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Chi-Med Plans to Submit NDA for Surufatinib Following Pre-NDA Meeting with the U.S. FDA

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Chi-Med Plans to Submit NDA for Surufatinib Following Pre-NDA Meeting with the U.S. FDA
June 1, 2020: “Hutchison China MediTech Limited announces that it has held its pre-New Drug Application meeting with the U.S.FDA for surufatinib for the treatment of patients with advanced neuroendocrine tumors (“NET”). 

Chi-Med has reached an agreement with the FDA that the completed SANET-ep (non-pancreatic NET) and SANET-p (pancreatic NET) studies, along with existing data from surufatinib in U.S. non-pancreatic and pancreatic NET patients, could form the basis to support a U.S. NDA submission.

The FDA granted Fast Track Designation status to surufatinib for the non-pancreatic and pancreatic NET development programs in April 2020. 

Chi-Med has initiated preparatory work for the U.S. NDA and intends to utilize a rolling submission under Fast Track Designation Status.

The rolling NDA allows completed portions of an NDA to be submitted and reviewed by the FDA on an ongoing basis.

Filing acceptance of the NDA is subject to FDA review of the complete application.  The planned start of the NDA submission is late 2020.

Surufatinib

Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. 

Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumour effects.

Chi-Med currently retains all rights to surufatinib worldwide.

NET in the U.S., Europe and Japan: In the U.S., surufatinib was granted Fast Track Designations for development in pancreatic and non-pancreatic (extra-pancreatic) NET in April 2020, and Orphan Drug Designation for pancreatic NET in November 2019. 

A U.S. FDA NDA submission is being prepared.  Regulatory interactions in Europe and Japan are also underway to confirm the clinical development strategy and potential path to registration. 

All such interactions are based on the robust data from the two positive Phase III studies of surufatinib in NET in China, and the ongoing multi-cohort Phase Ib study in the U.S. that began in November 2015 (clinicaltrials.gov identifier: NCT02549937).

Non-pancreatic neuroendocrine tumors in China: In November 2019, a NDA for surufatinib for the treatment of patients with advanced non-pancreatic NET was accepted for review by the China National Medical Products Administration (NMPA) and granted Priority Review status in December 2019. 

The NDA is supported by data from the successful SANET-ep study, a Phase III study of surufatinib in patients with advanced non-pancreatic neuroendocrine tumors in China for whom there is no effective therapy. 

A 198-patient interim analysis was conducted in June 2019, leading the Independent Data Monitoring Committee (“IDMC”) to determine that the study met the pre-defined primary endpoint of progression-free survival (“PFS”) and should be stopped early. 

The positive results of this trial were highlighted in an oral presentation at the 2019 European Society for Medical Oncology Congress (clinicaltrials.gov identifier: NCT02588170).

Pancreatic neuroendocrine tumors in China: In 2016, we initiated the SANET-p study, which is a pivotal Phase III study in patients with low- or intermediate-grade, advanced pancreatic NET in China. 

A second NDA for surufatinib for the treatment of patients with advanced pancreatic NET is being prepared for submission, following an interim analysis review conducted in January 2020 by the IDMC that recommended the registrational study be terminated early as the pre-defined primary endpoint of PFS had already been met (clinicaltrials.gov identifier: NCT02589821). 

Study results will be submitted for presentation at an upcoming scientific conference.

Biliary tract cancer in China: In March 2019, we initiated a Phase IIb/III study comparing surufatinib with capecitabine in patients with advanced biliary tract cancer whose disease progressed on first-line chemotherapy. 

The primary endpoint is overall survival (OS) (clinicaltrials.gov identifier NCT03873532).

Immunotherapy combinations: We have entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with anti-PD-1 monoclonal antibodies, including with tislelizumab (BGB-A317), Tuoyi® (toripalimab) and Tyvyt® (sintilimab), which are approved in China.”
https://www.chi-med.com/chi-med-plans-to-submit-surufatinib-nda-following-pre-nda-meeting-with-fda/

World’s First Study of a Potential COVID-19 Antibody Treatment in Humans

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World’s First Study of a Potential COVID-19 Antibody Treatment in Humans
June 1, 2020: “Eli Lilly and Company announced patients have been dosed in the world’s first study of a potential antibody treatment designed to fight COVID-19.

This investigational medicine, referred to as LY-CoV555, is the first to emerge from the collaboration between Lilly and AbCellera to create antibody therapies for the prevention and treatment of COVID-19. 

Lilly scientists rapidly developed the antibody in just three months after AbCellera and the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID) identified it from a blood sample taken from one of the first U.S. patients who recovered from COVID-19. LY-CoV555 is the first potential new medicine specifically designed to attack SARS-CoV-2, the virus that causes COVID-19.

The first patients in the study were dosed at major medical centers in the U.S., including NYU Grossman School of Medicine and Cedars-Sinai in Los Angeles.  

“We are committed to working with our industry partners to generate scientific evidence to meet the urgent need for treatments that reduce the severity of COVID-19 disease,” said Mark J. Mulligan, MD, director of the Division of Infectious Diseases and Immunology and director of the Vaccine Center at NYU Langone Health.

“Antibody treatments like the one being studied here hold promise to be effective medical countermeasures against this deadly infection,” said Dr. Mulligan, also the Thomas S. Murphy, Sr. Professor in the Department of Medicine at NYU Langone.

“We are grateful to collaborate with colleagues at AbCellera, NIAID, and the many academic institutions who have helped us reach this milestone in humanity’s fight against COVID-19 — a disease first characterized only six months ago.

We are privileged to help usher in this new era of drug development with the first potential new medicine specifically designed to attack the virus.

Antibody therapies such as LY-CoV555 may have the potential for both prevention and treatment of COVID-19 and may be particularly important for groups hardest hit by the disease such as the elderly and those with compromised immune systems,” said Daniel Skovronsky, M.D., Ph.D., Lilly’s chief scientific officer and president of Lilly Research Laboratories.

“Later this month, we will review the results of this first human study and intend to initiate broader efficacy trials. At the same time as we are investigating safety and efficacy, we also are starting large-scale manufacturing of this potential therapy.

If LY-CoV555 becomes part of the near-term solution for COVID-19, we want to be ready to deliver it to patients as quickly as possible, with the goal of having several hundred thousand doses available by the end of the year,” continued Skovronsky. 

Should Phase 1 results show the antibody can be safely administered, Lilly expects to move into the next phase of testing, studying LY-CoV555 in non-hospitalized COVID-19 patients.

The company also plans to study the drug in a preventative setting, focusing on vulnerable patient populations who historically are not optimal candidates for vaccines.

Lilly is researching multiple approaches to treating COVID-19.

Existing Lilly medicines are now being studied to understand their potential in treating complications of COVID-19, and the company is collaborating with two biotech companies to discover novel antibody treatments for COVID-19.

Lilly’s SARS-CoV-2 Antibody Program
LY-CoV555 is a potent, neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially preventing and treating COVID-19. 

Lilly intends to test this first antibody as well as other neutralizing antibodies against SARS-CoV-2 over the next several months. 

Lilly intends to test both single antibody therapy as well as combinations of Lilly antibodies (sometimes known as antibody cocktails) as potential therapeutics for COVID-19.

