On October 8, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that its myChoice HRD test identified more than double the number of patients who may benefit from treatment with niraparib than were identified by germline BRCA testing alone (Press release, Myriad Genetics, OCT 8, 2016, View Source [SID:SID1234515681]). The myChoice HRD test was evaluated in the NOVA study (NCT01847274) of nirarapib, an investigational oral PARP inhibitor being developed by TESARO (Nasdaq:TSRO).

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Today’s announcement follows publication of the NOVA study in the New England Journal of Medicine. NOVA is a well-controlled Phase 3 trial of niraparib that enrolled 553 patients with recurrent ovarian cancer who responded to their most recent platinum-based chemotherapy. This trial was designed to assess progression free survival (PFS) in a broad population of patients who were assigned to one of two cohorts based upon germline BRCA mutation status.

"Patients with ovarian cancer who tested positive with myChoice HRD experienced a clinically meaningful improvement in PFS," said Johnathan Lancaster, M.D., Ph.D., gynecologic oncologist and chief medical officer of Myriad Genetic Laboratories. "We estimate that myChoice HRD identifies more than double the number of patients who may benefit compared to germline BRCA testing alone."

The NOVA results showed that in patients who were germline BRCA mutation carriers, the median PFS for patients treated with niraparib was 21.0 months compared to 5.5 months for the control group (p<0.0001; HR 0.27,95% CI, 0.173-0.410). The median PFS benefit for patients with HRD-positive tumors who were treated with niraparib was 12.9 months compared to 3.8 months for the control group (P<0.0001; HR 0.38, 95% CI, 0.243-0.586). Additionally, the exploratory analysis showed that for patients who were determined to be HRD negative, the median PFS for patients treated with niraparib was 6.9 months compared to 3.8 months for the control group (p<0.0226; HR 0.58, 95% CI, 0.361-0.922).

The key findings are illustrated in the chart below.
View Source

The myChoice HRD test is being developed in parallel with the clinical development of niraparib. The collaboration with TESARO began in March 2014 and includes several ongoing clinical trials in a variety of tumor types.

About myChoice HRD
Myriad’s myChoice HRD is the most comprehensive homologous recombination deficiency test to detect when a tumor has lost the ability to repair double-stranded DNA breaks, resulting in increased susceptibility to DNA-damaging drugs such as platinum drugs or PARP inhibitors. The myChoice HRD score is a composite of three proprietary technologies: loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions. Positive myChoice HRD scores, reflective of DNA repair deficiencies, are prevalent in all breast cancer subtypes, ovarian and most other major cancers. In previously published data, Myriad showed that the myChoice HRD test predicted drug response to platinum therapy in certain patients with triple-negative breast and ovarian cancers. It is estimated that 1.4 million people in the United States and Europe who are diagnosed with cancers annually may be candidates for treatment with DNA-damaging agents.

On October 8, 2016 Novartis reported data from the Phase III COMBI-v study demonstrating an overall survival (OS) and a progression-free survival benefit for patients with BRAF V600 mutation-positive advanced melanoma when treated first-line with the combination of Tafinlar (dabrafenib) + Mekinist (trametinib) compared to vemurafenib monotherapy[1] (Press release, Novartis, OCT 8, 2016, View Source [SID:SID1234515678]). The results of this study, which was conducted in 704 patients[1], are being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen.

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"The three-year overall survival follow-up data from COMBI-v is remarkable because it is the second Phase III study this year to demonstrate a significant long-term survival benefit for BRAF mutation-positive melanoma patients treated with Tafinlar + Mekinist combination therapy compared to BRAF inhibitor monotherapy," said Caroline Robert, MD, PhD, Head of Dermatology, Institute Gustave-Roussy. "The results of this trial continue to reinforce Tafinlar + Mekinist as a standard of care and sets a new benchmark for treating patients with BRAF V600 mutation-positive advanced melanoma."

Results from the COMBI-v study found the estimated three-year survival rate to be 45% of patients receiving the combination of Tafinlar + Mekinist (95% CI, 39.1%-49.8%) compared with 31% of patients who received vemurafenib monotherapy (95% CI, 26.1%-36.4%)[1]. There were 34 patients who crossed over from the vemurafenib monotherapy arm to the combination arm after the combination demonstrated a significant OS benefit in a prior analysis[1]. Additionally, the estimated three-year progression-free survival rate was 24% (95% CI, 19.4%-28.8%) for the combination arm and 10% (95% CI, 5.9%-14.5%) for the vemurafenib monotherapy arm[1].

