On June 6, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported the first-time presentation of findings from KEYNOTE-087, the phase 2 study investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy in patients with relapsed or refractory classical Hodgkin lymphoma (cHL) (Press release, Merck & Co, JUN 6, 2016, http://www.mercknewsroom.com/news-release/oncology-newsroom/keytruda-pembrolizumab-shows-overall-response-rates-73-83-percent-com [SID:1234513048]).

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These data will be presented today at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago from 8:00 – 11:30 a.m. CDT (Location: Hall A) and in a poster discussion from 1:15 – 2:45 p.m. CDT (Location: E354b) (Abstract #7555).

Results included an analysis of outcome measurements from the study’s three patient cohorts: patients whose disease progressed following an autologous stem cell transplantation and subsequent treatment with brentuximab vedotin, an antibody drug conjugate (Cohort 1); patients who failed salvage chemotherapy and were ineligible for a transplant and whose disease progressed following treatment with brentuximab vedotin (Cohort 2); and patients whose disease progressed after transplant and who did not receive brentuximab vedotin after transplant (Cohort 3). Data showed that the overall response rate (ORR) was more than 70 percent across all three cohorts with the highest ORR, at 83 percent, observed in Cohort 2. Results also included an analysis of patients with primary refractory disease, defined as failure to achieve complete or partial response to first-line treatment. In this patient population, the ORR (by investigator review) was 78 percent. Additionally, 90 to 93 percent of patients experienced a reduction in tumor size across all three cohorts.

"Recurrence of Hodgkin lymphoma occurs in almost half of patients following autologous stem cell transplantation, and the prognosis for patients relapsing or refractory to second-line chemotherapy and transplant is particularly poor, which means there is a significant need to identify therapeutic options that provide meaningful clinical benefit," said Dr. Craig Moskowitz, clinical director, division of hematologic oncology, Memorial Sloan Kettering Cancer Center. "These early data are encouraging, as they demonstrate high response rates – up to 83 percent – with pembrolizumab in heavily pre-treated patients."

Data from KEYNOTE-087 supported the recent Breakthrough Therapy Designation granted to KEYTRUDA (pembrolizumab) by the U.S. Food and Drug Administration (FDA) for this type of blood cancer. Additionally, findings from this study support the continued development of KEYTRUDA in patients with cHL, including a phase 3 registration-enabling study (KEYNOTE-204) designed to evaluate monotherapy KEYTRUDA versus brentuximab vedotin in patients with relapsed or refractory cHL.

"Our extensive clinical development program is studying KEYTRUDA in a broad range of solid and blood cancers – including classical Hodgkin lymphoma, where there remains a significant unmet need for patients who do not respond to or relapse following initial treatment," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "These exciting data from KEYNOTE-087 reinforce the potential of KEYTRUDA in hematologic cancers and further invigorate our commitment to improving outcomes across a variety of blood cancers."

Results presented at ASCO (Free ASCO Whitepaper) were based on an analysis of 90 patients across three study cohorts. These data showed (per investigator review):

In Cohort 1 (progressed after transplant and subsequent brentuximab vedotin treatment; n=30), ORR was 73 percent (95% CI, 54-88) – with complete responses in 27 percent (95% CI, 12-46) and partial responses in 47 percent (95% CI, 28-66) of patients. Seventeen percent of patients had stable disease (95% CI, 6-35) and 10 percent of patients had progressive disease (95% CI, 2-27).
In Cohort 2 (progressed following salvage chemotherapy, transplant-ineligible, and progressed following brentuximab vedotin treatment; n=30), ORR was 83 percent (95% CI, 65-94) – with complete responses in 30 percent (95% CI, 15-49) and partial responses in 53 percent (95% CI, 34-72) of patients. Seven percent of patients had stable disease (95% CI, 1-22) and 7 percent of patients had progressive disease (95% CI, 1-22).
In Cohort 3 (progressed after transplant and not treated with brentuximab vedotin after transplant; n=30), ORR was 73 percent (95% CI, 54-88) – with complete responses in 30 percent (95% CI, 15-49) and partial responses in 43 percent of patients (95% CI, 26-63). Thirteen percent of patients had stable disease (95% CI, 4-31) and 13 percent of patients had progressive disease (95% CI, 4-31).
In patients with primary refractory disease (n=37), ORR was 78 percent (95% CI, 62-90) – with complete responses in 35 percent (95% CI, 20-53) and partial responses in 43 percent (95% CI, 27-61) of patients. Eleven percent of patients had stable disease (95% CI, 3-25) and 8 percent of patients had progressive disease (95% CI, 2-22).

