On June 4, 2018 AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported data which showed clinical improvement in median radiologic progression-free survival (rPFS) with LYNPARZA (olaparib) in combination with abiraterone compared to abiraterone monotherapy, a current standard of care, in metastatic castration-resistant prostate cancer (mCRPC) (Press release, Merck & Co, JUN 4, 2018, View Source [SID1234527144]). LYNPARZA is being jointly developed and commercialized by AstraZeneca and Merck.

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The results of Study 08, a randomized, double-blinded, multi-center Phase 2 trial, comparing LYNPARZA in combination with abiraterone (n=71) to abiraterone monotherapy (n=71) in patients with previously-treated mCRPC, regardless of homologous recombination repair (HRR) mutation status, were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting as a "Best of ASCO (Free ASCO Whitepaper) presentation" and were published online today in The Lancet Oncology. The primary endpoint was rPFS. Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

LYNPARZA is not FDA-approved for prostate cancer. LYNPARZA is indicated for the treatment of advanced ovarian cancer patients with a gBRCA mutation previously treated with three or more lines of chemotherapy; for the maintenance treatment of recurrent ovarian cancer in response to platinum-based chemotherapy regardless of BRCA mutation status; and for the treatment of gBRCA HER2-negative metastatic breast cancer after chemotherapy and prior endocrine therapy, if appropriate. Physicians should select advanced ovarian cancer and metastatic breast cancer patients for therapy based on a FDA-approved companion diagnostic. Please see Indications for LYNPARZA (olaparib) 100 mg in the U.S. below.

Noel Clarke, professor of urological oncology, Christie NHS Foundation Trust, Manchester, United Kingdom, said, "This is the first time we have seen an improvement with the use of a PARP inhibitor in combination with abiraterone in patients with metastatic castration-resistant prostate cancer, and this effect may be independent of HRR status. The data suggest this therapeutic combination may be a promising new treatment approach for this aggressive disease."

Sean Bohen, executive vice president, global medicines development and chief medical officer at AstraZeneca, said, "A previous trial demonstrated improvements in response rates with LYNPARZA monotherapy in metastatic castration-resistant patients with HRR mutations. The Study 08 combination data suggest that, regardless of their mutation status, men with metastatic castration-resistant prostate cancer may potentially benefit from LYNPARZA in combination with abiraterone."

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, "There is a significant unmet medical need for patients with metastatic castration-resistant prostate cancer as they are a high-risk group with limited treatment options. LYNPARZA is the first PARP inhibitor to demonstrate activity in combination with standard-of-care treatment in prostate cancer. These data from Study 08 represent another important milestone in the clinical development of LYNPARZA."

Median rPFS was 13.8 months with LYNPARZA and abiraterone compared to 8.2 months with abiraterone alone (HR=0.65 [95% CI, 0.44-0.97]; p=0.034). Median PFS2 was 23.3 months versus 18.5 months (HR=0.79 [95% CI, 0.51-1.21]). Median OS was 22.7 months with combination treatment versus 20.9 months with abiraterone alone (HR=0.91; [95% CI, 0.60-1.38]). Pre-specified exploratory subgroup analyses demonstrated an rPFS improvement in patients regardless of HRR status (see Table 1). Study 08 was not powered for subgroup analyses, PFS2 and OS. HRR mutation status was not known for all patients.

Table 1: rPFS by HRR status

Median rPFS
(months)

HR

95% CI
LYNPARZA +
abiraterone

abiraterone
Overall (n=142) 13.8 8.2 0.65 0.44-0.97
HRR-mutation (n=21)

17.8 6.5 0.74 0.26-2.12
Wild-type HRR (n=35) 15.0 9.7 0.52 0.24-1.15
Partially-characterized HRR status (n=86)*

13.1 6.4 0.67 0.40-1.13
*Those whose plasma and blood samples both tested negative for HRR mutations, but for whom no valid tumor test result was available

The safety of LYNPARZA in combination with abiraterone was also reported, as was the safety of abiraterone monotherapy. Grade ≥3 adverse events (AEs), serious AEs and treatment discontinuations due to AEs were more frequent with combination treatment than abiraterone alone (54% vs 28%; 34% vs 18%; 30% vs 10%, respectively). The most common grade ≥3 AEs in the combination arm were anemia (21%), pneumonia (6%) and myocardial infarction (6%). Serious cardiovascular events occurred in seven patients in the combination group and one patient in the abiraterone group. LYNPARZA is associated with a number of serious, potentially fatal risks, including MDS-AML, pneumonitis and embryo-fetal toxicity. Please see Important Safety Information for LYNPARZA (olaparib) tablets 100 mg below.

