On November 5, 2021Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a commercial-stage biopharmaceutical company developing innovative medicines to improve the lives of people with cancer, reported top-line results from the INTRIGUE Phase 3 clinical study of QINLOCK in patients with gastrointestinal stromal tumor (GIST) previously treated with imatinib (Press release, Deciphera Pharmaceuticals, NOV 5, 2021, View Source [SID1234594583]). The study did not meet the primary endpoint of improved progression-free survival (PFS) compared with the standard of care sunitinib.

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"While we are disappointed with these results, which we learned yesterday, we believe this was a robust, well-designed, and well-executed study. The full results from the INTRIGUE Phase 3 clinical study are expected to be presented at an upcoming medical meeting," said Steve Hoerter, President and Chief Executive Officer of Deciphera. "On behalf of the entire Deciphera team, I would like to thank the patients, their caregivers, and the healthcare professionals who participated in the INTRIGUE study. QINLOCK remains the standard of care and only approved therapy in patients with fourth-line GIST, and we are committed to ensuring that patients around the world in the fourth-line GIST treatment setting have access to QINLOCK."

The INTRIGUE Phase 3 clinical study is a randomized, global, multicenter, open-label study to evaluate the efficacy and safety of QINLOCK compared to sunitinib in patients with GIST previously treated with imatinib. In the study, 453 patients were randomized 1:1 to either QINLOCK 150 mg once daily or sunitinib 50 mg once daily for four weeks followed by two weeks without sunitinib.

The study did not achieve the primary efficacy endpoint of progression-free survival (PFS) as determined by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors (RECIST). The statistical analysis plan included a hierarchical testing sequence that included testing patients with a KIT exon 11 primary mutation and then in the all patient intent-to-treat (AP) population. In patients with a KIT exon 11 primary mutation, (n=327), QINLOCK demonstrated a median PFS (mPFS) of 8.3 months compared to 7.0 months for the sunitinib arm (Hazard Ratio [HR] 0.88, p=0.360). Although not formally tested due to the rules of the hierarchical testing sequence, in the AP population QINLOCK demonstrated a mPFS of 8.0 months compared to 8.3 months for the sunitinib arm (HR 1.05, nominal p=0.715).

Conference Call and Webcast

Deciphera will host a conference call and webcast to discuss this announcement today, November 5, 2021 at 8:00 AM ET. To access the live call by phone please dial (866) 930-5479 (domestic) or (409) 216-0603 (international); the conference ID is 3072405. A live audio webcast of the event may also be accessed through the "Investors" section of Deciphera’s website at www.deciphera.com. A replay of the webcast will be available for 30 days following the event.

About the INTRIGUE Study

The INTRIGUE Phase 3 clinical study is a randomized, global, multicenter, open-label study to evaluate the efficacy and safety of QINLOCK compared to sunitinib in patients with GIST previously treated with imatinib. In the study, 453 patients were randomized 1:1 to either QINLOCK 150 mg once daily or sunitinib 50 mg once daily for four weeks followed by two weeks without sunitinib. The primary endpoint is progression-free survival (PFS) as determined by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors (RECIST) in the pre-specified subgroup of patients with a KIT exon 11 mutation (exon 11) and then in the all patient intent-to-treat (AP) population. Secondary endpoints include Objective Response Rate (ORR) as determined by independent radiologic review using modified RECIST and Overall Survival (OS) in both the exon 11 and AP groups. The study is being conducted at 122 investigational sites in 22 countries.

About QINLOCK (ripretinib)

QINLOCK is a switch-control tyrosine kinase inhibitor that was engineered to broadly inhibit KIT mutated kinases by using a dual mechanism of action that regulates the kinase switch pocket and activation loop1,2.

Important Safety Information

There are no contraindications for QINLOCK.

Palmar-plantar erythrodysesthesia syndrome (PPES): In INVICTUS, Grade 1-2 PPES occurred in 21% of the 85 patients who received QINLOCK. PPES led to dose discontinuation in 1.2% of patients, dose interruption in 2.4% of patients, and dose reduction in 1.2% of patients. Based on severity, withhold QINLOCK and then resume at same or reduced dose.

New Primary Cutaneous Malignancies: In INVICTUS, cutaneous squamous cell carcinoma (cuSCC) occurred in 4.7% of the 85 patients who received QINLOCK with a median time to event of 4.6 months (range 3.8 to 6 months). In the pooled safety population, cuSCC and keratoacanthoma occurred in 7% and 1.9% of 351 patients, respectively. In INVICTUS, melanoma occurred in 2.4% of the 85 patients who received QINLOCK. In the pooled safety population, melanoma occurred in 0.9% of 351 patients. Perform dermatologic evaluations when initiating QINLOCK and routinely during treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Continue QINLOCK at the same dose.

