On June 6, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reporteded new data with KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy from two studies (KEYNOTE-012 and KEYNOTE-055) in heavily pre-treated patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) (Press release, Merck & Co, JUN 6, 2016, View Source [SID:1234513071]). Data are being presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.

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In KEYNOTE-012, for the primary endpoint, findings showed an overall response rate (ORR) of 18 percent (n=34/192) (95% CI, 13-24). At the time of analysis, 65 percent of responders (n=22/34) were continuing to respond – with responses observed in some patients for more than 30 months; median duration of response had not yet been reached. The secondary endpoint results showed a median overall survival (OS) rate of eight months (95% CI, 6-10) (Abstract #6012). The phase 1b KEYNOTE-012 study was the first clinical study investigating the role of a PD-1 inhibitor in recurrent or metastatic HNSCC. Based on the results of KEYNOTE-012, Merck is seeking approval for KEYTRUDA (200 mg fixed dose every three weeks) for previously treated recurrent or metastatic HNSCC. The U.S. Food and Drug Administration (FDA) granted Priority Review with a PDUFA, or action date, of August 9, 2016. The application will be reviewed under the FDA’s Accelerated Approval program.

For the second study, KEYNOTE-055, which enrolled patients regardless of PD-L1 tumor status, an analysis based on the first 50 patients showed an ORR (confirmed, partial responses) in nearly one in five, or 18 percent (n=9/50) (95% CI, 9-31) of patients treated with KEYTRUDA (Abstract #6011). Findings from 92 patients with six months of follow-up or more are also being presented. KEYNOTE-055 is a phase 2 study evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA (pembrolizumab) as a monotherapy (200 mg fixed dose every three weeks) in patients with recurrent or metastatic HNSCC with disease progression on platinum-based and cetuximab therapy.

"Head and neck cancer is an extremely difficult disease to treat – and despite our best efforts, bringing forward meaningful treatment advances has been challenging," said Dr. Ranee Mehra, chief of head and neck oncology, Fox Chase Cancer Center. "To see this level of response with pembrolizumab in patients with head and neck cancer is encouraging and provides further evidence of the potential for pembrolizumab in the treatment of this disease."

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. With four registration-enabling studies, Merck currently has the largest immuno-oncology clinical development program in head and neck cancer, encompassing all stages of advanced disease, and is conducting research investigating OS and progression-free survival (PFS) endpoints with KEYTRUDA as a monotherapy, as well as in combination with chemotherapy compared to standard of care.

"In Merck’s immuno-oncology clinical development program, we are rapidly evaluating the potential for KEYTRUDA to play a role in managing a range of difficult-to-treat cancers, and these data being presented at ASCO (Free ASCO Whitepaper) are the result of this effort," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "We look forward to bringing KEYTRUDA to more patients with our application for advanced head and neck cancer."

Findings from the KEYNOTE-012 Study (Abstract #6012)

KEYNOTE-012 is an ongoing multicenter, non-randomized, open-label, multi-cohort phase 1b trial evaluating KEYTRUDA as a monotherapy (10 mg/kg every two weeks or 200 mg fixed dose every three weeks) in patients with various advanced cancers, including head and neck. The head and neck cohorts include patients with recurrent or metastatic HNSCC, regardless of tumor human papilloma virus (HPV) status (23% positive; 77% negative). One cohort includes 60 patients who were considered PD-L1 positive; a second cohort includes 132 patients, regardless of PD-L1 tumor status. The primary endpoints include overall safety, tolerability, and ORR (as measured by RECIST v1.1); secondary endpoints include PFS, OS, and duration of response.

Findings presented at ASCO (Free ASCO Whitepaper) were based on long-term follow-up of a pooled analysis of the total population of patients across the two head and neck cohorts (n=192). Data showed an ORR (confirmed) of 18 percent (n=34/192) (95% CI, 13-24) – including eight complete responses and 26 partial responses. Thirty-three patients had stable disease and 93 patients had progressive disease. In total, 60 percent of patients experienced a decrease in their target lesions at the time of analysis. The median time to response was two months (range, 2-17 months). While median duration of response had not yet been reached (range, 2+ to 30+ months), 65 percent of responders (n=22/34) were continuing to respond at the time of analysis (85 percent of responses lasted for six months or more with 71 percent lasting for 12 months or more). An analysis of the survival measurements showed a median PFS of two months (95% CI, 1.9-2.1) – with a six-month PFS rate of 25 percent and 12-month PFS rate of 17 percent. The median OS was eight months (95% CI, 6-10) – with a six-month OS rate of 58 percent and a 12-month OS rate of 38 percent.

