chemotherapeutics and immunotherapy, as well as for maintenance therapy. LSKB has received notification designating rivoceranib as an orphan medicinal product for the treatment of gastric cancer from the European Commission in the European Union, the US FDA, as well as the MFDS in South Korea.

Rivoceranib was developed by Advenchen Laboratories in Southern California under the designation YN968D1. The compound was exclusively licensed to Hengrui in China (2005) and LSKB (2008) for rest of the world.

About Camrelizumab (SHR-1210)

Camrelizumab (SHR-1210) is an investigational humanized monoclonal antibody recognizing the programmed death-1 (PD-1) receptor. Camrelizumab functions as an immune checkpoint inhibitor by specifically blocking the interaction between PD-1 and PD-L1 and reversing the immunosuppressive signal of PD-1 on the T cell. Approximately 20 clinical trials on camrelizumab in multiple indications including lung cancer, liver cancer, gastric cancer, esophageal cancer, nasopharyngeal carcinoma, lymphoma, melanoma and other advanced solid tumors are being conducted in China and Australia as monotherapy or in combination with other therapeutic agents. A marketing application for camrelizumab for relapsed/refractory classic Hodgkin’s Lymphoma was submitted by Hengrui to China NMPA, which was accepted in April 2018, and is currently under review.

On October 21, 2018 Servier and Taiho Oncology, Inc. (U.S.), a subsidiary of Taiho Pharmaceutical Co., Ltd. (Japan), jointly announced today clinical data from the pivotal Phase III TAS-102 Gastric Study (TAGS) evaluating LONSURF (trifluridine/tipiracil, TAS-102) versus placebo and best supportive care in patients with heavily pre-treated metastatic gastric cancer who have progressed or are intolerant to previous lines of therapy (Press release, Servier, OCT 21, 2018, View Source [SID1234530014]). The study met its primary endpoint of prolonged overall survival (OS) and secondary endpoint measures of progression-free survival (PFS) consistently supported the OS results, as well as continuing to demonstrate the predictable safety and tolerability profile of trifluridine/tipiracil. Data from TAGS was presented by Dr. Hendrik-Tobias Arkenau, Executive Medical Director of the Sarah Cannon Research Institute UK and an investigator for TAGS, at the ESMO (Free ESMO Whitepaper) 2018 Congress in Munich, Germany during an oral session (Abstract #LBA25). The study results were simultaneously published in The Lancet Oncology.

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Based on the results, Servier filed a new application for an additional indication for gastric cancer to the European Medicines Agency (EMA) for LONSURF.

"Patients with metastatic gastric cancer currently have limited treatment options after first and second line therapies have failed," said Dr. Arkenau. "We are pleased to present new data that demonstrate the overall survival clinical benefit of trifluridine/tipiracil in metastatic gastric and gastroesophageal cancer."

In TAGS patients treated with trifluridine/tipiracil showed a clinically meaningful and statistically significant improvement in OS compared with placebo and a 31 percent risk reduction of death (HR 0.69 one sided p=0.00029), which translated into a prolonged median survival of 2.1 months (5.7 months for trifluridine/tipiracil versus 3.6 months for placebo). In addition, trifluridine/tipiracil demonstrated a statistically significant improvement in PFS and time to deterioration of ECOG performance status versus placebo, as well as a predictable and manageable safety profile consistent with that previously reported in patients with metastatic colorectal cancer.

"We’re very excited by the results of TAGS as they show trifluridine/tipiracil has the potential to make a difference to the lives of people living with metastatic gastric cancer who continue to struggle with this devastating disease," said Patrick Therasse, Head of Servier Research and Development Oncology Department.

Trifluridine/tipiracil is currently indicated in 61 countries, including those of the European Union, for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents.1

The abstract for the trifluridine/tipiracil presentation is available on the ESMO (Free ESMO Whitepaper) website and the manuscript is published online in The Lancet Oncology.

ENDS

About TAGS
TAGS (TAS-102 Gastric Study) is a Taiho-sponsored pivotal Phase III, multinational, randomized, double-blind study evaluating trifluridine/tipiracil, also known as TAS-102, plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic gastric cancer, including gastro esophageal junction cancer, refractory to standard treatments. The primary endpoint in the TAGS trial is overall survival (OS), and the main secondary endpoint measures include progression-free survival (PFS), and safety and tolerability, as well as quality of life.

TAGS enrolled 507 adult patients with metastatic gastric cancer who had previously received at least two prior regimens for advanced disease. The study was conducted in Japan, the United States, the European Union, Russia, Belarus, Israel, and Turkey.

For more information on TAGS, please visit www.ClinicalTrials.gov (View Source). The ClinicalTrials.gov Identifier is NCT02500043.

