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Taiho and Servier Announce Positive Results from LONSURF® (trifluridine/tipiracil) Study Presented at ESMO 2018 Congress and Published in The Lancet Oncology

On October 22, 2018 Taiho Pharmaceutical Co., Ltd. and Servier reported that the clinical data from the pivotal Phase III (TAGS) trial were presented at the ESMO (Free ESMO Whitepaper) 2018 Congress held in Munich, Germany, from October 19 to 23 (Press release, Taiho, OCT 22, 2018, View Source [SID1234530335]). The study results were simultaneously published in The Lancet Oncology. Based on the results, Servier filed a new application for an additional indication for gastric cancer to the European Medicines Agency (EMA) for LONSURF.

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The TAGS trial evaluates LONSURF (trifluridine/tipiracil, TAS-102) versus placebo and best supportive care in patients with heavily pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers who have progressed or are intolerant to previous lines of therapy. The trial 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 continued to demonstrate LONSURF’s predictable safety and tolerability profile. TAGS, a phase 3, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer (Abstract #LBA25), data were presented by Hendrik-Tobias Arkenau, MD, PhD, from the Sarah Cannon Research Institute UK at the ESMO (Free ESMO Whitepaper) 2018 Congress during an oral session on Sunday, October 21 at 11:10 AM CEST.

In the TAGS trial, patients treated with LONSURF showed a clinically meaningful and statistically significant improvement in OS compared with placebo, a 31 percent risk reduction of death (HR 0.69), which translated into a prolongation of median survival of 2.1 months (5.7 months for trifluridine/tipiracil versus 3.6 months for placebo). In addition, LONSURF 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 (mCRC). Taiho Pharmaceutical and Servier remain committed to making further contributions to patients and to medical practitioners engaged in the treatment of cancer.

About TAGS
The TAGS (TAS-102 Gastric Study) trial is a Taiho-sponsored pivotal Phase III multinational, randomized, double-blind study evaluating LONSURF (trifluridine/tipiracil), also known as TAS-102, plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic gastric cancer, including gastroesophageal 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.

The TAGS trial aimed to enroll 500 adults 18 years and older, with metastatic gastric cancer who had previously received at least two prior regimens for advanced disease. The trial enrolled 507 subjects and was conducted in Japan, the United States, the European Union, Russia, Belarus, Israel, and Turkey.

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

About Gastric Cancer
Gastric cancer 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 annually1 . In Japan, gastric cancer is
the most common cancer and the third most common cause of cancer-related death (after lung and colorectal cancer), causing around 45,000 deaths annually2
.
In recent years, the outcome for gastric cancer has improved remarkably, and survival has increased dramatically over the past 10 years. As cancer progresses, however, numerous complications can limit the usable drugs and preclude intensive chemotherapy. Prolonging survival and relieving symptoms in late-stage treatment for metastatic gastric cancer are issues for which it is thought important to increase the options for new therapeutic drugs. At present, nivolumab and irinotecan are recommended in Japan as the standard third line treatment for metastatic
gastric cancer.

About LONSURF
LONSURF (trifluridine/tipiracil) is an oral anticancer drug, which utilizes the combination of trifluridine (FTD) and tipiracil (TPI), whose dual mechanism of action is designed to maintain clinical activity and differs from conventional fluoropyrimidines. FTD is an antineoplastic nucleoside analogue, which is incorporated directly into the DNA, thereby interfering with the function of DNA. The blood concentration of FTD is maintained via TPI, which is an inhibitor of the FTD-degrading enzyme, thymidine phosphorylase.

In Japan, Taiho Pharmaceutical has been marketing LONSURF for the treatment of unresectable advanced or recurrent colorectal cancer since 2014. In the United States, beginning in 2015, Taiho Oncology, Inc., a U.S.
subsidiary of Taiho Pharmaceutical, began marketing the drug for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

In 2015, Taiho Pharmaceutical and Servier entered into an exclusive license agreement for the co-development and commercialization of LONSURF in Europe and other countries outside of the United States, Canada, Mexico and Asia. In parts of Asia outside of Japan, Taiho Pharmaceutical’s business partner TYY Biopharm launched LONSURF in
Taiwan in July 2018, and Jeil Pharmaceutical is preparing to bring the drug to market in South Korea.

