On May 10, 2017 Array BioPharma Inc. (Nasdaq: ARRY), a biopharmaceutical company focused on the discovery, development and commercialization of targeted small molecule cancer therapies, reported results for its third quarter of fiscal 2017 and provided an update on the progress of its key clinical development programs (Press release, Array BioPharma, MAY 10, 2017, View Source [SID1234519007]). Schedule your 30 min Free 1stOncology Demo! COLUMBUS PHASE 3 TRIAL: Positive Part 2 Results Announced
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On May 9, 2017, Array announced top-line results from Part 2 of the Phase 3 COLUMBUS study evaluating binimetinib, a MEK inhibitor, and encorafenib, a BRAF inhibitor, in patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The primary analysis of Part 2 compared progression free survival (PFS) in patients treated with binimetinib 45mg twice daily plus encorafenib 300mg daily (COMBO300) to patients treated with encorafenib 300mg daily as a single agent. The median PFS (mPFS) for patients treated with COMBO300 was 12.9 months compared to 9.2 months for patients treated with single agent encorafenib, with a HR of 0.77 [95% CI 0.61-0.97, p=0.029]. COMBO300 was generally well-tolerated and reported dose intensity and adverse events were consistent with binimetinib (45mg twice daily) plus encorafenib 450mg daily (COMBO450) results from Part 1 of the COLUMBUS trial. Part 2 of COLUMBUS was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300mg in the combination arm to allow for a comparison of equal doses across arms. Further results from Part 2 will be presented at a medical meeting during the second half of 2017.
"The robust PFS benefit and tolerability observed with binimetinib plus encorafenib in COLUMBUS suggest the combination represents a potential important addition to the MEK/BRAF treatment landscape for patients with BRAF-mutant melanoma," said Ron Squarer, Chief Executive Officer, Array BioPharma.
Based on the strength of data from Part 1 and Part 2, Array is on track to file an NDA for COLUMBUS in June or July 2017. The primary endpoint for the COLUMBUS trial is a PFS comparison of COMBO450 versus vemurafenib in Part 1. Array’s European partner, Pierre Fabre, remains on track to file the Marketing Authorization Application during the summer.
Melanoma is the fifth most common cancer among men and the sixth most common cancer among women in the United States, with more than 87,000 new cases and over 9,700 deaths from the disease expected in 2017. Novel therapies that target the RAS-RAF-MEK-ERK pathway have a strong scientific rationale for activity in this disease, as up to 50 percent of patients with metastatic melanoma have activating BRAF mutations, the most common gene mutation in this patient population. Currently marketed MEK/BRAF combination agents have a run rate approaching $1 billion in annual worldwide sales.
MERCK COLLABORATION: Binimetinib and KEYTRUDA combination trial announced in MSS colorectal cancer patients
Array entered into a clinical trial collaboration agreement with Merck to investigate the safety and efficacy of binimetinib with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in metastatic colorectal cancer patients with microsatellite stable tumors (MSS CRC). The companies entered into this collaboration based on the growing body of preclinical and clinical evidence that the immune activity of an anti-PD-1 therapy, such as KEYTRUDA, can be enhanced when combined with a MEK inhibitor, such as binimetinib.
Under the agreement, Array and Merck will collaborate on a clinical trial to investigate the safety and efficacy of the combination of binimetinib with KEYTRUDA, in MSS CRC patients. The trial is expected to establish a recommended dose regimen of binimetinib and KEYTRUDA, as well as explore the preliminary anti-tumor activity of several novel regimens. The study is expected to begin in the second half of 2017. Results from this first study will be used to determine optimal approaches to further clinical development of these combinations.
Merck will act as the sponsor of this clinical trial, and Array will supply Merck with binimetinib for use in the trial. This agreement does not include a non-competition provision that generally prohibits Merck or Array from entering into agreements with third parties to perform other clinical studies.
BEACON CRC PHASE 3 TRIAL: Randomized portion of trial now enrolling; patients receiving treatment
Array is advancing BEACON CRC, a global Phase 3 trial of encorafenib and Erbitux (cetuximab), with or without binimetinib, versus standard of care in patients with BRAF-mutant CRC who have previously received first- or second-line systemic therapy. Based on an attractive safety profile and with early encouraging clinical activity observed in the safety lead-in, the randomized portion of the trial is now enrolling and patients are receiving treatment. Array expects to present early data from the safety lead-in later this year.