Hypertension: In INVICTUS, Grade 1-3 hypertension occurred in 14% of the 85 patients who received QINLOCK, including Grade 3 hypertension in 7% of patients. Do not initiate QINLOCK in patients with uncontrolled hypertension. Monitor blood pressure as clinically indicated. Based on severity, withhold QINLOCK and then resume at same or reduced dose or permanently discontinue.

Cardiac Dysfunction: In INVICTUS, cardiac failure occurred in 1.2% of the 85 patients who received QINLOCK. In the pooled safety population, cardiac dysfunction (including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) occurred in 1.7% of 351 patients, including Grade 3 adverse reactions in 1.1% of patients.

In INVICTUS, Grade 3 decreased ejection fraction occurred in 2.6% of the 77 patients who received QINLOCK and who had a baseline and at least one post-baseline echocardiogram. Grade 3 decreased ejection fraction occurred in 3.4% of the 263 patients in the pooled safety population who received QINLOCK and who had a baseline and at least one post-baseline echocardiogram.

In INVICTUS, cardiac dysfunction led to dose discontinuation in 1.2% of the 85 patients who received QINLOCK. The safety of QINLOCK has not been assessed in patients with a baseline ejection fraction below 50%. Assess ejection fraction by echocardiogram or MUGA scan prior to initiating QINLOCK and during treatment, as clinically indicated. Permanently discontinue QINLOCK for Grade 3 or 4 left ventricular systolic dysfunction.

Risk of Impaired Wound Healing: QINLOCK has the potential to adversely affect wound healing. Withhold QINLOCK for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of QINLOCK after resolution of wound healing complications has not been established.

Embryo-Fetal Toxicity: QINLOCK 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 and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 week after the final dose. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for at least 1 week after the final dose. QINLOCK may impair fertility in males of reproductive potential.

Adverse Reactions: The most common adverse reactions (≥20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, PPES, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate.

The safety and effectiveness of QINLOCK in pediatric patients have not been established.

Administer strong CYP3A inhibitors with caution. Monitor patients who are administered strong CYP3A inhibitors more frequently for adverse reactions. Avoid concomitant use with strong CYP3A inducers.

On November 5, 2021 Humanigen, Inc. (Nasdaq: HGEN) ("Humanigen"), a clinical-stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm’ with its lead drug candidate, lenzilumab, reported two abstracts pertaining to the potential use of lenzilumab in CAR-T will be presented at the 63rd Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) taking place December 11-14, 2021 (Press release, Humanigen, NOV 5, 2021, View Source [SID1234594613]). The society counts more than 18,000 hematologists among its membership from more than 100 countries, and its annual meeting attracts over 30,000 professional attendees.

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"After completing a Phase 3 trial of lenzilumab, in 2021, for the treatment of patients hospitalized with COVID-19 pneumonia, we look forward to advancing our efforts to develop lenzilumab as a complementary therapy to potentially reduce CAR-T associated toxicities and to potentially improve outcomes for non-Hodgkin lymphoma patients," said Adrian Kilcoyne, Chief Medical Officer, Humanigen. "My experience working in the development of CAR-T therapies, which are now currently commercially available, suggests preventing toxicity and optimizing durable response rates remain challenges. Our plans include initiating the Phase 3 SHIELD study of lenzilumab in the first half of 2022 and we may be able to announce interim data at ASH (Free ASH Whitepaper) 2022."

Abstract #2777

Optimized Inhibition of GM-CSF in Preclinical Models of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy

Summary: The abstract describes the evaluation of differential targeting of the GM-CSF ligand using lenzilumab compared to targeting the GM-CSFα receptor using a different antibody in pre-clinical models. The research demonstrated significant differences on CAR-T cell functions and CAR-T cell-monocyte interactions when GM-CSF is neutralized with lenzilumab compared to blocking its receptor with other agents. A key finding is that lenzilumab neutralization of GM-CSF improved CAR-T cell proliferation, but the GM-CSFRα receptor blocking antibody may significantly inhibit CAR-T cell proliferation in a dose-dependent manner. This may have efficacy implications.

