On October 22, 2018 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported positive results from the Phase III IMpower130 study of Tecentriq (atezolizumab) plus chemotherapy (carboplatin and Abraxane [albumin-bound paclitaxel; nab-paclitaxel]) for the initial (first-line) treatment of people with previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC) (Press release, Genentech, OCT 22, 2018, View Source [SID1234530039]). The analysis showed that Tecentriq plus chemotherapy helped people live significantly longer compared to chemotherapy alone (median overall survival [OS] = 18.6 versus 13.9 months; hazard ratio [HR] = 0.79; 95 percent CI: 0.64–0.98; p=0.033) in the intention-to-treat wild-type (ITT-WT) population. The Tecentriq-based combination also significantly reduced the risk of disease worsening or death (progression-free survival; PFS) compared to chemotherapy alone (median PFS=7.0 versus 5.5 months; HR=0.64; 95 percent CI: 0.54–0.77; p<0.0001) in the ITT-WT population. Safety for the Tecentriq plus chemotherapy combination appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination.

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"Initial treatment with this Tecentriq-based combination provided a significant survival benefit for people with non-squamous non-small cell lung cancer, the most common form of lung cancer," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Lung cancer is a complex disease and this combination could offer a new potential treatment option. We will work with global health authorities to bring this regimen to people living with this disease as soon as possible."

The data will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress on October 22, 2018 from 9:15 – 9:30 a.m. CEST (Abstract LBA53; Hall A1 – Room 17).

About the IMpower130 study

IMpower130 is a Phase III, multicenter, open-label, randomized study evaluating the efficacy and safety of Tecentriq in combination with carboplatin and nab-paclitaxel versus chemotherapy (carboplatin and nab-paclitaxel) alone for chemotherapy-naïve patients with stage IV non-squamous NSCLC. The study enrolled 723 people who were randomized (2:1) to receive:

Tecentriq plus carboplatin and nab-paclitaxel (Arm A), or
Carboplatin and nab-paclitaxel (Arm B, control arm)
During the treatment-induction phase, people in Arm A received Tecentriq and carboplatin on day 1 of each 21-day cycle, and nab-paclitaxel on days 1, 8 and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit, whichever occurs first. People received Tecentriq during the maintenance treatment phase until loss of clinical benefit was observed.

During the treatment-induction phase, people in Arm B received carboplatin on day 1 and nab-paclitaxel on days 1, 8 and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression, whichever occurs first. People received best supportive care during the maintenance treatment phase. Switch maintenance to pemetrexed was also permitted. People who were consented prior to a protocol revision were given the option to crossover to receive Tecentriq as monotherapy until disease progression.

The co-primary endpoints were:

PFS as determined by the investigator using RECIST v1.1 in the ITT-WT population
OS in the ITT-WT population
IMpower130 met its co-primary endpoints of OS and PFS.

A summary of the results are included below:

Arm A (Tecentriq plus chemotherapy) vs Arm B (chemotherapy) in ITT-WT

Arm A
n=451

Arm B
n=228

Median OS, months (95% CI)

18.6
(16.0–21.2)

13.9
(12.0–18.7)

HR (95% CI); P value 0.79 (0.64, 0.98); p=0.033
1-year OS, % (95% CI) 63.1 (58.59–67.66) 55.5 (48.89–62.17)
Confirmed ORR, % (95% CI)
49.2 (44.49–53.96)

31.9 (25.84–38.36)

Median DoR, months (95% CI)

8.4
(6.9–11.8)

6.1
(5.5–7.9)

Median PFS (95% CI), months

7.0
(6.2–7.3)

5.5
(4.4–5.9)

HR (95% CI); P value 0.64 (0.54, 0.77); p<0.0001
1-year PFS rate, % (95% CI)

29.1
(24.83–33.44)

14.1
(9.37–18.76)

CI, confidence interval; DoR, duration of response; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival

Safety for the Tecentriq and chemotherapy combination appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination. Grade 3-4 treatment-related adverse events (AEs) were reported in 73.2 percent of people receiving Tecentriq plus chemotherapy compared to 60.3 percent of people receiving chemotherapy alone. The most common Grade 3-4 AEs in people receiving Tecentriq plus chemotherapy were: an abnormal low count of a certain type of white blood cell (neutropenia, 32.1 percent), a decrease in red blood cells (anemia, 29.2 percent) and a decreased neutrophil count (12.1 percent).