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

Intensity Therapeutics Announces Preliminary Data from Clinical Study of INT230-6 in Advanced Solid Tumors

On October 22, 2018 Intensity Therapeutics, Inc., a clinical-stage biotechnology company developing proprietary immune cell-activating cancer treatments, reported preliminary data from a Phase 1/2 clinical study demonstrated that INT230-6, the Company’s novel lead product candidate designed for direct intratumoral injection, was well tolerated in patients with advanced solid tumors (Press release, Intensity Therapeutics, OCT 22, 2018, View Source [SID1234530321]). The data were presented in a poster session on Saturday at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress in Munich, Germany.
INT230-6 is comprised of two proven, potent anti-cancer agents and a unique molecule that causes rapid drug dispersion throughout tumors and diffusion into cancer cells. In preclinical studies, INT230-6 demonstrated the ability to thoroughly saturate and kill injected tumors and induce an adaptive immune response that attacks non-injected tumors.

"We are pleased to share the first clinical data emerging from Intensity’s study evaluating INT230-6 in patients with different types of solid tumors. This early data indicates that INT230-6 can be safely injected into several different types of superficial and deep tumors, and the vast majority of the active components stay inside the tumor," said Ian B. Walters, MD, Chief Medical Officer of Intensity.

The presenting author and a study investigator, Anthony El-Khoueiry, MD, Associate Professor of Clinical Medicine and phase I program director at the University of Southern California Norris Comprehensive Cancer Center, said, "We have treated 20 patients in the study thus far, and the intratumoral injections of INT230-6 have been well tolerated. Most patients experienced mild to moderate transient local pain and swelling. Even at low doses, we are seeing some anti-tumor effects in injected tumors, as well as some evidence of immune activation in the blood. There are also early signs of anti-tumor effects in distal untreated tumors."

Dr. Walters added, "The study will continue to enroll patients with difficult-to-treat tumors as we explore higher doses. We look forward to adding more North American sites, as well as new centers outside the U.S. and Canada. In addition, we plan to move into combination arms with an anti-PD-1 antibody and begin Phase 2 expansion cohorts next year."

About INT230-6

INT230-6, Intensity’s lead product candidate designed for direct intratumoral injection, is comprised of two proven, potent anti-cancer agents and a penetration enhancer molecule that helps disperse the drugs throughout tumors and diffuse into cancer cells. INT230-6 is being evaluated in a Phase 1/2 clinical study (NCT03058289) in patients with various advanced solid tumors. In preclinical studies, INT230-6 eradicated tumors by a combination of direct tumor kill and recruitment of dendritic cells to the tumor micro-environment that induced anti-cancer T-cell activation. Treatment with INT230-6 in in vivo models of severe cancer resulted in substantial improvement in overall survival compared to standard therapies. Further, INT230-6 provided complete responder animals with long-term, durable protection from multiple re-inoculations of the initial cancer and resistance to other cancers. In mouse models, INT230-6 has shown strong synergy with checkpoint blockage, including anti-PD-1 and anti-CTLA4 antibodies. INT230-6 was discovered from Intensity’s DfuseRxSM platform.

About the Phase 1/2 Clinical Study

INT230-6 is being evaluated in a Phase 1/2 clinical study in patients with different types of advanced solid tumor malignancies. The study’s primary objective is to assess the safety and tolerability of multiple intratumoral doses of INT230-6. Secondary assessments are the measurement of injected and bystander tumor responses, and determination of the systemic pharmacokinetic profile of multiple doses of INT230-6’s drug substances after single and then multiple intratumoral injections. Exploratory analysis will characterize patient outcome, as well as evaluate various tumor and anti-tumor immune response biomarkers that may correlate with response. The study includes several adaptive components that will allow for adjustments in patient groups, dosing schedule and dose volumes administered. Data will be used to assess the progression free and overall survival in patients receiving INT230-6. For more information, please visit www.clinicaltrials.gov (NCT03058289).

