On June 4, 2018 Seattle Genetics, Inc. (Nasdaq:SGEN) reported that highlighted data from the phase 3 ECHELON-1 clinical trial evaluating ADCETRIS (brentuximab vedotin) in combination with chemotherapy in newly diagnosed stage III or IV classical Hodgkin lymphoma (HL) at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 1-5 in Chicago, Illinois (Press release, Seattle Genetics, JUN 4, 2018, View Source;p=RssLanding&cat=news&id=2353005 [SID1234527154]). In March 2018, the U.S. Food and Drug Administration (FDA) approved ADCETRIS in combination with chemotherapy for the treatment of adult patients with previously untreated stage III or IV classical HL based on the positive results of the phase 3 ECHELON-1 clinical trial. ADCETRIS is being evaluated globally as the foundation of therapy for HL in more than 50 ongoing clinical trials, including trials led by Seattle Genetics and its development and commercialization partner, Takeda, as well as by independent investigators.

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"For over 40 years, the standard of care for the treatment of frontline HL in North America has been combination chemotherapy with ABVD. Unfortunately, approximately 30 percent of advanced stage HL patients will not respond or relapse to this therapy," said Radhakrishnan Ramchandren, M.D., Barbara Ann Karmanos Cancer Center. "The ECHELON-1 phase 3 clinical trial is the first trial to demonstrate superior clinical activity utilizing a novel therapeutic agent, ADCETRIS, in combination with AVD in comparison to ABVD. At ASCO (Free ASCO Whitepaper) 2018, we presented outcomes specifically evaluating the North American population, which demonstrated a two-year modified progression-free survival benefit of approximately 11 percent over ABVD. Importantly, an analysis of traditional progression-free survival at two years also demonstrated a benefit for ADCETRIS plus AVD versus ABVD with a difference of 11.7 percent, a Hazard Ratio of 0.500 and a p-value of 0.002. These findings represent a significant and meaningful difference in outcomes for these patients."

"Our goal is to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas, including HL, and the data presented at ASCO (Free ASCO Whitepaper) continue to support this goal," said Nancy Whiting, Pharm.D., Senior Vice President, Clinical Affairs at Seattle Genetics. "Multiple posters featuring additional analyses from the ECHELON-1 trial for ADCETRIS combination use in the treatment of patients with stage III or IV classical HL demonstrate superior efficacy benefit when compared with ABVD. In addition, data from an ongoing phase 2 study evaluating frontline use of ADCETRIS in older HL patients demonstrate a durable efficacy benefit with both monotherapy and combination therapy. Our data at ASCO (Free ASCO Whitepaper) highlight the substantial potential for ADCETRIS to address the needs of patients with lymphoma."

Three poster presentations highlight analyses from the ECHELON-1 phase 3 clinical trial evaluating ADCETRIS in combination with AVD (Adriamycin, vinblastine and dacarbazine) compared to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) in stage III or IV frontline classical HL patients. The ECHELON-1 poster presentations include the results of the North American patient population, optimizing therapy with the use of primary prophylactic growth factors (G-CSF) and improvement of modified progression-free survival (PFS) outcomes in patients who received ADCETRIS plus AVD regardless of cycle 2 PET (PET2) status. In addition, long-term follow-up from an ongoing phase 2 clinical trial in newly diagnosed older HL patients was reported.

Brentuximab Vedotin plus Chemotherapy in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: North American Results (Abstract #7541, poster presentation on Monday, June 4, 2018)

Of the 1,334 advanced stage classical HL patients who participated in the ECHELON-1 clinical trial, 497 patients were treated in North America, with 250 patients in the ADCETRIS plus AVD arm and 247 patients in the ABVD control arm. The North American results presented by Dr. Radhakrishnan Ramchandren, Barbara Ann Karmanos Cancer Center, are included below and a video summary of the poster presentation can be found here:

Per Independent Review Facility (IRF) assessment, the two-year modified PFS rate for patients in the ADCETRIS plus AVD arm was 84.3 percent compared to 73.7 percent in the control arm (HR 0.596; p-value=0.012), which corresponds to a difference of 10.6 percent.
Per investigator assessment, the two-year modified PFS rate for patients in the ADCETRIS plus AVD arm was 86.4 percent compared to 73.6 percent in the control arm (HR 0.516; p-value=0.002), which corresponds to a difference of 12.8 percent.
Per investigator assessment, the two-year PFS rate for patients in the ADCETRIS plus AVD arm was 88.1 percent compared to 76.4 percent in the control arm (HR 0.500; p-value=0.002), which corresponds to a difference of 11.7 percent.
Consistent improvement in modified PFS per IRF was observed among patients treated with ADCETRIS plus AVD compared with ABVD across all pre-specified subgroups, including age, disease stage, International Prognostic Score and baseline ECOG score.
On the ADCETRIS plus AVD arm, peripheral neuropathy events were observed in 80 percent of patients compared to 56 percent on the ABVD arm. In the ADCETRIS plus AVD arm, the majority of peripheral neuropathy events were Grade 1 or 2 (41 percent and 21 percent, respectively). Grade 3 events were reported in 17 percent of patients. In the ABVD arm, Grade 3 events were reported in less than one percent of patients. There were no Grade 4 events on either arm. Across both arms of the study, approximately 75 percent of the patients with peripheral neuropathy reported resolution or improvement at last follow-up.
Febrile neutropenia during treatment was reported in 20 percent of patients in the ADCETRIS plus AVD arm compared with nine percent in the ABVD arm. In the ADCETRIS plus AVD arm, 35 patients received primary prophylactic G-CSF within five days of starting treatment and nine percent (three patients) reported febrile neutropenia.
Pulmonary toxicity was reported in three percent of patients in the ADCETRIS plus AVD arm versus ten percent of patients in the ABVD arm. Grade ≥3 events were reported in two percent versus six percent of patients, in the ADCETRIS plus AVD and ABVD arms, respectively.
Improving Outcomes with Brentuximab Vedotin plus Chemotherapy in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma (Abstract #7534, poster presentation on Monday, June 4, 2018)

During the ECHELON-1 clinical trial, an independent monitoring committee (IDMC) recommended the use of primary prophylactic G-CSF for patients in the ADCETRIS plus AVD arm of the study due to an increased risk of febrile neutropenia. In the ADCETRIS plus AVD arm, 83 patients received G-CSF primary prophylaxis (defined as receipt of G-CSF by day five of the first treatment cycle) and 579 patients did not. An analysis of these two patient populations in the ECHELON-1 study presented by Dr. David Straus, Memorial Sloan Kettering Cancer Center, included:

The two-year modified PFS rate for patients in the ADCETRIS plus AVD arm who received G-CSF primary prophylaxis was 84.6 percent compared to 81.7 percent for those who did not (HR 0.737; 95% CI, 0.396 to 1.372) and compared to 77.2 percent in the ABVD control arm (HR 0.586; 95% CI, 0.317 to 1.081).
Use of G-CSF primary prophylaxis in the ADCETRIS plus AVD arm was associated with a decrease in neutropenia (35 percent versus 73 percent), overall febrile neutropenia (11 percent versus 21 percent) and febrile neutropenia in the first treatment cycle (one percent versus 11 percent). Seven of the nine deaths that occurred in the ADCETRIS plus AVD arm were associated with neutropenia, none of whom had received primary prophylaxis with G-CSF before the onset of neutropenia.
There was no evidence of an association between use of G-CSF primary prophylaxis and pulmonary toxicity.
In the ADCETRIS plus AVD arm, incidence of peripheral neuropathy was 57 percent in patients with G-CSF primary prophylaxis versus 68 percent without.
Lastly, use of G-CSF primary prophylaxis was associated with a lower rate of ADCETRIS dose delays and dose reductions compared to those without.
Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin Lymphoma: Impact of Cycle 2 PET Result on Modified Progression-Free Survival (Abstract #7539, poster presentation on Monday, June 4, 2018)