About lung cancer

According to the American Cancer Society, it is estimated that more than 234,000 Americans will be diagnosed with lung cancer in 2018, and NSCLC accounts for 85 percent of all lung cancers. It is estimated that approximately 60 percent of lung cancer diagnoses in the United States are made when the disease is in the advanced stages.

About Tecentriq (atezolizumab)

Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1. Tecentriq is designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the re-activation of T cells. Tecentriq may also affect normal cells.

Abraxane is a registered trademark of Abraxis Bioscience, LLC, a wholly owned subsidiary of Celgene Corporation.

Tecentriq U.S. Indication (pronounced ‘tē-SEN-trik’)

Tecentriq is a prescription medicine used to treat:

A type of bladder and urinary tract cancer called urothelial carcinoma.

Tecentriq may be used when your bladder cancer:
has spread or cannot be removed by surgery, and if you have any one of the following conditions:
you are not able to take chemotherapy that contains a medicine called cisplatin, and your doctor has tested your cancer and found high levels of a specific protein on your cancer called programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test, or
you are not able to take chemotherapy that contains any platinum regardless of PD-L1 status on your cancer, or
you have tried chemotherapy that contains platinum, and it did not work or is no longer working
The approval of Tecentriq in these patients is based on a study that measured response rate and duration of response. There is an ongoing study to confirm clinical benefit.

A type of lung cancer called non-small cell lung cancer (NSCLC).

Tecentriq may be used when your lung cancer:
has spread or grown, and
you have tried chemotherapy that contains platinum, and it did not work or is no longer working
If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.

It is not known if Tecentriq is safe and effective in children.

Important Safety Information

What is the most important information about Tecentriq?

Tecentriq can cause the immune system to attack normal organs and tissues and can affect the way they work. These problems can sometimes become serious or life threatening and can lead to death.

Patients should call or see their healthcare provider right away if they get any symptoms of the following problems or these symptoms get worse.

Tecentriq can cause serious side effects, including:

Lung problems (pneumonitis)–signs and symptoms may include new or worsening cough, shortness of breath, and chest pain
Liver problems (hepatitis)–signs and symptoms of hepatitis may include yellowing of the skin or the whites of the eyes, severe nausea or vomiting, pain on the right side of the stomach area (abdomen), drowsiness, dark urine (tea colored), bleeding or bruising more easily than normal, and feeling less hungry than usual
Intestinal problems (colitis)–signs and symptoms of colitis may include diarrhea (loose stools) or more bowel movements than usual, blood or mucous in the stools or dark, tarry, sticky stools, and severe stomach area (abdomen) pain or tenderness
Hormone gland problems (especially the thyroid, adrenal glands, pancreas, and pituitary)–signs and symptoms that the hormone glands are not working properly may include headaches that will not go away or unusual headaches, extreme tiredness, weight gain or weight loss, dizziness or fainting, feeling more hungry or thirsty than usual, hair loss, changes in mood or behavior (such as decreased sex drive, irritability, or forgetfulness), feeling cold, constipation, the voice gets deeper, urinating more often than usual, nausea or vomiting, and stomach area (abdomen) pain
Problems in other organs–signs and symptoms may include severe muscle weakness, numbness or tingling in hands or feet, confusion, blurry vision, double vision, or other vision problems, changes in mood or behavior, extreme sensitivity to light, neck stiffness, eye pain or redness, skin blisters or peeling, chest pain, irregular heartbeat, shortness of breath, or swelling of the ankles
Severe infections–signs and symptoms of infection may include fever, cough, flu-like symptoms, pain when urinating, and frequent urination or back pain
Severe infusion reactions–signs and symptoms of infusion reactions may include chills or shaking, itching or rash, flushing, shortness of breath or wheezing, swelling of the face or lips, dizziness, fever, feeling like passing out, and back or neck pain
Getting medical treatment right away may help keep these problems from becoming more serious. A healthcare provider may treat patients with corticosteroid or hormone replacement medicines. A healthcare provider may delay or completely stop treatment with Tecentriq if patients have severe side effects.