Roche’s Alecensa (alectinib) significantly reduced the risk of disease worsening or death as a first-line treatment in Asian patients with ALK-positive advanced or metastatic non-small cell lung cancer

On October 22, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that it results from the phase III ALESIA study, showing that Alecensa (alectinib) met its primary endpoint of investigator-assessed (INV) progression-free survival (PFS) (Press release, Hoffmann-La Roche, OCT 22, 2018, View Source [SID1234530314]). Alecensa significantly reduced the risk of disease worsening or death by 78%, compared to crizotinib, when given as an initial (first-line) monotherapy treatment in Asian patients with anaplastic lymphoma kinase (ALK)-positive advanced or metastatic non-small cell lung cancer (NSCLC) (hazard ratio [HR]=0.22, 95% CI: 0.13-0.38).[1] Median PFS reported by the investigators was not yet reached in patients who received Alecensa (95% CI: 20.3 months-not reached) versus 11.1 months (95% CI: 9.1-13.0 months) in those who received crizotinib.[1] The safety profile of Alecensa was consistent with that observed in previous studies.[1]

"The ALESIA study supports the use of Alecensa as the standard of care for newly diagnosed advanced or metastatic ALK-positive lung cancer across multiple populations," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "Alecensa has received rapid regulatory approvals for first-line treatment in 65 countries to date, including in China."

Median PFS reported by an independent review committee (IRC), a secondary endpoint, was not yet reached in patients who received Alecensa (95% CI: 16.7 months-not reached), versus 10.7 months (95% CI: 7.4 months-not reached) in patients who received crizotinib (HR=0.37, 95% CI: 0.22-0.61).[1] The phase III ALESIA study also demonstrated that compared to crizotinib, Alecensa reduced the risk of disease progression in the central nervous system (CNS), another secondary endpoint in the study, by 86% (HR=0.14, 95% CI: 0.06-0.30).[1]

The ALESIA data are being officially presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress during a Presidential Symposium on 22 October at 16:30 (Abstract LBA10 Presidential Symposium).[3]

This is the third phase III study to show that Alecensa as a first-line treatment significantly reduced the risk of disease worsening or death (PFS) compared to crizotinib in patients with ALK-positive advanced or metastatic NSCLC.[2;3;4] The results reinforce the findings of the phase III global ALEX study, which found that Alecensa significantly reduced the risk of disease progression or death (PFS) by 57% (HR=0.43, 95% CI: 0.32-0.58) compared to crizotinib after two years of follow-up in people with ALK-positive metastatic NSCLC, as assessed by the investigator.[3] The ALEX study also showed that Alecensa more than tripled median PFS to nearly three years (34.8 months, 95% CI: 17.7 months-NE) compared to crizotinib (10.9 months, 95% CI: 9.1-12.9 months) and demonstrated superior efficacy compared to crizotinib regardless of the presence of CNS metastases at baseline, a secondary endpoint.[3] INV median PFS for people without CNS metastases at baseline was 34.8 months with Alecensa (95% CI: 22.4 months-NE) versus 14.7 months (95% CI: 10.8-20.3 months) with crizotinib (HR=0.47, 95% CI: 0.32-0.71).[3] INV median PFS for people with CNS metastases at baseline was 27.7 months in the Alecensa arm (95% CI: 9.2 months-NE) versus 7.4 months (95% CI: 6.6-9.6 months) in the crizotinib arm (HR=0.35, 95% CI: 0.22-0.56).[3]

The ALESIA study was a bridging study, designed to show consistency with the phase III ALEX study and was not powered to show superiority vs crizotinib. It completes a post-approval agreement with the National Drug Administration of China (CNDA) to demonstrate consistency between the ALESIA and ALEX studies, following the priority review and rapid approval of Alecensa in August this year.[5] The regulatory approval in China is one of the latest of 65 countries for the use of Alecensa as a first-line monotherapy for people with ALK-positive NSCLC.[6]

About the ALESIA study[7]
ALESIA (NCT02838420) is a randomised, multicentre, open-label phase III study evaluating the efficacy and safety of Alecensa versus crizotinib, and the pharmacokinetics of Alecensa in Asian patients with treatment-naive ALK-positive advanced or metastatic NSCLC. Patients were randomised (2:1) to receive either Alecensa or crizotinib. The primary endpoint of the ALESIA study is PFS as assessed by the investigator using the RECIST v1.1 criteria. Secondary endpoints include: PFS, time to CNS progression and CNS ORR assessed by IRC, objective response rate and duration of response assessed by the investigator, overall survival, health-related quality of life and safety. The multicentre study was conducted in 187 patients across 21 sites in three countries.