BEACON CRC was initiated based on results from a Phase 2 study including the combination of encorafenib and cetuximab in patients with advanced BRAF-mutant CRC, which were presented at the 2016 ASCO (Free ASCO Whitepaper) annual meeting. In this study median Overall Survival for these patients exceeded one year, which is more than double several historical published benchmarks for this population.
Colorectal cancer is the second most common cancer among men and third most common cancer among women in the United States, with more than 135,000 new cases and more than 50,000 deaths from the disease projected in 2017. In the United States, BRAF mutations occur in 8 to 15 percent of patients with colorectal cancer and represent a poor prognosis for these patients.
ARRY-382 + KEYTRUDA PHASE 1/2 TRIAL: Phase 1b/2 expansions to begin shortly
Array is advancing a Phase 1/2 dose escalation immuno-oncology trial of ARRY-382 in combination with KEYTRUDA, in patients with advanced solid tumors. ARRY-382 is a wholly-owned, highly selective and potent, small molecule inhibitor of CSF-1R kinase activity. Planned expansions include patients with melanoma and non-small cell lung cancer.
FINANCIAL HIGHLIGHTS
Novartis continues to substantially fund all ongoing trials with binimetinib and encorafenib that were active or planned as of the close of the Novartis Agreements in 2015, including the NEMO and COLUMBUS Phase 3 trials. Reimbursement revenue from Novartis was approximately $119 million for the previous 12 months, of which $26 million was recorded over the quarter ending March 31, 2017.
Third Quarter of Fiscal 2017 Compared to Second Quarter of Fiscal 2017 (Sequential Quarters Comparison)
Revenue for the third quarter of fiscal 2017 was $33.3 million, compared to $44.5 million for the prior sequential quarter. The decrease was primarily due to non-recurring milestones received in the prior quarter.
Cost of partnered programs for the third quarter of fiscal 2017 was $7.4 million, compared to $9.0 million for the prior quarter.
Research and development expense was $46.1 million, compared to $46.5 million in the prior quarter.
Loss from Operations for the quarter was $31.9 million, which includes $2.9 million of stock-based compensation and $0.5 million of depreciation expense. This compares to a loss from operations of $20.0 million in the previous quarter, which included $2.1 million of stock-based compensation and $0.5 million of depreciation expense.
Net loss for the third quarter was $35.3 million, or ($0.21) per share, compared to $23.3 million, or ($0.14) per share, in the prior quarter. The increase in net loss was primarily due to non-recurring milestones received in the prior quarter.
Cash, Cash Equivalents and Marketable Securities as of March 31, 2017 were $207 million.
Third Quarter of Fiscal 2017 Compared to Third Quarter of Fiscal 2016 (Prior Year Comparison)
Revenue for the third quarter of fiscal 2017 decreased $9.8 million compared to the same quarter of fiscal 2016. The decrease was primarily due to decreased reimbursement revenue for the Novartis transitioned studies.
Cost of partnered programs increased $1.6 million compared to the third quarter of fiscal 2016. The increase was primarily due to higher costs incurred for the BEACON CRC trial.
Research and development expense decreased $2.7 million, compared to the third quarter of fiscal 2016. The decrease was due to greater expenses associated with the Novartis transitioned binimetinib and encorafenib studies.
Net loss for the third quarter of fiscal 2017 was $35.3 million, or ($0.21) per share, compared to $22.7 million, or ($0.16) per share, for the same quarter in fiscal 2016.
LEADERSHIP
Array announced that Shalini Sharp, Chief Financial Officer and Executive Vice President of Ultragenyx Pharmaceutical Inc., joined the company’s Board of Directors, effective April 27, 2017. Ms. Sharp has been appointed to the Audit Committee of the Board.