A post-hoc analysis of the ECHELON-1 clinical trial was conducted to evaluate modified PFS outcomes and clinical characteristics by PET2 status per IRF. In the ADCETRIS plus AVD arm of the study, 588 patients were PET2-negative (Deauville score ≤3) and 47 were PET2-positive (Deauville score ≥4). In the ABVD arm of the study, 577 patients were PET2-negative and 58 were PET2-positive. The analysis presented by Dr. Robert Chen, City of Hope National Medical Center, included:

ADCETRIS plus AVD improved modified PFS outcomes in patients regardless of PET2 status. The modified PFS in PET2-negative patients in the ADCETRIS plus AVD arm was 85.2 percent compared to 80.9 percent in the ABVD arm (HR 0.774; 95% CI, 0.586 to 1.022). The modified PFS in PET2-positive patients in the ADCETRIS plus AVD arm was 57.5 percent compared to 42.0 percent in the ABVD arm (HR 0.609; 95% CI, 0.341 to 1.088). PET2-positive patients in the ADCETRIS plus AVD arm had superior results compared to historical controls.
The safety profile of ADCETRIS plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen. There were no notable differences in the safety profile between PET2-positive or PET2-negative subgroups in either arm of the study.
Long-Term Follow-Up of Brentuximab Vedotin +/- Dacarbazine as First-Line Therapy in Elderly Patients with Hodgkin Lymphoma (Abstract #7542, poster presentation on Monday, June 4, 2018)

Long-term follow-up results were presented from an ongoing phase 2 clinical trial evaluating ADCETRIS alone or in combination with dacarbazine as frontline therapy for HL patients age 60 years or older. Data were reported from 27 patients treated with ADCETRIS monotherapy and 22 patients treated with ADCETRIS in combination with dacarbazine. The median age of patients was 78 years in the ADCETRIS monotherapy arm and 69 years in the dacarbazine combination arm. Over 60 percent of patients in each arm had stage III/IV disease at the time of diagnosis and the majority were frail with multiple comorbidities. Long-term data highlighted by Dr. Jonathan Friedberg, University of Rochester, included:

In the ADCETRIS monotherapy arm, the median observation time from first dose was 42.6 months. Estimated three-year PFS and overall survival rates were 34 percent and 71 percent, respectively, with no deaths occurring within 30 days of last treatment. Median PFS was 10.48 months and median overall survival had not yet been reached.
In the dacarbazine combination arm, the median observation time from first dose was 37.8 months. Estimated three-year PFS and overall survival rates were 52 percent and 90 percent, respectively, with no deaths occurring within 30 days of last treatment. Both median PFS and overall survival had not yet been reached.
Treatment-emergent peripheral neuropathy of any grade was observed in 24 patients (89 percent) in the ADCETRIS arm and 19 patients (86 percent) in the dacarbazine combination arm, with most Grade 1 or 2 and sensory in nature. The majority of patients with treatment-emergent peripheral neuropathy had either complete resolution or some resolution or improvement.
Adverse events leading to treatment discontinuation in the ADCETRIS monotherapy arm were peripheral sensory neuropathy (30 percent), peripheral motor neuropathy (seven percent) and orthostatic hypotension (four percent). Adverse events leading to treatment discontinuation in the dacarbazine combination arm were peripheral sensory neuropathy (36 percent); asthenia, systemic lupus erythematosus, hypotension and non-cardiac chest pain (five percent each).
ADCETRIS in combination with dacarbazine is not approved for use in frontline HL.

About ECHELON-1

ECHELON-1 is a randomized, open-label, two-arm, multi-center phase 3 study designed to compare ADCETRIS plus (Adriamycin, vinblastine and dacarbazine) to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) as frontline therapy in patients with previously untreated advanced classical HL. The primary endpoint is modified progression-free survival (PFS) per Independent Review Facility (IRF). Modified PFS is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy per IRF followed by subsequent anticancer therapy. The study enrolled 1,334 patients who had histologically-confirmed diagnosis of Stage III or IV Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy.

