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 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 Incyte Corporation (Nasdaq:INCY) reported its updated data from its ongoing Phase 2 FIGHT-202 trial evaluating pemigatinib (INCB54828), its selective fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced/metastatic or surgically unresectable cholangiocarcinoma (bile duct cancer) who failed at least one previous treatment (Press release, Incyte, OCT 21, 2018, View Source [SID1234530010]). In patients with FGFR2 translocations who were followed for at least eight months, interim study results demonstrated an overall response rate (ORR) of 40 percent, the primary endpoint, and a median progression free survival (PFS) of 9.2 months, a key secondary endpoint.

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These results are being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress in Munich, Germany in a poster presentation on Sunday, October 21 from 12:45 p.m. CEST to 1:45 p.m. CEST (6:45 a.m. ET to 7:45 a.m. ET). (Location: Hall A3 – Poster Area Networking Hub; Abstract #756P)

"We are pleased to share updated interim results from our ongoing FIGHT-202 trial at ESMO (Free ESMO Whitepaper), which underscore the potential of pemigatinib as an effective new treatment option for patients with advanced cholangiocarcinoma who have FGFR2 translocations," said Steven Stein, M.D., Chief Medical Officer, Incyte. "If the full data set warrant it, we look forward to submitting our new drug application to the FDA in 2019, seeking approval of pemigatinib as a first-in-class selective FGFR inhibitor to treat patients with advanced cholangiocarcinoma, a devastating disease."

Cholangiocarcinoma is a cancer that arises from the cells within the bile ducts. It is often diagnosed late (stages III and IV) and the prognosis is poor. It is most common in those over 70 years old and is more common in men than women. FGFR2 fusion genes are drivers of the disease – occurring almost exclusively in patients with intrahepatic cholangiocarcinoma (iCCA), a subset of the disease – and are found in up to 20 percent of iCCA patients. The incidence of cholangiocarcinoma with FGFR2 translocation is increasing and is currently estimated at 2,500-3,000 patients in the U.S., Europe and Japan.

Key Findings from FIGHT-202

Updated, longer-term follow-up data from the interim analysis presented today at ESMO (Free ESMO Whitepaper) (data cut as of July 24, 2018) show that in patients with advanced/metastatic or surgically unresectable iCCA with FGFR2 translocations treated with pemigatinib who had at least eight months of follow up (Cohort A, n=47), the combined overall response rate (ORR) was 40 percent, including 19 (40 percent) patients with confirmed partial responses and 21 (45 percent) patients with stable disease (SD). The combined disease control rate (DCR) was 85 percent (40/47). Additionally, median progression free survival (PFS) was 9.2 months and median overall survival (OS) was 15.8 months.

Pemigatinib was well-tolerated. The most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (61 percent), alopecia (42 percent), diarrhea (39 percent), decreased appetite (37 percent) and fatigue (36 percent). Grade ≥3 TEAEs (observed >5 percent of patients) were hypophosphatemia (14 percent), hyponatremia (8 percent), abdominal pain (7 percent) and arthralgia (7 percent). Five patients had TEAEs with a fatal outcome, none of which were related to study treatment.

"I am extremely encouraged by the interim results of the FIGHT-202 study, which demonstrated meaningful clinical activity and promising preliminary progression-free survival estimates, and, as a practicing clinician, I am excited about the potential of pemigatinib to provide a new treatment option for my patients suffering from the life-threatening nature of advanced cholangiocarcinoma," said Antoine Hollebecque, M.D., Institut de Cancérologie Gustave Roussy, Villejuif, France.

About FIGHT-202

The FIGHT-202 open-label, multicenter study (NCT02924376) is evaluating the safety and efficacy of pemigatinib (INCB54828), Incyte’s investigational, selective, potent, oral fibroblast growth factor receptor (FGFR) inhibitor in adult (age ≥ 18 years) patients with advanced/metastatic or surgically unresectable cholangiocarcinoma with known fibroblast growth factor (FGF)/FGFR alterations and who have failed at least one previous treatment.

Patients were enrolled into one of three cohorts – Cohort A (FGFR2 translocations), Cohort B (other FGF/FGFR genetic alterations [GA]) or Cohort C (no FGF/FGFR GAs). All patients received 13.5 mg pemigatinib orally once daily (QD) on a 21-day cycle (two weeks on/one week off) until radiological disease progression or unacceptable toxicity.