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Merrimack Reports First Quarter 2017 Financial Results
On May 10, 2017 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK) reported its first quarter 2017 financial results for the period ended March 31, 2017 (Press release, Merrimack, MAY 10, 2017, View Source [SID1234519006]). Schedule your 30 min Free 1stOncology Demo! "The first quarter of 2017 was transformative for Merrimack. Following our pipeline prioritization and the strategic review of our business, we emerged with clear priorities as a refocused research and clinical development company. We outlined three programs – MM-121, MM-141 and MM-310 – as the most promising clinical programs on which we will focus our development efforts going forward," said Richard Peters, M.D., Ph.D., President and Chief Executive Officer. "Critical to this transition was the sale of assets to Ipsen, including ONIVYDE, our first commercial product. The reduced operational costs and proceeds from the sale will pave our redefined path forward and allow us to pay down our debt, pay a special dividend to stockholders and fund our expected operations into the second half of 2019. As we look forward to the year ahead, we are confident that the significant potential of our programs in development, our strong cash position and our refined strategy will drive Merrimack’s long-term success."
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First Quarter and Recent Highlights
In April 2017, Merrimack launched as a new, refocused research and clinical development company. In conjunction with this strategic shift, key events from the first quarter and more recently include:
Prioritization of three clinical programs: MM-121 (seribantumab) targeting heregulin positive non-small cell lung cancer and heregulin positive, hormone receptor positive, HER2 negative metastatic breast cancer; MM-141 (istiratumab) targeting high IGF1 expression in metastatic pancreatic cancer patients; and MM-310, the antibody-directed nanotherapeutic (ADN) containing a prodrug of docetaxel for solid tumors;
Initiation of a Phase 1 clinical study to assess safety, pharmacology and preliminary activity of MM-310 in solid tumors. Merrimack expects to report safety data and a recommended Phase 2 dose from this study in 2018;
Closing of the sale of ONIVYDE and Merrimack’s generic version of doxorubicin hydrochloride liposome injection to Ipsen S.A. for $575 million in cash upon closing and up to $450 million in additional regulatory approval-based milestone payments. Merrimack also retained the right to receive net milestone payments of up to $33 million that may become payable pursuant to its previous license and collaboration agreement with Shire plc for the ex-U.S. development and commercialization of ONIVYDE;
Authorization by the Board of Directors of a special cash dividend of $140 million to holders of Merrimack’s common stock, which is payable on May 26, 2017 from the proceeds of the asset sale to Ipsen; and
Appointment of Daryl Drummond, Ph.D. as Head of Research.
Upcoming Milestones
Merrimack anticipates the following upcoming clinical milestones:
Initiation this year of a Phase 2 randomized clinical study of MM-121 in patients with heregulin positive, hormone receptor positive, HER2 negative metastatic breast cancer;
Top-line results in 2018 from the Phase 2 randomized clinical study of MM-121 in patients with heregulin positive non-small cell lung cancer;
Top-line results in 2018 from the Phase 2 randomized clinical study of MM-141 in patients with front-line metastatic pancreatic cancer who have high serum levels of free IGF-1; and
Safety data and the recommended Phase 2 dose in 2018 from the Phase 1 clinical study of MM-310 in patients with solid tumors.
First Quarter 2017 Financial Results
The following summarizes Merrimack’s financial results for the three months ended March 31, 2017:
In connection with the completion of the sale of ONIVYDE and Merrimack’s generic version of doxorubicin hydrochloride liposome injection to Ipsen on April 3, 2017, the commercial business has been recorded in the financial statement within discontinued operations;
Research and development expenses were $21.6 million for the three months ended March 31, 2017, compared to $28.0 million for the three months ended March 31, 2016, a decrease of $6.4 million, or 23%. This decrease was primarily attributable to the transition to the refocused clinical and preclinical pipeline;
General and administrative expenses were $5.6 million for the three months ended March 31, 2017, compared to $6.5 million for the three months ended March 31, 2016, a decrease of $0.9 million, or 14%. This decrease was primarily attributable to lower headcount related to the restructuring activities that occurred in the fourth quarter of 2016; and
Net loss attributable to Merrimack for the three months ended March 31, 2017, was $29.7 million, or $0.23 per share, compared to a net loss attributable to Merrimack of $38.5 million, or $0.33 per share, for the three months ended March 31, 2016.