About Metastatic Gastric Cancer
Gastric cancer, also known as stomach cancer, is a disease in which malignant cells form in the lining of the stomach. It is the fifth most common cancer worldwide and the third most common cause of cancer-related death (after lung and liver cancer), with an estimated 723,000 deaths annually.2　

When cancer spreads it is called advanced cancer. Locally advanced cancer is when the cancer has grown outside the organ it started in but hasn’t spread to other parts of the body. When the cancer spreads to other parts of the body this is called metastatic cancer. In the last two decades, the proportion of patients with gastric cancer who present with metastases has risen to over 40%.3

Standard chemotherapy regimens for advanced gastric cancer include fluoropyrimidines, platinum derivatives, and taxanes (with ramucirumab), or irinotecan. The addition of trastuzumab to chemotherapy is standard of care for patients with HER2-neu-positive advanced gastric cancer. However, after failure of first- and second-line therapies, standard third-line treatments are limited.

About LONSURF (trifluridine and tipiracil, TAS-102)
LONSURF is an oral anticancer drug, comprising a combination of trifluridine (FTD) and tipiracil (TPI), whose dual mechanism of action is designed to maintain clinical activity. LONSURF is registered in Japan, USA, European Union, and in many other countries. In the European Union, LONSURF is indicated for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan- based chemotherapies, anti-VEGF agents, and anti-EGFR agents.1

LONSURF is recommended by the National Institute for Health and Care Excellence (NICE),4 NCCN5,6 and ESMO (Free ESMO Whitepaper) Guidelines7 for the treatment of adult patients with metastatic CRC.

In June 2015, Servier and Taiho Pharmaceutical entered into an exclusive license agreement for the co-development and commercialization of LONSURF.

As of October 2018, LONSURF has been approved as a treatment for mCRC in 61 countries and regions worldwide.

On October 21, 2018 Ipsen Biopharmaceuticals, an affiliate of Ipsen (Euronext: IPN; ADR: IPSEY), reported results from a retrospective, observational analysis examining the real-world dosing patterns of patients with metastatic pancreatic cancer (mPC) treated with ONIVYDE (irinotecan liposome injection), at this year’s European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) annual congress taking place in Munich, Germany, Oct. 19-23, 2018 (Press release, Ipsen, OCT 21, 2018, View Source [SID1234530015]).

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Using the Flatiron Health electronic health record (EHR)-derived database, a longitudinal and nationally representative database comprising patient-level structured and unstructured data that is curated via technology-enabled abstraction, researchers identified 257 metastatic pancreatic cancer patients (median age: 67y; IQR: 61–74) who received ONIVYDE + fluorouracil (5-FU) and leucovorin (LV) therapy between November 2015 to August 2017 and analyzed their treatment data to assess dose intensity (DI) over the first 6 weeks of treatment, dose modifications during treatment, and overall duration of exposure (DOE) to ONIVYDE.

The real-world analysis (Poster 735P) describes how ONIVYDE was incorporated in the treatment sequencing that contained prior gemcitabine in the treatment of metastatic pancreatic cancer. In this analysis, the mean dose intensity was 177.8 mg/m2 (SD: 74.9 mg/m2). The median dose at initiation was 69.4 mg/m2 (IQR: 56.7–70.2); the recommended dose for ONIVYDE is 70 mg/m2. In addition, median duration of exposure was 8.9 weeks (IQR: 3.9/19 weeks) in first and second line and 6.3 weeks (IQR: 3.4/12.1 weeks) in third or plus lines.

These results are generally consistent with the NAPOLI-1 trial, however, dose modifications in the real-world analysis were lower (27.2% vs 45% in NAPOLI-1). In the NAPOLI-1 phase 3 trial, dose intensity over 6 weeks and duration of exposure for combination therapy with ONIVYDE was 167.5 mg/m2 (SD 44.8) and 8.7 weeks (IQR: 5.4 – 22.0), respectively. Despite these real-world patients being older, having worse performance status and more prior lines of treatment than patients in NAPOLI-1, more than half (59.1%) of patients started ONIVYDE + 5-FU/LV treatment with the recommended ONIVYDE dose (70 mg/m2).

NAPOLI-1 is the largest global, phase 3, randomized, open-label, multicenter trial in patients (N=417) with metastatic pancreatic cancer whose disease had progressed following gemcitabine-based therapy. Patients in the NAPOLI-1 trial being treated with ONIVYDE in combination with fluorouracil (5-FU) and leucovorin (LV) had improved overall survival (OS; primary endpoint) vs 5-FU/LV (6.1 mos vs 4.2 mos; HR = 0.67, 95% CI 0.49–0.92; P = 0.012). ONIVYDE monotherapy had no effect on OS.