In addition to Study 08, other studies are underway to explore the potential of LYNPARZA as a monotherapy for HRR-mutated mCRPC, including PROfound, which is testing LYNPARZA monotherapy versus enzalutamide or abiraterone in patients with previously-untreated mCRPC. Additional trials are planned to explore LYNPARZA in combination for the treatment of mCRPC regardless of HRR status. LYNPARZA was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in 2016 for the treatment of BRCA-mutated or ataxia telangiectasia mutated (ATM) gene-mutated mCRPC.

LYNPARZA is a first-in-class PARP inhibitor approved in the U.S. for certain patients with recurrent ovarian and metastatic breast cancer and has treated nearly 5,500 patients 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, including prostate and pancreatic cancers.

Indications for LYNPARZA (olaparib) 100 mg in the U.S.

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.

Important Safety Information for LYNPARZA (olaparib) tablets 100 mg

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 (olaparib) 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 (olaparib) 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 (olaparib). 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).

About Study 08

Study 08 was a global, randomized, double-blinded, multi-center Phase 2 trial of 142 patients, assessing the efficacy and safety of LYNPARZA tablets (300 mg twice daily) and abiraterone tablets (4 x 250 mg once daily) (n=71) compared to matched placebo and abiraterone tablets (4 x 250 mg once daily) (n=71) in patients regardless of HRR status. Prednisone/prednisolone (5 mg twice daily) was administered to patients in both treatment arms.

Patients in Study 08 had previously received docetaxel for mCRPC. Prior to enrollment, patients had received no more than two lines of chemotherapy.

The primary endpoint was radiologic progression-free survival (rPFS) (time from randomization to radiologic progression or death). rPFS is increasingly used in clinical trials of mCRPC as a clinically-meaningful endpoint focusing on the impact of treatment on disease progression to areas where spread of prostate cancer is common, notably soft tissue and bone.

Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

About Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Prostate cancer is the second most common cancer in men, with an estimated 1.6 million new cases diagnosed worldwide in 2015, and is associated with a significant mortality rate. Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. Metastatic castration-resistant prostate cancer (mCRPC) occurs when prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones. Approximately 10-20 percent of men with advanced prostate cancer will develop mCRPC within five years, and at least 84 percent of these will have metastases at the time of mCRPC diagnosis. Of men with no metastases at mCRPC diagnosis, 33 percent are likely to develop metastases within two years. Despite an increase in the number of available therapies for men with mCRPC, five-year survival is only 28 percent.

About LYNPARZA (olaparib)

LYNPARZA was 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.

On June 4, 2018 TG Therapeutics, Inc. (NASDAQ: TGTX), reported updated clinical data from its ongoing Phase 2 study evaluating umbralisib (TGR-1202), the Company’s PI3K delta inhibitor, in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) who are intolerant to prior BTK or PI3K delta inhibitor therapy (Press release, TG Therapeutics, JUN 4, 2018, View Source [SID1234527143]). Data from this trial are being presented today during the 54th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

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Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer, stated, "We are extremely pleased with the data presented today during the ASCO (Free ASCO Whitepaper) annual meeting. We believe there is a need for novel treatment options for patients who are intolerant to the currently approved BTK and PI3K therapies and believe the data shown today demonstrates that umbralisib can be used effectively in these patients." Mr. Weiss, continued, "We continue to be pleased with the safety and efficacy profile of umbralisib and believe umbralisib single agent, or umbralisib plus ublituximab referred to as ‘U2’, can become important treatment options across multiple b-cell malignancies. We also look forward to presenting updated umbralisib integrated safety data at the European Hematology Association (EHA) (Free EHA Whitepaper) annual congress in a couple of weeks, as well as the topline response rate data from the UNITY-CLL Phase 3 trial by the end of summer 2018."

