On June 4, 2017 Radius Health, Inc. (Nasdaq:RDUS), a fully integrated science-driven biopharmaceutical company that is committed to developing innovative therapeutics in the areas of osteoporosis, oncology and endocrine diseases, reported positive data from a fully enrolled ongoing Phase 1 study of elacestrant (RAD1901), an oral selective estrogen receptor degrader (SERD), in patients with estrogen receptor positive (ER+) breast cancer (Press release, Radius, JUN 4, 2017, View Source [SID1234519414]). These data were presented this morning at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting in Chicago, Illinois.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

As of the cut-off date of April 28, 2017, 40 patients have been treated in the fully enrolled elacestrant Phase I dose escalation and expansion cohorts at the 400 mg dose. These patients are all heavily pretreated ER+, HER2-negative advanced breast cancer patients who have received a median of 3 prior lines of systemic therapy and have evaluable advanced or metastatic disease. Of the enrolled patients, 22 patients met the RECIST measurable disease criteria at baseline and there were five confirmed partial responses in this group. Elacestrant was well-tolerated with the most common adverse events being low grade nausea and dyspepsia.

"While still early, the single-agent clinical activity and safety profile demonstrated with elacestrant in this heavily pretreated advanced hormone receptor positive breast cancer patient population is encouraging when compared to the results shown for other agents in a similar setting," said Dr. Aditya Bardia, Director of Precision Medicine and attending physician at Center for Breast Cancer, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA. "This is important for patients because it could potentially offer another endocrine therapy option even upon progression on standard endocrine therapy and could potentially delay the use of toxic chemotherapy, which is a meaningful clinical goal, and additional studies are needed."

On June 4, 2017, at the 2017 ASCO (Free ASCO Whitepaper) Annual Meeting, the following abstract was presented as a poster and will be included in the Poster Discussion Session later today: Abstract 1014

"Evaluation of Elacestrant (RAD1901), a novel investigational, selective estrogen receptor degrader (SERD), for the treatment of ER-positive (ER+) advanced breast cancer" Abstract 1014, 8:00 AM – 11:30 AM, Hall A, Poster Board #6, POSTER SESSION, Breast Cancer-Metastatic

Discussed at the Poster Discussion Session, 4:45 PM – 6:00 PM, Hall B1, Aditya Bardia, MD, MPH – First Author, Massachusetts General Hospital Cancer Center and Harvard Medical School

About Elacestrant (RAD1901)

Elacestrant is a selective estrogen receptor down-regulator/degrader (SERD), which at high doses is being evaluated for potential use as an oral non-steroidal treatment for estrogen receptor positive breast cancer, the most common form of the disease. Studies completed to date indicate that the compound has the potential for use as a single agent or in combination with other therapies for the treatment of breast cancer.

Additional information on the clinical trial program of elacestrant (RAD1901) is available on www.clinicaltrials.gov.

About RAD140

RAD140 is a non-steroidal selective androgen receptor modulator (SARM). The androgen receptor (AR) is frequently expressed in many estrogen receptor (ER)-positive, ER-negative, and triple-negative breast cancers. Because of its receptor and tissue selectivity, potent activity, oral bioavailability, and long half-life, RAD140 could have clinical potential in the treatment of breast cancer. RAD140 resulted from an internal drug discovery program focused on the androgen receptor pathway, and exhibits a differentiated mechanism of action compared to ER-targeted therapy.

On June 4, 2017 Novartis reported results from a Phase II study showing a durable survival benefit for some patients with BRAF V600 mutation-positive metastatic melanoma (MM) when treated with the combination of Tafinlar (dabrafenib) + Mekinist (trametinib)[1] (Press release, Novartis, JUN 4, 2017, View Source [SID1234519405]). The findings from the landmark five-year analysis of the trial, BRF113220, represent the longest follow-up to date of a BRAF and MEK inhibitor combination therapy in this patient population, and were presented today at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract #9505).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