The safety profile was consistent with that observed in previously reported KEYTRUDA (pembrolizumab) studies. The treatment-related adverse events observed in this trial (any grade occurring in 5 percent or more of patients) were fatigue (n=42), hypothyroidism (n=19), rash (n=18), pruritus (n=16), decreased appetite (n=16), pyrexia (n=12), and nausea (n=11). Grade 3-4 treatment-related adverse events observed (occurring in 2 or more patients) were ALT increase (n=3), AST increase (n=3), fatigue (n=2), decreased appetite (n=2), hyponatremia (n=2), pneumonitis (n=2), facial swelling (n=2), and hypothyroidism (n=2). Twelve patients discontinued due to a treatment-related adverse event; there were no treatment-related deaths.

These data are being presented today, June 6, in an oral session by Dr. Ranee Mehra of Fox Chase Cancer Center from 12:18 – 12:30 p.m. CDT (Location: S100bc).

Findings from the KEYNOTE-055 Study (Abstract #6011)

KEYNOTE-055 is an ongoing multicenter phase 2 trial evaluating KEYTRUDA as a monotherapy (200 mg fixed dose every three weeks) in patients with advanced HNSCC, regardless of PD-L1 status, who have progressed on platinum-based and cetuximab therapy. The primary endpoints include overall safety, tolerability, and ORR (as measured by RECIST v1.1); secondary endpoints include PFS, OS, and duration of response.

Data presented at ASCO (Free ASCO Whitepaper) were based on an early analysis conducted on the first 50 patients enrolled in the study to receive KEYTRUDA and on an analysis of 92 patients with six months of follow-up or more. The first analysis (n=50) showed an ORR (confirmed, partial responses) of 18 percent (n=9/50) (95% CI, 9-31); nine patients had stable disease and 30 had progressive disease.

The analysis of the results observed in patients with six or more months follow-up (n=92) showed an ORR (confirmed, partial responses) of 17 percent (n=16/92) (95% CI, 10-27); 17 patients had stable disease and 51 had progressive disease. Analysis of results based on tumor HPV status showed an ORR of 22 percent (n=4/18) (95% CI, 6-48) in HPV-positive patients and 16 percent (n=12/74) (95% CI, 9-27) in HPV-negative patients. An analysis based on PD-L1 expression showed an ORR of 17 percent (n=13/76) (95% CI, 9-28) in patients whose tumors expressed PD-L1 and eight percent (n=1/13) (95% CI, 0.2-36) in patients whose tumors did not express PD-L1. Overall, 54 percent experienced a decrease in their target lesions. The median time to response was two months (range, 2-5 months). Median follow-up duration was seven months (range, 0-14 months) with 75 percent of responders remaining in response at the time of analysis. An analysis of the survival measurements showed a median PFS of 2.1 months (95% CI, 2.0-2.3), with a six-month PFS rate of 24 percent, and a median OS of eight months (95% CI, 8-11), with a six-month OS rate of 65 percent.

The safety profile was consistent with that observed in previously reported

KEYTRUDA (pembrolizumab) studies. The treatment-related adverse events observed in this trial (any grade occurring in five percent or more of patients) were fatigue (n=20), hypothyroidism (n=13), diarrhea (n=10), decreased appetite (n=9), nausea (n=9), AST increase (n=9), and rash (n=9). Grade 3-5 treatment-related adverse events observed (occurring in 2 or more patients) were anemia (n=2), AST increase (n=2), Alkaline Phosphatase increase (n=2), and hepatitis (n=2). There was one treatment-related death due to pneumonitis; three additional patients discontinued due to a treatment-related adverse event.