Highlights from today’s presentation include the following:

Poster Presentation: KI Intolerance Study: A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) In Patients with Chronic Lymphocytic Leukemia (CLL) Who Are Intolerant to Prior BTK or PI3K-delta Inhibitor Therapy (Abstract Number 4314)

This poster presentation includes data from patients with CLL who are intolerant to prior BTK or PI3K delta inhibitor therapy who were then treated with single agent umbralisib (TGR-1202). To be eligible for the study patients had to have received prior treatment with a BTK inhibitor (ibrutinib, acalabrutinib) or a PI3K delta inhibitor (idelalisib, duvelisib) and discontinued therapy due to intolerance within 12 months of starting treatment on this study. Forty-seven patients were evaluable for safety of which 46 were evaluable for Progression Free Survival (PFS), (1 patient had a confirmed Richter’s Transformation (RT) at enrollment which did not meet eligibility criteria).

Highlights from this poster include:

●Umbralisib demonstrated a favorable safety profile in patients intolerant to prior BTK or PI3K therapy
●Only 13% discontinued due to an adverse event, of which only one patient discontinued due to a recurrent adverse event (AE) also experienced with prior KI therapy
●Nodal reductions were seen in nearly all patients evaluable for response with 3 patients achieving complete resolution of nodal disease, of which 1 patient with 17p del achieved a bone marrow confirmed Complete Response (CR)
●Median progression free survival (PFS) has not been reached with a median follow-up of 9.5 months
●In this relapsed/refractory CLL population, of which 77% required treatment within 6 months of prior KI discontinuation, 68% had a high-risk molecular / genetic marker and 6% had an ibrutinib resistance mutation, significant clinical activity has been observed

PRESENTATION DETAILS
The above referenced presentation is now available on the Publications page, located within the Pipeline section, of the Company’s website at www.tgtherapeutics.com/publications.cfm.

On June 4, 2018 Kyowa Hakko Kirin Co., Ltd., (Kyowa Kirin) reported that additional analyses from the pivotal MAVORIC trial are being presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), June 1-5, Chicago (Press release, Kyowa Hakko Kirin, JUN 4, 2018, View Source [SID1234527142]). MAVORIC was the open-label randomized multi-center phase 3 trial evaluated mogamulizumab versus vorinostat for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. MF and SS are the most common subtypes of cutaneous T-cell lymphoma (CTCL).

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Presentation title at the 2018 ASCO (Free ASCO Whitepaper) Annual Congress:
Quality of life in cutaneous T-cell lymphoma subjects treated with anti-CCR4 monoclonal antibody mogamulizumab versus vorinostat: results from the Phase 3 MAVORIC trial [Abstract #7577; Poster #214; Monday, June 4, 8:00-11:30AM CDT]

Progression free survival (PFS) was the primary endpoint; the results that demonstrated mogamulizumab had a clinically relevant and statistically significant increase in progression free survival over vorinostat have already been presented. Infusion reaction and rash were the most common adverse events associated with mogamulizumab. QOL measurements were secondary endpoints and included Skindex29 (SDX-29), Functional Assessment of Cancer Therapy-General (FACT-G) and EuroQol-5D. SDX-29 and FACT-G were reported in ASCO (Free ASCO Whitepaper).

"Quality of life may be severely impacted in patients living with CTCL, and the MAVORIC study included evaluation of the effect of both treatments on a range of QOL instruments," said Jeffrey S. Humphrey, M.D., President of Kyowa Kirin Development. "We are encouraged by the QOL data and look forward to working with investigators and patient advocates to further understand how mogamulizumab might help patients with MF and SS."

The Kyowa Hakko Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

About Mogamulizumab
Mogamulizumab is a humanized monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4),
which is frequently expressed on leukemic cells of certain hematologic malignancies including CTCL. Mogamulizumab
was produced using Kyowa Hakko Kirin’s proprietary POTELLIGENT platform, which is associated with enhanced
antibody-dependent cellular cytotoxicity. Mogamulizumab is an investigational product currently under review at
FDA and EMA.