ONIVYDE can cause severe, life-threatening neutropenia and diarrhea (see complete Boxed Warning in full prescribing information). ONIVYDE can also cause severe and fatal Interstitial Lung Disease (ILD) and hypersensitivity reactions. These serious adverse events may require withholding or discontinuing treatment with ONIVYDE, a dose reduction and/or supportive treatment. The most common adverse reactions in NAPOLI-1 (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%).

"Patients are at the heart of what we do, with unmet need guiding our development strategy and driving how we innovate for patient care," said Dr. Sotirios Stergiopoulos, Senior Vice President, Head of Global Medical Affairs and Chief Medical Officer. "This real-world data analysis provides further evidence in support of the dose intensity and duration of exposure of ONIVYDE and 5-FU/LV observed in the NAPOLI-1 phase 3 trial. This retrospective analysis allows us to further understand how patients with pancreatic cancer are receiving and managing their treatment in real-world settings."

Dr. Afsaneh Barzi, Study Investigator, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, Calif., notes, "As a physician who treats patients with metastatic pancreatic cancer, I find it reassuring and welcome the unique evidence the Flatiron dosing analysis provides in demonstrating the real-world usage of ONIVYDE + 5-FU/LV in a large sample of metastatic pancreatic cancer patients being treated in a clinical oncology setting when compared to a clinical trial setting. Data from our real-world practice for clinical analysis serve to further our knowledge about how to continue to effectively treat our patients."

About Pancreatic Cancer

Pancreatic cancer is a rare and deadly disease with about 55,440 people (29,200 men and 26,240 women) being diagnosed with pancreatic cancer in the United States alone.1 More than half are diagnosed with metastatic disease, which has an overall 5-year survival rate of less than three percent (3%)1, and often rapidly progresses during or shortly after receiving chemotherapy.2 Pancreatic cancer accounts for about 3% of all cancers, and is the third leading cause of cancer-related death in the United States, surpassing breast cancer.1 It is expected to become the second leading cause of cancer-related death in the U.S. by the year 2030, surpassing colorectal cancer.1,3

About ONIVYDE

ONIVYDE is an encapsulated formulation of irinotecan. This long-circulating liposomal form is designed to increase length of tumor exposure to both irinotecan and its active metabolite, SN38. ONIVYDE is approved by the U.S. FDA, EMA and many other countries. In the U.S., ONIVYDE is approved for use 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. ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas. Ipsen has gained exclusive commercialization rights for the current and potential future indications for ONIVYDE in the U.S., as well as the current licensing agreements with Servier for commercialization rights ex-U.S. and PharmaEngine for Taiwan.

IMPORTANT SAFETY INFORMATION:

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 fluorouracil (5-FU) and leucovorin (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.

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

On October 21, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that updated phase 1 safety and efficacy data for [fam-] trastuzumab deruxtecan, an investigational HER2 targeting antibody drug conjugate (ADC), were presented for a subgroup of patients with heavily pretreated HER2 expressing colorectal cancer at the 2018 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Munich, Germany (Press release, Daiichi Sankyo, OCT 21, 2018, https://www.prnewswire.com/news-releases/daiichi-sankyo-presents-updated-results-of-fam–trastuzumab-deruxtecan-ds-8201-in-patients-with-her2-expressing-advanced-colorectal-cancer-at-2018-european-society-for-medical-oncology-esmo-congress-300734400.html [SID1234530016]).

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An updated subgroup analysis in 19 evaluable patients with heavily pretreated HER2 expressing (defined as IHC ≥1+ or amplified) colorectal cancer receiving a recommended expansion dose of 6.4 mg/kg showed that [fam-] trastuzumab deruxtecan demonstrated a confirmed overall response rate of 15.8 percent (3 of 19 patients) and a disease control rate of 84.2 percent (16 of 19 patients). Median duration of response has not been reached and median progression-free survival was 3.9 months (95 percent CI: 2.1, 8.3) for this subgroup of patients. These patients had tumors with varying degrees of HER2 expression based on central IHC assessment of archival tissue, including six patients with HER2 IHC of zero (0). Tumor shrinkage primarily was observed in tumors with higher levels of HER2 IHC.

"We are encouraged by these preliminary results with [fam-] trastuzumab deruxtecan, particularly given the unmet medical need for patients with HER2 expressing colorectal cancer that has progressed on one or more prior therapies," said Takayuki Yoshino, MD, PhD, Director of Gastroenterology and Gastrointestinal Oncology at National Cancer Center Hospital East, Kashiwa, Japan, a study investigator. "These initial findings support further evaluation of [fam-] trastuzumab deruxtecan in this specific type of colorectal cancer."