Presenter: Evandro Bezerra, MD, Mayo Clinic in Rochester, MN.
Session: 703. Cellular Immunotherapies: Basic and Translational: Poster II
Date: December 12, 2021; 6:00-8:00 PM EST

Abstract #175

A Phase 3 Randomized, Placebo-Controlled, Open-Label, Multi-Center Trial of Lenzilumab to Improve the Safety and Efficacy of CAR-T Cell Therapy in Adults with Relapsed or Refractory Large B-Cell Lymphoma* (The SHIELD Study)

Summary: The abstract describes a planned Phase 3 study of prophylactic lenzilumab administration in sequenced therapy with commercially available CAR-Ts to treat non-Hodgkin lymphoma. The study aim is to determine if lenzilumab can break the efficacy/toxicity linkage associated with CAR-T therapy thereby improving the toxicity and tolerance of CAR-T while maintaining or improving efficacy by neutralizing GM-CSF.

Presenter: Saad Kenderian, MD, principal investigator in the T Cell Engineering Lab at Mayo Clinic in Rochester, MN.
Session: 704. Cellular Immunotherapies: Clinical: Poster I
Date: December 11, 2021; 5:30 PM-7:30 PM EST

* The SHIELD study protocol has been adapted since submission of the abstract to include a broader patient population

On November 5, 2021 Philogen reported that Stifel Conference provides an opportunity for investors to get a perspective of Philogen progresses and to meet CEO Dario Neri through a series of one-on-one meetings (Press release, Philogen, NOV 5, 2021, View Source [SID1234594677]).

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Co-founder, CEO and CSO, Prof. Dario Neri is giving a presentation on November 16, 2021.

On November 5, 2021 Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage, precision oncology biopharmaceutical company, reported the promotion of current vice president and head of clinical development, Dr. Emil T. Kuriakose, to chief medical officer (CMO) (Press release, Calithera Biosciences, NOV 5, 2021, View Source [SID1234594584]). Dr. Kuriakose will succeed Dr. Keith Orford, who has been appointed to Calithera’s board of directors.

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"Emil has a proven track record of leading clinical programs across multiple disease areas, and he is well-suited to assume this role at Calithera based on his accomplishments and four-year tenure with the company," said Susan Molineaux, PhD, chief executive officer of Calithera. "Keith played a critical role in building the company’s clinical team during his seven years at Calithera. We are deeply appreciative of his contributions to-date and look forward to his continued strategic input in his new role as a member of our board."

During his time at Calithera, Dr. Kuriakose has overseen the advancement of the company’s clinical development programs, including the arginase inhibitor programs in oncology and cystic fibrosis, as well as multiple telaglenastat trials. As an integral member of the diligence team, Dr. Kuriakose played a key role in the company’s recent successful acquisition of sapanisertib and mivavotinib from Takeda Pharmaceuticals, and he led formulation of the clinical development plan for the newly acquired assets. Prior to Calithera, Dr. Kuriakose led global clinical development programs, most recently with Novartis. Dr. Kuriakose completed his clinical training in hematology/oncology at Weill Cornell Medical College, including a research fellowship at Memorial Sloan Kettering Cancer Center, and he completed his residency training in internal medicine at UT Southwestern Medical Center in Dallas, TX. Dr. Kuriakose received his medical degree from Stony Brook University School of Medicine and his Bachelor of Science in neuroscience from New York University.

"I have great confidence in our new strategic focus to develop targeted therapies for biomarker-specific patient populations," said Dr. Kuriakose. "I have had the privilege of working alongside Keith for the last four years and look forward to continuing our partnership as he joins the board."

Dr. Orford will assume the seat being vacated by current board member Jean M. George. Ms. George, a biotech investment and business development industry veteran, has served on the Calithera Board of Directors since 2012.

On November 5, 2021 Castle Biosciences, Inc. (Nasdaq: CSTL), a company applying innovative diagnostics to inform disease management and improve patient outcomes, reported the publication of a study validating performance of a novel algorithm designed to integrate the DecisionDx-Melanoma gene expression profile (GEP) test with clinicopathologic features (i31-GEP SLNB) to determine sentinel lymph node biopsy (SLNB) positivity risk in patients with cutaneous melanoma (Press release, Castle Biosciences, NOV 5, 2021, View Source [SID1234594614]).

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DecisionDx-Melanoma is Castle’s risk-stratification GEP test that is designed to predict 5-year risk of metastasis as well as metastasis to the SLN. The test’s Integrated Test Result (ITR) includes the traditional class designation of lowest risk (Class 1A), increased risk (Class 1B/2A) or highest risk (Class 2B), as well as a more precise risk prediction for both SLNB positivity and risk of recurrence, distant metastasis and melanoma survival in patients with stage I, II or III melanoma through the i31- GEP algorithms (SLNB and Risk of Recurrence). The i31-GEP SLNB and ROR are distinct independently validated algorithms that integrate clinicopathologic features with the DecisionDx-Melanoma score.