These data are being presented today, June 6, in an oral session by Dr. Joshua Bauml of the University of Pennsylvania from 12:06 – 12:18 p.m. CDT (Location: S100bc).

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 (pembrolizumab) 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 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 (pembrolizumab) 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 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 (pembrolizumab).

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 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 (pembrolizumab).

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 prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

On June 6, 2016 Castle Biosciences, Inc., a provider of molecular diagnostics to improve cancer treatment decisions, reported the results from a study evaluating the performance of its gene expression profile (GEP) test, DecisionDx-Melanoma, in 334 new melanoma patients (Press release, Castle Biosciences, JUN 6, 2016, View Source [SID:1234513096]). The data confirmed the positive results from two previously published multicenter clinical validation studies demonstrating the test’s ability to identify patients’ risk of melanoma recurrence in the 5 years following diagnosis. The data were presented in a poster session at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL. A second, independent, prospective study of DecisionDx-Melanoma was also presented further confirming the results of the three prior multicenter studies.

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Expanded Multicenter Performance Study

In a study titled "Performance of a 31-Gene Expression Profile in a Previously Unreported Cohort of 334 Cutaneous Melanoma Patients" (Abstract # 9581), 334 cutaneous melanoma tumors from 12 centers in the U.S. were analyzed using the DecisionDx-Melanoma test. Tumors were classified as either low-risk Class 1 or high-risk Class 2. The test’s prognostic results were compared to actual clinical outcomes over a 5-year period, as well as traditional methods for disease staging and prognosis including sentinel lymph node (SLN) biopsy, ulceration, Breslow thickness and mitotic rate. Study endpoints included recurrence-free survival (RFS), defined as time to either a regional or distant metastatic event; distant metastasis-free survival (DMFS), defined as time to any metastatic event beyond the regional node; and melanoma-specific survival (MSS), defined as time from diagnosis to death documented as specifically resulting from melanoma. A summary of the results is below:

RFS DMFS MSS
5-year rate # of events 5-year rate # of events 5-year rate # of events
Class 1 (n=181) 86% 29 91% 19 98% 5
Class 2 (n=153) 51% 69 60% 54 75% 31
The study also highlighted the GEP test’s ability to predict which patients are not likely to recur (Negative Predictive Value, or NPV) when used by itself, and in combination with other standard prognostic techniques such as SLN biopsy. While both the DecisionDx-Melanoma test and SLN biopsy were shown to have strong sensitivity to detect patients at risk of metastasis, a combination of the two was the most effective. Results include:

MSS SLN Status GEP Class SLN + GEP
Sensitivity 67% (49-81%) 86% (71-95%) 94% (81-99%)
Specificity 72% (66-77%) 59% (53-65%) 48% (42-54%)
PPV 22% (15-31%) 20% (14-28%) 18% (13-24%)
NPV 95% (91-97%) 97 (94-99%) 99% (95-100%)
95% confidence interval shown in parentheses

Study authors also combined previously studied populations, reviewing the total of 514 patient cases from validation and performance studies of the GEP test to date. Results from the Stage I/II and Stage III patients are shown below:

MSS Stage I/II (n=356) Stage III (n=158)
Sensitivity 80% (52-96%) 87% (70-96%)
Specificity 65% (60-70%) 32% (24-41%)
PPV 9% (5-15%) 24% (16-33%)
NPV 99% (96-100%) 91% (79-98%)
95% confidence interval shown in parentheses

"These study results confirm the prognostic accuracy of this GEP test, demonstrating its ability to provide prognostic information that is independent of and additive to conventional staging," commented Jonathan S. Zager, MD, FACS, lead study author and Professor of Surgery in the Cutaneous Oncology and Sarcoma Departments at the Moffitt Cancer Center. "For melanoma-specific survival, combining this GEP test with SLN status improves sensitivity to 94% and Negative Predictive Value to 99% over SLN status or the GEP test alone – providing support for low-risk management/surveillance plans for Class 1 patients. For Class 2 patients, increased surveillance per guidelines for high-risk patients appears to be warranted."