A total of 162 patients received either Tafinlar monotherapy (150 mg BID) (n = 54) or the Tafinlar + Mekinist combination (150 mg BID/2 mg QD) (n = 54). After five years, 20 patients (37%) remain in the study, including seven (13%) in the Tafinlar monotherapy arm and 13 (24%) in the combination therapy arm, demonstrating that overall survival (OS) with combination therapy is superior to monotherapy[1]. The four-and five-year OS rates with monotherapy were 23% and 21%, respectively. The four- and five-year OS rates with combination therapy were 30% and 28%, respectively, reflecting a stabilization of OS in patients enrolled in the study[1]. Progression-free survival (PFS) in the monotherapy arm was consistently 3% whereas PFS at both four and five years was 13%, also demonstrating stabilization[1]. Forty-five of 54 patients (83%) in the Tafinlar monotherapy arm included in this updated analysis had crossed over to Tafinlar + Mekinist combination (150 mg BID/2 mg QD); the survival outcomes in these crossover patients continued to be followed under the Tafinlar arm.

"These recent results from the longest follow-up of a BRAF and MEK inhibitor targeted study show that a significant cohort of patients with metastatic melanoma positive for the BRAF V600 mutation can achieve long-term survival with Tafinlar + Mekinist combination therapy," said lead investigator Jeff Weber, MD, PhD, Deputy Director, Laura and Isaac Perlmutter Cancer Center, Co-Director, Melanoma Program & Head of Experimental Therapeutics NYU Langone Medical Center. "This combination of targeted therapy should be considered by physicians when making treatment decisions."

Adverse events were consistent with other Tafinlar + Mekinist studies, and additional follow-up revealed no new safety signals[1].
"These data demonstrate the long-term benefit of Tafinlar in combination with Mekinist for certain patients living with metastatic melanoma," said Vas Narasimhan, Global Head Drug Development and Chief Medical Officer, Novartis. "We are gratified to see these data showing that patients can benefit long-term from Tafinlar + Mekinist, and we look forward to evaluating additional Phase III long-term survival data."

Additionally, Novartis presented results from a Phase II study showing a positive, statistically significant intracranial response for patients with BRAF V600 mutation-positive metastatic melanoma (MM) when treated with the combination of Tafinlar + Mekinist (Abstract #9506)[2]. The findings from the 30-month trial, COMBI-MB, represent the first report of a Phase II trial evaluating a BRAF and MEK inhibitor combination therapy in patients with BRAF V600-mutant melanoma brain metastases (MBM).

The COMBI-MB study evaluated Tafinlar + Mekinist in 125 patients enrolled in four cohorts. In Cohort A (patients who were BRAF V600E mutation-positive, had asymptomatic MBM and no local prior treatment), investigator-assessed intracranial response rate (IRR) was 58% (95% CI: 46, 69)[2]. Extracranial response rate (ERR) was 55% (95% CI: 43, 67) and overall response rate (ORR) was 58% (95% CI: 46, 69)[2]. Median PFS was 5.6 months (95% CI: 5.3, 7.4)[1]. Six-month OS was 79%; with 31 patients (41%) still in follow-up. Preliminary median OS was 10.8 months (95% CI: 8.7, 19.6)[2].

Adverse events across cohorts (any, 98%; grade 3/4, 48%) were consistent with prior Tafinlar + Mekinist studies; 10% of patients (8% in cohort A) discontinued due to adverse events[2].

Results of the COMBI-MB study were simultaneously published in the June issue of The Lancet Oncology, available online on Sunday, June 4, at 10:00 AM[8].

Additional poster and oral presentations related to the investigational use of Tafinlar and Mekinist were also presented at the meeting, including an updated five year landmark analysis of Phase II (BREAK-2) and Phase III (BREAK-3) studies evaluating Tafinlar monotherapy in patients with BRAF V600-mutant melanoma, and studies in BRAF V600E-mutated advanced thyroid cancer (ATC) and non-small cell lung cancer (NSCLC).