"The majority of patients who undergo the SLNB surgical procedure receive a negative result," said Robert Cook, Ph.D., senior vice president of research and development of Castle Biosciences and study author. "The i31-GEP SLNB clinical validation data showed that integrating clinicopathologic risk factors with the DecisionDx-Melanoma test provided very high correlation between the predicted and the actual, or observed, rates and a high sensitivity in identifying patients at low risk for SLN metastasis who may be able to safely avoid the SLNB procedure. Importantly, the study demonstrated that the DecisionDx-Melanoma test result was the most important variable in predicting SLN positivity."

The article, titled "Integrating 31-Gene Expression Profiling with Clinicopathologic Features to Optimize Cutaneous Melanoma Sentinel Lymph Node Metastasis Prediction," was published in the peer-reviewed journal JCO Precision Oncology and can be accessed here. The study highlights the development and validation of the i31-GEP SLNB algorithm.

Study background:

National guidelines recommend that an SLNB be offered to patients with >10% likelihood of SLN positivity (typically thought to encompass T2-T4 tumors), but do not recommend SLNB for patients who are thought to have <5% likelihood of a positive SLN (typically thought to encompass T1a tumors without high-risk features).
The decision to perform SLNB is less certain for patients with higher-risk T1 melanomas (T1a tumors with high-risk features or T1b tumors) in which a positive node is expected 5%-10% of the time.
The integrated DecisionDx-Melanoma test result for SLNB (i31-GEP SLNB) was designed to combine DecisionDx-Melanoma’s output, a risk assignment based on GEP analysis, with clinicopathologic risk factors.
The study describes the development and validation of the i31-GEP SLNB, which utilizes a neural network algorithm to integrate the continuous DecisionDx-Melanoma result with patient histologic and clinical features.
The i31-GEP SLNB algorithm was developed in a cohort of 1,398 patients and independently validated on a cohort of 1,674 patients.
Study findings:

In comparison to all clinicopathologic features considered, the DecisionDx-Melanoma continuous score was the most important variable for prediction of a positive SLN, with a P value of less than 0.001.
The i31-GEP SLNB algorithm demonstrated a very high correlation comparing predicted versus observed SLN positivity rates of 0.999 (1.0 is complete correlation).
The i31-GEP SLNB algorithm demonstrated a highly sensitive prediction of SLN positivity rates (95.1%) compared to observed rates.
In patients with T1-T4 tumors, the i31-GEP SLNB increased the percentage of patients predicted to have <5% SLN positivity risk from 8.5%, using current staging guidelines, to 27.7%.
Specifically, for patients predicted to have 5%-10% risk by current guidelines, the i31-GEP SLNB restratified 63% of cases to an SLN positivity risk of <5% or >10%.
The i31-GEP SLNB identified patients with <5% SLN positivity risk, who might forego SLNB, or those with >10% SLN positivity risk, who might be offered SLNB, according to current guidelines.
These data demonstrated that the i31-GEP SLNB could provide personalized risk estimates for SLN positivity, potentially reducing the number of SLNBs and provide additional information to appropriately identify patients at the highest risk of having a positive SLN.
This personalized information may help clinicians and their patients make more informed decisions about the SLNB surgical procedure.
About DecisionDx-Melanoma

DecisionDx-Melanoma is a gene expression profile test that uses an individual patient’s tumor biology to predict individual risk of cutaneous melanoma metastasis or recurrence, as well as sentinel lymph node positivity, independent of traditional staging factors, and has been studied in more than 5,700 patient samples. Using tissue from the primary melanoma, the test measures the expression of 31 genes. The test has been validated in four archival risk of recurrence studies of 901 patients and six prospective risk of recurrence studies including more than 1,600 patients. Impact on patient management plans for one of every two patients tested has been demonstrated in four multicenter and single-center studies including more than 560 patients. The consistent performance and accuracy demonstrated in these studies provides confidence in disease management plans that incorporate DecisionDx-Melanoma test results. To predict risk of recurrence and likelihood of sentinel lymph node positivity, the Company utilizes its proprietary algorithms, i31-ROR and i31-SLNB, to produce an integrated DecisionDx-Melanoma test result. Through June 30, 2021, DecisionDx-Melanoma has been ordered 78,277 times for use in patients with cutaneous melanoma.

More information about the test and disease can be found at www.CastleTestInfo.com.