The safety profile of KEYTRUDA (pembrolizumab) was consistent with that observed in previously reported studies. Grade 3-4 treatment-related adverse events were observed in 4 percent of patients and included neutropenia (n=1), increased amylase (n=1), cytokine release syndrome (n=1), herpes zoster (n=1), increased lipase (n=1), lichenoid dermatosis (n=1), colitis (n=1), and diarrhea (n=1). Two patients discontinued due to treatment-related adverse events (Grade 2 infusion-related reaction and Grade 2 pneumonitis; both Cohort 2). The immune-mediated adverse events (any grade) were rash (n=4, all Grade 1), pneumonitis (n=2, both Grade 2), and colitis (n=1, Grade 3). There were no treatment-related deaths.

The KEYTRUDA clinical development program includes more than 30 tumor types in more than 270 clinical trials, including more than 100 trials that combine KEYTRUDA with other cancer treatments. For hematologic malignancies specifically, Merck is conducting a broad immuno-oncology clinical development program. To date, the program is assessing the role of monotherapy and combination regimens with KEYTRUDA across a variety of hematologic malignancies including leukemia, lymphomas, and myeloma, and includes five registration-enabling studies.

About KEYNOTE-087

KEYNOTE-087 is a multicenter, open-label, multi-cohort, activity-estimating phase 2 trial evaluating KEYTRUDA (200 mg fixed dose every three weeks) monotherapy in patients with relapsed or refractory cHL across three cohorts. The primary endpoints include overall safety, tolerability, and ORR (per central review); secondary endpoints include ORR (per investigator review), progression-free survival (PFS), and overall survival (OS). The patient cohorts are intended to assess the outcome measures in patients whose disease progressed following an autologous stem cell transplantation and subsequent treatment with brentuximab vedotin, an antibody drug conjugate (Cohort 1); patients who failed salvage chemotherapy and were ineligible for a transplant and whose disease progressed following treatment with brentuximab vedotin (Cohort 2); and patients whose disease progressed after transplant and who did not receive brentuximab vedotin after transplant (Cohort 3).

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-mediated pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 32 (2.0%) of 1567 patients with melanoma, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%) pneumonitis. Pneumonitis occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis and more frequently in patients with a history of asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic radiation (6.0%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-mediated colitis occurred in 31 (2%) of 1567 patients with melanoma, including Grade 2 (0.5%), 3 (1.1%), and 4 (0.1%) colitis. Immune-mediated colitis occurred in 4 (0.7%) of 550 patients with NSCLC, including Grade 2 (0.2%) or 3 (0.4%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA (pembrolizumab) for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in patients receiving KEYTRUDA. Hepatitis occurred in 16 (1%) of 1567 patients with melanoma, including Grade 2 (0.1%), 3 (0.7%), and 4 (0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 13 (0.8%) of 1567 patients with melanoma, including Grade 2 (0.3%), 3 (0.3%), and 4 (0.1%) hypophysitis. Hypophysitis occurred in 1 (0.2 %) of 550 patients with NSCLC, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 51 (3.3%) of 1567 patients with melanoma, including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 127 (8.1%) of 1567 patients with melanoma, including Grade 3 (0.1%) hypothyroidism. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in patients receiving KEYTRUDA. Nephritis occurred in 7 (0.4%) of 1567 patients with melanoma including, Grade 2 (0.2%), 3 (0.2%), and 4 (0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA (pembrolizumab) for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 1567 patients with melanoma: arthritis (1.6%), exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients with NSCLC: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In Trial 6, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA (pembrolizumab) vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In Trial 2, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 14% of 550 patients with NSCLC. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 270 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On June 6, 2016 Exelixis, Inc. (NASDAQ:EXEL) and Ipsen (Euronext: IPN; ADR: IPSEY) reported the presentation of positive data from subgroup analyses of the pivotal METEOR trial comparing CABOMETYX (cabozantinib) tablets with everolimus in 658 patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy (Press release, Exelixis, JUN 6, 2016, View Source [SID:1234513040]).

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The data will be presented in two posters today at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held June 3-7 in Chicago, by Bernard Escudier, M.D., chair, Genitourinary Oncology Committee, Institut Gustave Roussy and Thomas Powles, M.D., clinical professor of genitourinary oncology, Barts Cancer Institute. The findings demonstrate that benefits of CABOMETYX in progression-free survival (PFS) and overall survival (OS) were independent of the presence of bone metastases, prior anti-PD-1/PD-L1 therapy, and the type of prior vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) therapy.

"These additional analyses demonstrate the value of CABOMETYX for advanced kidney cancer, showing consistent improvement in PFS and OS across multiple subgroups of patients in the METEOR trial," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "We are dedicated to exploring the full potential of CABOMETYX to help as many patients as possible."