About Classical Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2018 and more than 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

About ADCETRIS (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 clinical trials, including two ongoing phase 3 studies: the ECHELON-2 trial in frontline mature T-cell lymphomas (also known as peripheral T-cell lymphoma) and the CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA regular approval for five indications in adult patients with: (1) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with chemotherapy, (2) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (3) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (4) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (5) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in 71 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On June 4, 2018 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi reported that pivotal data from two trials evaluating cemiplimab in advanced cutaneous squamous cell carcinoma (CSCC) were published today in the New England Journal of Medicine (NEJM) and presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Regeneron, JUN 4, 2018, View Source [SID1234527153]). Advanced CSCC, the deadliest nonmelanoma skin cancer, encompasses both patients with metastatic CSCC and those with locally advanced CSCC who are not candidates for surgery; there is currently no approved treatment for these patients. Cemiplimab is an investigational human monoclonal antibody targeting the immune checkpoint PD-1 (programmed cell death protein 1).

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"The strong results seen with cemiplimab are noteworthy given that advanced CSCC is a very serious condition that currently has no approved treatments once surgery is no longer an option," said Michael R. Migden, M.D., co-lead author and Associate Professor in the Departments of Dermatology and Head and Neck Surgery at The University of Texas MD Anderson Cancer Center. "Advanced CSCC tumors were shown to be responsive to cemiplimab in both metastatic and locally advanced patients, with the results being clinically meaningful and consistent between the Phase 1 and Phase 2 trials."

Data published in NEJM and/or presented at ASCO (Free ASCO Whitepaper), and confirmed by independent central review, include:

Phase 2 EMPOWER-CSCC-1 trial:
Cemiplimab-treated patients had a 47.5 percent response rate (28 of 59 patients, including 4 complete responses and 24 partial responses [PRs]) with a median observed time to response of 2 months as of the data cut-off date. The durable disease control rate (DCR) was 61 percent (36 of 59 patients) and was defined as the proportion of patients without progressive disease for at least 105 days.
The median duration of response (DOR), median progression free survival, and median overall survival have not been reached as of the data cut-off date (median follow-up for all patients: 8 months). Of the responding patients, 82 percent remained in response and continued on cemiplimab. The estimated progression-free probability at 12 months was 52.5 percent, and the estimated probability of survival at 12 months was 81 percent.
The most common treatment-emergent adverse events were diarrhea (27 percent), fatigue (24 percent), nausea (17 percent), constipation and rash (each 15 percent). Grade 3 or higher adverse events regardless of attribution were reported in 25 patients (42 percent), of whom seven (12 percent) were considered related to treatment. Three patients (5 percent) had adverse events with the outcome of death; however, none were considered related to treatment.
Data are from 59 metastatic CSCC patients who received cemiplimab (3 mg/kg every 2 weeks) for up to 96 weeks.
CSCC expansion cohorts of Phase 1 trial:
Cemiplimab-treated patients had a response rate of 50 percent (13 of 26 patients, all of which were PRs) with a median observed time to response of 2 months as of the data cut-off date. The durable DCR was 65 percent (17 of 26 patients). The median DOR has not been reached as of the data cut-off date (median follow-up for all patients: 11 months).
The most common treatment-emergent adverse events of any grade were fatigue (27 percent), constipation, decreased appetite, diarrhea, hypercalcemia, hypophosphatemia, nausea and urinary tract infection (each 15 percent). Grade 3 or higher adverse events regardless of attribution were reported in 12 patients (46 percent), of which five (19 percent) were considered related to treatment. Two patients (8 percent) had adverse events related to treatment that led to treatment discontinuation.
Data are from 26 advanced CSCC patients who participated in two Phase 1 expansion cohorts and received cemiplimab (3 mg/kg every 2 weeks) for up 48 weeks. Patients either had metastatic CSCC or locally advanced CSCC who were not candidates for surgery.
These findings formed part of the data set used for regulatory applications for cemiplimab as a potential treatment for advanced CSCC. These applications were accepted earlier this year for priority review by the U.S. Food and Drug Administration (FDA) and review by the European Medicines Agency (EMA). The FDA target action date is October 28, 2018, and the EMA review process is expected to be complete by the first half of 2019. Regulatory applications in additional countries are also being considered for submission later in 2018. There are currently no FDA- or EMA-approved treatments for patients with metastatic CSCC or patients with locally advanced CSCC who are not candidates for surgery.