LY-CoV555 Phase 1 Trial
Study J2W-MC-PYAA is a randomized, placebo-controlled, double-blind Phase 1 trial that aims to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of LY-CoV555 following a single dose administered to participants hospitalized for COVID-19.”
https://investor.lilly.com/news-releases/news-release-details/lilly-begins-worlds-first-study-potential-covid-19-antibody

FDA Ok’s Lilly’s Taltz® for the Treatment of Non-Radiographic Axial Spondyloarthritis

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FDA Ok’s Lilly’s Taltz® for the Treatment of Non-Radiographic Axial Spondyloarthritis
June 1, 2020: Eli Lilly and Company announced that U.S.FDA has approved a supplemental Biologics License Application (sBLA) for Taltz® (ixekizumab) injection 80 mg/mL for the treatment of active non-radiographic axial spondyloarthritis (nr-axSpA) in patients with objective signs of inflammation.

Another first-in-class milestone for the treatment, today’s approval makes Taltz the first IL-17A antagonist to be approved by the FDA for nr-axSpA.

Axial spondyloarthritis (axSpA), which includes both AS and nr-axSpA, is a disease predominantly affecting the sacroiliac joints and the spine, resulting in chronic inflammatory back pain and fatigue.

 It is estimated that 2.3 million people in the U.S. have axSpA, and approximately half of those individuals live with nr-axSpA.

For patients with AS, the disease is characterized by the presence of structural damage of the sacroiliac joints that appears on an X-ray, while patients with nr-axSpA do not have clearly detectable structural damage radiographically.

 These two patient subsets share a similar burden of disease and similar clinical features, but approved biologic treatment options for patients with nr-axSpA are much more limited and patients are often underdiagnosed.

“We recognize that many patients living with this condition suffer from chronic inflammatory back pain and other symptoms of inflammation for years before being diagnosed, and we’re excited about the possibility of these patients finding relief with Taltz,” said Patrik Jonsson, senior vice president and president of Lilly Bio-Medicines.

“This approval reflects Lilly’s continued growth and commitment to supporting rheumatologists and people with autoimmune conditions, including nr-axSpA.”

This approval is based on the results from the Phase 3 COAST-X trial, which evaluated improvement in signs and symptoms of nr-axSpA as measured by the proportion of patients who achieved Assessment of Spondyloarthritis International Society 40 (ASAS40) response criteria compared to placebo.

ASAS40 measures disease signs and symptoms such as pain, inflammation and function.

The safety profile of Taltz in patients with nr-axSpA was consistent with previous experience with Taltz in other approved indications.

Taltz should not be used in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients.

Taltz may increase the risk of infection. Other warnings and precautions for Taltz include pre-treatment evaluation for tuberculosis, hypersensitivity, inflammatory bowel disease, and immunizations.

“There are limited treatment options that can address both AS and nr-axSpA symptoms, and people living with these conditions are often underdiagnosed and undertreated,” said Cassie Shafer, chief executive officer of the Spondylitis Association of America.

“This approval represents an important milestone in providing relief to patients where there has been a significant unmet need.”

This approval reaffirms the long track record that Taltz has in providing efficacy for patients in multiple indications.

This is the fifth approval for Taltz, which was first approved by the FDA in March 2016 for the treatment of moderate to severe plaque psoriasis (PsO) in adult patients who are candidates for systemic therapy or phototherapy.

The FDA also approved Taltz for the treatment of adults with active psoriatic arthritis (PsA) in December 2017, for the treatment of adults with active AS in August 2019 and for moderate to severe plaque PsO in pediatric patients 6 years of age and older who are candidates for systemic therapy or phototherapy in March 2020.

In COAST-X, the safety and efficacy of Taltz was demonstrated in a Phase 3, multicenter, randomized, double-blind, placebo-controlled 52-week study of adult patients with active nr-axSpA with objective signs of inflammation.

The primary endpoint of the study was the proportion of patients achieving ASAS40 at Week 52. The proportion of Taltz patients (n=96) achieving the primary endpoint was superior to placebo (n=105), with 30 percent of patients treated with Taltz 80 mg every four weeks achieving ASAS40 response compared to 13 percent of patients treated with placebo at Week 52 (P=0.0045).

A major secondary endpoint was ASAS40 response at Week 16 with 35 percent of Taltz patients compared to 19 percent of placebo patients achieving that endpoint (P<0.01).

“In the COAST-X study, Taltz provided relief to nr-axSpA patients living with debilitating symptoms such as chronic back pain and fatigue,” said Atul Deodhar, M.D., professor of medicine, Oregon Health & Science University and clinical investigator for the COAST pivotal trial program.

“The study results indicate that Taltz is safe and effective in patients suffering from this condition. Today’s FDA approval provides patients with a much-needed treatment option targeting IL-17A to improve the signs and symptoms of nr-axSpA.”

Other major secondary endpoints of the study included Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity (BASDAI), the proportion of patients achieving low disease activity (ASDAS <2.1) and the 36-Item Short Form Health Survey (SF-36) Physical Component Summary (PCS) Score.

An estimated 137,000 patients have been treated with Taltz worldwide since launch, with approximately 80,000 of those in the U.S., giving rheumatologists confidence in making informed prescribing decisions for patients with PsO, PsA, AS and nr-axSpA.7

Lilly will work with insurers, health systems and providers to ensure patients are able to access this treatment.

We recognize that COVID-19 may be impacting the ability for people to afford their medications, and the Taltz TogetherTM program helps ensure patients pay the lowest amount possible and can have Taltz delivered straight to their homes. Patients, physicians, pharmacists or other healthcare professionals with questions about Taltz should contact

INDICATIONS AND USAGE FOR TALTZ
Taltz is approved for the treatment of adult patients with active non-radiographic axial spondyloarthritis with objective signs of inflammation, active psoriatic arthritis, or active ankylosing spondylitis, and for the treatment of patients 6 years of age and older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

IMPORTANT SAFETY INFORMATION FOR TALTZ

CONTRAINDICATIONS
Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients.

WARNINGS AND PRECAUTIONS
Infections
Taltz may increase the risk of infection. In clinical trials of adult patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%).

A similar increase in risk of infection was seen in placebo-controlled trials of adult patients with psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and pediatric patients with plaque psoriasis.

Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.

Pre-Treatment Evaluation for Tuberculosis
Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz.

Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Closely monitor patients receiving Taltz for signs and symptoms of active TB during and after treatment.

Hypersensitivity
Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz. If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.
https://investor.lilly.com/news-releases/news-release-details/lillys-taltzr-ixekizumab-first-il-17a-antagonist-receive-us-fda

CytoDyn Files Request With FDA for Priority Review of BLA for First Approval

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CytoDyn Files Request With FDA for Priority Review of BLA for First Approval
June 01, 2020: “CytoDyn announced that it has filed with the U.S. FDA a request seeking Priority Review designation for the Company’s Biologics License Application (BLA) for leronlimab as a combination therapy for HIV indication. 

Under the Prescription Drug User Fee Act (PDUFA), FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times – Standard Review and Priority Review.

A Priority Review designation means FDA’s goal is to take action on an application within 6 months (compared to 10 months under standard review).

FDA informs the applicant of a Priority Review designation within 60 days.

A Priority Reviewdesignation will direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

Significant improvement may be demonstrated by the following examples:

  • evidence of increased effectiveness in treatment, prevention, or diagnosis of condition;
  • elimination or substantial reduction of a treatment-limiting drug reaction;
  • documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes; or
  • evidence of safety and effectiveness in a new subpopulation.