In the first of the two presentations, treatment with CABOMETYX was associated with improved PFS and OS in patients who had bone metastases at baseline (n=142). Median PFS was 7.4 months with CABOMETYX versus 2.7 months with everolimus (HR=0.33, 95% CI 0.21-0.51), and median OS was 20.1 months versus 12.1 months, respectively (HR=0.54, 95% CI 0.34-0.84).

For patients who had both bone and visceral metastases (n=112), median PFS was 5.6 months with CABOMETYX and 1.9 months with everolimus (HR=0.26, 95% CI 0.16-0.43). Median OS was 20.1 months versus 10.7 months, respectively (HR=0.45, 95% CI 0.28-0.72). The safety profile of CABOMETYX for the subgroup with bone metastases was consistent with that of the overall METEOR trial.

"Patients whose kidney cancer has spread to their bones traditionally have a poorer prognosis and worse treatment outcomes compared with those who do not have bone involvement," said Dr. Escudier. "CABOMETYX demonstrated a clinically meaningful benefit for those with bone metastases, which is encouraging for physicians and patients who are seeking additional therapeutic options."

In the second presentation, outcomes were evaluated based on the prior therapy patients had received before entering the METEOR trial. OS and PFS benefits were consistent across all subgroups evaluated (see table below), including number of prior VEGFR TKIs (one or more than one), specific prior VEGFR TKI (sunitinib or pazopanib) in patients who had only one prior VEGFR TKI therapy, and prior treatment with anti-PD-1/PD-L1 therapies. Adverse events in the treatment subgroups were similar to those in the overall study population and were managed with dose reductions.

Table. OS and PFS in METEOR by Subgroup


Subgroup n Median OS (months)
OS
Hazard
Ratio
(95% CI)

Median PFS (months)

PFS
Hazard
Ratio
(95% CI)
CABOMETYX Everolimus CABOMETYX Everolimus
Number of prior VEGFR TKIs
1 464 21.4 16.5 0.65 (0.50-0.85) 7.4 3.8 0.52 (0.41-0.66)
≥2 194 20.8 17.2 0.73 (0.48-1.10) 7.4 4.0 0.51 (0.35-0.74)
Only prior VEGFR TKI
Sunitinib 267 21.4 16.5 0.66 (0.47-0.93) 9.1 3.7 0.43 (0.32-0.59)
Pazopanib 171 22.0 17.5 0.66 (0.42-1.04) 7.4 5.1 0.67 (0.45-0.99)
Prior anti-PD-1/PD-L1 therapy
No 626 21.4 16.5 0.68 (0.54-0.85) 7.4 3.9 0.54 (0.44-0.66)
Yes 32 Not estimable 16.3 0.56 (0.21-1.52) Not estimable 4.1 0.22 (0.07-0.65)

"These findings demonstrate that the benefit of CABOMETYX for patients was robust and consistent regardless of prior treatment, location and extent of tumor metastases," said Marc de Garidel, Chairman and CEO, Ipsen.

On April 25, 2016 CABOMETYX was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. CABOMETYX, which was granted Fast Track and Breakthrough Therapy designations by the FDA, is the first approved single agent therapy to demonstrate, in a phase 3 trial for patients with advanced RCC, robust and clinically meaningful improvements in all three key efficacy parameters — OS, PFS and objective response rate.

Please see Important Safety Information below and full U.S. prescribing information for CABOMETYX (cabozantinib) tablets at View Source

About the METEOR Phase 3 Pivotal Trial

METEOR was an open-label, event-driven trial of 658 patients with advanced renal cell carcinoma who had failed at least one prior VEGFR TKI therapy. The primary endpoint was PFS in the first 375 patients treated. Secondary endpoints included OS and objective response rate in all enrolled patients. The trial was conducted at approximately 200 sites in 26 countries, and enrollment was weighted toward Western Europe, North America, and Australia. Patients were randomized 1:1 to receive 60 mg of CABOMETYX daily or 10 mg of everolimus daily and were stratified based on the number of prior VEGFR TKI therapies received and on MSKCC risk criteria. No cross-over was allowed between the study arms.

METEOR met its primary endpoint of significantly improving PFS. Compared with everolimus, CABOMETYX was associated with a 42 percent reduction in the rate of disease progression or death. Median PFS for CABOMETYX was 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). CABOMETYX also significantly improved the objective response rate compared with everolimus (P<0.0001). These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.1

CABOMETYX also demonstrated a statistically significant and clinically meaningful increase in OS in the METEOR trial. Compared with everolimus, CABOMETYX was associated with a 34 percent reduction in the rate of death. Median OS was 21.4 months for patients receiving CABOMETYX versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).