About Mycosis Fungoides (MF) and Sézary Syndrome (SS)
MF and SS are the two most common subtypes of CTCL, a rare type of non-Hodgkin’s lymphoma, which is
characterized by localization of malignant T lymphocytes to the skin, and depending on the stage, the disease may
involve skin, blood, lymph nodes, and viscera.

News Release

About MAVORIC
MAVORIC is a Phase 3 open-label, multi-center, randomized study of mogamulizumab versus vorinostat in patients
with MF and SS who have failed at least one prior systemic treatment. The study was conducted in the U.S.,Europe,
Japan and Australia, and randomized 372 patients to receive either mogamulizumab or vorinostat.

On June 4, 2018 Infinity Pharmaceuticals, Inc. (NASDAQ: INFI), reported that data to be presented today at the ASCO (Free ASCO Whitepaper) 2018 Annual Meeting demonstrates that IPI-549, a first-in-class immuno-oncology product candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma), in combination with nivolumab was well tolerated and demonstrated evidence of clinical activity in indications not typically responsive to anti-PD1 therapy.i 40% (12 of 30) of evaluable patients demonstrated disease control with 10 patients with stable disease and two patients who achieved rapid, deep and durable partial responses, including one patient with adrenocortical cancer and one with microsatellite stable (MSS) gallbladder cancer (Press release, Infinity Pharmaceuticals, JUN 4, 2018, View Source [SID1234527141]). In addition, IPI-549 reduced immune suppression and induced immune activation, as indicated by analyses of peripheral blood and paired tumor biopsies.

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"We were encouraged to see rapid, deep and durable responses in some patients with the combination of IPI-549 and nivolumab in dose escalation, and we look forward to continuing to evaluate this combination in specific patient populations through the seven combination expansion cohorts," said Dr. Ryan J. Sullivan, Massachusetts General Hospital, and an investigator on the IPI-549 Phase 1/1b study. "There remains a critical unmet need for patients with a number of solid tumors who do not benefit from anti-PD1 therapy, and IPI-549 in combination with nivolumab may offer an important therapeutic alternative."

IPI-549 combined with nivolumab in dose escalation was well tolerated at all doses tested, up to the recommended expansion dose of IPI-549 at 40mg once daily plus nivolumab at 240mg once every two weeks. No maximum tolerated dose (MTD) was determined, and there were no treatment-related deaths. Additionally, the pharmacokinetic/pharmacodynamic profile of IPI-549 (up to 40mg QD) was unaffected by nivolumab co-administration.

IPI-549 as a monotherapy also continued to be well tolerated at all doses studied up to the recommended dose for expansion of 60 mg once daily. IPI-549 demonstrated evidence of monotherapy clinical activity, with one durable partial response in peritoneal mesothelioma, where a patient remains on study after 20 months.

"IPI-549 combined with nivolumab demonstrated compelling responses in two patients, one with adrenocortical cancer and one with MSS gallbladder cancer, and translational studies demonstrated evidence of on-mechanism IPI-549-mediated effects," said Adelene Perkins, Chief Executive Officer and Chair of Infinity Pharmaceuticals. "We are very pleased by the rapidity, depth and durability of the responses in combination with nivolumab, along with a promising safety profile. Enrollment in the seven combination expansion cohorts has been robust, and we look forward to reporting data in the second half of this year from these six disease-specific cohorts and a seventh cohort of patients selected for high baseline blood levels of myeloid derived suppressor cells. Data from these expansion cohorts will further inform our development and regulatory strategy for this first-in-class product candidate."

Data from peripheral blood and paired tumor biopsies suggest that IPI-549 reduces immune suppression and induces immune activation, consistent with the mechanism of action demonstrated in pre-clinical studies. Monotherapy paired tumor biopsies showed decreased CD163 M2 macrophage marker expression and peripheral blood data revealed a dose-related increase in proliferation of exhausted memory T cells on top of fixed-dose nivolumab. Finally, there is a statistically significant increase in exhausted T cell proliferation in combination dose escalation patients with tumor shrinkage. This statistically significant increase was also demonstrated in patients who remained on study for over 16 weeks.