The primary endpoint of FIGHT-202 is overall response rate (ORR) in Cohort A, assessed by independent review per RECIST v1.1. Secondary endpoints include ORR in Cohorts B, C and A plus B, progression free survival (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR) and safety.

The FIGHT-202 study is fully recruited outside of Japan, and updated data are expected to be presented in the second half of 2019. For more information about FIGHT-202, visit View Source

About FIGHT

Phase 2 studies investigating the safety and efficacy of pemigatinib monotherapy across several FGFR-driven malignancies are ongoing—the FIGHT (FIbroblast Growth factor receptor in oncology and Hematology Trials) clinical trial program currently comprises FIGHT-201 in patients with metastatic or surgically unresectable bladder cancer, including with activating FGFR3 alterations; FIGHT-202 in patients with metastatic or surgically unresectable cholangiocarcinoma who have failed previous therapy, including with activating FGFR2 translocations; and FIGHT-203 in patients with myeloproliferative neoplasms with activating FGFR1 translocations. FIGHT-302, a randomized Phase 3 trial in newly-diagnosed patients with cholangiocarcinoma and activating FGFR2 translocations, is expected to be initiated before the end of 2018 (NCT03656536).

About FGFR and Pemigatinib (INCB54828)

Fibroblast growth factor receptors (FGFRs) play an important role in tumor cell proliferation and survival, migration and angiogenesis (the formation of new blood vessels). Activating mutations, translocations and gene amplifications in FGFRs are closely correlated with the development of various cancers.

Pemigatinib is a potent, selective, oral inhibitor of FGFR isoforms 1, 2 and 3 which, in preclinical studies, has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations.

On October 21, 2018 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical stage targeted oncology company, reported the completed stage 1 safety and efficacy data from the ongoing Phase 1b clinical trial of single agent sitravatinib in patients with certain classes of oncogenic mutations (Press release, Mirati, OCT 21, 2018, View Source [SID1234530009]). The data for a cohort of patients harboring CBL mutations were presented in a proffered poster session (oral presentation) on Sunday, October 21st, 2018, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress in Munich, Germany.

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"For patients whose tumors are driven by the CBL mutation, there are limited viable treatment options," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer, Mirati Therapeutics, Inc. "Our sitravatinib single agent program will focus on NSCLC and melanoma patients with CBL inactivating mutations, who we believe could benefit most from single agent sitravatinib therapy."

Update from Sitravatinib Single Agent Study with CBL Inactivating Mutations

The presentation provided an update from the pre-planned expansion cohort of the Phase 1b clinical trial of single agent sitravatinib in patients with CBL inactivating mutations. Eight patients were evaluable as of the data cut-off on August 27, 2018.

In the subset of evaluable NSCLC patients, 1/2 confirmed partial responses were observed with 2/2 patients experiencing tumor regression.

In the subset of evaluable melanoma patients, 1/2 confirmed partial responses in evaluable patients were observed with 1/2 patients experiencing tumor regression.

In the subset of evaluable patients with other solid tumors, 2/4 had stable disease with 2/4 experiencing tumor regression.
CBL mutations are present in 1.5% of NSCLC, 3.5% of melanoma, and 2% of cancers of unknown origin.

About Sitravatinib

Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being evaluated in combination with nivolumab (OPDIVO), an anti-PD-1 checkpoint inhibitor, in patients who have experienced documented disease progression following treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.

Sitravatinib is also being evaluated as a single agent in a Phase 1b expansion clinical trial enrolling patients whose tumors harbor specific mutations in the CBL kinase. When CBL is inactivated by mutation, multiple RTKs, including TAM, VEGFR2 and KIT, are dysregulated and may act as oncogenic tumor drivers in NSCLC and melanoma. Sitravatinib potently inhibits these RTKs and is being investigated as a treatment option for cancer patients with CBL mutations.

On October 21, 2018 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported results from an integrated analysis of the pivotal Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials that showed the investigational personalized medicine entrectinib shrank tumors (objective response rate; ORR) in more than half (57.4 percent) of people with neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive solid tumors. Objective responses to entrectinib were seen across 10 different solid tumor types (median duration of response [DoR] = 10.4 months), including in people with and without central nervous system (CNS) metastases at baseline. Importantly, entrectinib shrank tumors that had spread to the brain in over half of people (intracranial response; IC ORR=54.5 percent), with more than a quarter of these people having a complete response (Press release, Genentech, OCT 21, 2018, View Source [SID1234530008]). The safety profile of entrectinib was consistent with that seen in previous analyses.