About BRF113220
The BRF113220 study is an open-label, Phase II trial. Patients with BRAF V600-mutant MM were randomly assigned to receive Tafinlar monotherapy (150 mg BID), Tafinlar + Mekinist (150 mg BID/1 mg QD), or Tafinlar + Mekinist (150 mg BID/2 mg QD). Patients who progressed on Tafinlar alone could cross over to the Tafinlar + Mekinist 150/2 arm. Patient disposition, patient demographics, and four- and five-year efficacy and safety were analyzed for the Tafinlar monotherapy and Tafinlar + Mekinist (approved 150/2 dose) arms.

About COMBI-MB
The COMBI-MB study is an open-label, Phase II trial and included four patient cohorts based on mutation status, MBM symptoms and history of treatment: (A) BRAF V600E, asymptomatic MBM, and no prior local therapy (76 patients); (B) BRAF V600E, asymptomatic MBM, and prior local therapy (16 patients); (C) BRAF V600D/K/R, asymptomatic MBM, with or without prior local therapy (16 patients); and (D) BRAF V600D/E/K/R, symptomatic MBM, with or without prior local therapy (17 patients).

The primary endpoint was intracranial response (IR) in cohort A patients. Secondary endpoints included IR in cohorts B, C, and D; intracranial disease control; extracranial response (ER); overall response (OR); duration of IR, ER, and OR; PFS; OS; and safety.

About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates[3],[4]. Only about 20% of people will survive for at least five years following a diagnosis with late-stage disease[3],[4]. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma[3],[5],[6]. Gene tests can determine whether a tumor has a BRAF mutation[3],[7].

About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Australia, Canada and other countries.

Tafinlar and Mekinist target different kinases within the serine/threonine kinase family – BRAF and MEK1/2, respectively – in the RAS/RAF/MEK/ERK pathway, which is implicated in non-small cell lung cancer (NSCLC) and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indication.

Tafinlar and Mekinist are also indicated in more than 50 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Tafinlar + Mekinist Combination Important Safety Information for Metastatic Melanoma

TAFINLAR and MEKINIST, in combination, may cause serious side effects such as the risk of new cancers, including both skin cancer and non-skin cancer. Patients should be advised to contact their doctor immediately for a new wart, skin sore, or bump that bleeds or does not heal, or a change in the size or color of a mole.

When TAFINLAR is used in combination with MEKINIST, it can cause serious bleeding problems, especially in the brain or stomach, and can lead to death. Patients should be advised to call their health care provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," or have red or black stools that look like tar.

MEKINIST, alone or in combination with TAFINLAR, can cause inflammation of the colon and bleeding in the stomach or intestines that can lead to death. Patients should report to their health care provider immediately if they have diarrhea, stomach or abdominal pain, fever, or nausea.

TAFINLAR, in combination with MEKINIST, can cause blood clots in the arms or legs, which can travel to the lungs and can lead to death. Patients should be advised to get medical help right away if they have the following symptoms: chest pain, sudden shortness of breath or trouble breathing, pain in their legs with or without swelling, swelling in their arms or legs, or a cool or pale arm or leg.

The combination of TAFINLAR and MEKINIST can cause heart problems, including heart failure. A patient’s heart function should be checked before and during treatment. Patients should be advised to call their health care provider right away if they have any of the following signs and symptoms of a heart problem: feeling like their heart is pounding or racing, shortness of breath, swelling of their ankles and feet, or feeling lightheaded.

TAFINLAR, in combination with MEKINIST, can cause severe eye problems that can lead to blindness. Patients should be advised to call their health care provider right away if they get: blurred vision, loss of vision, or other vision changes, seeing color dots, halo (seeing blurred outline around objects), eye pain, swelling, or redness.

TAFINLAR, in combination with MEKINIST, can cause lung or breathing problems. Patients should be advised to tell their health care provider if they have new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.

Fever is common during treatment with TAFINLAR in combination with MEKINIST, but may also be more serious. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Patients should be advised to call their health care provider right away if they get a fever.

Rash is a common side effect of TAFINLAR in combination with MEKINIST. TAFINLAR, in combination with MEKINIST, can also cause other skin reactions. In some cases these rashes and other skin reactions can be severe, and may need to be treated in a hospital. Patients should be advised to call their health care provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, or skin redness.