"We are pleased to see the continued benefit of Tafinlar + Mekinist targeted combination therapy beyond three-years in another study," said Alessandro Riva, MD, Global Head, Oncology Development & Medical Affairs. "As we’ve come to understand, this combination of targeted inhibitors has demonstrated an unprecedented ability to block the known resistance pathways and extend overall survival for BRAF mutation-positive patients. These results underscore our commitment to advancing the practice of precision oncology and extending patients’ lives through treatment options that target the root cause of their cancer."

At three years of follow up, the combination of Tafinlar + Mekinist continued to demonstrate a benefit on the measures of duration of response (DoR) and overall response rate (ORR), in line with results seen at the two-year follow up analysis[1].

The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for vemurafenib monotherapy; no new safety concerns were observed.

About the COMBI-v Study
COMBI-v is a two-arm, open-label, Phase III study comparing the combination of Tafinlar + Mekinist with vemurafenib monotherapy in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma. The primary endpoint of this study was OS. The Independent Data Monitoring Committee (IDMC) stopped the trial early based on efficacy results observed in the Tafinlar + Mekinist study arm as part of a planned interim analysis[1].

About Melanoma
Advanced melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates[2],[3]. Only about 20% of people will survive for at least five years following a diagnosis with late-stage disease[2]. There are about 200,000 new cases of melanoma diagnosed worldwide each year[4], approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma[2],[5]. Gene tests can determine whether a tumor has a BRAF mutation[2],[6].

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

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

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

Tafinlar and Mekinist are also indicated in more than 40 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Tafinlar + Mekinist Combination Important Safety Information for Metastatic Melanoma
Tafinlar + Mekinist combination may cause serious side effects.

Tafinlar in combination with Mekinist should only be used to treat melanoma with a change (mutation) in the BRAF gene; therefore, doctors should test their patients before treatment, as patients without a BRAF mutation and with a RAS mutation can be at risk of increased cell proliferation in the presence of a BRAF inhibitor.

Doctors should also consider other treatment options for their patients if they had been previously treated with a BRAF inhibitor as single agent, as the limited data available have shown that the efficacy of Tafinlar + Mekinist is lower in these patients.

When Tafinlar is used in combination with Mekinist, or when Tafinlar is administered as monotherapy, it can cause new cancers (both skin cancer and non-skin cancer). Patients should be advised to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause severe bleeding, and in some cases can lead to death. Patients should be advised to call their healthcare provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," have red or black stools that look like tar, or any unusual signs of bleeding.

Tafinlar in combination with Mekinist, or either drug alone, can cause severe eye problems that can lead to blindness. Patients should be advised to call their healthcare provider right away if they get these symptoms of eye problems: 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, or Tafinlar alone, can cause fever which may be serious. When taking Tafinlar in combination with Mekinist, fever may happen more often or may be more severe. 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 healthcare provider right away if they get a fever above 38.5oC (101.3oF) while taking Tafinlar.

Tafinlar in combination with Mekinist, or Mekinist alone, can affect how well the heart pumps blood. A patient’s heart function should be checked before and during treatment. Patients should be advised to call their healthcare 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, or Tafinlar alone, can cause abnormal kidney function or inflammation of the kidney. Abnormal kidney function may happen more often for patients with fever or too much fluid loss. Patients should be advised to call their healthcare provider right away if they have a fever above 38.5oC (101.3oF), decreased urine, fatigue, loss of appetite or discomfort in lower abdomen or back. Tafinlar has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause abnormal liver function. A patient may feel tired, lose appetite, yellow skin, dark urine colour, or discomfort in abdomen. The liver function abnormality needs to be assessed by laboratory test of the blood. Patients should consult their healthcare provider if they have such experience. Administration of Tafinlar or Mekinist should be done with caution in patients with moderate to severe hepatic impairment.

Elevations in blood pressure have been reported in association with Mekinist in combination with Tafinlar, or with Mekinist alone, in patients with or without pre-existing hypertension. Patients should be advised to monitor blood pressure during treatment with Mekinist and control potential hypertension by standard therapy, as appropriate.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause inflammation of the lung tissue. Patients should notify their doctor if they experience any new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.

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

Tafinlar in combination with Mekinist, or Mekinist alone, can cause muscle breakdown, a condition called Rhabdomyolysis. Patients experiencing muscle pain, tenderness, weakness or a swelling of their muscles should contact their healthcare provider immediately.

Tafinlar in combination with Mekinist, or Tafinlar alone, can uncommonly cause an inflammation of the pancreas (pancreatitis). Patients should be promptly investigated if they experience unexplained abdominal pain and closely monitored if they re-start Tafinlar after a prior episode of pancreatitis.

Tafinlar in combination with Mekinist, or Mekinist alone, 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.