About Alecensa
Alecensa (RG7853/AF-802/RO5424802/CH5424802) is a highly selective, CNS active, oral medicine created at Chugai Kamakura Research Laboratories and is being developed for people with NSCLC whose tumours are identified as ALK-positive.[6] ALK-positive NSCLC is often found in younger people who have a light or non-smoking history.[8] It is almost always found in people with a specific type of NSCLC called adenocarcinoma.[8] Alecensa is now approved in 65 countries as an initial (first-line) treatment for ALK-positive, metastatic NSCLC, including in the US, Europe, Japan and China.[6]

Roche’s Tecentriq plus chemotherapy (carboplatin and Abraxane) as an initial treatment helped people with advanced non-squamous non-small cell lung cancer live significantly longer compared to chemotherapy alone

On October 22, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported positive results from the Phase III IMpower130 study of Tecentriq (atezolizumab) plus chemotherapy (carboplatin and Abraxane [albumin-bound paclitaxel; nab-paclitaxel]) for the initial (first-line) treatment of people with previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC) (Press release, Hoffmann-La Roche, OCT 22, 2018, View Source [SID1234530310]). The analysis showed that Tecentriq plus chemotherapy helped people live significantly longer compared to chemotherapy alone (median overall survival [OS] =18.6 versus 13.9 months; hazard ratio [HR]=0.79; 95% CI: 0.64–0.98; p=0.033) in the intention-to-treat wild-type (ITT-WT) population.[1] The Tecentriq-based combination also significantly reduced the risk of disease worsening or death (progression-free survival; PFS) compared to chemotherapy alone (median PFS=7.0 versus 5.5 months; HR=0.64; 95% CI: 0.54–0.77; p<0.0001) in the ITT- WT population.1 Safety for the Tecentriq plus chemotherapy combination appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination.

"Initial treatment with this Tecentriq-based combination provided a significant survival benefit for people with non-squamous non-small cell lung cancer, the most common form of lung cancer," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "Lung cancer is a complex disease and this combination could offer a new potential treatment option. We will work with global health authorities to bring this regimen to people living with this disease as soon as possible."

The data will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress on 22 October 2018, 09:15–09:30 am; Hall A1 – Room 17 (Abstract LBA53).

About the IMpower130 study
IMpower130 is a Phase III, multicentre, open-label, randomised study evaluating the efficacy and safety of Tecentriq in combination with carboplatin and nab-paclitaxel versus chemotherapy (carboplatin and nab-paclitaxel) alone for chemotherapy-naïve patients with stage IV non-squamous NSCLC. The study enrolled 723 people who were randomised (2:1) to receive:

Tecentriq plus carboplatin and nab-paclitaxel (Arm A), or
Carboplatin and nab-paclitaxel (Arm B, control arm)
During the treatment-induction phase, people in Arm A received Tecentriq and carboplatin on day 1 of each 21-day cycle, and nab-paclitaxel on days 1, 8 and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit, whichever occurs first. People received Tecentriq during the maintenance treatment phase until loss of clinical benefit was observed.

During the treatment-induction phase, people in Arm B received carboplatin on day 1 and nab-paclitaxel on days 1, 8 and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression, whichever occurs first. People received best supportive care during the maintenance treatment phase. Switch maintenance to pemetrexed was also permitted. People who were consented prior to a protocol revision were given the option to crossover to receive Tecentriq as monotherapy until disease progression.

The co-primary endpoints were:

PFS as determined by the investigator using RECIST v1.1 in the ITT-WT population
OS in the ITT-WT population
IMpower130 met its co-primary endpoints of OS and PFS.

A summary of the results is included below:

Safety for the Tecentriq and chemotherapy combination appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination. Grade 3 – 4 treatment-related adverse events (AEs) were reported in 73.2% of people receiving Tecentriq plus chemotherapy compared to 60.3% of people receiving chemotherapy alone. The most common Grade 3 – 4 AEs in people receiving Tecentriq plus chemotherapy were: an abnormal low count of a certain type of white blood cell (neutropenia, 32.1%), a decrease in red blood cells (anaemia, 29.2%), and a decreased neutrophil count (12.1%).