"We are extremely pleased with the continued strong performance of our GEP test," commented Federico A. Monzon, M.D., FCAP, Chief Medical Officer of Castle Biosciences. "The test, when used with standard melanoma staging tools, provides the most accurate prognostic information from which to plan follow-up care. In addition to improving patient care, the GEP test offers the opportunity to improve clinical trial design to advance adjuvant treatment in patients who have a Class 2, high-risk test result."

Second, Independent, Prospective Study Also Presented

Also at the meeting, a study titled "Prospective Validation of Gene Expression Profiling in Primary Cutaneous Melanoma" (Abstract #9565), was presented by Eddy C. Hsueh, M.D., Professor and Director, Division of Surgical Oncology, St. Louis University Hospital. This study evaluated 159 prospectively enrolled melanoma patients undergoing SLN biopsy and successful testing with the DecisionDx-Melanoma GEP test. The data show that GEP classification is significantly associated with early recurrence in patients diagnosed with melanoma. With a median follow-up time of 18 months, the study found a Negative Predictive Value of 98% for disease-free survival. To date, all Stage III patients with a Class 1 result are recurrence free. The DecisionDx-Melanoma test correctly identified 16 of 18 patients who had recurrence events as high-risk (Class 2). Overall the high-risk Class 2 group had a 38% recurrence rate. Patients who were both high-risk Class 2 and Stage III had a 77% recurrence rate compared to 43% with Stage III status alone.

"An important milestone in test development is demonstrated consistency in prospective studies," added Derek Maetzold, President and CEO of Castle Biosciences. "This prospective study represents the second such DecisionDx-Melanoma study presented in the last six weeks, and provides further independent confirmation for the consistent results seen in Castle Biosciences’ sponsored multicenter studies."

About Melanoma
Cutaneous melanoma is diagnosed in approximately 76,000 people in the U.S. each year, according to the American Cancer Society. Seventy-five percent are diagnosed as Stage I or II, meaning there is no evidence of the melanoma spreading beyond the primary tumor. It is not the most prevalent form of skin cancer, but it is the most aggressive. Unlike other more common skin malignancies such as basal cell and squamous cell carcinomas, melanoma often spreads to other parts of the body, either via the lymphatic or blood system, resulting in cancers of distant organs including the brain or lungs. So, while it represents just 4% of skin cancers, melanoma accounts for about 80% of skin cancer-related deaths.

On June 6, 2016 Peloton Therapeutics, Inc., a drug discovery and development company focused on advancing first-in-class, small molecule cancer therapies targeting unexploited molecular vulnerabilities, reported first-in-human Phase 1 clinical data on its lead investigational candidate, PT2385, at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, IL (Press release, Peloton Therapeutics, JUN 6, 2016, View Source [SID:1234513120]). PT2385 is the first clinical stage antagonist of hypoxia inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney and other cancers.

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In an oral presentation titled "A Phase 1 Dose-Escalation Trial of PT2385, a first-in-class oral HIF-2α Inhibitor, in Patients with Advanced Clear Cell Renal Cell Carcinoma," it was shown that PT2385 was well tolerated with no dose-limiting toxicities and had pharmacologic activity with encouraging clinical efficacy.

Patients with advanced clear cell renal cell carcinoma (ccRCC) and at least one prior therapy with a VEGF inhibitor were treated with PT2385 to determine the recommended Phase 2 dose and evaluate safety, pharmacokinetics and pharmacodynamics.
Twenty-six patients were enrolled in dose escalation and received PT2385 from 100 to 1800 mg twice per day. Patients were heavily pretreated prior to study entry, with greater than 50 percent having four or more prior therapies. Exposure increased with doses up to the 800 mg cohort without a further increase from 800 to 1800 mg. No dose limiting toxicities were observed at any dose level. Circulating plasma levels of the HIF-2α transcriptional target erythropoietin (EPO) rapidly decreased with treatment with PT2385 and remained suppressed. Based on safety, pharmacokinetic and EPO pharmacodynamic data, 800 mg twice per day was selected as the recommended Phase 2 dose. An additional 25 patients were enrolled in an expansion cohort at the recommended Phase 2 dose.