"There are no therapies specifically approved for patients with HER2 expressing colorectal cancer, and continued study of [fam-] trastuzumab deruxtecan will provide a better understanding of the potential role of a HER2 targeting antibody drug conjugate in these patients," said Gilles Gallant, BPharm, PhD, Vice President, DS-8201 Global Team Leader, Oncology Research and Development, Daiichi Sankyo. "Patient enrollment is underway into our global phase 2 study evaluating safety and efficacy of [fam-] trastuzumab deruxtecan in patients with HER2 expressing advanced colorectal cancer."

Updated overall safety data as of August 10, 2018 across all subgroups of the ongoing phase 1 study with [fam-] trastuzumab deruxtecan in various HER2 expressing cancers were also reported at ESMO (Free ESMO Whitepaper). Among 259 patients who received at least one dose of [fam-] trastuzumab deruxtecan 5.4 or 6.4 mg/kg in Part 1 or Part 2 of the study (regardless of tumor type), the most common adverse events (≥30 percent, any Grade) included nausea (74.1 percent), decreased appetite (56.8 percent;) vomiting (43.6 percent), anemia (37.8 percent), alopecia (37.5 percent), fatigue (34.0 percent), diarrhea (33.6 percent) and constipation (32.8 percent). A total of 54.1 percent of patients experienced a ≥ Grade 3 adverse event and 22.8 percent had a serious adverse event, including 4.6 percent of patients who experienced an adverse event that led to death. As previously presented, five cases of Grade 5 interstitial lung disease (ILD)/pneumonitis were reported by the investigators for the overall population of the phase 1 study, none of which was observed in patients with colorectal cancer. Any reported cases of ILD/pneumonitis in the [fam-] trastuzumab deruxtecan clinical development program are evaluated by an independent adjudication committee.

Unmet Need in Colorectal Cancer
Colorectal cancer is the third most common cancer worldwide. In 2012, there were approximately 1.36 million new cases diagnosed and 690,000 deaths worldwide.1 Approximately 25 percent of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs, and about 50 percent of patients with colorectal cancer will eventually develop metastases.2 Prognosis for these patients remains poor.3

An increase in the number of approved targeted therapies for advanced colorectal cancer over the past decade has helped improve outcomes for some patients, however efficacy and tolerability of second and third-line treatments remain limited.4,5,6,7,8 Approximately 3 percent of colorectal cancers overexpress the HER2 protein, which is a well-established therapeutic target in breast and gastric cancer.4 In addition, research indicates that HER2 amplification may be associated with resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy and shorter survival.9,10 Currently, no approved HER2 targeting therapies exist for patients with colorectal cancer.

About the [Fam-] Trastuzumab Deruxtecan Phase 1 Study
An open-label, two-part phase 1 study is currently evaluating [fam-] trastuzumab deruxtecan in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objective of the dose escalation phase of this study was to assess the safety and tolerability of [fam-] trastuzumab deruxtecan and determine the maximum tolerated dose. Data from this part of the study were published in the Lancet Oncology.11

In the dose expansion part of the phase 1 study, [fam-] trastuzumab deruxtecan is given in one of two doses (5.4 mg/kg and 6.4 mg/kg) to patients with HER2 positive advanced or metastatic breast cancer and gastric cancer, HER2 low expressing breast cancer and other HER2 expressing solid tumors including colorectal cancer. Overall, 292 patients have been enrolled into this phase 1 study of [fam-] trastuzumab deruxtecan. For more information about the study, visit ClinicalTrials.gov.

About [Fam-] Trastuzumab Deruxtecan
[Fam-] trastuzumab deruxtecan (DS-8201; [fam-] trastuzumab deruxtecan in U.S. only; trastuzumab deruxtecan in other regions of world) is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, [fam-] trastuzumab deruxtecan is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

A broad and comprehensive development program with [fam-] trastuzumab deruxtecan is underway in North America, Europe and Asia. [Fam-] trastuzumab deruxtecan is in phase 3 development versus ado-trastuzumab emtansine (T-DM1) (DESTINY-Breast03) and versus investigator’s choice post T-DM1 (DESTINY-Breast02) for HER2 positive metastatic breast cancer; pivotal phase 2 clinical development for HER2 positive metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01); pivotal phase 2 development for HER2 positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01); phase 2 development for HER2 expressing advanced colorectal cancer; phase 2 development for metastatic non-squamous HER2 overexpressing or HER2 mutated NSCLC; and, phase 1 development in combination with nivolumab for HER2 expressing metastatic breast and bladder cancer.

[Fam-] trastuzumab deruxtecan has been granted Breakthrough Therapy designation for the treatment of patients with HER2 positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after T-DM1, and Fast Track designation for the treatment of HER2 positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2 targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). [Fam-] trastuzumab deruxtecan has received SAKIGAKE Designation for the treatment of HER2 positive advanced gastric or gastroesophageal junction cancer by the Japan Ministry of Health, Labour and Welfare (MHLW).

[Fam-] trastuzumab deruxtecan is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.