Mekinist, alone or in combination with Tafinlar, may increase the risk of developing holes in the stomach or intestine (gastrointestinal perforation). Treatment with Mekinist alone or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including concomitant use of medications with a recognised risk of gastrointestinal perforation.

Tafinlar and Mekinist both can cause harm to an unborn baby when taken by a pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.

The most common side effects of Tafinlar + Mekinist combination include fever, tiredness, nausea, headache, chills, diarrhea, rash, joint pain, high blood pressure, vomiting and cough. The incidence and severity of fever is increased when Mekinist is used in combination with Tafinlar. Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Tafinlar + Mekinist combination. For more information, patients should ask their doctor or pharmacist.

Patients should take Tafinlar + Mekinist combination exactly as their health care provider tells them. Patients should not change their dose or stop taking Tafinlar + Mekinist combination unless their health care provider advises them to. Mekinist should be taken only once daily (either in the morning or evening, at the same time as Tafinlar). The first and second doses of Tafinlar should be taken approximately 12 hours apart. Patients should take Tafinlar + Mekinist at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or break Tafinlar capsules. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist.

Please see full Prescribing Information for Tafinlar and Mekinist.

On October 8, 2016 AstraZeneca reported data from the Phase III FALCON trial demonstrating superior median progression-free survival (PFS) for Faslodex (fulvestrant) 500mg compared to Arimidex (anastrozole) 1mg in the 1st line treatment of postmenopausal women with locally-advanced or metastatic breast cancer (Press release, AstraZeneca, OCT 8, 2016, View Source [SID:SID1234515667]). The primary endpoint was PFS, and the FALCON trial enrolled 462 patients.1

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The results, announced at the 2016 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, show that median PFS was 2.8 months longer with fulvestrant than anastrozole (Hazard ratio: 0.797; 95% confidence interval: 0.637-0.999; p=0.0486). The median PFS was 16.6 months in the fulvestrant arm compared, with 13.8 months in the anastrozole arm.1 Aromatase inhibitors, such as anastrozole, are the current standard of care in 1st line treatment for postmenopausal women with hormone-receptor positive (HR+) advanced breast cancer.2,3,4

Professor Matthew Ellis, Principal Investigator of the FALCON trial, said: "These data document a benefit for fulvestrant in delaying disease progression as a 1st line therapy, an important goal for women with metastatic breast cancer. The results are supported by a previous trial which also showed an advantage for fulvestrant over anastrozole. The results are clinically meaningful and suggest that fulvestrant could be a 1st line therapy for women with advanced breast cancer."

The safety and tolerability profile was in line with current experience with fulvestrant and anastrozole. The most commonly reported adverse events (AEs) in the fulvestrant and anastrozole arms were arthralgia (16.7% vs. 10.3%), hot flush (11.4% vs. 10.3%), and nausea (10.5% vs. 10.3%), respectively.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "Fulvestrant has over 10 years of clinical evidence to support its use, and we are continuing to evaluate its full potential in advanced breast cancer, where we believe patient need is currently the greatest. AstraZeneca has a long, rich heritage in breast cancer research, and we remain committed to investigating innovative potential medicines for the treatment of women with all types of advanced disease."

About FALCON

The FALCON (Fulvestrant and AnastrozoLe COmpared in hormonal therapy Naïve advanced breast cancer) trial is a Phase III, randomised, double-blind, multicentre trial. It compared the antitumour effects and tolerability profile of a 500mg dose of fulvestrant plus placebo with a 1mg dose of anastrozole plus placebo, in postmenopausal women with HR+, locally-advanced or metastatic breast cancer who had not been treated previously with any hormonal therapy.

The FALCON trial was designed on the basis of positive results from the Phase II FIRST trial, which demonstrated a median overall survival nearly six months longer with fulvestrant compared to anastrozole.4

About Advanced Breast Cancer

Advanced/metastatic breast cancer refers to Stages III and IV breast cancer. Stage III disease may be referred to as locally-advanced breast cancer. Metastatic breast cancer is the most advanced stage of breast cancer (Stage IV), and occurs when cancer cells have spread beyond the initial tumour site to other parts of the body outside the breast. Since there is no cure for the disease, the goal of current treatment is to delay disease progression.5

About Fulvestrant

Fulvestrant is indicated for the treatment of postmenopausal women with oestrogen receptor-positive (ER+), locally-advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on therapy with an anti-oestrogen.2

In the US, fulvestrant is also approved, in combination with palbociclib, for the treatment of women with HR+, HER2- advanced or metastatic breast cancer, whose cancer has progressed after endocrine therapy.3 Fulvestrant represents a hormonal therapy approach that helps to slow tumour growth by blocking and degrading the oestrogen receptor – a key driver of disease progression.3,6

On October 8, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported positive findings from the phase 2 KEYNOTE-052 study investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in previously untreated patients with unresectable (inoperable) or metastatic urothelial cancer who are ineligible for cisplatin-based therapy. Data presented at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology, showed an overall response rate (ORR) of 24 percent (n=24/100) (95% CI, 16-34) in the total study population, which included patients with and without PD-L1 expression.