Before receiving Tecentriq, patients should tell their healthcare provider about all of their medical conditions, including if they:

have immune system problems (such as Crohn’s disease, ulcerative colitis, or lupus); have had an organ transplant; have lung or breathing problems; have liver problems; have a condition that affects the nervous system (such as myasthenia gravis or Guillain-Barre syndrome); or are being treated for an infection
are pregnant or plan to become pregnant. Tecentriq can harm an unborn baby. Patients should tell their healthcare provider right away if they become pregnant or think they may be pregnant during treatment with Tecentriq. If patients are able to become pregnant:
A healthcare provider should do a pregnancy test before they start treatment with Tecentriq.
They should use an effective method of birth control during their treatment and for at least 5 months after the last dose of Tecentriq.
are breastfeeding or plan to breastfeed. It is not known if Tecentriq passes into the breast milk. Do not breastfeed during treatment and for at least 5 months after the last dose of Tecentriq
Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Tecentriq in people with urothelial carcinoma include:

feeling tired
decreased appetite
nausea
constipation
urinary tract infection
diarrhea
fever
The most common side effects of Tecentriq in people with non-small cell lung cancer include:

feeling tired
decreased appetite
muscle pain
cough
shortness of breath
Tecentriq may cause fertility problems in females, which may affect the ability to have children. Patients should talk to their healthcare provider if they have concerns about fertility.

These are not all the possible side effects of Tecentriq. Patients should ask their healthcare provider or pharmacist for more information. Patients should call their doctor for medical advice about side effects.

On October 22, 2018 Exelixis, Inc. (NASDAQ:EXEL) reported results from the dose-escalation stage of the phase 1b COSMIC-021 study of cabozantinib in combination with atezolizumab in previously untreated advanced renal cell carcinoma (RCC) (Press release, Exelixis, OCT 22, 2018, View Source;p=RssLanding&cat=news&id=2372610 [SID1234530024]). The primary objective of the dose-escalation stage of the trial was to determine the recommended dose of cabozantinib in combination with the standard dose of atezolizumab for the expansion stage of the trial. The findings demonstrate encouraging clinical activity for the combination, supporting further evaluation of the 40 mg dose of cabozantinib in combination with the standard dose of atezolizumab in the ongoing expansion phase of the trial. The findings were presented during a poster session (abstract 872P) on Monday, October 22 at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress, which is being held October 19-23, 2018 in Munich, Germany.

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Twelve patients with previously untreated advanced RCC including ten patients with clear cell RCC and two patients with non-clear cell RCC were treated in the dose-escalation stage, with six patients at each cabozantinib dose level — 40 mg or 60 mg daily — in combination with the standard dosing regimen of atezolizumab (1,200 mg infusion once every three weeks).

As of the August 21, 2018 data cut-off, all patients remained on treatment. Median follow-up was 33.4 weeks. Eight of the ten (80 percent) clear cell RCC patients achieved a response per RECIST 1.1. Among all 12 patients enrolled, including the 2 non-clear cell RCC patients, the response rate was 67 percent. The disease control rate (ORR plus stable disease) for all 12 patients was 100 percent.

No dose-limiting toxicities or serious adverse events were noted at either cabozantinib dose. Dose reductions and higher grade AEs were less frequent with the 40 mg cabozantinib dosing cohort. Grade 3 adverse events (83 percent of patients) in the 40 mg cabozantinib dose cohort included hypertension (50 percent), hypophosphatemia (17 percent), hyperglycemia (17 percent), gamma glutamyltransferase increased (17 percent) and muscular weakness (17 percent). Grade 3 adverse events (100 percent of patients) in the 60 mg cabozantinib dose cohort included diarrhea (33 percent), hypertension (33 percent), aspartate aminotransferase increased (17 percent), alanine aminotransferase increased (17 percent), lymphopenia (17 percent), hypophosphatemia (17 percent) and lipase increased (17 percent). No Grade 4 or 5 adverse events were observed.