FY 2017 Updated Financial Outlook
On April 3, 2017, Merrimack received a $575.0 million upfront cash payment from Ipsen. Merrimack used these proceeds to redeem the $175 million in outstanding Senior Secured Notes due in 2022, plus approximately $20 million of costs associated with the redemption. Merrimack has also declared a special cash dividend of $140.0 million to stockholders that is payable on May 26, 2017. Merrimack has also invested $125.0 million in the further development of its streamlined oncology pipeline. If certain milestones are met pursuant to its previous license and collaboration agreement with Shire, Merrimack expects to receive up to an aggregate of $33.0 million in net milestone payments within its cash runway. Merrimack believes that at its currently forecasted spending rates, its financial resources existing immediately following the completion of the asset sale, together with the net milestone payments it expects to receive from Shire, will be sufficient to fund its operations into the second half of 2019.
Special Cash Dividend to Stockholders
The special cash dividend of $140 million that is payable on May 26, 2017 will be paid in U.S. dollars. Merrimack expects that the distribution will be treated as paid out of its current earnings and profits, and thus would be taxable as a dividend for U.S. federal income tax purposes. Stockholders should consult their own tax advisors concerning the U.S. federal income tax consequences of the special cash dividend to them, in light of their particular circumstances, and any consequences arising under the laws of any state, local or foreign taxing jurisdiction.
FDA Approves Merck’s KEYTRUDA® (pembrolizumab) as First-Line Combination Therapy with Pemetrexed and Carboplatin for Patients with Metastatic Nonsquamous Non-Small Cell Lung Cancer (NSCLC), Irrespective of PD-L1 Expression
On May 10, 2017 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in combination with pemetrexed (brand name Alimta) and carboplatin (pem/carbo), a commonly used chemotherapy regimen, for the first-line treatment of metastatic nonsquamous NSCLC, irrespective of PD-L1 expression (Press release, Merck & Co, MAY 10, 2017, View Source [SID1234519005]). Under the FDA’s accelerated approval regulations, this indication is approved based on tumor response rate and progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
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The approval was based on data from KEYNOTE-021, Cohort G1, in 123 previously untreated patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations and irrespective of PD-L1 expression. In this trial, KEYTRUDA + pem/carbo demonstrated an objective response rate (ORR) that was nearly double the ORR of pem/carbo alone (55 percent [95% CI: 42, 68] compared to 29 percent [95% CI: 18, 41], respectively; all responses were partial responses). Among patients who received KEYTRUDA + pem/carbo, 93 percent had a duration of response of six months or more (range 1.4+ to 13.0+ months) compared to 81 percent who received pem/carbo alone (range 1.4+ to 15.2+ months). In addition, findings demonstrated an improvement in PFS (HR 0.53 [95% CI, 0.31-0.91; p=0.0205]), with a median PFS of 13.0 months (95% CI, 8.3-not estimable) for patients treated with KEYTRUDA + pem/carbo compared to 8.9 months (95% CI, 4.4-10.3) with pem/carbo alone.
Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered when appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions; for Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA (pembrolizumab). Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated and infusion-related adverse reactions and use in pregnancy, see "Selected Important Safety Information" below.
"The improved responses seen with the KEYTRUDA plus pemetrexed/carboplatin regimen are significant, and highlight the importance of finding new approaches that address the unmet needs of patients with metastatic nonsquamous non-small cell lung cancer," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "Today’s approval further supports our commitment to improve the lives of people with cancer."
"This approval marks an important milestone in the treatment of lung cancer. Now, pembrolizumab in combination with pemetrexed and carboplatin can be prescribed in the first-line setting for patients with metastatic nonsquamous non-small cell lung cancer, irrespective of PD-L1 expression," said Dr. Corey Langer, director of thoracic oncology and professor of medicine at the Hospital of the University of Pennsylvania. "Physicians should continue to use each patient’s individual characteristics – including biomarker status, histology, and other clinical factors – to determine the best treatment plan for each person."
The combination therapy indication makes KEYTRUDA an option for more patients. KEYTRUDA is the only anti-PD-1 approved in the first-line setting as both monotherapy and combination therapy for appropriate patients with metastatic NSCLC. KEYTRUDA is approved as monotherapy in the first-line setting for patients with metastatic NSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] ≥50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. KEYTRUDA as monotherapy is also indicated for the second-line or greater treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) 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.