Among the 51 patients in total, the most common all-grade adverse events (AEs) were anemia, peripheral edema and fatigue. No cardiovascular AEs were noted. To date, one patient had a complete response, three patients had a partial response, and 16 patients had stable disease for 16 or more weeks. Ten percent of patients remain in this ongoing clinical trial for at least one year.
"Research at our institution has shown than HIF-2α is strongly implicated in renal cell carcinoma. PT2385 is the first agent to target this transcription factor and is very well tolerated. Its efficacy in patients with advanced clear cell renal cell carcinoma is promising," said Toni Choueiri, M.D., from the Dana-Farber Cancer Institute and Harvard Medical School, the senior author of the study.
"We are encouraged by the initial efficacy results in this heavily pretreated population and the fact that PT2385 does not have the cardiovascular toxicities of most other kidney cancer treatments, most notably VEGFR tyrosine kinase inhibitors. In light of this favorable safety profile and preclinical evidence of synergistic activity of our HIF-2α antagonists in combination with immune checkpoint inhibitors shown at the recent AACR (Free AACR Whitepaper) conference, we have opened a clinical trial of PT2385 in combination with nivolumab (Opdivo). Additionally, we are planning clinical studies of PT2385 as monotherapy and with other combination regimens," said John Josey, Ph.D., Peloton’s Chief Executive Officer.

About PT2385
PT2385 is a first-in-class small molecule inhibitor of hypoxia-inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney cancer. It is currently being investigated in a Phase 1 clinical trial for the treatment of advanced or metastatic clear cell renal cell carcinoma (ccRCC). Loss of the von Hippel-Lindau tumor suppressor (VHL) is the key oncogenic event in up to 95% of patients with ccRCC. With the loss of the VHL protein (pVHL), the transcription factor HIF-2α accumulates and drives the unbalanced expression of numerous gene products. Preclinical data indicate that orally bioavailable PT2385 disrupts HIF-2α activity in ccRCC and thereby blocks the expression of multiple tumorigenic factors responsible for unrestrained cancer cell growth and proliferation, tumor angiogenesis, and suppression of anti-tumor immune responses characteristic of ccRCC.

About Renal Cell Cancer
The American Cancer Society estimates that more than 62,000 new cases of kidney cancer will be diagnosed and more than 14,000 people will die from this disease this year. The National Cancer Institute reports that the prognosis for any treated renal cell cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage.
About Peloton Therapeutics

On June 6, 2016 Kite Pharma, Inc. (Nasdaq:KITE) ("Kite") reported results to be presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from a study of low-dose chemotherapy conditioning followed by anti-CD19 chimeric antigen receptor (CAR) T-cell therapy (Press release, Kite Pharma, JUN 6, 2016, View Source [SID:1234513027]). The results showed that CAR T-cell therapy was effective in inducing a high response rate in patients with advanced non-Hodgkin lymphoma (NHL). The results will be presented today as a Late Breaking Abstract by James N. Kochenderfer, M.D., an investigator in the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI) Center for Cancer Research (Hall D2, Time: 4:42PM CDT, Abstract #3010).

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In this study of 22 patients (19 diffuse large B-cell lymphoma, 2 follicular lymphoma, and 1 mantle cell lymphoma), objective responses were seen in 16 patients (73%). Twelve of 22 patients (55%) achieved complete responses following low-dose chemotherapy conditioning regimen. Kite is using a similar conditioning regimen in its ZUMA-1 Study of KTE-C19, an anti-CD19 CAR T cell therapy. Nine of 19 patients (47%) with diffuse large B-cell lymphoma (DLBCL) achieved complete responses, which are all ongoing with a duration of 7+ to 20+ months. Additionally, the three patients with mantle cell lymphoma and follicular lymphoma achieved complete responses. Reversible grade 3 or 4 neurotoxicity including confusion, dysphasia, encephalopathy, and gait disturbances was observed in 55% of treated patients.

"Patients with chemorefractory DLBCL have few effective treatment options," said Jeff Wiezorek, M.D., M.S., Kite’s Senior Vice President, Clinical Development. "These early results are encouraging and served as the foundation for Kite’s ongoing KTE-C19 ZUMA-1 Study."