"These early stage results demonstrate that the combination of cabozantinib and atezolizumab was well tolerated and showed promising anti-tumor activity in advanced kidney cancer," said Sumanta Kumar Pal, M.D., associate clinical professor, Department of Medical Oncology and Therapeutics Research, co-director, Kidney Cancer Program, City of Hope. "We look forward to continuing to advance this trial to understand whether this combination may benefit patients with multiple tumor types."

"As we explore cabozantinib in combination with a variety of immune checkpoint inhibitors in a broad spectrum of tumor types, we are pleased with the initial results in the dose-escalation phase of COSMIC-021," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "This combination is being studied across 12 different tumor types in the expansion phase, and we are excited to see how it may improve outcomes for this range of patients."

As previously announced, the cabozantinib starting dose for the expansion phase is 40 mg. The expansion phase includes multiple solid tumor types, including RCC. More information about this trial is available at ClinicalTrials.gov.

Please see Important Safety Information below and full U.S. prescribing information at View Source

About the COSMIC-021 Study

COSMIC-021 is a multicenter, phase 1b, open-label study that is divided into two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase was designed to enroll patients either with advanced RCC with or without prior systemic therapy or with inoperable, locally advanced, metastatic or recurrent UC (including renal, pelvis, ureter, urinary bladder and urethra) after prior platinum-based therapy. Ultimately, all patients enrolled in this stage of the trial were patients with advanced RCC. The dose-escalation phase of the study determined the optimal dose of cabozantinib to be 40 mg daily when given in combination with atezolizumab (1200 mg infusion once every 3 weeks).

In the expansion phase, the trial is enrolling 18 expansion cohorts in 12 tumor types: RCC, urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer, triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, hepatocellular carcinoma (HCC), gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, head and neck cancer, and differentiated thyroid cancer. Up to a total of 1,000 patients may enroll in this phase of the trial: each expansion cohort will initially enroll approximately 30 patients; up to 80 patients may enroll in up to eight of those cohorts, including the cohorts with UC or NSCLC patients who have been previously treated with an immune checkpoint inhibitor; and in two exploratory cohorts, approximately 30 patients in each cohort will be treated with cabozantinib as a single-agent.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2018 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.1 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment, and an estimated 14,000 patients in the U.S. each year are in need of a first-line treatment for advanced kidney cancer. 3

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.4,5 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.6,7,8,9 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.5,6

About CABOMETYX (cabozantinib)

CABOMETYX tablets are approved in the United States for the treatment of patients with advanced RCC. CABOMETYX tablets are also approved in: the European Union, Norway, Iceland, Australia, Switzerland, South Korea and Canada for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy, and in the European Union for previously untreated intermediate- or poor-risk advanced RCC. In March 2017, the FDA granted orphan drug designation to cabozantinib for the treatment of advanced HCC. In May 2018, the FDA accepted Exelixis’ supplemental New Drug Application for CABOMETYX as a treatment for patients with previously treated HCC and assigned it a Prescription Drug User Fee Act action date of January 14, 2019. On March 28, 2018, Ipsen announced that the European Medicines Agency validated its application for a new indication for cabozantinib as a treatment for previously treated advanced HCC in the European Union; on September 20, 2018 the CHMP provided a positive opinion for CABOMETYX as a monotherapy for the treatment of HCC in adults who have been previously treated with sorafenib. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan.

The combination of cabozantinib and atezolizumab is not indicated for previously untreated advanced RCC.