Nader Pourhassan, Ph.D., President and Chief Executive Officer of CytoDyn, commented, “We look forward to the FDA’s decision on our important request and are hopeful that we can bring leronlimab therapy to highly treatment experienced HIV patients by late 2020. Leronlimab’s potential for many other indications could be expedited, should the Company receive its first approval. All other potential indications (and we believe there are many) could have a much faster approval process as label expansion approvals.”

Coronavirus Disease 2019
CytoDyn is currently enrolling patients in two clinical trials for COVID-19, a Phase 2 randomized clinical trial for mild-to-moderate COVID-19 population in the U.S. and a Phase 2b/3 randomized clinical trial for severe and critically ill COVID-19 population in several hospitals throughout the country.

SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China.

The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain, and the virus is highly contagious. COVID-19 typically transmits person to person through respiratory droplets, commonly resulting from coughing, sneezing, and close personal contact.

Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals.

For confirmed COVID-19 infections, symptoms have included fever, cough, and shortness of breath. The symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure.

Clinical manifestations in patients have ranged from non-existent to severe and fatal. At this time, there are minimal treatment options for COVID-19.

Leronlimab (PRO 140) and BLA Submission for the HIV Combination Therapy
The FDA has granted a “Fast Track” designation to CytoDyn for two potential indications of leronlimab for deadly diseases. The first as a combination therapy with HAART for HIV-infected patients and the second is for metastatic triple-negative breast cancer. 

Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases, including NASH. 

Leronlimab has completed nine clinical trials in over 800 people, including meeting its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells.

Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab could significantly reduce or control HIV viral load in humans.

The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

The Company filed its BLA for Leronlimab as a Combination Therapy for Highly Treatment Experienced HIV Patients with the FDA on April 27, 2020, and submitted additional FDA requested clinical datasets on May 11, 2020.

After the BLA submission is deemed completed, the FDA sets a PDUFA goal date. CytoDyn has Fast Track designation for leronlimab and a rolling review for its BLA, as previously assigned by the FDA, and the Company filed a request for Priority Review designation for the BLA with the FDA.

A Priority Review designation means the FDA’s goal is to take action on the marketing application within six months  (compared with 10 months under standard review).

In the setting of cancer, research has shown that CCR5 may play a role in tumor invasion, metastases, and tumor microenvironment control. Increased CCR5 expression is an indicator of disease status in several cancers.

Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model.

CytoDyn is, therefore, conducting a Phase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019. 

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation. It may be crucial in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions.

Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells.

CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to support further the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD, blocking the CCR5 receptor from recognizing specific immune signaling molecules is a viable approach to mitigating acute GvHD.

The FDA has granted “orphan drug” designation to leronlimab for the prevention of GvHD.”

https://www.cytodyn.com/newsroom/press-releases/detail/435/cytodyn-files-request-with-fda-for-priority-review-of-bla

Libtayo® longer-term results presented at ASCO 2020 in advanced cutaneous squamous cell carcinoma

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Libtayo® longer-term results presented at ASCO 2020 in advanced cutaneous squamous cell carcinoma
Libtayo® (cemiplimab-rwlc) longer-term results in advanced cutaneous squamous cell carcinoma presented at ASCO 2020 show durable responses that deepen over time.

May 29, 2020: “New, longer-term data were shared today for PD-1 inhibitor Libtayo® (cemiplimab-rwlc) from a pivotal Phase 2 trial in advanced cutaneous squamous cell carcinoma (CSCC), the deadliest non-melanoma skin cancer.

These results demonstrate both longer durability and higher complete response (CR) rates than previously reported.

Furthermore, the data make up part of the largest and most mature prospective clinical dataset in patients with metastatic CSCC (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or radiation.

The data were presented during the virtual 2020 American Society of Clinical Oncology (ASCO) Annual Meeting. 

“The three-year follow-up data demonstrate significant long-term outcomes with Libtayo, which is now standard-of-care for patients with advanced CSCC in many countries,” said Dr. Danny Rischin, Director, Department of Medical Oncology at Peter MacCallum Cancer Centre, Victoria, Australia. “The Libtayo data on duration of response and overall survival provide new insights into the longer-term treatment of advanced CSCC, with the median still not reached for either measure. Remarkably, it is exciting to see the number of complete responses increase with longer follow-up, which reinforces the potential ongoing benefit of Libtayo treatment in this aggressive skin cancer.”

With up to three years of follow-up, results from the pivotal Phase 2 trial showed 46% of patients (95% CI: 39%-53%) experienced tumor shrinkage following Libtayo treatment, with a median time to response of 2 months (interquartile range: 2-4 months). Furthermore, more patients (16%) saw their tumors disappear completely over time compared to previous analyses. Among patients with metastatic disease who had the longest available follow-up (Group 1 in table below), 20% of patients have now achieved a CR, increasing from 7% in the 2017 primary analysis. Among patients who achieved a CR in any group, median time to complete response was 11 months (interquartile range: 7-15 months). Median overall survival and median duration of response have yet to be reached for any treatment group.

Results by treatment group were as follows:

No new safety signals were identified. The most common treatment-emergent adverse events (AEs) were fatigue (35%), diarrhea (28%) and nausea (24%). The most common grade 3 or higher treatment-related AEs were pneumonitis (3%), autoimmune hepatitis (2%), anemia, colitis and diarrhea (each 1%). No new AEs resulting in death were reported compared to previous reports.

Related News: Sanofi/Regeneron’s Libtayo® (cemiplimab) shows benefit in BCC

Sanofi: Phase 3 trial of Libtayo® (cemiplimab) as monotherapy for first-line advanced non-small cell lung cancer stopped early due to highly significant improvement in overall survival

In addition to the updated efficacy and safety data, a separate post-hoc analysis of health-related quality of life (HRQL) outcomes from the Phase 2 trial was presented for the first time. A large majority (83%) of patients reported improved or stable overall HRQL and 43% of patients experienced a clinically meaningful reduction in pain within 4 months of treatment. The analysis was based on patient responses to the European Platform of Cancer Research cancer specific 30-item HRQL questionnaire (QLQ-C30).

The open-label, single-arm, global, pivotal Phase 2 trial (Study 1540) enrolled 193 patients with laCSCC or mCSCC who were not candidates for curative surgery or radiation. The initial primary analysis of the trial, along with results from a Phase 1 trial (Study 1423), supported the U.S. Food and Drug Administration (FDA) approval of Libtayo in late 2018. Together, the trials represent the largest and most mature prospective clinical dataset in advanced CSCC.

Libtayo is being jointly developed by Sanofi and Regeneron under a global collaboration agreement.

About CSCC
CSCC is the second most common type of skin cancer in the world, accounting for approximately 20% of all skin cancers, and the number of newly diagnosed cases is expected to rise substantially in many countries. 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. While estimates vary, sources suggest that 7,000 patients in the U.S. die annually of advanced CSCC, which is comparable to the number of deaths caused by melanoma.

About Libtayo
Libtayo is a fully-human monoclonal antibody targeting the immune checkpoint receptor PD-1 on T-cells. By binding to PD-1, Libtayo has been shown to block cancer cells from using the PD-1 pathway to suppress T-cell activation.

Libtayo is the first and only immunotherapy approved in the U.S., EU, and other countries for adults with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation. In the U.S., the generic name for Libtayo in its approved indication is cemiplimab-rwlc, with rwlc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration.