According to the American Cancer Society, NHL is one of the most common cancers in the United States and DLBCL is the most common form of the disease accounting for one out of every three cases of NHL.1 It is estimated that approximately 26,000 people will be diagnosed with DLBCL in the United States in 2016. DLBCL is an aggressive and fast growing lymphoma, but considered curable in patients who respond to initial treatment with a chemotherapy-based regimen. Patients with chemorefractory DLBCL face limited treatment options and historically poor outcomes.

This study was performed pursuant to a Cooperative Research and Development Agreement (CRADA) between the NCI and Kite.

On June 6, 2016 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company focused on bringing novel immuno-oncology medicines to patients, reported the presentation of data from two studies on two posters highlighting the combination therapeutic potential of indoximod, an indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitor, at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, NewLink Genetics, JUN 6, 2016, View Source [SID:1234513051]).

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Both posters are available online here.

Updates on Phase 1b/2 trial of the IDO inhibitor indoximod plus checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma

The trial design allows for the combination of indoximod with either ipilimumab or one of the PD-1 checkpoint inhibitors pembrolizumab or nivolumab. The combination of indoximod with other checkpoint inhibitors has been well tolerated thus far with no increase in toxicity noted in this Phase 1b/2 study. Overall, 40 patients had been enrolled in the combined Phase 1b/2 study long enough to have response data available at the time of data cut off. The poster data presented at ASCO (Free ASCO Whitepaper) were based on data via site reported RECIST criteria available from 28 subjects, the objective response rate, comprised of complete response plus partial response, for these patients is 36 percent (10 of 28) with three complete responses. Interestingly, the subset of 15 patients who received indoximod in combination with pembrolizumab had an objective response rate of 53 percent (8 of 15) with two complete responses (13 percent). The trial continues to enroll, with 55 patients currently enrolled in Phase 2.

"Although early, the 53 percent response rate in patients with metastatic melanoma treated with indoximod and pembrolizumab appears promising," said Zakharia Yousef, M.D., Assistant Professor of Medicine, Division of Hematology, Oncology and Blood & Marrow Transplantation at the University of Iowa and Holden Comprehensive Cancer Center.

Phase 2 trial of the IDO pathway inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: interim analysis

The combination of indoximod and gemcitabine/nab-paclitaxel continues to be well tolerated by patients with metastatic pancreatic cancer. These data come from the Phase 1/2 trial in which treatment-naïve metastatic pancreatic cancer patients were treated with the combination therapy in continuous four week cycles. As of the data cut off for the analysis, a total of 45 patients (Phase 1 and 2) were enrolled in the trial long enough to potentially have cycle 4 imaging available by the ASCO (Free ASCO Whitepaper) presentation. Data via site reported RECIST criteria were available on 31 patients. At the time of this analysis, objective response rate was 45 percent (14 of 31) and multiple durable responses ≥6 months were observed. Two patients achieved a complete response (6 percent), both at Cycle 8, showing delayed kinetics that may indicate an immune based mechanism. The trial continues to enroll patients and a biopsy cohort expansion is underway.

"The objective response rate, observance of complete responses, and delayed and durable response patterns are promising for this combination regimen for patients with metastatic pancreas cancer," said Andrea Wang-Gillam, M.D., Ph.D., Assistant Professor of Medicine, Division of Oncology, Section of Medical Oncology, at Washington University School of Medicine.

Further Study of Indoximod Combinations Planned

"These are promising data as indoximod continues to demonstrate potential in combination therapies with other checkpoint inhibitors and with chemotherapies for different cancers, with encouraging rates for objective responses while being well-tolerated," said Charles Link, Jr., M.D., Chairman and Chief Executive Officer. "We believe these data further support that the IDO pathway is one of the key immune checkpoint targets. We anticipate continued clinical progress in these and additional indoximod combinations during 2016."

About Indoximod

Indoximod is an orally available small molecule that has shown the potential to interfere with multiple targets within the indoleamine 2,3-dioxygenase (IDO) pathway. It is designed to be used in combination with other therapeutic agents to maximize the body’s immune response against a range of tumor types. Indoximod is currently in multiple Phase 2 clinical trials for the treatment of patients with breast, prostate, pancreatic, melanoma and brain cancers and in Phase 1 clinical trials for the treatment of pediatric patients with primary malignant brain tumors.