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In two RCC studies, the incidence of Grade ≥ 3 hemorrhagic events was 3% in CABOMETYX-treated patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: In RCC studies, fistulas were reported in 1% of CABOMETYX-treated patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations were reported in 1% of CABOMETYX-treated patients. Monitor patients for symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. In RCC studies, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension, including hypertensive crisis. In RCC studies, hypertension was reported in 44% (18% Grade ≥ 3) of CABOMETYX-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: In RCC studies, diarrhea occurred in 74% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Palmar-Plantar Erythrodysesthesia (PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE) occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-fetal Toxicity may be associated with CABOMETYX. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.
Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On October 22, 2018 Novartis reported a new data analysis of COMBI-AD, a phase III multi-center study evaluating Tafinlar (dabrafenib) in combination with Mekinist (trametinib) in stage III adjuvant resected BRAF V600-mutant melanoma (Press release, Novartis, OCT 22, 2018, https://www.novartis.com/news/media-releases/novartis-combi-ad-study-tafinlar-mekinist-continues-demonstrate-relapse-free-survival-benefit-patients-braf-v600-mutant-stage-iii-melanoma [SID1234530040]). With extended study follow up, Tafinlar in combination with Mekinist continued to show more than 50% risk reduction in relapse free survival (RFS) versus placebo in patients with resected BRAF V600-mutant stage III melanoma. The updated COMBI-AD data was also used to generate a statistical cure-rate model that estimated the fraction of patients who may not relapse. The cure rate was 54% (95% CI, 49%-59%) in the Tafinlar + Mekinist arm compared to 37% (95% CI, 32%-42%) in the placebo arm[1]. These data were presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) in Munich, Germany (Abstract #LBA43) today and simultaneously published in The Journal of Clinical Oncology.

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A separate biomarker analysis was conducted to identify predictors of clinical outcome and treatment response. These analyses showed that subgroups of patients at a higher risk of relapse could be defined based on specific immune gene expression signatures (GES) and tumor mutation burden (TMB). Exploratory analysis of RFS in the treatment vs. placebo arms in all TMB/immune GES subgroups suggested that specific subgroups may have a greater RFS benefit, but the predictive value of TMB and immune GES warrants further validation in a prospective study[2].

"In addition to confirming prior relapse free survival results in the adjuvant setting, this biomarker analysis of COMBI-AD provides important information about the prognostic and potentially predictive value of TMB and immune gene expression signatures in resected BRAF V600-mutant melanoma patients," said Georgina Long, BSc., PhD, MBBS, FRACP, Medical Oncologist, Melanoma Institute Australia, The University of Sydney.

In the phase III COMBI-AD global study, at median follow-ups of 44 months (Tafinlar + Mekinist) and 42 months (placebo), the three- and four-year RFS rates were 59% ([95% CI, 0.55-0.64]) and 54% ([95% CI, 0.49-0.59]) in the Tafinlar + Mekinist arm and 40% ([95% CI, 0.35-0.45]) and 38% ([95% CI, 34%-44%]) in the placebo arm, respectively (HR, 0.49 [95% CI, 0.40-0.59]). RFS was also analyzed by subgroups defined by baseline disease stage by the American Joint Committee on Cancer 7th and 8th editions and included nodal metastatic burden, and ulceration status. A cure rate model estimated that the fraction of patients who may not relapse was 54% (95% CI, 49%-59%) in the Tafinlar + Mekinist arm compared with 37% (95% CI, 32%-42%) in the placebo arm[1]. The fraction of patients remaining relapse free long term was estimated using a Weibull mixture cure-rate model. No updated safety analysis was performed as all patients have completed treatment at the time of the updated RFS analysis[1].

"The data generated from the COMBI-AD study have the ability to transform treatment decisions for patients with BRAF V600 melanoma," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "Not only do the results from the extended analysis continue to provide confirmation of the long-term benefit with adjuvant Tafinlar and Mekinist, but the comprehensive biomarker analysis of the largest adjuvant dataset to date highlight important prognostic information to identify patients at higher risk of relapse."

The BRAF gene belongs to a class of genes known as oncogenes and provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell’s nucleus. This protein is part of a signaling pathway known as the RAS/MAPK pathway, which controls several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration) and the self-destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth. When mutated, oncogenes have the potential to cause normal cells to become cancerous. During cancer treatment, targeted therapies may inhibit the mutation from occurring, thus slowing the growth of the cancer tumor[3].

About COMBI-AD
The COMBI-AD study evaluated Tafinlar + Mekinist among patients with stage III, BRAF V600-mutant melanoma without prior anticancer therapy, randomized within 12 weeks of complete surgical resection. Patients received the Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432). In the initial primary analysis, and after a median follow-up of 2.8 years, the primary endpoint was met in that the combination therapy significantly reduced the risk of disease recurrence or death by 53% vs. placebo (HR: 0.47 [95% CI: 0.39-0.58]; median not yet reached vs. 16.6 months, respectively; p<0.001). The combination treatment group also saw an improvement in a key secondary endpoint of OS (HR: 0.57 [95% CI: 0.42-0.79] p=0.0006, which did not cross the predefined interim analysis boundary of p=0.000019 to claim statistical significance).