The extensive clinical program for Libtayo is focused on difficult-to-treat cancers. In skin cancer, this includes a pivotal trial in advanced basal cell carcinoma and additional trials in adjuvant and neoadjuvant CSCC. Libtayo is also being investigated in pivotal Phase 3 trials in non-small cell lung cancer and cervical cancer, as well as in trials combining Libtayo with novel therapeutic approaches for both solid tumors and blood cancers. These potential uses are investigational, and their safety and efficacy have not been evaluated by any regulatory authority.”
http://www.globenewswire.com/news-release/2020/05/29/2040886/0/en/Libtayo-cemiplimab-rwlc-longer-term-results-in-advanced-cutaneous-squamous-cell-carcinoma-presented-at-ASCO-2020-show-durable-responses-that-deepen-over-time.html?print=1

CHMP recommends EU approval of Roche’s Rozlytrek

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CHMP recommends EU approval of Roche’s Rozlytrek
CHMP recommends EU approval of Roche’s Rozlytrek for people with NTRK fusion-positive solid tumours and for people with ROS1-positive, advanced non-small cell lung cancer

May 29, 2020: “Roche announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion under conditional marketing authorisation for Rozlytrek® (entrectinib) for the treatment of adult and paediatric patients 12 years of age and older with solid tumours expressing a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and who have not received a prior NTRK inhibitor, who have no satisfactory treatment options.

The CHMP has also recommended Rozlytrek for the treatment of adults with ROS1-positive, advanced non-small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.

“Once approved, Rozlytrek could become Roche’s first tumour-agnostic therapy in Europe,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development.

“This milestone therefore represents additional progress in personalised healthcare. Based on genomic testing, Rozlytrek provides an effective first-line treatment for many people whose cancers harbour NTRK or ROS1 gene fusions, including tumours that have progressed to the brain.”

The positive CHMP opinion is based on results from the integrated analysis of the pivotal phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials, and data from the phase I/II STARTRK-NG study. Results showed:

  • Rozlytrek shrank tumours in more than half of people with NTRK fusion-positive, locally advanced or metastatic solid tumours (overall response rate [ORR]= 63.5%; N=74), and objective responses were observed across 14 tumour types (median duration of response [DoR] = 12.9 months [9.3 months – not reached], N=21 out of 47).
  • In ROS1-positive, advanced NSCLC, Rozlytrek shrank tumours in 73.4% of people with the disease (ORR; N=94 with 12 months follow up), with a median DoR of 16.5 months (14.6 – 28.6 months). In a group of 161 patients with 6 months follow up, including 29% of patients with central nervous system (CNS) metastases at baseline, ORR was observed to be 67.1%.
  • Objective responses to Rozlytrek were seen in people with CNS metastases at baseline, in both the NTRK and ROS1 populations.
  • In paediatric patients, Rozlytrek shrank tumours (ORR) in all children and adolescents who had NTRK gene fusions (N=5), with two achieving a complete response (CR). Two patients with primary high-grade tumours in the CNS had objective responses, including one patient with a CR.

Across these studies, Rozlytrek was evaluated in several solid tumour types, including sarcoma, non-small cell lung, salivary MASC, secretory and non-secretory breast, thyroid, colorectal, neuroendocrine, pancreatic, ovarian, endometrial carcinoma, cholangiocarcinoma, gastrointestinal cancers and neuroblastoma.

Rozlytrek was well tolerated. The most common adverse reactions (≥20 percent) with Rozlytrek were fatigue, constipation, altered sense of taste (dysgeusia), swelling (oedema), dizziness, diarrhoea, nausea, nervous system disorders (dysaesthesia), shortness of breath (dyspnoea), anaemia, increased weight, increased blood creatinine, pain, cognitive disorders, vomiting, cough, and fever (pyrexia).

Rozlytrek has been granted Priority Medicines (PRIME) designation by the EMA for the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumours in adult and paediatric patients who have either progressed following prior therapies or who have no acceptable standard therapies.

A final decision regarding the approval of Rozlytrek by the European Commission is expected in the coming months.

Biomarker testing for NTRK gene fusions and ROS1 in NSCLC across all solid tumours is the only way to identify people who are most eligible for treatment with Rozlytrek.

Roche is leveraging its expertise in developing personalised medicines and advanced diagnostics, in conjunction with Foundation Medicine, to develop a companion diagnostic that will help identify people with NTRK and ROS1 gene fusions.

Integrated analysis
The CHMP recommendation is based on an integrated analysis including data from 74 people with locally advanced or metastatic NTRK fusion-positive solid tumours (14 tumour types) and 161 people with ROS1-positive NSCLC from the phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials.

 It is also based on data from the phase I/II STARTRK-NG study in paediatric patients.1 The studies enrolled people across 15 countries and more than 150 clinical trial sites. Safety was assessed from an integrated analysis of 504 people across these four trials.

NTRK fusion-positive cancer
NTRK fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC) that can activate signalling pathways involved in the proliferation of certain types of cancer.

NTRK gene fusions are present in tumours irrespective of site of origin.

These fusions have been identified in a broad range of solid tumour types, including sarcoma, non-small cell lung, salivary MASC, secretory and non-secretory breast, thyroid, colorectal, neuroendocrine, pancreatic, ovarian, endometrial carcinoma, cholangiocarcinoma, gastrointestinal cancers and neuroblastoma.

ROS1-positive NSCLC
ROS1 is a tyrosine kinase, which plays a role in controlling how cells grow and proliferate.

When a ROS1 gene fusion occurs, cancer cells grow and proliferate in an uncontrolled manner. Blocking this abnormal signalling can cause tumour cells to shrink or die.

ROS1 gene fusions account for 1-2% of non-small-cell lung cancer (NSCLC).

 Lung cancer is the leading cause of cancer-related death across the world. Each year, more than one and a half million people die as a result of the disease globally, equating to more than 4,000 deaths every day.

NSCLC is the most common type of lung cancer and accounts for up to 85% of all lung cancer diagnoses. While the ROS1 gene fusion can be found in any patient with NSCLC, young never-smokers with NSCLC have the highest incidence of ROS1 gene fusions.

Rozlytrek
Rozlytrek® (entrectinib) is a tumour-agnostic, once-daily oral medicine in development for the treatment of locally advanced or metastatic solid tumours that harbour NTRK1/2/3 or ROS1 gene fusions. It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer.

 Rozlytrek can block NTRK and ROS1 kinase activity and may result in the death of cancer cells with NTRK or ROS1 gene fusions.

Rozlytrek was granted accelerated approval in August 2019 by the US Food and Drug Administration (FDA), following receipt of Breakthrough Therapy designation, for the treatment of adult and paediatric patients 12 years of age and older with solid tumours that have a NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy, and was approved for the treatment of adults with ROS1-positive, metastatic NSCLC.

In June 2019, Rozlytrek was also approved by Japan’s Ministry of Health, Labour and Welfare (MHLW) for the treatment of adult and paediatric patients with NTRK fusion-positive, advanced recurrent solid tumours, and was later approved in ROS1 positive NSCLC in February 2020. Rozlytrek has also received approvals by health authorities in Australia, Canada, Hong Kong, Israel and South Korea.”
https://www.roche.com/media/releases/med-cor-2020-05-29b.htm

Pfizer’s update on phase 3 Pallas Trial of Ibrance® in HR+, HER2- early Breast Cancer

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Pfizer’s update on phase 3 Pallas Trial of Ibrance® in HR+, HER2- early Breast Cancer

May 29, 2020: “Pfizer announced by the Austrian Breast & Colorectal Cancer Study Group and the Alliance Foundation Trials, LLC, Pfizer Inc. reports that following a preplanned efficacy and futility analysis, the independent Data Monitoring Committee (DMC) of the collaborative Phase 3 early breast cancer PALbociclib CoLlaborative Adjuvant Study (PALLAS) determined that the trial is unlikely to show a statistically significant improvement in the primary endpoint of invasive disease-free survival (iDFS).