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"We have a growing body of evidence of KEYTRUDA’s activity in a range of cancers and treatment settings including the first-line treatment of patients with advanced urothelial cancer who will not tolerate cisplatin-based therapy," said Dr. Roger Dansey, senior vice president, oncology late-stage development, Merck Research Laboratories.

The KEYTRUDA clinical development program includes more than 30 tumor types in more than 350 clinical studies, including more than 100 trials that combine KEYTRUDA with other cancer treatments. Merck has the largest immuno-oncology clinical development program in bladder cancer with 27 trials involving KEYTRUDA, including four registration-enabling studies currently underway.

"There have been very few advancements in the treatment of bladder cancer in the past several decades, and patients with urothelial cancer who are ineligible for cisplatin-based therapy are in significant need of new approaches to care," said Dr. Dean F. Bajorin, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. "These data are exciting and demonstrate the potential for an anti-PD-1 therapy, such as pembrolizumab, to address the unmet treatment need that exists today for cisplatin-ineligible patients with this type of urothelial cancer."

Findings from KEYNOTE-052 are being presented at the ESMO (Free ESMO Whitepaper) 2016 Congress by Dr. Arjun V. Balar, medical oncologist and assistant professor of medicine at the Perlmutter Cancer Center at NYU Langone Medical Center, on Oct. 8 from 9:30 – 9:45 a.m. CEST (Abstract: # LBA32_PR) and are featured in the official ESMO (Free ESMO Whitepaper) press program.

Additional Findings from KEYNOTE-052

KEYNOTE-052 is an open-label, phase 2 study evaluating KEYTRUDA (pembrolizumab) (200 mg every three weeks) monotherapy as a first-line treatment in an estimated 350 patients with unresectable (inoperable) or metastatic urothelial cancer (a type of bladder cancer) who are ineligible for cisplatin-based therapy. The primary endpoints include ORR in all patients enrolled in the study (total study population) and in patients with PD-L1 positive tumors (expression of one percent or more). Secondary endpoints include duration of response, progression-free survival (PFS), and overall survival (OS). Tumor response was measured according to RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 as assessed by blinded independent central review.

Findings presented at the ESMO (Free ESMO Whitepaper) 2016 Congress are from the planned interim analysis of the first 100 patients, which was intended to evaluate ORR and determine the PD-L1-high expression cut-point as examined by expression in tumor and immune cells. Forty-five percent of patients (n=45/100) had an ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) score of two, 30 percent (n=30/100) had a PS score of one, and 24 percent (n=24/100) had a PS score of zero.

In the total study population, ORR was 24 percent (n=24/100) (95% CI, 16-34) with a complete response rate of six percent (n=6/100) (95% CI, 2-13). Review of the outcomes based on PD-L1 expression showed that in patients with PD-L1 expression of less than one percent, ORR was 18 percent (n=6/33) (95% CI, 7-36) with a complete response rate of three percent (n=1/33) (95% CI, 0.1-16); in patients with PD-L1 expression greater than or equal to one percent and less than 10 percent, ORR was 15 percent (n=5/33) (95% CI, 5-32) with no complete responses; and, in patients expressing PD-L1 at levels equal to or greater than 10 percent, ORR was 37 percent (n=11/30) (95% CI, 20-56) with a complete response rate of 13 percent (n=4/30) (95% CI, 4-31). Among the 24 percent of patients in the total study population who were responding to treatment, the median duration of response had not been reached (range 1.4+ to 9.8+ months), with 83 percent of patients (n=20/24) having responses of six months or longer.

The safety profile of KEYTRUDA (pembrolizumab) was consistent with that observed in previously reported KEYTRUDA studies. The treatment-related adverse events observed in this trial (any grade occurring in five percent or more of patients) were fatigue (n=14), pruritus (n=12), pyrexia (n=8), decreased appetite (n=7), diarrhea (n=7), rash (n=7), chills (n=6), hypothyroidism (n=6), and nausea (n=6). Grade 3-4 treatment-related adverse events observed (occurring in 2 or more patients) were fatigue (n=4), muscle spasms (n=2), decreased appetite (n=1), and diarrhea (n=1). Immune-mediated adverse events of Grade 3-4 were nephritis (n=1) and pneumonitis (n=2). Five patients discontinued due to a treatment-related adverse event; there were no treatment-related deaths.