Some people may develop high blood sugar or worsening diabetes during treatment with TAFINLAR in combination with MEKINIST. For patients who are diabetic, their health care provider should check their blood sugar levels closely during treatment. Their diabetes medicine may need to be changed. Patients should be advised to tell their health care provider if they have increased thirst, urinate more often than normal, or produce an increased amount of urine.

TAFINLAR, in combination with MEKINIST, may cause healthy red blood cells to break down too early in people with G6PD deficiency. This may lead to a type of anemia called hemolytic anemia, where the body does not have enough healthy red blood cells. Patients should be advised to tell their health care provider if they have yellow skin (jaundice), weakness or dizziness, or shortness of breath.

TAFINLAR, in combination with MEKINIST, can cause new or worsening high blood pressure (hypertension). A patient’s blood pressure should be checked during treatment. Patients should be advised to tell their health care provider if they develop high blood pressure, their blood pressure worsens, or if they have severe headache, lightheadedness, or dizziness.

The most common side effects of TAFINLAR, in combination with MEKINIST, include nausea, chills, diarrhea, vomiting, high blood pressure (hypertension), swelling of the face, arms, or legs, headache, joint aches, and cough.

Please see full prescribing information for TAFINLAR and MEKINIST at View Source (link is external).

On June 4, 2017 Halozyme Therapeutics (NASDAQ: HALO) reported encouraging results from a Phase 2 randomized, multi-center clinical trial in pancreas cancer patients were presented today at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual conference (Press release, Halozyme, JUN 4, 2017, View Source [SID1234519372]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Principal Investigator Sunil R. Hingorani, M.D., Ph.D., a pancreas cancer expert at Fred Hutchinson Cancer Research Center and professor at University of Washington School of Medicine expanded on findings from patient data as of December 2016 in the HALO-202 study of investigational new drug, PEGPH20 (pegvorhyaluronidase alpha) in combination with ABRAXANE (nab-paclitaxel) and gemcitabine.

The study met its primary endpoints and the key secondary endpoint of progression-free survival (PFS) in patients with high levels of a biomarker, hyaluronan (HA-High). PEGPH20 plus standard chemotherapy of ABRAXANE and gemcitabine improved median PFS by 77 percent over chemotherapy alone in HA-High patients.

An exploratory endpoint of objective response rate by RECIST v1.1 in the HA-High population, reported for the first time today, was 45 percent in the PEGPH20 plus chemotherapy arm, including one Complete Response, compared to 31 percent in patients receiving chemotherapy alone. Key patient baseline characteristics also reported for the first time today were generally well balanced across both arms of the study.

Halozyme is currently conducting a global Phase 3 clinical trial, HALO-301, in a similar population of HA-High stage IV pancreas cancer patients.

"The HALO-202 study met key safety and efficacy objectives and confirmed in a randomized Phase 2 trial that a biomarker may be able to identify patients who will have a meaningfully greater response when PEGPH20 is added to standard-of-care chemotherapy," said Dr. Hingorani. "The new data reported today suggest potentially important progress in this very difficult to treat cancer."

Dr. Helen Torley, president and chief executive officer of Halozyme, said, "We are driven in our study of PEGPH20 by the goal of providing new options to patients affected by some of the hardest to treat cancers. The HALO-202 results in HA-High pancreas cancer patients provide encouraging insights into a potentially new treatment option and support our ongoing study of PEGPH20 in the global Phase 3 HALO-301 study."

Pancreas cancer is the third-leading cause of cancer related death in the United States, and more than 65,000 people in the U.S. and top five European countries are diagnosed annually with advanced cases of the disease.

About HALO-301 and HALO-202
HALO-301 is a phase 3 global, randomized, double-blind placebo controlled clinical trial evaluating investigational new drug PEGPH20 as a first-line therapy for potential treatment of patients with metastatic pancreas cancer. The trial will be conducted at approximately 200 sites with two primary endpoints, progression free survival and overall survival in patients receiving investigational new drug PEGPH20 in combination with gemcitabine and ABRAXANE (nab-paclitaxel) compared to gemcitabine and nab-paclitaxel alone. Secondary endpoints also include objective response rate and overall survival. More information may be found at clinicaltrials.gov (search HALO 301 or trial identifier NCT02715804) or www.HALO301.com.