Patients currently receiving palbociclib in the study will be advised about next steps by their physicians and long-term follow up of all patients will proceed as planned. No unexpected new safety signals were observed in patients receiving palbociclib.

The PALLAS trial compares palbociclib plus standard adjuvant endocrine therapy to standard adjuvant endocrine therapy alone in women and men with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early (stage 2 and 3) breast cancer and is an academically-led global collaboration, involving more than 400 centres in 21 countries around the globe.

“We are disappointed in this outcome. Breast cancer is a leading cause of death around the world and delaying or preventing the development of metastatic disease is a significant unmet need.

PALLAS is a large study with many subgroups and we are actively collaborating to determine if there are patients who may benefit from adjuvant treatment with the palbociclib combination,” said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development.

“Since its initial approval in 2015, IBRANCE has helped change the treatment landscape for people with HR+, HER2- metastatic breast cancer. We are grateful to all patients, health care providers and our academic partners who have devoted so much to make this important study possible.”

“This result is not what we hoped for, but we are steadfast in our commitment to advancing the science and care for people living with breast cancer,” said Albert Bourla, Pfizer Chairman and CEO.

“Given the continued breadth of our marketed portfolio and strength of our pipeline, our growth projections are not reliant upon any individual marketed medicine or pipeline opportunity.

Consequently, we remain highly confident in our ability to deliver, following the closing of the proposed combination of Upjohn with Mylan N.V., a compound annual growth rate for revenues of at least 6% through 2025.”

Health authorities and trial investigators have been notified of this decision. When available, the full results from the PALLAS study will be shared with the scientific community at a later date.

Palbociclib is also being studied in patients with high-risk early breast cancer and results from the collaborative PENELOPE-B trial are expected later this year.

In the U.S., IBRANCE is approved for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women or in men; or with fulvestrant in patients with disease progression following endocrine therapy.

IBRANCE is not indicated in early breast cancer. The collaborative Phase 3 PENELOPE-B study (NCT01864746) continues to explore the potential of IBRANCE in patients with early breast cancer at high risk of recurrence who have residual disease after neoadjuvant chemotherapy.

PALLAS Trial

PALLAS is a randomized (1:1), prospective, international, multicenter, open-label Phase 3 study comparing the combination of palbociclib and standard adjuvant endocrine therapy for two years followed by continuing standard adjuvant therapy to complete five years versus at least five years of standard adjuvant endocrine therapy for pre- and postmenopausal women or men with HR+, HER2- early invasive (Stage 2 and Stage 3) breast cancer, including those at moderate to high risk of recurrence.

The trial is co-sponsored by the Austrian Breast & Colorectal Cancer Study Group and the Alliance Foundation Trials as part of a clinical research collaboration with Pfizer and other study groups, including PrECOG, LLC; NSABP Foundation Inc; and the Breast International Group (BIG).

IBRANCE® (palbociclib) 125 mg tablets and capsules

IBRANCE is an oral inhibitor of CDKs 4 and 6, which are key regulators of the cell cycle that trigger cellular progression

In the U.S., IBRANCE is indicated for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; or with fulvestrant in patients with disease progression following endocrine therapy.

IBRANCE currently is approved in more than 95 countries and has been prescribed to more than 300,000 patients globally.

The full U.S. Prescribing Information for the IBRANCE tablets and the IBRANCE capsules can be found here and here.

IMPORTANT IBRANCE®(palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%).

In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3.

One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 15 of first 2 cycles and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with CDK4/6 inhibitors, including IBRANCE when taken in combination with endocrine therapy.

Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4, and no fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnea).

In patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose.

IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients to consider sperm preservation before taking IBRANCE. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose.

Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.”

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-phase-3-pallas-trial-ibrancer

XTANDI® extends overall survival in men with non-metastatic castration-resistant prostate cancer

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XTANDI® extends overall survival in men with non-metastatic castration-resistant prostate cancer
May 29, 2020: “Pfizer Inc. and Astellas Pharma Inc. have announced final results from the overall survival (OS) analysis of the Phase 3 PROSPER trial, which evaluated XTANDI® (enzalutamide) plus androgen deprivation therapy (ADT) versus placebo plus ADT in men with non-metastatic castration-resistant prostate cancer (nmCRPC).

In the trial, XTANDI plus ADT reduced the risk of death by 27% (n=1,401; hazard ratio [HR]=0.73; [95% confidence interval [CI]: 0.61-0.89]; p=0.001) compared to placebo plus ADT.

The median OS was 67.0 months (95% CI: 64.0 to not reached) for men who received XTANDI plus ADT compared to 56.3 months (95% CI: 54.4 to 63.0) with placebo plus ADT. OS was a key secondary endpoint of the trial.

These data were simultaneously published online in the New England Journal of Medicine and presented during the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.

“Overall survival is a critical endpoint in evaluating a prostate cancer medicine,” said Cora N. Sternberg, M.D., F.A.C.P., Clinical Director, Englander Institute for Precision Medicine and Professor of Medicine in Hematology & Oncology, Weill Cornell Medicine and NewYork-Presbyterian.

“These results add to the body of evidence supporting XTANDI’s potential to reduce the risk of death in men with castration-resistant prostate cancer.”

Related News: Enzalutamide Approved by FDA for metastatic castration-sensitive prostate cancer (mCSPC) Treatment

In findings published in the New England Journal of Medicine in 2018, the PROSPER trial met its primary endpoint of metastasis-free survival (MFS), demonstrating a significant reduction in the risk of developing metastasis or death with XTANDI plus ADT compared to ADT alone in men with nmCRPC (HR=0.29 [95% CI: 0.24-0.35]; p<0.001).

MFS was measured as the time from patients entering the trial until their cancer was radiographically detected as having metastasized, or until death, within 112 days of treatment discontinuation.

The safety profile observed in the final OS analysis was consistent with the 2018 primary analysis and the established safety profile of enzalutamide. 

The most common adverse reactions irrespective of relationship to study drug that occurred more frequently (≥10%) in XTANDI plus ADT-treated patients in the PROSPER OS analysis were fatigue (37% vs 16%), hypertension (17% vs 6%), asthenia (10% vs 7%), back pain (13% vs 8%), dizziness (12% vs 6%), diarrhea (12% vs 10%), nausea (13% vs 9%), hot flush (14% vs 8%), fall (18% vs 5%), arthralgia (13% vs 8%), constipation (13% vs 8%), hematuria (10% vs 9%), headache (11% vs 5%) and decreased appetite (12% vs 5%). 

In this analysis of the PROSPER trial, Grade 3 or higher adverse reactions were reported in 48% of men treated with XTANDI plus ADT and in 27% of men treated with placebo plus ADT.

Non-Metastatic Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) refers to the subset of men whose prostate cancer progresses on androgen deprivation therapy (ADT) despite castrate levels of testosterone (i.e., less than 50 ng/dL).

Non-metastatic CRPC means there is no clinically detectable evidence of cancer spreading to other parts of the body (metastases), and there is a rising prostate-specific antigen (PSA) level.

Many men with non-metastatic CRPC and a rapidly rising PSA level go on to develop metastatic CRPC.