Cabozantinib benefit in OS was robust and consistent across all pre-specified subgroups. In particular, benefit was observed regardless of risk category, location and extent of tumor metastases, and tumor MET expression level. These results were presented on June 5, 2016 at the ASCO (Free ASCO Whitepaper) Annual Meeting and concurrently published in The Lancet Oncology.2

At the time of the analysis, the median duration of treatment in the trial was 8.3 months with CABOMETYX versus 4.4 months with everolimus. Dose reductions occurred for 62 percent and 25 percent of patients, respectively. Discontinuation rate due to an adverse event not related to disease progression was 12 percent with CABOMETYX and 11 percent with everolimus.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2016 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.3 Clear cell RCC is the most common type of kidney cancer in adults.4 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.3 Approximately 17,000 patients in the U.S. and 37,000 globally require second-line or later treatment.5

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.6,7 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.8-11 MET and AXL may provide escape pathways that drive resistance to VEGFR inhibitors.7,8

About CABOMETYX

CABOMETYX targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

CABOMETYX, the tablet formulation of cabozantinib, is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy.

On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days. On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.

Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-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. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-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: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. 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. Dose modification due to diarrhea occurred in 26% of patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): 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: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.

Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.

Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.

Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see full Prescribing Information at View Source.

On June 6, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported results from two trials evaluating the Opdivo and Yervoy combination regimen in advanced melanoma (Press release, Bristol-Myers Squibb, JUN 6, 2016, View Source [SID:1234513034]).

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In the pivotal Phase 3 trial, CheckMate -067 trial, at a minimum follow-up of 18 months, the Opdivo and Yervoy combination demonstrated continued clinical benefit with a 58% reduction in the risk of disease progression versus Yervoy monotherapy (HR=0.42 [99.5% CI: 0.31-0.57; p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk reduction versus Yervoy alone (HR=0.55 [99.5% CI: 0.43-0.76; p<0.0001]). Durable responses were also observed with the combination regimen in a subgroup of patients who discontinued therapy due to treatment-related adverse events (n=35) and appeared consistent with the overall randomized patient population (n=95), based on a post-hoc analysis from the Phase 2 study, CheckMate -069. Among this subgroup of patients, the objective response rate was 66%, and 20% achieved a complete response, with a minimum follow-up of two years. At two years, the median duration of response was not reached and 74% remain in response. The safety profile of the Opdivo and Yervoy combination regimen in both CheckMate -067 and -069 was consistent with previously reported studies of the combination, and most treatment-related adverse events were managed using established algorithms.

"The data from CheckMate -067 provide new insights on the long-term durability of the progression-free survival benefit seen with the nivolumab and ipilimumab combination regimen in advanced melanoma relative to ipilimumab monotherapy," said Jedd D. Wolchok, M.D., Ph.D., Chief, Melanoma and Immunotherapeutics Service, at Memorial Sloan Kettering Cancer Center. "In addition, in a post-hoc analysis from CheckMate -069, we observed that even for patients who discontinue treatment with the combination regimen due to toxicity, efficacy outcomes appeared consistent with that seen in the overall study population. These data are encouraging and provide additional important information about the efficacy and safety of the combination regimen in these patients."

The CheckMate -067 data will be presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in an oral abstract session on Monday, June 6, from 2:39 PM – 2:51 PM CDT (Abstract #9505). The CheckMate -069 data were presented in a poster discussion session on Saturday, June 4 (Abstract #9518).

Vicki Goodman, M.D., Development Lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb, commented, "With the CheckMate -067 and -069 data presented at ASCO (Free ASCO Whitepaper), we observe, with longer follow-up, the durability of progression-free survival and response for the Opdivo and Yervoy combination regimen in advanced melanoma. These findings further validate our research strategy to study the combination of Immuno-Oncology agents, and we remain committed to building on this research and evaluating more ways to improve long-term survival and patient outcomes in advanced cancers."

About CheckMate -067

CheckMate -067 is a Phase 3, double-blind, randomized study that evaluated the Opdivo and Yervoy combination regimen or Opdivo monotherapy versus Yervoy monotherapy in patients with previously untreated advanced melanoma, including both BRAF V600 mutation positive or BRAF wild-type advanced melanoma. A total of 945 patients were randomized to receive the Opdivo and Yervoy combination regimen (Opdivo 1 mg/kg plus Yervoy 3 mg/kg every 3 weeks administered intravenously for 4 doses followed by Opdivo 3 mg/kg every 2 weeks thereafter; n=314), Opdivo monotherapy (Opdivo 3 mg/kg every 2 weeks administered intravenously; n=316) or Yervoy monotherapy (Yervoy 3 mg/kg every 3 weeks administered intravenously for 4 doses followed by placebo every 2 weeks; n=315). Patients were treated until progression or unacceptable toxic effects. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS); secondary endpoints included PFS and objective response rate (ORR), as well as safety and tolerability. The study is ongoing in its evaluation for OS.