HALO-202 (Halo 109-202) is a phase 2 multi-center, randomized clinical trial evaluating investigational new drug PEGPH20 as a first-line therapy for potential treatment of patients with metastatic pancreas cancer. The primary outcome of the trial is to measure improvement in progression-free survival in patients receiving investigational new drug PEGPH20 in combination with gemcitabine and nab-paclitaxel compared to gemcitabine and nab-paclitaxel alone. A second primary endpoint assesses the thromboembolic event rate in the PEGPH20 treatment arm. Secondary endpoints also include objective response rate and overall survival.

About PEGPH20 (pegvorhyaluronadase alpha)
PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase under clinical development for the potential systemic treatment of tumors that accumulate hyaluronan. PEGPH20 is an enzyme that temporarily degrades HA, a dense component of the tumor microenvironment that can accumulate in higher concentrations around certain cancer cells, potentially constricting blood vessels and impeding the access of other therapies.

FDA granted orphan drug designation to PEGPH20 for treatment of pancreas cancer and fast track designation for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreas cancer. Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreas cancer.

– See more at: View Source#sthash.aOaOHqlE.dpuf

On June 4, 2017 Five Prime Therapeutics, Inc. (Nasdaq:FPRX) reported that a poster featuring initial clinical data from the ongoing Phase 1/2 clinical trial of cabiralizumab in patients with PVNS was presented today at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Five Prime Therapeutics, JUN 4, 2017, View Source [SID1234519370]). The poster, titled "A Phase 1/2 Dose Escalation and Expansion Study of Cabiralizumab (FPA008), an anti-CSF1R antibody, in Tenosynovial Giant Cell Tumor (TGCT, Diffuse Pigmented Villonodular Synovitis, D-PVNS)" (Abstract #11078), is available at View Source

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Cabiralizumab clearly demonstrates clinical benefit in patients with PVNS, including reduction in tumor size and improvements in pain and functional status," said Helen Collins, M.D., Senior Vice President and Chief Medical Officer of Five Prime. "Our recent market research indicates that patients with PVNS have significant unmet needs, especially in alleviating the pain and functional impairment caused by this chronic joint disease. The encouraging safety and efficacy results support continued development of cabiralizumab for this condition for which there are no currently approved medical treatments. We plan to have discussions with regulatory authorities about a potential pivotal trial in this orphan indication."

This Phase 1/2 clinical trial is an open-label, dose escalation and dose expansion study designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of cabiralizumab in patients with PVNS. The protocol was amended to allow for continued treatment with cabiralizumab with asymptomatic creatine kinase (CK) elevations. After the amendment, 21 additional patients were enrolled between November 2016 and March 2017. The efficacy results included in the poster and summarized below include only the 11 patients treated prior to the protocol amendment.

Safety Results

PK and PD of cabiralizumab support dosing at 4 mg/kg every two weeks or less frequently
No dose-limiting toxicities (DLTs) were observed at doses up to 4mg/kg
Most frequently reported adverse events (AEs) of periorbital and eyelid edema, rash and pruritus are similar to AEs reported in other agents in this drug class
— 3 out of 11 patients enrolled prior to the protocol amendment discontinued drug due to asymptomatic laboratory elevations of CK
Efficacy Results

Cabiralizumab demonstrates clinical benefit in patients with PVNS at 4mg/kg every two weeks
— Most patients enrolled at the 4 mg/kg dose prior to the amendment experienced tumor reduction
— 5 out of 11 patients had a radiographic response (4 confirmed)
— Improvement in median Ogilvie-Harris composite score of pain and function was reported in both responders and non-responders (per RECIST v1.1 on MRI)
— 12 additional patients enrolled after the amendment were considered efficacy evaluable with evidence of early shrinkage in tumor, but it was too early to assess overall response as of the data cut-off date
About PVNS
PVNS is a rare, locally aggressive tumor of the synovium. It is characterized by local over-expression of CSF-1, which recruits macrophages into the joints, forming the non-malignant tumor mass. It is associated with high morbidity, and there are no approved therapies for the condition. Five Prime is conducting a Phase 1/2 clinical trial studying cabiralizumab as a treatment for PVNS.

