On October 21, 2018 IntegraGen reported that it presented data on the company’s proprietary miR-31 microRNA biomarkers during the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Annual Congress being held in Munich, Germany (link) (Press release, Integragen, OCT 21, 2018, View Source [SID1234529994]). The study, entitled "miR-31 as a prognostic and predictive marker of disease-free survival (DFS) in resected stage III colon cancer: a retrospective analysis of the PETACC-8 trial," was based on an analysis of tumor samples from over 1,400 patients enrolled in the PETACC-8 Phase III Clinical Trial.

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Key findings from the study included:

miR‐31‐3p and miR‐31‐5p levels were prognostic of disease-free survival (DFS) and overall survival (OS) in several subpopulations of patients with resected stage III colon cancer.

Low miR‐31‐3p and miR‐31‐5p expression levels identified patients who benefited from the additional of cetuximab to FOLFOX adjuvant therapy.

miR‐31‐5p expression level was predictive of cetuximab efficacy in three separate subpopulations which were studied.

"The present study provides additional evidence of the ability of miR-31 to predict response to cetuximab therapy in patients with colorectal cancer," stated Severine Martin-Lannerée, PhD, R&D project leader at IntegraGen and co-author of the study. "While our previous studies with these biomarkers focused on patients with advanced stage metastatic colorectal cancer, this new data demonstrates that low miR-31 expression can identify the potential benefits of adding cetuximab to adjuvant therapy during an earlier stage of colorectal cancer for several subpopulations of patients, potentially expanding the clinical application of this marker."

On October 21, 2018 AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported detailed results from the Phase 3 SOLO-1 trial testing LYNPARZA 300 mg tablets twice daily as a maintenance treatment for patients with newly-diagnosed advanced BRCA-mutated (BRCAm) ovarian cancer who were in complete or partial response following first-line standard platinum-based chemotherapy (Press release, AstraZeneca (Australia), OCT 21, 2018, View Source [SID1234530011]).

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Results of the trial confirm the statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for LYNPARZA as compared to placebo, reducing the risk of disease progression or death by 70 percent (HR=0.30 [95% CI, 0.23-0.41]; p<0.001). At 41 months of follow-up, the median PFS for patients treated with LYNPARZA was not reached compared to 13.8 months for patients treated with placebo. Of those receiving LYNPARZA, 60.4 percent remained progression-free at 36 months, compared to 26.9 percent of women in the placebo arm. The data were presented at the Presidential Symposium of the ESMO (Free ESMO Whitepaper) 2018 Congress in Munich, Germany and published simultaneously online in the New England Journal of Medicine (NEJM).

Sean Bohen, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said, "There is currently a significant unmet need in the treatment of advanced ovarian cancer because 70 percent of women relapse within the first three years after their initial treatment. The remarkable results of the SOLO-1 trial, which showed that 60 percent of women with newly-diagnosed, advanced BRCA-mutated ovarian cancer remained progression-free at three years, highlight the potential of LYNPARZA as a first-line maintenance therapy in this setting."

Dr. Roy Baynes, senior vice president and head of Global Clinical Development, chief medical officer, Merck Research Laboratories, said, "Our collective goal in oncology research is to improve long-term outcomes for people living with cancer. Based on the SOLO-1 trial results, LYNPARZA is the only PARP inhibitor to have demonstrated a significant and clinically-meaningful improvement in reducing the risk of progression or death for newly-diagnosed patients with advanced BRCA-mutated ovarian cancer following platinum-based chemotherapy. We are working with regulatory authorities as quickly as possible to seek approval of LYNPARZA for these patients."