About NSCLC
Lung cancer is the leading cause of cancer death globally.[2] Each year 1.76 million people die as a result of the disease; this translates into more than 4,800 deaths worldwide every day.[2] Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.[3] NSCLC comprises non-squamous and squamous-cell lung cancer, the squamous form of which is characterised by flat cells covering the airway surface when viewed under a microscope.[3]

About Tecentriq
Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

Currently, Roche has eight Phase III lung cancer studies evaluating Tecentriq alone or in combination with other medicines.

Tecentriq is already approved in the European Union, United States and more than 70 countries for people with previously treated metastatic NSCLC and for certain types of untreated or previously treated metastatic urothelial carcinoma (mUC).

Inovio Presents Progression Free Survival & PSA Doubling Time Improvements in Prostate Cancer Patients Treated with INO-5150

On October 22, 2018 Inovio Pharmaceuticals, Inc. (NASDAQ:INO) reported that new data from the company’s recently completed Phase 1b study with INO-5150 demonstrated a slowing of Prostate-Specific Antigen Doubling Time (PSADT) in men with prostate cancer (Press release, Inovio, OCT 22, 2018, View Source;PSA-Doubling-Time-Improvements-in-Prostate-Cancer-Patients-Treated-with-INO-5150/default.aspx [SID1234530272]). Eighty six percent (86%) of patients remained progression-free at Week 72 of the study. These data were presented in a poster entitled "Synthetic DNA immunotherapy in Biochemically Relapsed Prostate Cancer" at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 congress in Munich today.

In this study, Inovio evaluated the tolerability and immunogenicity of INO-5150, a DNA vaccine encoding PSA and PSMA, with or without INO-9012 (encoding IL-12 immune adjuvant), in men with biochemically relapsed prostate cancer. The study demonstrated a slowing of PSA doubling time, a measure of disease progression, in a majority of patients on the study. In addition, 86% of patients were progression-free at Week 72 of the study, which in this treatment-refractory, high-risk patient population, is thought to be clinically promising. Importantly, analyses demonstrated that immunogenicity was observed in 77% (47/61) of patients by multiple immunologic assessments.

Previous results from the Phase 1b study were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting and demonstrated that of the 61 evaluable patients, 77% (47/61) demonstrated T cell immunogenicity, and 38% (19/50) exhibited CD38+, Perforin+CD8+ T cell responses. Results presented at ASCO (Free ASCO Whitepaper) provided clinical data through week 72 and immunology data through week 27. The latest results being presented at ESMO (Free ESMO Whitepaper) update these data and report that 80% of evaluable patients in the trial demonstrated either INO-5150 specific T cell or antibody reactivity.

Dr. J. Joseph Kim, Inovio’s President and Chief Executive Officer, said, "The follow-up data and opportunity to showcase INO-5150 from our Phase 1 prostate cancer study further helps Inovio’s efforts to enter into a strategic development partnership to expand into a Phase 2 study. These follow-up results support the rationale for further development and provides the basis for a novel checkpoint combination cancer trial."

This patented approach of INO-5150 in combination with CELLECTRA delivery device is designed to help the body’s immune system overcome its "self-tolerance" to prostate cancer cells and mount a strong targeted CD8+ killer T cell response to eliminate the cancerous cells displaying these antigens. Moreover, PSMA is also one of 3 antigens comprising INO-5401, which is being tested in two separate Phase 1/2 trials as an immunotherapy to treat glioblastoma and metastatic bladder cancer in combination with Regeneron and Genentech/Roche’s checkpoint inhibitors, respectively.

About Prostate Cancer and Biochemically Recurrent Prostate Cancer (BRPC)

Prostate cancer is the second most frequently diagnosed cancer in men. Nearly three-quarters of the registered cases occur in developed countries. Accounting for nearly 300,000 deaths each year, prostate cancer is the sixth leading cause of death from cancer in men. There are about 60,000 patients each year in the US that develop biochemically recurrent prostate cancer (BRPC). The development of a new treatment for prostate cancer would be a significant medical advance given that current standard-of-care treatment options (surgery, radiation and hormone deprivation), while somewhat effective, all carry deleterious side effects and are often not a long-term cure.