At a minimum follow-up of 18 months, the Opdivo and Yervoy combination demonstrated a 58% reduction in the risk of disease progression versus Yervoy monotherapy in previously untreated patients with advanced melanoma (HR=0.42 [99.5% CI: 0.31-0.57; p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk reduction versus Yervoy monotherapy (HR=0.55 [99.5% CI: 0.43-0.76; p<0.0001]). At a minimum follow-up of 18 months, the median PFS for the combination regimen was 11.5 months (95% CI: 8.9-16.7) and 6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy versus 2.9 months (95% CI: 2.8-3.4) for Yervoy monotherapy. At 18 months, the PFS rate was 46% for the combination regimen (HR=0.42 [99.5% CI: 0.31-0.57; p<0.00001]), 39% for Opdivo monotherapy (HR=0.55 [99.5% CI: 0.43-0.76; p<0.00001]), and 14% for Yervoy.

The Opdivo and Yervoy combination regimen and Opdivo monotherapy also demonstrated a higher ORR (58% and 44%, p<0.0001, respectively) versus Yervoy monotherapy (19%). There were 38 (12%) complete responses and 143 (46%) partial responses seen in patients treated with the combination regimen, and 31 (10%) complete responses and 107 (34%) partial responses seen in patients treated with Opdivo monotherapy, versus 7 (2%) complete responses and 53 (17%) partial responses seen in patients treated with Yervoy alone. The median duration of response had not been reached for those patients treated with the Opdivo and Yervoy combination regimen, and was 22.3 months for Opdivo monotherapy and 14.4 months for Yervoy alone. In the study, a change in tumor burden was seen with the Opdivo and Yervoy combination regimen and Opdivo monotherapy, with a median decrease of 51.9% and 34.5%, respectively, and 5.9% increase for Yervoy alone.

As part of a pre-planned, descriptive analysis of data from CheckMate -067, a greater improvement in PFS for the combination of Opdivo with Yervoy, relative to Opdivo monotherapy, was only observed in patients with low tumor PD-L1 expression. Overall response rates were higher for the combination of Opdivo and Yervoy relative to Opdivo monotherapy, regardless of tumor PD-L1 expression levels. In addition, efficacy of the Opdivo and Yervoy combination regimen and Opdivo monotherapy was observed, regardless of BRAF mutational status.

With longer follow-up, the safety of the Opdivo and Yervoy combination regimen in CheckMate -067 was consistent with previously reported studies of the combination regimen and most treatment-related select adverse events (AEs) were managed with immune-modulating medications. Grade 3-4 treatment-related AEs were reported more frequently with the combination regimen (56.5%), relative to the Opdivo monotherapy (19.8%) versus Yervoy alone (27%). Treatment-related AEs of any grade led to discontinuation in 38.7% of patients treated with the combination regimen, 10.5% for patients treated with Opdivo monotherapy, and 15.4% of patients treated with Yervoy alone. No treatment-related deaths occurred in the Opdivo and Yervoy combination regimen arm. The most common treatment-related select AEs of any grade with the combination regimen versus Yervoy alone included increased ALT (17.9% vs. 3.9%), increased AST (15.7% vs. 3.9%), diarrhea (45.4 % vs. 33.8%), colitis (11.5% vs. 11.3%), rash (28.4% vs. 21.2%), pruritus (35.1% vs. 36.3%), hypothyroidism (16% vs. 4.5%), hyperthyroidism (10.2% vs. 1%), elevated creatinine (4.2% vs. 1.6%), and pneumonitis (6.7% vs. 1.6%).

About CheckMate -069

CheckMate -069 is a Phase 2, double-blind, randomized study that evaluated 142 patients with previously untreated unresectable or metastatic melanoma who received either the Opdivo and Yervoy combination regimen (n=95) or Yervoy alone (n=47). The trial included patients with BRAF wild-type and BRAF V600 mutation-positive melanoma, and randomization was stratified by BRAF mutation status. The primary endpoint was objective response rate (ORR) in patients with BRAF wild-type tumors. Secondary endpoints included progression-free survival (PFS) in patients with BRAF wild-type tumors, ORR in patients with BRAF V600 mutation positive tumors, and safety. Overall survival (OS) was an exploratory endpoint.

Based on a post-hoc analysis at a minimum follow-up of two years, OS and response rates in patients who discontinued treatment with the Opdivo and Yervoy combination regimen due to treatment-related adverse events (AEs, n=35) appeared consistent with the overall population. The two-year OS rate in patients who discontinued treatment with the Opdivo and Yervoy combination regimen due to AEs was 71%. In the original exploratory analysis of the overall study population, the OS rate was 64% at two years for the Opdivo and Yervoy combination regimen and 54% for Yervoy alone (HR=0.74 [95% CI: 0.43-1.26]).