"The combination of this immunotherapy with pemetrexed and carboplatin is more good news for patients," said Bonnie J. Addario, a lung cancer survivor and founder of the Bonnie J. Addario Lung Cancer Foundation. "Congratulations to Merck and the FDA for moving so swiftly on this important addition to our patients’ options for treatment. With this approval, hope for lung cancer patients continues to improve."
Data Supporting the Approval
The efficacy of KEYTRUDA (pembrolizumab) was investigated in patients enrolled in the open-label, multicenter, multi-cohort KEYNOTE-021 study; the efficacy data are limited to patients with metastatic nonsquamous NSCLC randomized within the single cohort (Cohort G1). The KEYNOTE-021G1 trial was conducted in collaboration with Eli Lilly and Company, the maker of pemetrexed. The key eligibility criteria for this cohort were locally advanced or metastatic nonsquamous NSCLC, regardless of tumor PD-L1 expression status, and no prior systemic treatment for metastatic disease. Patients with autoimmune disease that required systemic therapy within two years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Patients in KEYNOTE-021G1 were randomized to receive KEYTRUDA + pem/carbo (n=60) or pem/carbo alone (n=63). Patients in the KEYTRUDA combination arm received KEYTRUDA (200 mg), pemetrexed (500 mg/m2), and carboplatin (AUC 5 mg/mL/min) every three weeks for four cycles followed by KEYTRUDA every three weeks. In the control arm, patients received pemetrexed (500 mg/m2) and carboplatin (AUC 5 mg/mL/min) alone for four cycles. At the investigator’s discretion, maintenance pemetrexed (500 mg/m2) every three weeks was permitted in both treatment arms. Treatment with KEYTRUDA continued until Response Evaluation Criteria in Solid Tumors (RECIST) 1.1-defined progression of disease as determined by blinded independent central review (BICR), unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.
The major efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Additional efficacy outcome measures were PFS as assessed by BICR using RECIST 1.1, duration of response, and overall survival (OS).
Findings from this cohort demonstrated an ORR with KEYTRUDA + pem/carbo of 55 percent (95% CI: 42, 68) compared to 29 percent (95% CI: 18, 41) for pem/carbo alone. KEYTRUDA in this combination also reduced the risk of disease progression or death by 47 percent (HR, 0.53 [95% CI, 0.31, 0.91]; p=0.0205).
Exploratory analyses found similar results in patients with or without PD-L1 expression, with an ORR in patients whose tumors did not express PD-L1 (TPS <1%) of 57 percent with KEYTRUDA + pem/carbo compared to 13.0 percent with pem/carbo alone; in patients with PD-L1 TPS ≥1%, the ORR was 54 percent with KEYTRUDA + pem/carbo compared to 38 percent with pem/carbo alone.
Efficacy Results from KEYNOTE-021, Cohort G1
Endpoint
KEYTRUDA + Pem/Carbo
(n=60)
Pem/Carbo
(n=63)
Overall Response Rate
Overall Response Rate 55% 29%
(95% CI) (42, 68) (18, 41)
Complete Response 0% 0%
Partial Response 55% 29%
p-value* 0.0032
Duration of Response
% with duration ≥6-months† 93% 81%
Range (months) 1.4+ to 13.0+ 1.4+ to 15.2+
PFS
Number of events (%) 23 (38%) 33 (52%)
Progressive Disease 15 (25%) 27 (43%)
Death 8 (13%) 6 (10%)
Median in months (95% CI) 13.0 (8.3, NE) 8.9 (4.4, 10.3)
Hazard ratio‡ (95% CI) 0.53 (0.31, 0.91)
p-value§ 0.0205
* Based on Miettinen-Nurminen method stratified by PD-L1 status (TPS < 1% vs. TPS ≥ 1%)
† Based on Kaplan-Meier estimation
‡ Based on the Cox proportional hazard model stratified by PD-L1 status (TPS < 1% vs. TPS ≥ 1%)
§ Based on the log-rank test stratified by PD-L1 status (TPS < 1% vs. TPS ≥ 1%)
NE = not estimable
In the KEYNOTE-021G1 trial, safety was evaluated in 59 patients who received KEYTRUDA (pembrolizumab) + pem/carbo and 62 patients who received pem/carbo alone. KEYNOTE-021 was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA plus chemotherapy, as compared to chemotherapy alone, for any specified adverse reaction listed in the chart below.