Cemiplimab is being jointly developed by Regeneron and Sanofi under a global collaboration agreement, and was invented by Regeneron using the company’s proprietary VelocImmune technology that yields optimized fully-human antibodies. In addition to CSCC, cemiplimab is also being investigated in potentially pivotal/pivotal trials in non-small cell lung cancer, basal cell carcinoma and cervical cancer alongside exploratory trials in squamous cell carcinoma of the head and neck, melanoma, colorectal cancer, prostate cancer, multiple myeloma, Hodgkin lymphoma and non-Hodgkin lymphoma.

Cemiplimab is currently under clinical development, and its safety and efficacy have not been evaluated by any regulatory authority.

About CSCC
CSCC is the second most common type of skin cancer in the U.S., accounting for approximately 20 percent of all skin cancers and with the number of newly diagnosed cases expected to rise annually. Although CSCC has a good prognosis when caught early, the cancer can prove especially difficult to treat effectively when it is advanced, and patients can experience reduced quality of life due to the impact of the disease as it progresses. Advanced CSCC is the deadliest non-melanoma skin cancer. While estimates vary, sources suggest that between 4,000 to 8,000 people in the U.S. die annually of advanced CSCC.

About Regeneron Pharmaceuticals, Inc.
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents life-transforming medicines for people with serious diseases. Founded and led for 30 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to six FDA-approved treatments and numerous product candidates in development, all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye disease, heart disease, allergic and inflammatory diseases, pain, cancer, infectious diseases and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite technologies, such as VelocImmune which produces optimized fully-human antibodies, and ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.

On June 4, 2018 Portola Pharmaceuticals, Inc. (Nasdaq:PTLA) reported new interim results from the Company’s ongoing Phase 2a study of cerdulatinib, an investigational, oral SYK/JAK inhibitor, in patients with specific subtypes of B-cell and T-cell Non-Hodgkin Lymphoma (NHL), including relapsed/refractory follicular lymphoma (FL) and peripheral T-cell lymphoma (PTCL), and chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL) (Press release, Portola Pharmaceuticals, JUN 4, 2018, View Source;p=RssLanding&cat=news&id=2352989 [SID1234527152]). The data will be presented today by Paul Hamlin, M.D., medical director for the David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center, during a Poster Discussion Session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (June 1-5). Data from this ongoing study also will be presented during a Poster Presentation Session at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Stockholm (June 14-17).

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Among the 114 patients enrolled across five cohorts, 101 were evaluable as of May 4, 2018. The objective response rate (ORR) across all tumor types was 47 percent, with demonstration of clinical activity across tumor types and a new signal in the PTCL and cutaneous T-cell lymphoma (CTCL) cohorts.

Seven of the 20 patients in the PTCL cohort achieved a complete response (CR), including:

Five out of seven with angioimmunoblastic T-cell lymphoma (AITL), for an ORR of 71 percent.
Two out of eight patients with PTCL not otherwise specified (PTCL-NOS), for an ORR of 25 percent.
Five of the seven responding PTCL patients remain on study drug, including one at 12+ months and one at 9+ months. Of the remaining two patients, one received a bone marrow transplant after achieving CR and one discontinued due to Grade 3 colitis. All patients were previously on at least three prior therapies, including belinostat, pralatrexate and romidepsin. Additionally, data demonstrate an initial signal in CTCL, with the first patient enrolled achieving a CR.

Cerdulatinib also showed consistent activity among the 35 patients with FL, with an ORR of 46 percent and a median duration of response of eight months or more. Among the 28 patients with CLL/SLL, the ORR was 61 percent. All patients in these cohorts were previously on at least three prior therapies.

Cerdulatinib was generally well-tolerated. The most common serious adverse events occurring in ≥10 percent of patients were: lipase increase (18 percent), neutropenia (17 percent) and pneumonia/lung infection (11 percent). Additionally, five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) were considered related to study drug. These occurred primarily in patients with CLL/SLL.