For the overall patient population and the subgroup of patients who discontinued the Opdivo and Yervoy combination regimen due to AEs, the median PFS has still not been reached. In addition, based on the post-hoc analysis, the PFS rate at two years for those patients who discontinued the Opdivo and Yervoy combination regimen due to treatment-related AEs was 52% (95% CI: NR; 7.03-NR). The PFS rate observed in the original exploratory analysis at two years was 51% (95% CI: NR; 7.36-NR) in all patients treated with the combination regimen and 12% with Yervoy alone.

Objective response rates among patients who discontinued the Opdivo and Yervoy combination regimen was 66% (95% CI: 48-81), and 20% achieved a complete response. The ORR observed in the original exploratory analysis was 59% (95% CI: 48-69), and 22% achieved a complete response. Median duration of response was not reached in either group, with ongoing responses seen in 80% of the overall patient population, and in 74% patients who discontinued the combination regimen due to AEs. In addition, exploratory results showed a median reduction of 69% in tumor burden in those patients who discontinued the Opdivo and Yervoy combination regimen.

The rates of overall treatment-related adverse events (AEs) leading to discontinuation remained consistent with previously reported results from CheckMate -069. The most common treatment-related select AEs of any grade for patients treated with the Opdivo and Yervoy combination regimen were rash (43%), pruritus (40%), diarrhea (45%), colitis (18%), increased ALT (26%), increased AST (28%), hypothyroidism (17%), hypophysitis (13%), pneumonitis (10%), and increased creatinine (2%).

About Advanced Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average five-year survival rate is 15% – 20%.

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

At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.

We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for overall survival and other important measures like durability of response. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents, and continue to study the role of combinations in cancer.

We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.

Our collaboration with academia, as well as small and large biotech companies, to research the potential of Immuno-Oncology and non-Immuno-Oncology combinations, helps achieve our goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the way patients live with cancer.

About Opdivo

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating overall survival as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 51 countries including the United States, Japan, and in the European Union.

U.S. FDA APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post- transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

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

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

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

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in Checkmate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In Checkmate 057, immune- mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In Checkmate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In Checkmate 205 and 039, diarrhea or colitis occurred in 30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune- mediated hepatitis. In Checkmate 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Dermatitis

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In Checkmate 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25), and Grade 1 (n=3). In Checkmate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 069 and 067, adrenal insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In Checkmate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In Checkmate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 205 and 039, adrenal insufficiency (Grade 2) occurred in 0.4% (1/263) of patients receiving OPDIVO. In Checkmate 069 and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In Checkmate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 205 and 039, hypothyroidism/thyroiditis occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2 (n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5% (4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1 (n=1). In Checkmate 069 and 067, diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In Checkmate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1). In Checkmate 025, hyperglycemic adverse events occurred in 9% (37/406) patients.

Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1). In Checkmate 205 and 039, diabetes mellitus occurred in 0.8% (2/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 069 and 067, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In Checkmate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6). In Checkmate 205 and 039, nephritis and renal dysfunction occurred in 4.9% (13/263) of patients treated with OPDIVO. This included one reported case (0.3%) of Grade 3 autoimmune nephritis.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In Checkmate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In Checkmate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune- mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In Checkmate 205 and 039, rash occurred in 22% (58/263) of patients receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In Checkmate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO. In Checkmate 205 and 039, encephalitis occurred in 0.8% (2/263) of patients after allogeneic HSCT after OPDIVO.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune- mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In Checkmate 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In Checkmate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In Checkmate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In Checkmate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In Checkmate 205 and 039, hypersensitivity/infusion- related reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic SCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune- mediated adverse reactions, and intervene promptly.

Embryo-fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]).

Common Adverse Reactions

In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (reported in at least 20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

CHECKMATE Trials and Patient Populations

Checkmate 069 and 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 057 – non-squamous non-small cell lung cancer (NSCLC); Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma

On June 6, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported updated clinical data on brigatinib, its investigational anaplastic lymphoma kinase (ALK) inhibitor, from the pivotal ALTA trial in patients who had experienced disease progression on crizotinib therapy (Press release, Ariad, JUN 6, 2016, View Source [SID:1234513032]).

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The data show that, of patients on the 180 mg regimen (Arm B) with a median follow-up of 8.3 months, 54 percent achieved a confirmed objective response, the trial’s primary endpoint. In this arm, the median progression free survival (PFS) exceeded one year (12.9 months) in this post-crizotinib setting. Additionally, a 67 percent confirmed intracranial objective response rate (ORR) was achieved in patients with measurable brain metastases. These data will be presented today, for the first time, at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), reflecting an additional 12 weeks of patient follow up and new data on central nervous system (CNS) activity compared to the abstract released last month.