About Cabiralizumab (FPA008)
Cabiralizumab is an investigational antibody that inhibits the CSF-1 receptor and has been shown in preclinical models to block the activation and survival of monocytes and macrophages. Inhibition of CSF1R in preclinical models of several cancers reduces the number of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment, thereby facilitating an immune response against tumors. Cabiralizumab is currently in a Phase 1/2 clinical trial in pigmented villonodular synovitis (PVNS) and a Phase 1 clinical trial in oncology indications. Cabiralizumab is being developed under an exclusive worldwide license and collaboration agreement entered into with Bristol-Myers Squibb (BMS) in October 2015.

On June 4, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported results of an interim descriptive analysis from an ongoing National Cancer Institute (NCI) Phase 3 randomized study evaluating Yervoy (ipilimumab) 3 mg/kg and Yervoy 10 mg/kg in patients with stage III or resectable stage IV melanoma who are at high risk of recurrence following complete surgical resection (Press release, Bristol-Myers Squibb, JUN 4, 2017, View Source [SID1234519363]). In this unplanned analysis of relapse-free survival (RFS) in concurrently randomized patients between the two experimental arms RFS at three years was 56% (n=367) for Yervoy 3 mg/kg (95% CI: 0.50, 0.61) and 54% (n=406) for Yervoy 10 mg/kg (95% CI: 0.49, 0.60).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

All-Cause Grade 3/4 adverse events (AEs) were experienced by 53% of patients in the Yervoy 3mg/kg arm (n=516) and 66% of patients in the Yervoy 10 mg/kg (n=503) arm. Treatment-related Grade 3/4 AEs were experienced by 37% and 57% of patients in the Yervoy 3mg/kg and 10 mg/kg arms, respectively. Treatment-related AEs led to discontinuation in 35% of patients taking Yervoy 3 mg/kg and 54% taking Yervoy 10 mg/kg. There were eight deaths in the Yervoy 10 mg/kg arm and two in the Yervoy 3 mg/kg arm that were considered at least possibly treatment-related. These data will be presented during an oral session today from 8:00 – 8:12 a.m. CT during the Melanoma/Skin Cancers session in the Arie Crown Theater at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2017.

"Adjuvant therapy with ipilimumab represents an important option for appropriate stage III melanoma patients following complete resection who have a significant risk of disease recurrence; however, management of adverse events is essential to help ensure that appropriate patients are able to benefit from treatment," said Ahmad A. Tarhini, MD, PhD, University of Pittsburgh Cancer Institute. "These data are important because they advance our understanding of the benefits and risks of ipilimumab in the adjuvant setting."

"There is a need for safe and effective treatment options for melanoma patients after surgery who are at high-risk of relapse, only about half of whom receive treatment," said Vicki Goodman, M.D., development lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb. "This analysis provides valuable information that may help inform treatment decisions."

E1609 is a Phase 3 study that enrolled 1,673 adult patients between May 2011 and August 2014 at multiple clinical sites, all belonging to the research groups in the NCI’s National Clinical Trials Network that design and lead trials focused on adult cancers: the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research Group, NRG Oncology, and SWOG. The study is comparing the effect of adjuvant Yervoy at either 3 mg/kg or 10 mg/kg versus high-dose interferon in adult patients with high-risk stage III or IV melanoma that has been removed by surgery. The study was not designed to compare the two Yervoy arms to each other. This analysis was performed to inform the effect of dose on efficacy and safety in the adjuvant setting. Co-primary endpoints of the study are overall survival and RFS comparing Yervoy versus high dose interferon α-2b. Secondary outcome measures include global quality of life and the safety profile of adjuvant Yervoy (10 mg/kg and 3 mg/kg) versus high-dose recombinant interferon α-2b. In this descriptive analysis, data was presented on the efficacy and safety of Yervoy 3 mg/kg and Yervoy 10 mg/kg at a median follow up of 3.1 years.