PROSPER Trial

The Phase 3 randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,401 patients with nmCRPC at sites in the United States, Canada, Europe, South America and the Asia-Pacific region.

PROSPER enrolled patients with prostate cancer that had progressed, based on a rising PSA level despite ADT, but who had no symptoms and no prior or present evidence of metastatic disease.

Of the total patients enrolled, 933 patients were treated with XTANDI at a dose of 160 mg taken orally once daily plus ADT and 468 patients were treated with placebo plus ADT.  

 The primary endpoint of the PROSPER trial, MFS, was measured as the time from patients entering the trial until their cancer was radiographically detected as having metastasized, or until death, within 112 days of treatment discontinuation.

Key secondary endpoints included OS, time to PSA progression and time to first use of antineoplastic therapy.

 For more information on the PROSPER trial, go to www.clinicaltrials.gov. 

XTANDI® (enzalutamide)
XTANDI (enzalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Novartis announces long-term, relapse-free survival benefit for high-risk, stage III melanoma patients

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Novartis announces long-term, relapse-free survival benefit for high-risk, stage III melanoma patients
May 29, 2020: “Novartis announced updated results from the landmark COMBI-AD clinical trial, demonstrating that treatment with Tafinlar® (dabrafenib) and Mekinist® (trametinib) following the surgical removal of melanoma offers a long-term and durable relapse-free survival (RFS) benefit to high-risk patients diagnosed with stage III, BRAF-mutation positive melanoma.

Researchers reported that 52% (95% CI, 48%-58%) of patients treated with adjuvant Tafinlar + Mekinist were alive and relapse-free at five years.

Among patients in the study’s placebo arm, 36% (95% CI, 32%-41%) were alive and relapse-free at the time of this analysis, generally consistent with typical melanoma relapse-free survival rates seen among patients with resected stage III disease without treatment.

Consistent RFS benefit was observed across all AJCC 7 stage III subgroups.

Median RFS, or the length of time when 50% of patients are still alive and relapse-free, was not yet reached at the 5-year data cut-off for patients on Tafinlar + Mekinist treatment, suggesting long-term benefit of targeted therapy in the adjuvant (post-surgical) setting (NR; 95% CI, 47.9 mo-NR).

Median RFS was 16.6 months for patients taking a placebo (95% CI, 12.7-22.1 mo). Treatment with Tafinlar + Mekinist reduced the risk of relapse or death by 49% compared to placebo (hazard ratio [HR] 0.51; 95% CI 0.42, 0.61).

“Our goal as clinicians is to give our stage III patients the best chance for relapse-free survival,” said Prof. Axel Hauschild, MD, Professor of Dermatology, University Hospital Schleswig-Holstein, Germany.

“Results from COMBI-AD show that adjuvant treatment with Tafinlar + Mekinist after surgical resection gives melanoma patients the chance for long-term relapse-free survival.

Five years is a clinically and emotionally significant milestone for patients. Recurrent BRAF+ melanoma, once spread to other organs, can be more dangerous and difficult to treat.

The durable, long-term results seen among patients in the COMBI-AD trial clearly point to the important role targeted therapy plays in the adjuvant setting.”

The COMBI-AD study results are drawn from a prospective analysis of 870 patients with BRAF V600-mutated melanoma treated with Tafinlar + Mekinist after their surgery.

This study represents the largest collection of data and the longest follow-up to date in this patient population treated with targeted therapy.

The findings were presented at the ASCO20 Virtual Scientific Program (Abstract #10001).

“The five-year survival mark is an important and predictive milestone for people with melanoma and the doctors who care for them,” said John Tsai, MD, Head of Global Drug Development and Chief Medical Officer, Novartis.

“We see an almost 50% risk reduction in melanoma relapse or death in the COMBI-AD data announced today, and we believe patients will find this information helpful in choosing a treatment after surgery.

We thank the patients and their families who participated in this long-term clinical trial. 

Their participation and commitment is helping the community learn how a BRAF-targeted therapy can reimagine outcomes for patients with resectable stage III melanoma.”

COMBI-AD Study
COMBI-AD is a pivotal Phase III study evaluating Tafinlar (dabrafenib) + Mekinist (trametinib) among patients with stage III, BRAF V600E/K-mutant melanoma without prior anticancer therapy.

It is the longest follow-up, at 60 months, and largest dataset to date of patients with Stage III melanoma receiving targeted therapy for adjuvant treatment.  
                                                             
It is a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection.

Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility.

Subjects were randomized to receive either dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) combination therapy or two placebos for up to one year.

The primary endpoint is recurrence-free survival, and secondary endpoints include overall survival, distant metastasis-free survival, freedom from relapse analysis and safety.

Melanoma staging assessed based on AJCC guidelines version 7.

During the five-year follow-up, updated safety analyses were not performed because no patients remained on therapy during the extended follow‐up period.

Melanoma
There are more than 285,000 new diagnoses of melanoma (Stages 0-IV) worldwide each year, approximately half of which have a BRAF mutation. Genetic tests can determine whether a tumor has a BRAF mutation.

One way melanoma is staged is by how far it has metastasized.

In stage III melanoma, tumors have spread to the regional lymph nodes, presenting a higher risk of recurrence or metastases. Patients who receive surgical treatment for stage III melanoma may have a high risk of recurrence because melanoma cells may remain in the body after surgery.

Generally, the majority of relapses in stage III melanoma occur within 5 years. Patients should ask their doctor if they are at risk for melanoma returning.

Tafinlar + Mekinist Combination
TAFINLAR and MEKINIST are prescription medicines that can be used in combination to treat people with a type of skin cancer called melanoma:

  • That has spread to other parts of the body (metastatic) or cannot be removed by surgery (unresectable), and
  • That has a certain type of abnormal “BRAF” (V600E or V600K mutation-positive) gene

TAFINLAR and MEKINIST are prescription medicines that can be used in combination to help prevent melanoma that has a certain type of abnormal “BRAF” gene from coming back after the cancer has been removed by surgery.

TAFINLAR and MEKINIST are prescription medications that can be used in combination to treat a type of lung cancer called non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic NSCLC), and that has a certain type of abnormal “BRAF V600E” gene.

TAFINLAR and MEKINIST are prescription medications that can be used in combination to treat a type of thyroid cancer called anaplastic thyroid cancer (ATC):

  • that has spread to other parts of the body and you have no satisfactory treatment options and
  • that has a certain type of abnormal “BRAF” gene

TAFINLAR, in combination with MEKINIST, should not be used to treat people with wild-type BRAF melanoma. MEKINIST should not be used to treat people who already have received a BRAF inhibitor for treatment of their melanoma and it did not work or is no longer working.

Your health care provider will perform a test to make sure that TAFINLAR and MEKINIST, in combination, are right for you.

It is not known if TAFINLAR and MEKINIST are safe and effective in children.

TAFINLAR and MEKINIST, in combination, may cause serious side effects such as the risk of new cancers, including both skin cancer and nonskin cancer. Patients should be advised to contact their health care provider immediately for any skin changes, including 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, that can lead to death.

Patients should be advised to call their health care provider and get medical help right away if they have any signs of bleeding, including headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like “coffee grounds,” or red or black stools that look like tar.

MEKINIST, alone or in combination with TAFINLAR, can cause inflammation of the intestines or tears in the stomach or intestines that can lead to death.