"Most patients with ALK-positive non-small cell lung cancer who are treated with crizotinib eventually experience disease progression, often due to acquired ALK resistance mutations or metastases in the central nervous system," said presenting author Dong-Wan Kim, M.D., Ph.D., head of the Cancer Clinical Trials Center at the Seoul National University Hospital in South Korea. "For these patients, we are very excited by the brigatinib ALTA trial data, which showed compelling efficacy and safety data, including complete responses and activity in the CNS."

The ALTA trial

The primary endpoint of the ALTA (ALK in Lung Cancer Trial of AP26113) trial is investigator-assessed confirmed objective response rate (ORR) as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Key secondary endpoints include progression free survival (PFS), confirmed ORR assessed by an independent review committee (IRC), CNS response (IRC-assessed intracranial ORR and PFS), overall survival, safety and tolerability. Brigatinib was granted the U.S. Food and Drug Administration (FDA) Orphan Drug designation for ALK+ non-small cell lung cancer (NSCLC) and the FDA Breakthrough Therapy designation for the treatment of patients with ALK+ non-small cell lung cancer (NSCLC) that is resistant to crizotinib.

The trial enrolled 222 patients with ALK+ NSCLC who had been treated with and experienced disease progression on crizotinib. Patients were randomized one-to-one to receive either 90 mg of brigatinib once per day (QD) (Arm A), or 180 mg QD with a seven day lead-in at 90 mg QD (Arm B).

In addition, patients were stratified by the presence of brain metastases at baseline and best response to prior crizotinib.

Key Data from the ALTA Trial

Brigatinib Efficacy and Safety in ALK+ NSCLC Patients:

Data as of February 29, 2016

A total of 222 patients with ALK+ NSCLC treated with prior crizotinib therapy were randomized in the study (110 patients in Arm B at the 180 mg dose level with 7-day lead-in at 90 mg and 112 patients in Arm A at the 90 mg dose level). The last patient enrolled in the study in September 2015.
The median follow-up was 8.3 months in Arm B (range 0.1—20.2) and 7.8 months in Arm A (range 0.1—16.7).
Investigator-assessed confirmed ORR in Arm B was 54 percent, including four complete responses. Confirmed ORR in Arm A was 45 percent, including one complete response.
Responses in Arm B included a confirmed partial response in a patient with the ALK kinase domain G1202R mutation at baseline, which is associated with resistance to all approved tyrosine kinase inhibitors (TKIs).
Median PFS was 12.9 months and 9.2 months in Arm B and Arm A, respectively. Probability of overall survival (OS) at 1-year was 80 percent and 71 percent in Arm B and Arm A, respectively.
An evaluation of the efficacy of brigatinib in ALK+ NSCLC patients with intracranial CNS metastases at baseline was also included in the ASCO (Free ASCO Whitepaper) presentation.
In an independent central review of brain magnetic resonance imaging (MRI) scans, 18 patients in Arm B and 25 patients in Arm A were identified as having measurable CNS metastases at baseline.
Among patients with measurable CNS metastases at baseline, the IRC-assessed confirmed intracranial ORR was 67 percent (12/18) in Arm B and 36 percent (9/25) in Arm A; among the subset of patients with measurable, active brain metastases, confirmed intracranial ORR was 73 percent (11/15) in Arm B and 36 percent (7/19) in Arm A. Measurable, active brain metastases are defined as having had no prior radiotherapy or progression following radiotherapy.
Median intracranial PFS for patients with intracranial CNS metastases at baseline was not yet reached in Arm B and was 15.6 months in Arm A.
The most common treatment-emergent adverse events (TEAEs; ≥ 25% of all patients, [Arm B/A]), regardless of relationship to treatment, were nausea (40%/33%), diarrhea (38%/19%), cough (34%/18%), and headache (27%/28%).
TEAEs, ≥ grade 3, occurring in ≥ 5 percent of all patients (Arm B/A), were increased blood creatine phosphokinase (9%/3%) and hypertension (6%/6%).
A subset of pulmonary adverse events with early onset (median: Day 2; range: Day 1-9) occurred in 6 percent of all patients (≥ grade 3 in 3% of patients); no such events with early onset occurred after dose escalation to 180 mg QD in Arm B.
Discontinuations and dose reductions due to AEs (Arm B/A) were 8 percent/3 percent and 20 percent/7 percent, respectively. Discontinuations due to progressive disease (Arm B/A) were 17 percent and 30 percent.
"The ALTA trial data support our planned NDA submission with a recommendation for dosing with 180 mg once daily following a seven-day lead-in at 90 mg. We are on track for submission in the third quarter," stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "We believe brigatinib’s antitumor activity both on disease in the lungs and in the central nervous system, safety profile, and once-daily dosing regimen taken with or without food, provide the potential for brigatinib to be an important new therapeutic option for the crizotinib-resistant patient population."