Kathleen Moore, co-principal investigator of the SOLO-1 trial and associate director, Stephenson Cancer Center at The University of Oklahoma, Oklahoma City, Oklahoma, said, "Women with ovarian cancer are often diagnosed with advanced disease, which unfortunately is associated with poor long-term survival rates. The newly-diagnosed setting is our best opportunity to achieve a sustained remission, since once a patient’s ovarian cancer recurs, it is typically incurable. The SOLO-1 results demonstrate the potential of LYNPARZA maintenance therapy earlier in the treatment pathway and reinforce the importance of identifying a patient’s BRCA mutation status at the time of diagnosis – these results could change the way we treat women with advanced BRCA-mutated ovarian cancer."

The SOLO-1 safety profile was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥ 20 percent were nausea (77%), fatigue (64%), vomiting (40%), anemia (39%) and diarrhea (34%). The most common ≥ Grade 3 AEs were anemia (22%) and neutropenia (8%). Seventy-one percent of patients on LYNPARZA remained on the recommended starting dose. Additionally, 88 percent of patients on LYNPARZA continued treatment without an AE-related discontinuation. Further, 48 percent of patients on LYNPARZA did not have a dose interruption as a result of an AE.

Per SOLO-1 protocol guidelines, patients who demonstrated a complete response (no radiological evidence of disease) at two years stopped treatment with LYNPARZA; patients who demonstrated a partial response and, who in the opinion of the treating physician can derive further benefit from continuous treatment, were treated beyond two years.

AstraZeneca and Merck are exploring additional trials in ovarian cancer, including the ongoing GINECO/ENGOTov25 Phase 3 trial, PAOLA-1. This trial is testing the effect of LYNPARZAin combination with bevacizumab as a maintenance treatment for patients with newly-diagnosed advanced ovarian cancer regardless of their BRCA status. Results are expected during the second half of 2019.

LYNPARZA is a first-in-class poly ADP-ribose polymerase (PARP) inhibitor approved in the U.S. since 2014. LYNPARZA has a broad clinical development program and AstraZeneca and Merck are working together to deliver LYNPARZA as quickly as possible to more patients across multiple cancer types.

LYNPARZA is not currently FDA-approved for advanced BRCAm ovarian cancer treatment in the first-line maintenance setting. LYNPARZA is indicated for the maintenance treatment of recurrent ovarian cancer in response to platinum-based chemotherapy regardless of BRCA mutation status, and for the treatment of advanced ovarian cancer patients with a germline BRCA mutation previously treated with three or more lines of chemotherapy. Physicians should select advanced ovarian cancer patients for therapy based on a FDA-approved companion diagnostic. Please see complete indications below.

Important Safety Information

Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals,

LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of

reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in >25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

Drug Interactions

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Indications

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm,human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please see complete Prescribing Information , including Patient Information (Medication Guide).

About the SOLO-1 Phase 3 Trial

SOLO-1 is a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial to evaluate the efficacy and safety of LYNPARZA tablets (300 mgtwice daily) as maintenance monotherapy compared with placebo in newly-diagnosed patients with advanced BRCA-mutated ovarian cancer following platinum-based chemotherapy. The trial randomized 391 patients with a deleterious or suspected deleterious BRCA1 or BRCA2 mutation who were in clinical complete or partial response following platinum-based chemotherapy. Patients were randomized (2:1) to receive LYNPARZA or placebo for up to two years or until disease progression (at the investigator’s discretion). The primary endpoint was investigator-assessed progression-free survival and key secondary endpoints include time to second disease progression or death, time to first subsequent treatment and overall survival.

About Ovarian Cancer

Approximately 20,000 women in the U.S. are diagnosed with ovarian cancer (including ovarian, fallopian tube and primary peritoneal cancers) each year. Among women in the U.S., it is the ninth most common cancer and the fifth leading cause of cancer death.

The risk of developing ovarian cancer is increased in women with specific inherited genetic abnormalities, including BRCA mutations.

About BRCA Mutations

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role in maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About LYNPARZA (olaparib)

LYNPARZA is the first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.LYNPARZA is being tested in a range of DDR-deficient tumor types.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development program, and AstraZeneca and Merck are working together to deliver it as quickly as possible to more patients across multiple cancer types.

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.