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"These data demonstrate the potential of entrectinib to treat a range of difficult-to-treat and rare cancers regardless of their site of origin," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Entrectinib has the potential to redefine personalized medicine, which can utilize tests such as next-generation sequencing to find the right treatment for each individual patient. People with NTRK fusion-positive solid tumors need more options, and we look forward to working with health authorities to bring this potential treatment to patients as soon as possible."

Genentech is leveraging its expertise in developing personalized medicines and advanced diagnostics, in conjunction with Foundation Medicine, to develop a novel diagnostics approach using next-generation sequencing that will help identify people with NTRK gene fusions likely to benefit from entrectinib.

Entrectinib has been granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) for the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumors in adult and pediatric patients who have either progressed following prior therapies or have no acceptable standard therapies. Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases and to help ensure people have access to them through FDA approval as soon as possible.

These NTRK fusion-positive results will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress in Munich, Germany on Sunday, October 21, 2018 from 11:24–11:36 a.m. CEST (Abstract LBA17; Hall B3 – Room 22). Follow Genentech on Twitter via @Genentech and keep up to date with ESMO (Free ESMO Whitepaper) 2018 Congress news and updates by using the hashtag #ESMO2018.

Genentech also recently presented positive results at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer (WCLC) that showed entrectinib shrank tumors (ORR) in 77.4 percent of people with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). In addition, entrectinib demonstrated a durable response of more than two years (DoR = 24.6 months). Importantly, entrectinib was shown to shrink tumors in more than half of people with cancer in the CNS (IC ORR: 55.0 percent). The safety profile of entrectinib was consistent with that seen in previous analyses.

Genentech plans to submit results from these integrated analyses to global health authorities for the treatment of NTRK fusion-positive solid tumors and ROS1-positive NSCLC.

About the integrated analysis

The integrated analysis included data from 54 people with locally advanced or metastatic NTRK fusion-positive solid tumors (10 tumor types, >19 histopathologies) from the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials. The studies enrolled people across 15 countries and more than 150 clinical trial sites. Tumor types evaluated in the studies to date included breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

STARTRK-2 is a Phase II, global, multicenter, open-label basket study in people with solid tumors that harbor an NTRK1/2/3, ROS1 or ALK-positive gene fusion. The primary endpoint is ORR, and DoR is a secondary endpoint. Other secondary outcome measures include time to response, clinical benefit rate, intracranial tumor response, progression-free survival (PFS), CNS PFS and overall survival (OS).
STARTRK-1 is a Phase I, multicenter, open-label dose escalation study of a daily continuous dosing schedule in people with solid tumors with NTRK1/2/3, ROS1 or ALK gene fusions in the U.S. and South Korea. The trial assessed the safety and tolerability of entrectinib via a standard dose escalation scheme and determined the recommended Phase II dose.
ALKA-372-001 is Phase I, multicenter, open-label dose escalation study of an intermittent and continuous entrectinib dosing schedule in people with advanced or metastatic solid tumors with TRKA/B/C, ROS1 or ALK gene fusions in Italy.
Overall, entrectinib was well tolerated and the majority of adverse events were Grade 1-2, reversible, and managed with treatment interruption or dose reduction. Treatment-related adverse events leading to discontinuation occurred in 3.9 percent of patients. The most common treatment-related adverse events were altered sense of taste (dysgeusia), fatigue and dizziness.

About entrectinib

Entrectinib (RXDX-101) is an investigational, oral medicine in development for the treatment of locally advanced or metastatic solid tumors that harbor NTRK1/2/3 or ROS1 gene fusions. It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer. Entrectinib can block ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions. Entrectinib is being investigated across a range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

About NTRK gene fusions

Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC) that can activate signaling pathways involved in proliferation of certain types of cancer. NTRK gene fusions are tumor-agnostic, meaning they are present in tumors irrespective of site of origin. These fusions have been identified in a broad range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers. There is a high unmet medical need for treatments for people with life-threatening and hard-to-treat NTRK fusion-positive tumors.