Other secondary endpoints in the initial primary analysis where the combination demonstrated a clinically meaningful benefit included distant metastasis-free survival (DMFS) (HR: 0.51 [95% CI: 0.40-0.65]), and freedom from relapse (FFR) (HR: 0.47 [95% CI: 0.39-0.57])[4]. In a separate analysis, Tafinlar + Mekinist also demonstrated benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration[5]. Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies and no new safety signals were reported. Of patients treated with the combination, 97% experienced an AE, with 41% having grade 3/4 AEs and 26% having AEs leading to treatment discontinuation (vs. 88%, 14%, and 3%, respectively, with placebo)[4].

Based on updated data with median follow up of 44 months (Tafinlar + Mekinist) and 42 months (matching placebo), the 3- and 4- year relapse-survival benefit maintained at 59% (95% CI, 55%-64%) and 54% (95% CI, 49%-59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35%-45%) and 38% (95% CI, 34%-44%) in the placebo arm, respectively (HR, 0.49 [95% CI, 0.40-0.59]). The relapse-free survival benefit among the combination arm was observed across all patient subgroups, including stage III A, B and C. The estimated one-year, two-year, three-year, and four-year RFS were consistently higher than placebo (one year: 88% vs. 56%; two year: 67% vs. 44%; three year: 59% vs. 40%; four year: 54% vs. 38%). The combination treatment group also saw an improvement in the secondary endpoint of distant metastasis-free survival (DMFS) (HR: 0.53 [95% CI: 0.42-0.67]). No new safety analysis was performed[1].

About Melanoma
There are about 280,000 new diagnoses of melanoma (stages 0-IV) worldwide each year[6], approximately half of which have BRAF mutations[3]. Biomarker tests can determine whether a tumor has a BRAF mutation[7].

Melanoma is staged 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[8]. Patients who receive surgical treatment for Stage III melanoma may have a high risk of recurrence because melanoma cells can remain in the body after surgery; almost half (44%) of patients receiving placebo per the COMBI-AD study had a recurrence of disease within the first year[4],[9]. Adjuvant therapy is additional treatment given after surgical resection, and may be recommended for patients with high-risk melanoma to help reduce the risk of melanoma returning[9].

About Tafinlar + Mekinist
Tafinlar + 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 melanoma and NSCLC, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone.

Tafinlar + Mekinist have been investigated for the treatment of a variety of cancers as part of an ongoing clinical trial program. Tafinlar + Mekinist are approved in more than 60 countries, for uses including:

as monotherapy and in combination for the treatment of subjects with unresectable or metastatic melanoma with a BRAFV600 mutation
in combination for the adjuvant treatment of patients with Stage III melanoma with a BRAFV600 mutation, following complete resection
in combination for the treatment of patients with advanced NSCLC with a BRAFV600 mutation
in combination for the treatment of patients with locally advanced or metastatic ATC with a BRAFV600 mutation
Approved indications vary worldwide. Please refer to local labeling for indication language in a particular country.

Tafinlar + Mekinist Combination Important Safety Information
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 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, and may need to be treated in a hospital. Patients should be advised to call their health care provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, or skin redness.

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

Tafinlar, in combination with Mekinist, may cause healthy red blood cells to break down too early in people with 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.

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

On October 22, 2018 Epigenomics AG (Frankfurt Prime Standard: ECX, OTCQX: EPGNY) reported that the Centers for Medicare & Medicaid Services (CMS) published a final rate of $192 for Epi proColon, the first and only FDA-approved blood test for colorectal cancer screening (Press release, Epigenomics, OCT 22, 2018, View Source [SID1234530232]).

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This announcement confirms the preliminary gapfill rate as determined by the Medicare Administrative Contractors, published on June 11, 2018. The $192 per test rate will be included in the 2019 Clinical Laboratory Fee Schedule that is expected to be published in November 2018.