KEYTRUDA was discontinued for adverse reactions in 10 percent of patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%).
Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-021, Cohort G1
KEYTRUDA + Pem/Carbo
n=59
Pem/Carbo
n=62
Adverse Reaction
All Grades*
(%)
Grade 3-4
(%)
All Grades
(%)
Grade 3-4
(%)
General Disorders and Administration Site Conditions
Fatigue 71 3.4 50 0
Peripheral Edema 22 0 18 0
Gastrointestinal Disorders
Nausea 68 1.7 56 0
Constipation 51 0 37 1.6
Vomiting 39 1.7 27 0
Diarrhea 37 1.7 23 1.6
Skin and Subcutaneous Tissue Disorders
Rash† 42 1.7 21 1.6
Pruritus 24 0 4.8 0
Alopecia 20 0 3.2 0
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea 39 3.4 21 0
Cough 24 0 18 0
Metabolism and Nutrition Disorders
Decreased Appetite 31 0 23 0
Nervous System Disorders
Headache 31 0 16 1.6
Dizziness 24 0 16 0
Dysgeusia 20 0 11 0
Psychiatric Disorders
Insomnia 24 0 15 0
Infections and Infestations
Upper respiratory tract infection 20 0 3.2 0
Musculoskeletal and Connective Tissue Disorders
Arthralgia 15 0 24 1.6
* Graded per NCI CTCAE v4.0
† Includes rash, rash generalized, rash macular, rash maculo-papular, and rash pruritic.
When administering KEYTRUDA in combination with pem/carbo, KEYTRUDA should be administered first prior to chemotherapy when given on the same day. In metastatic NSCLC, KEYTRUDA is approved at a fixed dose of 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression; pemetrexed and carboplatin should be administered according to their FDA-approved labels.
About KEYTRUDA (pembrolizumab) Injection
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that 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.
Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 450 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.
KEYTRUDA (pembrolizumab) Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) 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.
KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.
Head and Neck Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA (pembrolizumab) is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Selected Important Safety Information for KEYTRUDA (pembrolizumab)
KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). 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.
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), 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.
KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA (pembrolizumab) for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.
KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. 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.
KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.
KEYTRUDA can cause other clinically important immune-mediated adverse reactions. 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 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.
Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA (pembrolizumab). Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.
KEYTRUDA can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 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.
Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. 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.
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.
KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).
When KEYTRUDA (pembrolizumab) was administered in combination with pemetrexed and carboplatin, KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%).The most common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs. 23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24%vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia (15% vs 24%). The study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA plus chemotherapy, as compared to chemotherapy alone, for any specified adverse reaction.
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.
Adaptimmune Reports First Quarter 2017 Financial Results
On May 10, 2017 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported financial results and business updates for the quarter ended March 31, 2017 (Press release, Adaptimmune, MAY 10, 2017, View Source [SID1234518992]). Schedule your 30 min Free 1stOncology Demo! "Adaptimmune is now funded through to late 2019, providing us with a clear runway to deliver clinical data from multiple SPEAR T-cell therapies," commented James Noble, Adaptimmune’s Chief Executive Officer. "We have also just initiated a study with our AFP SPEAR T-cells and expect to deliver initial data from all our wholly-owned assets in 2017 and 2018, as well as data from the NY-ESO program under option to GSK. Additionally, we will be providing an update from our NY-ESO synovial sarcoma program in an oral presentation at the upcoming ASCO (Free ASCO Whitepaper) annual meeting."
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Recent Corporate Highlights:
· Completed March 2017 public offering and April 2017 registered direct offering to Matrix Capital Management
Company, LP ("Matrix"), raising total net proceeds of $103.2 million;
· Initiated AFP SPEAR T-cell therapy study in hepatocellular carcinoma;
· Announced FDA acceptance of IND application for SPEAR T-cell therapy targeting MAGE-A4 in multiple solid tumors;
· Announced nomination by GlaxoSmithKline of second target, PRAME, under strategic multi-target collaboration;
· Fully enrolled Cohort 4 of a pilot study of NY-ESO SPEAR T-cells in synovial sarcoma, and expanded this cohort to include an additional five patients; a data update on all cohorts in this study will be presented in an oral presentation at the upcoming ASCO (Free ASCO Whitepaper) annual meeting in June;
· Received FDA notification of permission to proceed with new cell manufacturing process for NY‑ESO phase I/II studies, and this process is being used for clinical manufacture; and
· Announced that Dr. Helen Tayton-Martin had assumed new role of Chief Business Officer, and that William Bertrand had joined Adaptimmune as Chief Operating Officer.