"Cerdulatinib continues to demonstrate promising results across a wide range of B- and T-cell malignancies, including early indications of the potential for durable responses," said Dr. Hamlin. "The new signals in relapsed/refractory PTCL and CTCL are particularly compelling when you consider the limited treatment options for patients that fail front-line therapy. I am encouraged by these data and the potential of cerdulatinib to provide a significant clinical benefit to a group of patients with limited treatment options."

"These interim results provide evidence for cerdulatinib’s unique mechanism of action of possibly disrupting two key cell signaling pathways, and its potential to control relapsed/refractory B-cell and T-cell malignancies in combination with standard and investigational therapies," said John Curnutte, M.D., Ph.D., executive vice president, research and development of Portola. "We look forward to continuing discussions with the U.S. Food and Drug Administration regarding next steps for the development of cerdulatinib, including the potential for an accelerated approval pathway in the U.S. for certain tumor subtypes."

ASCO Poster Session Details

Monday, June 4, 2018

The Dual SYK/JAK Inhibitor Cerdulatinib Demonstrates Rapid Tumor Responses in a Phase 2 Study in Patients with Relapsed/Refractory B- and T-Cell Non-Hodgkin Lymphoma (NHL) (Abstract #7511) (Poster Board #148)
• Poster Session: 8:00 a.m. – 11:30 a.m. CT (Hall A, McCormick Place)
• Poster Discussion Session: 1:15 – 2:30 p.m. CT (E450, McCormick Place)
EHA Poster Presentation Details

Friday, June 15, 2018 from 17:30 p.m. – 19:00 p.m. CEST

The Novel SYK/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in a Phase 2a Study in Relapsed/Refractory Peripheral T-Cell Lymphoma
(Abstract #PF261)

The Dual SYK/JAK Inhibitor Cerdulatinib Demonstrates Rapid Tumor Responses in a Phase 2 Study in Patients with Relapsed/Refractory B- and T-Cell Non-Hodgkin Lymphoma (NHL)
(Abstract #PF437)

Preclinical Data: JAK/SYK Inhibition is Vital to Prevent B-Cell Receptor Signaling and its Regulation by the Tumour Microenvironment in Chronic Lymphocytic Leukemia
(Abstract #PF321)
Saturday, June 16, 2018 from 17:30 p.m. – 19:00 p.m. CEST

Preclinical Data: Cerdulatinib Synergises with BCL-2 and MCL-1 Inhibitors to Induce Superior Cell Death in Chronic Lymphocytic Leukemia (Abstract #PS1067)
About Cerdulatinib
Cerdulatinib is an investigational oral, dual spleen tyrosine kinase (SYK) and janus kinase (JAK) inhibitor that uniquely inhibits two key cell signaling pathways implicated in certain hematologic malignancies and autoimmune diseases. There is a strong rationale for inhibiting both SYK (B-cell receptor pathway) and JAK (cytokine receptors) in B-cell malignancies where both targets have been shown to promote cancer cell growth and survival. In addition, pre-clinical data suggest an important role for SYK and JAK in peripheral T-cell lymphoma (PTCL) tumor survival.

Cerdulatinib is being developed to treat patients with follicular lymphoma (FL), PTCL and other hematologic cancers, specifically those who have relapsed or who have not responded to prior therapies.

On June 4, 2018 Pfizer Inc. (NYSE:PFE) reported overall survival (OS) data from the ARCHER 1050 trial evaluating dacomitinib as a first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR-activating mutations compared to gefitinib (Press release, Pfizer, JUN 4, 2018, View Source [SID1234527151]). The trial showed a median OS of 34.1 months for patients receiving dacomitinib (95% CI: 29.5, 37.7), representing a more than seven-month improvement compared to 26.8 months with gefitinib (95% CI: 23.7, 32.1). The OS data from ARCHER 1050 were presented today as an oral presentation [Abstract #9004] at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago and have been published simultaneously in the Journal of Clinical Oncology.