"The final CMS rate of $192 is an important accomplishment for the company as it appropriately values our innovative blood-based colorectal cancer screening test," said Greg Hamilton, CEO of Epigenomics AG. "Medicare pricing sets a benchmark for value and it’s an important component of our commercialization strategy."

About Epi proColon

Epi proColon is indicated for colorectal cancer screening in average-risk patients who are unwilling or unable to perform colorectal cancer screening by colonoscopy and stool-based methods.

For patients, the test only requires a simple blood sample drawn as part of routine healthcare provider visits. There are no dietary restrictions or alterations in medication required for the test. The sample will be analyzed at a national or regional diagnostic laboratory.

On October 22, 2018 NuCana plc (NASDAQ: NCNA), a clinical-stage biopharmaceutical company focused on significantly improving treatment outcomes for patients with cancer, reported combined results from cohorts one and two of the ABC-08 Study at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2018 in Munich, Germany (Press release, Nucana BioPharmaceuticals, OCT 22, 2018, View Source [SID1234530269]). In this Phase Ib multi-center, open-label study in front-line treatment of patients with advanced biliary tract cancer, Acelarin combined with cisplatin was observed to continue to achieve approximately a doubling of the response rate expected with the standard of care, gemcitabine plus cisplatin. In addition, results showed the combination was well-tolerated and several patients achieved significant reductions in their tumor volume as well as further tumor shrinkage over time.

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Fourteen patients with advanced/metastatic biliary tract cancer received Acelarin (625mg/m2 or 725mg/m2) and cisplatin (25mg/m2) on days one and eight of a three-week cycle. In the intent-to-treat group of patients, a Complete Radiological Response was achieved in one patient and a Partial Response in six patients, resulting in an Objective Response Rate of 50%. In the eleven Efficacy Evaluable patients (defined as those patients who received at least one cycle of therapy), an Objective Response Rate of 64% was achieved.

"Building upon the interim analysis presented in January 2018 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium, these data continue to be encouraging and suggest that the combination of Acelarin and cisplatin may represent an important advance in the standard of care treatment of advanced biliary tract cancer, a devastating disease for which there are no approved medicines," remarked Professor Juan Valle, Co-Chief Investigator of the ABC-08 Study and Professor and Honorary Consultant in Medical Oncology at the University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom.

Dr. Mairéad McNamara, Co-Chief Investigator of the ABC-08 Study and Senior Lecturer and Honorary Consultant in Medical Oncology at the University of Manchester and The Christie NHS Foundation Trust, added, "In addition to the encouraging response rate observed, which is approximately double that of the standard of care, I believe the ability of this combination to continue to shrink the tumor volume over time is also noteworthy. Some patients showed sustained and durable tumor shrinkage, which is not typically seen in this setting."

Additionally, the combination of Acelarin and cisplatin was well-tolerated over multiple cycles with no unexpected adverse events, no dose-limiting toxicities, no discontinuations due to Acelarin-associated toxicity and no Grade 4 adverse events.

Based on these data from the ABC-08 study and discussions with the U.S. Food and Drug Administration (FDA), NuCana anticipates initiating a global randomized Phase III clinical study comparing Acelarin (625mg/m2) and cisplatin (25mg/m2) with gemcitabine (1,000mg/m2) and cisplatin (25mg/m2) in patients with front-line advanced biliary tract cancer.

Hugh Griffith, NuCana’s Chief Executive Officer, said: "We are excited by the results achieved in this study. We have also been encouraged by the ongoing constructive dialogue with the FDA and look forward to initiating a front-line Phase III study of Acelarin plus cisplatin in patients with advanced biliary tract cancer."

A comparison of these data from the ABC-08 Study and the earlier ABC-02 Study, that established the current standard of care, is provided in the table below:

Objective Response Rates in ABC-08 and ABC-02

ABC-08 Study

ABC-02 Study*

NUC-1031 + cisplatin

625 mg/m2 or 725 mg/m2 + 25 mg/m2

gemcitabine + cisplatin

000 mg/m2 + 25 mg/m2

Complete Response

7% (1/14)

0.6% (1/161)

Partial Response

43% (6/14)

25.5% (41/161)

Objective Response Rate

50% (7/14)

26.1% (42/161)

*Valle et al. N Eng J Med 2010; 363:1273-1281