Financial Results for the Three Months ended March 31, 2017
· Cash / liquidity position: As of March 31, 2017, Adaptimmune had $170.6 million of cash and cash equivalents and $33.1 million of short-term deposits representing a total liquidity position1 of $203.7 million. This position is after inclusion of net proceeds from the March 2017 public offering ($61.4 million), but prior to inclusion of net proceeds from the April 2017 registered direct offering to Matrix ($41.8 million).
· Revenue: Revenue represents the upfront and milestone payments, which are recognized over the period the Company delivers services to GSK. Revenue for the three months ended March 31, 2017 was $2.9 million, which was consistent with the same period of 2016.
· Research and development ("R&D") expenses: R&D expenses for the three months ended March 31, 2017 were $18.6 million, compared to $14.5 million for the same period of 2016. The increase was primarily due to increased costs associated with ongoing clinical trials of the Company’s NY-ESO and MAGE-A10 SPEAR T-cell therapies; preparation for studies with the Company’s SPEAR T-cell therapy targeting AFP and MAGE-A4; costs of developing manufacturing capability in the Company’s U.S. facility and increased personnel expenses.
· General and administrative ("G&A") expenses: G&A expenses for the three months ended March 31, 2017 were $6.5 million, compared to $5.3 million for the same period of 2016. The increase was primarily due to increased personnel costs.
· Net loss: Net loss attributable to holders of the Company’s ordinary shares for the three months ended March 31, 2017 was $21.8 million $(0.05) per ordinary share or $(0.30) per American Depositary Share ("ADS") compared to $15.6 million $(0.04) per ordinary share or $(0.22) per ADS in the same period of 2016.
Financial Guidance
As of March 31, 2017, Adaptimmune had $170.6 million of cash and cash equivalents, and $33.1 million of short-term deposits representing a total liquidity position2 of $203.7 million. The Company believes that this position, combined with the net proceeds from the April 10, 2017 registered direct offering of $41.8 million, will fund the Company’s current operating plan through to late 2019.
1 Total liquidity position is a non-GAAP financial measure, which is explained and reconciled to the most directly comparable financial measures prepared in accordance with GAAP below.
2 Total liquidity position is a non-GAAP financial measure, which is explained and reconciled to the most directly comparable financial measures prepared in accordance with GAAP below.
Sierra Oncology Receives Clearance to Enhance Ongoing Clinical Trials for SRA737
On May 10, 2017 Sierra Oncology, Inc. (NASDAQ: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported that it has received clearance from regulators in the UK to amend the two ongoing Phase 1 trials for its Chk1 inhibitor, SRA737 (Press release, Sierra Oncology, MAY 10, 2017, View Source [SID1234518991]). The amended trials will include cohort expansions of prospectively selected patients with tumors identified to have genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition. Schedule your 30 min Free 1stOncology Demo! "Collaborating closely with our investigators and The Institute of Cancer Research, London, and The Royal Marsden in the UK, we have designed significant enhancements to our ongoing clinical trials for SRA737, which can now be implemented immediately and that are intended to enrich these studies with patients we believe are promising candidates for treatment with our drug," said Dr. Nick Glover, President and CEO of Sierra Oncology. "Furthermore, between these two studies, we will have the opportunity to evaluate preliminary efficacy across seven distinct cancer indications exploring the possibility of inducing synthetic lethality with SRA737-driven inhibition of Chk1 in tumors with defined genetic alterations. An initial update from these trials is anticipated in early 2018."
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"Sierra is pursuing a leading-edge strategy for the development of SRA737 that thoughtfully leverages Chk1’s fundamental biological role in cancer and the DDR network with the objective of enhancing patient selection and maximizing potential responses. With the advancement of sophisticated genetic analysis tools, a novel genetically-driven clinical development approach such as this becomes feasible, furthering our progress towards personalized oncology therapy," added the studies’ Chief Investigator Dr. Udai Banerji, Deputy Director of the Drug Development Unit at The Institute of Cancer Research and The Royal Marsden.