The data will be presented in three events today during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

Investor Event 6:30 a.m. CT – 7:30 a.m. CT
Infinity Pharmaceuticals is hosting an investor event on this morning at 6:30 a.m. CT with Dr. Ryan Sullivan from Massachusetts General Hospital, an investigator on the IPI-549 Phase 1/1b study, to review the IPI-549 data being presented at ASCO (Free ASCO Whitepaper). The event will be webcast live and can be accessed on the Investors/Media section of Infinity’s website at www.infi.com for 30 days following the event.

Poster Session 8:00 a.m. CT – 11:00 a.m. CT
Title: Initial results from first-in-human study of IPI-549, a tumor macrophage-targeting agent, combined with nivolumab in advanced solid tumors.
Session Title: Developmental Therapeutics – Immunotherapy
Session Date and Time: Monday, June 4, 2018, 8:00 a.m. CT – 11:00 a.m. CT
Poster Board: 227
Abstract Number: 3013
First Author: Ryan J. Sullivan, MD, Massachusetts General Hospital
Location: Hall A, McCormick Place convention center

Poster Discussion Session 11:30 a.m. CT – 12:45 p.m. CT
Title: Initial results from first-in-human study of IPI-549, a tumor macrophage-targeting agent, combined with nivolumab in advanced solid tumors.
Session Title: Developmental Therapeutics – Immunotherapy
Session Date and Time: Monday, June 4, 2018, 11:30 a.m. CT – 12:45 p.m. CT
Abstract Number: 3013
First Author: Ryan J. Sullivan, MD, Massachusetts General Hospital
Location: Hall B1, McCormick Place convention center

About IPI-549 and the Ongoing Phase 1/1b Study
IPI-549 is an investigational first-in-class, oral, immuno-oncology product candidate targeting tumor-associated myeloid cells through selective phosphoinositide-3-kinase-gamma (PI3K-gamma) inhibition, thereby reducing pro-tumor macrophage function and increasing anti-tumor macrophage function. In preclinical studies, IPI-549 demonstrated the ability to reprogram macrophages from a pro-tumor (M2), immune suppressive function, to an anti-tumor (M1) immune activating function and enhance the activity of, and overcome resistance to, checkpoint inhibitors.ii iii As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially additive or synergistic approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

The ongoing Phase 1/1b study being conducted by Infinity is designed to evaluate the safety, tolerability, activity, pharmacokinetics and pharmacodynamics of IPI-549 as a monotherapy and in combination with nivolumab (Opdivo) in approximately 200 patients with advanced solid tumors.iv The study includes monotherapy and combination dose-escalation components, in addition to monotherapy expansion and combination expansion components. The monotherapy dose-escalation and expansion components are complete. The combination dose-escalation component is also complete, and combination expansion cohorts are enrolling.

The combination expansion component of the study includes multiple cohorts designed to evaluate IPI-549 in patients with specific types of cancer, including patients with non-small cell lung cancer (NSCLC), melanoma and head and neck cancer whose tumors show initial resistance or initially respond to but subsequently develop resistance to immune checkpoint blockade therapy. The combination expansion component also includes a cohort of patients with triple negative breast cancer (TNBC) who have not been previously treated with immune checkpoint blockade therapy, a cohort of patients with mesothelioma, a cohort of patients with adrenocortical carcinoma and a cohort of patients with high baseline blood levels of MDSCs.

IPI-549 is an investigational compound and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.

On June 4, 2018 Patients with metastatic uveal melanoma (mUM) treated with IMCgp100 continued to experience a durable tumour response with a median follow up of 19.1 months, without yet reaching median overall survival (OS), according to new Phase I research to be reported at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.2 IMCgp100 is the wholly-owned, lead programme from Immunocore Limited, a leading T-cell receptor (TCR) company focused on delivering first-in-class biological therapies that transform lives (Press release, Immunocore, JUN 4, 2018, View Source [SID1234527140]).