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"Overall survival is an important measure to assess efficacy of investigational compounds. These data presented today are particularly significant as dacomitinib is the first EGFR tyrosine kinase inhibitor in a Phase 3 head-to-head study comparing two tyrosine kinase inhibitors to show an improvement in overall survival," said Professor Tony Mok, Chair of Department of Clinical Oncology, The Chinese University of Hong Kong. "I look forward to having dacomitinib as a potential first-line treatment option for non-small cell lung cancer patients with EGFR-activating mutations."

Overall survival was a secondary endpoint of ARCHER 1050, a randomized, open label Phase 3 study comparing the efficacy and safety of dacomitinib to gefitinib for the first-line treatment of locally advanced or metastatic NSCLC in subjects with EGFR-activating mutations. At the OS data cutoff, median OS was 34.1 months with dacomitinib (95% CI: 29.5, 37.7) compared to 26.8 months with gefitinib (95% CI: 23.7, 32.1). Patients receiving dacomitinib had a 56.2 percent survival rate at 30 months compared with 46.3 percent for patients who received gefitinib. Subgroup analyses were consistent with the primary OS analysis across most baseline characteristics, including patients with common sub-mutations exon 19 and 21.

The adverse events (AEs) observed with dacomitinib in the study were consistent with findings from previous dacomitinib trials. The most common AEs were diarrhea (87%), nail changes (62%), rash/dermatitis acneiform (49%) and mouth sores (44%). The most common Grade 3 AEs with dacomitinib were rash (14%) and diarrhea (8%). Grade 4 AEs occurred in two percent of dacomitinib-treated patients. There was one case of Grade 5 diarrhea and one case of Grade 5 liver disease. The discontinuation rate due to treatment-related AEs for dacomitinib was 10 percent compared to seven percent for gefitinib.

"What is most encouraging about these results is that patients with non-small cell lung cancer harboring EGFR-activating mutations who received dacomitinib achieved a median overall survival of nearly three years, a marked improvement compared to an established treatment in this setting," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development. "With today’s podium presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting and the U.S. Food and Drug Administration Priority Review granted earlier this year, we are encouraged by these data and committed to deliver this promising investigational medicine to patients as quickly as possible."

In April 2018, the U.S. Food and Drug Administration (FDA) granted priority review for dacomitinib for the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR-activating mutations. The FDA Prescription Drug User Fee Act (PDUFA) target action date is in September 2018. The European Medicines Agency also accepted the Marketing Authorization Application for dacomitinib for the same indication.

About Dacomitinib

Dacomitinib is an investigational, oral, once-daily, irreversible pan-human epidermal growth factor receptor tyrosine kinase inhibitor (TKI). It has not received regulatory approval in any country.

In 2012, Pfizer and SFJ Pharmaceuticals entered into a collaborative development agreement to conduct ARCHER 1050 across multiple sites.

About Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide.1 Non-small cell lung cancer (NSCLC) accounts for about 85 percent of lung cancer cases and remains difficult to treat, particularly in the metastatic setting.2 Biomarker therapies dramatically changed the care of patients with metastatic NSCLC. Approximately 75 percent of NSCLC patients are diagnosed late with metastatic or advanced disease where the five-year survival rate is only five percent.2,3,4

EGFR is a protein that helps cells grow and divide. When the EGFR protein is mutated it can cause cancer cells to form. EGFR mutations occur in 10 to 35 percent of NSCLC tumors globally, yet the disease is associated with low survival rates and disease progression remains a challenge.5,6

On June 4, 2018 Merck KGaA, Darmstadt, Germany, which operates its biopharmaceutical business as EMD Serono in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported that updated efficacy and safety data from the pivotal JAVELIN Merkel 200 trial of BAVENCIO (avelumab) in patients with metastatic Merkel cell carcinoma (mMCC), will be presented as an oral abstract session at the 54th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on Monday, June 4 from 10:12-10:24 a.m. CDT in Chicago, IL (Press release, Pfizer, JUN 4, 2018, View Source [SID1234527150]). At this two year follow-up update of the pivotal study, BAVENCIO continues to demonstrate clinically meaningful durable responses and stable rates of progression-free survival (PFS) and overall survival (OS) from previous analyses in patients who responded to this treatment. Clinical activity was observed across all patient subgroups, irrespective of PD-L1 expression in tumor tissue or Merkel cell polyomavirus status. The safety profile for BAVENCIO in this trial has not changed with longer follow-up and remains consistent with that observed in the overall JAVELIN clinical development program.