Adjuvant Therapy in Melanoma

Melanoma is separated into five staging categories (stages 0-4) based on the in-situ feature, thickness and ulceration of the tumor, whether the cancer has spread to the lymph nodes, and how far the cancer has spread beyond lymph nodes.

Stage 3 melanoma has reached the regional lymph nodes but has not yet spread to distant lymph nodes or to other parts of the body (metastasized), and requires surgical resection of the primary tumor as well as the involved lymph nodes. Some patients may also be treated with adjuvant therapy, although adjuvant treatment options are very limited. Despite surgical intervention and possible adjuvant treatment, most patients experience disease recurrence and progress to metastatic disease. By five years, the majority of stage 3B and 3C patients (68% and 89%, respectively) and a third of stage 3A patients (37%) have experienced disease recurrence.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance the I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how a patient’s tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Yervoy

Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types.

Indications and Important Safety Information for YERVOY (ipilimumab)

Indications

YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

YERVOY (ipilimumab) is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

Important Safety Information

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose.

Recommended Dose Modifications

Endocrine: Withhold YERVOY for systemic endocrinopathy. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for symptomatic reactions lasting 6 weeks or longer or an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.

Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4 reactions not improving to Grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment.

All Other Organ Systems: Withhold YERVOY for Grade 2 adverse reactions. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer, an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day, and Grade 3 or 4 adverse reactions.

Immune-mediated Enterocolitis:

Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent). Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3-5 days or recurring after symptom improvement. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. Infliximab was administered to 5 (8%) of the 62 patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients (14%). Seven (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications.

Immune-mediated Hepatitis:

Immune-mediated hepatitis, including fatal cases, can occur with YERVOY. Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution. Withhold YERVOY in patients with Grade 2 hepatotoxicity. Permanently discontinue YERVOY in patients with Grade 3-4 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3-5) occurred in 8 YERVOY-treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4%. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2). In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3-4 hepatitis showed evidence of toxic or autoimmune hepatitis.

Immune-mediated Dermatitis:

Immune-mediated dermatitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically; administer topical or systemic corticosteroids if there is no improvement within 1 week. Withhold YERVOY in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 YERVOY-treated patients (2.5%); 1 patient (0.2%) died as a result of toxic epidermal necrolysis and 1 additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate Grade 2 dermatitis.

Immune-mediated Neuropathies:

Immune-mediated neuropathies, including fatal cases, can occur with YERVOY. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities). Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities), such as Guillain-Barre-like syndromes. Institute medical intervention as appropriate for management for severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. In patients receiving YERVOY 3 mg/kg in Trial 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).

Immune-mediated Endocrinopathies:

Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY. Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated. Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY in symptomatic patients and consider referral to an endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. In patients receiving YERVOY 3 mg/kg in Trial 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 YERVOY-treated patients (1.8%). All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies occurred in 93 patients (20%). Of the 39 patients with Grade 3-4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with 1 or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The median time to onset of Grade 3-4 immune-mediated endocrinopathy was 2.2 months (range: 2 days-8 months). Twenty-seven (69.2%) of the 39 patients were hospitalized for immune-mediated endocrinopathies. Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with 1 or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. The median time to onset of Grade 2 immune-mediated endocrinopathy was 2.1 months (range: 9 days-19.3 months).

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions. Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy. In Trial 1, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. In Trial 2, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients unless specified: eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis and fatal myocarditis. Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with <1% incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, hemolytic anemia, and nephritis.

Embyro-fetal Toxicity

Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with a YERVOY-containing regimen and for 3 months after the last dose of YERVOY.

Lactation

It is not known whether YERVOY is secreted in human milk. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Common Adverse Reactions:

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritis (31%), rash (29%), and colitis (8%). The most common adverse reactions (≥5%) in patients who received YERVOY at 10 mg/kg were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%).

Please see Full Prescribing Information for YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions.

Yervoy is a registered trademark of Bristol-Myers Squibb Company.