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Although rare, uveal melanoma is the most common form of adult eye cancer.3 When it metastasises beyond the eye, less than half of patients will survive for one year.4 Of the 19 HLA-A*0201+ patients enrolled in Phase I of the Phase I/II dose escalation trial, 17 were evaluated for efficacy. Among these patients, treatment with IMCgp100 was associated with an objective response rate of 18% (90% confidence interval [4,30]) and a one-year overall survival rate of 74% (95% confidence interval [48,88]) at the time of data cut-off.2

"Survival rates in uveal melanoma have remained largely unchanged for decades, and it is difficult to treat once it advances to metastatic disease," said Dr. Takami Sato, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University and lead investigator. "These data provide compelling evidence that IMCgp100 may offer hope to this underserved patient population."

Additional exploratory survival analyses also indicated prolonged OS was associated with a number of pharmacodynamic outcomes, including lymphocyte trafficking, providing encouraging evidence supporting the proposed mechanism of action of IMCgp100.2

"Immunocore is focused on transforming the lives of patients with some of the most challenging diseases, such as metastatic uveal melanoma, for which there is currently no standard of care," said Andrew Hotchkiss, Chief Executive Officer at Immunocore. "Although these are early findings, we are encouraged by the emerging clinical data and focused on advancing our pivotal trials."

The most common adverse events in the Phase I arm included pruritus (severe itching of the skin; 90%), pyrexia (fever) and fatigue (84%), and hypotension (74%).2 Dose limiting toxicities were observed in 3 patients; all were reversible abnormalities in liver function tests (Grade 3 or 4 ALT/AST changes). There were no IMCgp100-related AEs that resulted in discontinuation or death.2

About Metastatic Uveal Melanoma
Uveal melanoma is an aggressive form of melanoma which affects the eye, with a poor prognosis and no standard of care.5 Although it is the most common primary intraocular malignancy in adults,3 the diagnosis is rare, with approximately 4,000 new patients diagnosed globally each year (1,500 cases/year in US).1 Up to 50% of people with uveal melanoma will eventually develop metastatic disease.5,6 When the cancer spreads beyond the eye, only approximately 40% of patients will survive for one year.4

About the IMCgp100-102 Phase I/II Trial
In this study, IMCgp100 is administered on a weekly basis with an intra-patient escalation dosing regimen. The dose escalation portion of the study has been completed, which identified the recommended Phase II intra-patient dose. The Phase II portion of the study is ongoing evaluating both the safety and efficacy in patients with metastatic uveal melanoma. The currently enrolling cohort is assessing IMCgp100 in patients who have experienced disease progression after 1 or 2 prior lines of therapy, which may include up to 1 line of liver directed therapy. Approximately 150 patients will be enrolled in the Phase II portion and the estimated enrolment completion date is September 2019.

About the IMCgp100 Programme
IMCgp100 is a novel bi-specific biologic T cell redirection therapy that specifically targets the melanoma-associated antigen gp100, and which is now in pivotal studies for mUM. IMCgp100 was granted Orphan Drug Designation by the US Food and Drug Administration in 2016 and Promising Innovative Medicine designation under UK Early Access to Medicines Scheme in 2017. For more information about enrolling IMCgp100 clinical trials for metastatic uveal melanoma, please visit ClinicalTrials.gov (NCT02570308, NCT03070392).

About ImmTAC Molecules
Immunocore’s proprietary TCR (T Cell Receptor) technology generates a novel class of bi-specific biologics called ImmTAC (Immune mobilising monoclonal TCRs Against Cancer) molecules that enable the immune system to recognise and kill cancerous cells. ImmTAC molecules are based on synthetic, soluble TCRs engineered to recognise intracellular cancer antigens with ultra-high affinity and selectively kill cancer cells via an anti-CD3 immune-redirecting effector function. ImmTAC molecules can access up to nine-fold more target antigens than typical antibody-based approaches, including monoclonal antibodies. Based on the demonstrated mechanism of T cell infiltration into human tumours, the ImmTAC mechanism of action holds the potential to tackle solid "cold" low mutation rate tumours, the majority of tumours that do not adequately respond to currently available immunotherapies.