Patients should report to their health care provider immediately if they have any of the following symptoms: bleeding, diarrhea (loose stools) or more bowel movements than usual, stomach-area (abdomen) pain or tenderness, 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 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 and other skin reactions are common side effects of TAFINLAR in combination with MEKINIST. In some cases these rashes and other skin reactions can be severe or serious,  may need to be treated in a hospital, or lead to death.

Patients should be advised to call their health care provider if they get any of the following symptoms: blisters or peeling of skin, mouth sores, blisters on the lips or around the mouth or eyes, high fever or flu-like symptoms, and/or enlarged lymph nodes.

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 may cause healthy red blood cells to break down too early in people with glucose-6-phosphate dehydrogenase 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, blurry vision, or dizziness.

Men (including those who have had a vasectomy) should use condoms during sexual intercourse during treatment with TAFINLAR and MEKINIST and for at least 4 months after the last dose of TAFINLAR and MEKINIST. For women of reproductive potential, TAFINLAR and MEKINIST, in combination, may harm your unborn baby.

Use effective birth control (contraception) during treatment with TAFINLAR and MEKINIST in combination, and for 4 months after stopping treatment with TAFINLAR and MEKINIST.

The most common side effects for patients with metastatic melanoma are: pyrexia, nausea, rash, chills, diarrhea, headache, vomiting, hypertension, arthralgia, peripheral edema, and cough.

The most common side effects for patients with stage III melanoma receiving the combination as adjuvant therapy are: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

The most common side effects for patients with NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.”
https://www.novartis.com/news/media-releases/novartis-announces-long-term-relapse-free-survival-benefit-high-risk-stage-iii-melanoma-patients-treated-tafinlar-mekinist-following-surgery

Novartis Piqray® receives positive CHMP opinion to treat HR+/HER2- advanced breast cancer with a PIK3CA mutation

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Novartis Piqray® receives positive CHMP opinion to treat HR+/HER2- advanced breast cancer with a PIK3CA mutation

May 29, 2020: “Novartis announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion recommending approval of Piqray® (alpelisib) in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine therapy as monotherapy.

“PIK3CA is the most commonly mutated gene in HR+/HER2- advanced breast cancer, affecting approximately 40% of patients.

If approved, alpelisib has the potential to transform the way we treat this cancer in Europe, offering physicians a clear treatment for patients with a PIK3CA mutation that nearly doubles the time to disease progression,” said Fabrice André, MD, PhD, research director and head of INSERM Unit U981, a professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France, and global SOLAR-1 principal investigator.

The CHMP opinion is based on results of the Phase III SOLAR-1 trial that showed Piqray plus fulvestrant nearly doubled median progression-free survival (PFS) compared to fulvestrant alone in HR+/HER2- advanced breast cancer patients with tumours harbouring a PIK3CA mutation (median PFS 11.0 months vs. 5.7 months; HR=0.65, 95% CI: 0.50-0.85; p<0.001), the study’s primary endpoint.

PFS subgroup analyses demonstrated consistent efficacy in favor of Piqray, irrespective of presence or absence of lung/liver metastases.

“We are excited about today’s CHMP opinion, recommending the first and only treatment option for European patients specifically developed to target the PIK3CA mutation in their cancer,” said Susanne Schaffert, PhD, President, Novartis Oncology.

“Piqray is another example of how we are reimagining cancer care to bring new targeted therapies to patients with high unmet needs that help them live longer without disease progression.”

In SOLAR-1, most adverse events were mild to moderate in severity and generally manageable through dose modifications and medical management.

Of these, the most common grade 3/4 events (≥7%) were plasma glucose increased (39.1%), rash (19.4%), gamma-glutamyltransferase increased (12.0%), lymphocyte count decreased (9.2%), diarrhea (7.0%) and lipase increased (7.0%). No patients developed diabetes as a result of transient hyperglycemia.

The European Commission will review the CHMP recommendation and usually delivers a final decision within approximately two months.

The decision will be applicable to all 27 European Union member states plus the United Kingdom, Iceland, Norway and Liechtenstein. Additional regulatory filings are underway with other health authorities worldwide.

Patients with HR+/HER2- advanced breast cancer should be selected for treatment with Piqray based on the presence of a PIK3CA mutation in tumor or plasma specimens, using a validated test.

If a mutation is not detected in a plasma specimen, tumor tissue should be tested if available.

Piqray® (alpelisib)
Piqray is a kinase inhibitor developed for use in combination with fulvestrant for the treatment of postmenopausal women, and men, with HR+/HER2-, PIK3CA-mutated, advanced or metastatic breast cancer, as detected by a validated test following progression on or after endocrine-based regimen.

Piqray is approved in the U.S., and 12 other countries around the world.

SOLAR-1
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying Piqray in combination with fulvestrant for postmenopausal women, and men, with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor.

The trial randomized 572 patients. Patients were allocated based on central tumor tissue assessment to either a PIK3CA-mutated cohort (n=341) or a PIK3CA non-mutated cohort (n=231).

Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with Piqray (300 mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant. Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment.

Patients and investigators are blinded to PIK3CA mutation status and treatment.

The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with a PIK3CA mutation.

The key secondary endpoint is overall survival, and additional secondary endpoints include, but are not limited to, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety and tolerability.

SOLAR-1 is ongoing to assess overall survival and other secondary endpoints.

Piqray® (alpelisib) Important Safety Information from the U.S. Prescribing Information
Patients should not take PIQRAY if they have had a severe allergic reaction to PIQRAY or are allergic to any of the ingredients in PIQRAY.

PIQRAY may cause serious side effects. PIQRAY can cause severe allergic reactions.

Patients should tell their health care provider or get medical help right away if they have trouble breathing, flushing, rash, fever, or fast heart rate during treatment with PIQRAY.

PIQRAY can cause severe skin reactions. Patients should tell their health care provider or get medical help right away if they get severe rash or rash that keeps getting worse, reddened skin, flu-like symptoms, blistering of the lips, eyes or mouth, blisters on the skin or skin peeling, with or without fever.

PIQRAY can cause high blood sugar levels (hyperglycemia). Hyperglycemia is common with PIQRAY and can be severe. Health care providers will monitor patients’ blood sugar levels before they start and during treatment with PIQRAY.

Health care providers may monitor patients’ blood sugar levels more often if they have a history of Type 2 diabetes.

Patients should tell their health care provider right away if they develop symptoms of hyperglycemia, including excessive thirst, dry mouth, urinate more often than usual or have a higher amount of urine than normal, or increased appetite with weight loss.

PIQRAY can cause lung problems (pneumonitis). Patients should tell their health care provider right away if they develop new or worsening symptoms of lung problems, including shortness of breath or trouble breathing, cough, or chest pain.

Diarrhea is common with PIQRAY and can be severe. Severe diarrhea can lead to the loss of too much body water (dehydration) and kidney problems. Patients who develop diarrhea during treatment with PIQRAY should tell their health care provider right away.

Before taking PIQRAY, patients should tell their health care provider if they have a history of diabetes, skin rash, redness of skin, blistering of the lips, eyes or mouth, or skin peeling, are pregnant, or plan to become pregnant as PIQRAY can harm their unborn baby.

Females who are able to become pregnant should use effective birth control during treatment with PIQRAY and for 1 week after the last dose.

Do not breastfeed during treatment with PIQRAY and for 1 week after the last dose.

Males with female partners who are able to become pregnant should use condoms and effective birth control during treatment with PIQRAY and for 1 week after the last dose.

Patients should also read the Full Prescribing Information of fulvestrant for important pregnancy, contraception, infertility, and lactation information.