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"These efficacy and safety results build upon the data that supported our FDA approval," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the Biopharma business of Merck KGaA, Darmstadt, Germany. "Alongside our other data at ASCO (Free ASCO Whitepaper), this two-year analysis is a significant advance in our understanding of the utility of BAVENCIO in MCC patients."

In JAVELIN Merkel 200 – an open-label, single-arm Phase II study – patients with histologically confirmed mMCC whose disease had progressed on or after chemotherapy administrated for distant metastatic disease received BAVENCIO 10 mg/kg intravenously every two weeks until disease progression or unacceptable toxicity. Eighty-eight patients were followed for a median of 29.2 months (range 24.8-38.1 months). The confirmed overall response rate (ORR) of 33% (95% confidence interval [CI] 23.3-43.8; complete response in 11.4%) remained unchanged from previous analyses reported at both one year and 18 months. Responses remained ongoing in 19 of 29 patients who responded to treatment, including 12 patients whose duration of response exceeded two years. Durable responses led to stable rates of PFS (29% at 12 months, 29% at 18 months and 26% at 24 months). Median OS was 12.6 months (95% CI 7.5-17.1) and the two-year OS rate was 36% (50% at 12 months and 39% at 18 months). With a minimum follow-up of two years, no new safety signals were identified for BAVENCIO and was consistent with prior reports. Sixty-seven patients (76.1%) had a treatment-related adverse event (TRAE), 10 patients (11.4%) had a Grade 3 or less TRAE and 20 patients (22.7%) had an immune-related adverse event. No treatment-related deaths occurred.

"These results represent a key milestone for patients with mMCC, as chemotherapy has historically been the only treatment option for this devastating disease," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-Oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "These data, alongside the additional real-world data which are also being presented at ASCO (Free ASCO Whitepaper), strengthen our confidence in BAVENCIO as a treatment option for this rare and aggressive skin cancer."

In addition to these updated JAVELIN Merkel 200 data, results from a global expanded access program for BAVENCIO as a second-line treatment for patients with mMCC will be presented. These data will be presented during a poster session on Monday, June 4 from
1:15-4:45 p.m. CDT.

The alliance’s JAVELIN clinical development program involves at least 30 clinical programs, including seven Phase III trials, and nearly 8,300 patients across more than 15 tumor types.

BAVENCIO (avelumab) was first approved in the US in 2017 by the US Food and Drug Administration (FDA) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC). In addition to the FDA accelerated approval in mMCC, avelumab is also approved in the US under accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

About JAVELIN Merkel 200

JAVELIN Merkel 200 is an international, multicenter, open-label, single-arm Phase II study of BAVENCIO conducted in 88 patients with metastatic MCC. Patients in this study were generally elderly (median age was 72.5 years, range 33-88 years) and pre-treated, with at least one line of chemotherapy (one [59.1%], two [29.5%] or three or more [11.4%] previous treatments). Patients received BAVENCIO 10 mg/kg intravenously once every two weeks. The protocol-defined analysis set for efficacy and safety consisted of all patients who received at least one dose of study treatment. The cut-off date for the planned primary analysis was six months after start of study treatment of the last patient. The primary endpoint of the study was confirmed best overall response according to RECIST v1.1 and assessed by an independent review committee. Secondary endpoints were duration of response, PFS, OS, response status by RECIST at six and 12 months, safety and tolerability, pharmacokinetics, and immunogenicity of BAVENCIO.

About Avelumab

Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.[2]-[4] Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[4]-[6] In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Approved Indications in the US

The FDA granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information from the US FDA Approval Label

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis, and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1,738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).