Investor and Analyst Briefing and Webcast

A breakfast meeting featuring D. Ross Camidge, M.D., Ph.D., director of thoracic oncology at the Colorado University Cancer Center, to review the updated brigatinib clinical data from the ALTA trial will be webcast live along with slides and can be accessed by visiting the investor relations section of ARIAD’s website at View Source


Date: Monday, June 6, 2016
Time: 7:00 a.m. to 8:00 a.m. (CT)
Location: Hyatt McCormick Place

A replay of the investor event will be available on the ARIAD website approximately three hours after the presentation and will be archived on the site for four weeks. To ensure a timely connection to the live webcast, participants should log onto the webcast at least 15 minutes prior to the scheduled start time.

About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD Pharmaceuticals, Inc. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell cancer (NSCLC) whose disease is resistant to crizotinib. Brigatinib is currently being evaluated in the global Phase 2 ALTA trial that is anticipated to form the basis for its initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy of brigatinib in comparison to crizotinib. More information on brigatinib clinical trials, including the expanded access program (EAP) can be found here.

Brigatinib Oral Presentation

The oral presentation, "Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)- refractory ALK+ non–small cell lung cancer (NSCLC): first report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA)," (Abstract #9007) will be presented today, Monday, June 6 in the Arie Crown Theater at 11:57 a.m. CT.

On June 6, 2016 OncoSec Medical Incorporated ("OncoSec") (NASDAQ: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, reported that its collaborators at the University of California San Francisco (UCSF) presented results at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, demonstrating the utility of a T-cell exhaustion marker to predict response to anti-PD-1 monotherapies (Press release, OncoSec Medical, JUN 6, 2016, View Source [SID:1234513012]).

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Authors of this poster discussion session from UCSF include Adil Daud, MD, Alain Algazi, MD, and Michael Rosenblum, MD, PhD. This "low-tumor infiltrating lymphocyte" (TIL) marker is currently being used to select patients for the ongoing Phase II investigator-sponsored clinical trial evaluating the combination of OncoSec’s investigational therapy, ImmunoPulse IL-12, and the approved anti-PD-1 therapy, pembrolizumab, in patients with unresectable metastatic melanoma.

Using samples from prior trials, authors presented results from a total of 53 patients evaluable for both response and the T-cell exhaustion marker (TEx). Fifteen patients were treated with a combination of ipilimumab and nivolumab, and 38 with monotherapy anti-PD-1. Patients determined to be "low-TIL" (TEx ≤20%) had 0/12 (0%) responses to anti-PD-1 therapy, while patients who were "high-TIL" (TEx >20%) had 21/26 (81%) responses. Median TEx was 40.3% for responders and 16% for non-responders. Using a threshold of TEx at 20%, the negative predictive value for response was 100% and the positive predictive value was 81%. For patients treated with the combination of ipilimumab and nivolumab, the TEx threshold predictive of response was much lower. The authors concluded that this novel T-cell exhaustion marker (% TEx) is an accurate predictor of response to monotherapy, but not response to combination therapy with ipilimumab and nivolumab.

OncoSec is currently enrolling patients into the Phase II clinical trial led by UCSF to assess the anti-tumor activity, safety, and tolerability of the combination of ImmunoPulse IL-12 and pembrolizumab. This multi-center, open-label, single-arm trial is the first study to select patients for "low-TIL" status using UCSF’s T-cell exhaustion marker assay. The study will test the hypothesis as to whether the addition of ImmunoPulse IL-12 to pembrolizumab can increase the response rate in low-TIL melanoma patients, who have a low likelihood of responding to monotherapy with anti-PD-1 blockade. The key endpoints of the study include: best overall response rate (BORR) by RECIST v1.1 and immune-related Response Criteria (irRC); safety and tolerability; duration of response; 24-week landmark progression-free survival; median progression-free survival; and overall survival.

"We are delighted that our collaborators are presenting data at ASCO (Free ASCO Whitepaper) demonstrating the utility of the flow cytometric TIL assay," said Robert H. Pierce, MD, Chief Scientific Officer at OncoSec. "Our ongoing investigator-sponsored combination trial of ImmunoPulse IL-12 and pembrolizumab hinges on the strong predictive value for poor treatment outcomes from this assay. Given these data, we are confident that we will be able to robustly identify a combination efficacy signal in our ongoing single-arm trial."

For more information about this trial, please visit: View Source