Amended Phase 1 SRA737 monotherapy study (ClinicalTrials.gov identifier: NCT02797964)
This study, as originally designed, is investigating the safety and tolerability of SRA737 and seeking to identify its optimal dose, schedule, and maximum tolerated dose (MTD) as a monotherapy. The amended design will now also concurrently evaluate preliminary efficacy in prospectively-selected, genetically-defined subjects.
The study will now consist of two phases, a Dose Escalation Phase and a Cohort Expansion Phase, being run concurrently.
In the Dose Escalation Phase, cohorts consisting initially of a single subject will receive escalating doses of SRA737, administered orally on a continuous daily dosing schedule in 28-day cycles. Once an SRA737-related Grade 2 toxicity is observed in a dose escalation cohort during Cycle 1, that cohort will be expanded to three to six subjects, and subsequent dose level cohorts will follow a rolling six design until the MTD has been identified.
In the parallel Cohort Expansion Phase, subjects with genetically-defined tumors that harbor genomic alterations hypothesized to confer sensitivity to checkpoint kinase 1 (Chk1) inhibition will be prospectively enrolled into several indication-specific cohorts to explore the preliminary efficacy of SRA737. These indications include:
· colorectal cancer;
· ovarian cancer;
· castration-resistant prostate cancer;
· non-small cell lung cancer; and
· head and neck squamous cell carcinoma.
To qualify for enrolment in the Cohort Expansion Phase, the subject’s tumor must have a confirmed minimum of two different types of genetic alterations, determined using Next-Generation Sequencing. These include 1) a deleterious mutation in a key tumor suppressor gene, such as TP53, and 2) at least one of the following:
· a loss of function or deleterious mutation in the DNA damage repair machinery such as ATM, BRCA1, BRCA2, or other gene in the DNA damage response pathway implicated in Chk1 pathway sensitivity;
· a genetic indicator of replicative stress, defined as gain of function or amplification of CHEK1 or ATR or other related gene; or
· a gain of function mutation or amplification of an oncogenic driver such as MYC, RAS, or other gene implicated in Chk1 pathway sensitivity.
Colorectal cancer patients with high microsatellite instability are eligible if they also have evidence of a deleterious mutation in a key tumor suppressor gene. A deleterious mutation in a key tumor suppressor gene is not required for head and neck squamous cell carcinoma patients with HPV-positive disease.
Amended Phase 1 study of SRA737 in combination with DNA-targeting chemotherapy (gemcitabine) (ClinicalTrials.gov identifier: NCT02797977)
This study, as originally designed, is seeking to establish the safety profile, determine the MTD and to propose a recommended dose of SRA737 in combination with gemcitabine for further development. The amended study will now also evaluate the preliminary efficacy of SRA737 in combination with gemcitabine in prospectively-selected, genetically-defined subjects once an MTD and dosing schedule have been determined.
The study will now consist of two stages:
Stage 1, which has concluded enrollment, consists of a Dose Escalation Phase where subjects are given SRA737 in addition to gemcitabine and cisplatin.
Stage 2 consists of two phases where subjects will be given SRA737 in addition to gemcitabine.
Initially, in the Dose Escalation Phase of Stage 2, cohorts of three to six subjects will be given escalating doses of SRA737 on an intermittent schedule in addition to gemcitabine until the combination MTD is reached.
After the MTD has been identified, the Cohort Expansion Phase of Stage 2 will explore the preliminary efficacy of SRA737 plus gemcitabine in prospectively enrolled subjects with tumors that harbor genomic alterations hypothesized to confer sensitivity to Chk1 inhibition. Qualifying patients will be enrolled into two indication-specific cohort expansions, bladder cancer and pancreatic cancer, as these indications are predicted to have a high prevalence of genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition, and because gemcitabine is often an important component of the standard-of-care treatment for these indications. To qualify for enrolment into these cohorts, the subject’s tumor must have a confirmed minimum of two different types of genetic abnormalities, similar to those defined for the monotherapy trial, determined using Next Generation Sequencing.