Patients should tell their health care provider all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

PIQRAY and other medicines may affect each other causing side effects. Know the medicines you take. Keep a list of them to show your health care provider or pharmacist when you get a new medicine.

The most common side effects of PIQRAY, when used with fulvestrant, are rash, nausea, tiredness and weakness, decreased appetite, mouth sores, vomiting, weight loss, hair loss, and changes in certain blood tests.”
https://www.novartis.com/news/media-releases/novartis-piqray-receives-positive-chmp-opinion-treat-hrher2-advanced-breast-cancer-pik3ca-mutation

Coronavirus (COVID-19) Update: Daily Roundup May 29, 2020

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Coronavirus (COVID-19) Update: Daily Roundup May 29, 2020

May 29, 2020: “The U.S. Food and Drug Administration announced the following actions taken in its ongoing response effort to the COVID-19 pandemic:

  • FDA is making its previously developed FDA MyStudies app available to investigators as a free platform to securely obtain patients’ informed consent for eligible clinical trials when face-to-face contact is not possible or practical due to COVID-19 control measures.

    FDA MyStudies is now referred to as COVID MyStudies in the Apple App store and in the Google Play store.
  • As part of the FDA’s efforts to protect consumers, the agency issued warning letters to two companies for selling fraudulent COVID-19 products.

    There are currently no FDA-approved products to prevent or treat COVID-19. Consumers concerned about COVID-19 should consult with their health care provider.
    • The first seller to whom FDA sent a warning letter was Quadrant Sales & Marketing, Inc., which offers non-alcohol-based hand sanitizer products for sale in the United States with false or misleading claims including that the products maintain their effectiveness for up to 24 hours.

      Time-specific extended efficacy claims may give users the false impression that they need not rigorously adhere to interventions such as social distancing and engaging in good hygienic practices that have been demonstrated to curb the spread of COVID-19.
    • The second seller to whom FDA sent a warning letter was StayWell Copper Products, which offers copper “Germ Stopper” products for sale in the United States with misleading claims that the products are safe and/or effective for the prevention of COVID-19.

      last update: https://lifepronow.com/blog/2020/05/29/coronavirus-covid-19-update-daily-roundup-may-28-2020/
  • Today, the FDA took steps to further support the development of COVID-19 tests for at-home self-collection by providing on its website a template that may be used to facilitate submission of requests for emergency use authorizations (EUA) for at-home sample collection kits.

    As explained in FDA’s guidance, Policy for COVID-19 Tests During the Public Health Emergency (Revised), this template reflects FDA’s current thinking on the data and information that developers should submit to facilitate the EUA process.

    In particular, this template includes recommendations for use by laboratories and commercial manufacturers who may choose to use it to facilitate the preparation and submission of a EUA request.

    Currently, developers can offer a COVID-19 test for at-home self-collection where specifically authorized under a EUA or as part of an Institutional Review Board (IRB)-approved study.
  • Testing updates:
    • During the COVID-19 pandemic, the FDA has worked with more than 400 test developers who have already submitted or said they will be submitting, EUA requests to the FDA for tests that detect the virus or antibodies to the virus.
    • To date, the FDA has authorized 114 tests under EUAs, which include 101 molecular tests, 12 antibody tests, and 1 antigen test.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.

The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.”
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-may-29-2020

FDA Approves New Option to Treat Heavy Menstrual Bleeding Associated with Fibroids

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FDA Approves New Option to Treat Heavy Menstrual Bleeding Associated with Fibroids
May 29, 2020: “The U.S. FDA granted approval to Oriahnn (an estrogen and progestin combination product consisting of elagolix, estradiol and norethindrone acetate) capsules, co-packaged for oral use, for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.

“Uterine fibroids are the most common benign tumors affecting premenopausal women, and one of the most common symptoms from fibroids is heavy menstrual bleeding,” said Christine P. Nguyen, MD, Acting Director, Division of Urology, Obstetrics and Gynecology in FDA’s Center for Drug Evaluation and Research.

“Although surgical treatments, such as hysterectomy, are available, patients may not qualify for surgery or want the procedure. Various non-surgical therapies are used to treat fibroid-related heavy menstrual bleeding, but none have been FDA-approved specifically for this use.

Today’s approval provides an FDA-approved medical treatment option for these patients.”

Fibroids are benign (non-cancerous) muscle tumors of the uterus that can cause heavy menstrual bleeding, pain, bowel or bladder problems and infertility.

Some women may not experience any symptoms, but many do, including heavy bleeding with periods. Fibroids can occur at any age but are most common in women 35 to 49 years of age.

They typically resolve after menopause but are a leading reason for hysterectomy (surgical removal of the uterus) in the United States when they cause severe symptoms.

The efficacy of Oriahnn was established in two clinical trials in which a total of 591 premenopausal women with heavy menstrual bleeding received the drug or placebo for six months.

Heavy menstrual bleeding at baseline was defined as having at least two menstrual cycles with greater than 80 mL (about a third of a cup) of menstrual blood loss (MBL).

]The primary endpoint was the proportion of women who achieved MBL volume less than 80 mL at the final month and 50% or greater reduction in MBL volume from the start of the study (baseline) to the final month.

In the first study, 68.5% of patients who received Oriahnn achieved this endpoint (compared to 8.7% of patients who received placebo).

In the second study, 76.5% of patients who received Oriahnn achieved this endpoint (compared to 10.5% of patients who received placebo).

Oriahnn may cause bone loss over time, and the loss in some women may not be completely recovered after stopping treatment.

Because bone loss may increase the risk for fractures, women should not take Oriahnn for more than 24 months. Health care professionals may recommend a bone density scan (called DXA scan) when starting women on Oriahnn and periodically while on treatment.

The most common side effects of Oriahnn were hot flushes (sudden feelings of warmth), headache, fatigue and irregular vaginal bleeding.

The drug label for Oriahnn includes a Boxed Warning about the risk of vascular events (strokes) and thrombotic or thromboembolic disorders (blood clots), especially in women at increased risk for these events.

Patients should stop Oriahnn if a blood clot, heart attack or stroke occurs. Oriahnn is contraindicated (not to be used under any circumstance) in women with a history of or current blood clots and in women at increased risk for blood clots, including women over 35 years of age who smoke or women with uncontrolled hypertension (high blood pressure).

Other contraindications include known osteoporosis, a history of or current breast cancer or other hormonally-sensitive cancer, liver disease or undiagnosed abnormal uterine bleeding.

Oriahnn does not prevent pregnancy. Women should use non-hormonal contraception during treatment and for one week after discontinuing the medication. Oriahnn may delay the detection of a pregnancy because it changes menstrual bleeding patterns.

Oriahnn may increase blood pressure, which should be monitored in women with controlled hypertension during treatment with Oriahnn. Patients should be advised on signs and symptoms of liver injury.

Patients are advised to seek medical attention if they experience suicidal ideation or behavior, new onset or worsening depression, anxiety or other mood changes.

Patients taking Oriahnn may experience hair loss (alopecia). There is a risk of allergic reaction with Oriahnn because its inactive ingredient, FD&C Yellow No. 5 (tartrazine) may cause allergic-type reactions (including bronchial asthma) in some women.

Oriahnn must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

The approval of Oriahnn was granted to AbbVie Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.

The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.”
https://www.fda.gov/news-events/press-announcements/fda-approves-new-option-treat-heavy-menstrual-bleeding-associated-fibroids-women

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