On May 29, 2020 Kite, a Gilead Company (Nasdaq: GILD), reported results from an interim analysis of ZUMA-5, a global, multicenter, single-arm, open-label Phase 2 study evaluating Yescarta (axicabtagene ciloleucel) in adult patients with relapsed or refractory indolent (slow growing) non-Hodgkin lymphoma (NHL) after at least two prior lines of therapy (Press release, Kite Pharma, MAY 29, 2020, View Source [SID1234558706]). After a single infusion of Yescarta, 93 percent of patients (n=96 evaluable for efficacy) responded, with 80 percent of patients achieving a complete response (CR) as assessed by an independent review committee. The data were presented in an oral session during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting held from May 29-31 (Abstract #8008). The presentation has also been selected for a Highlights of the Day session as part of ASCO (Free ASCO Whitepaper)’s 2020 Virtual Scientific Program on Saturday, May 30 at 11:30 am ET. The Highlights sessions recap the most impactful science from the oral sessions.

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Pending results from the primary analysis at 12 months, Kite plans to submit a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) later this year to expand the indication for Yescarta. Yescarta has previously been granted a Breakthrough Therapy Designation (BTD) by the FDA for relapsed or refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL) (two types of indolent NHL) after at least two prior therapies. If approved, Yescarta would become the first and only chimeric antigen receptor (CAR) T therapy approved for the treatment of relapsed or refractory indolent NHLs.

"People living with certain indolent non-Hodgkin lymphomas, such as follicular lymphoma, can experience relapses with increasing frequency and develop a more aggressive disease over time despite available treatments," said Caron A. Jacobson, MD, Medical Director, Immune Effector Cell Therapy Program, Dana-Farber Cancer Institute and Assistant Professor of Medicine, Harvard Medical School. "Thus, the strong overall response and complete response rates demonstrating the potential of this therapy is extremely promising for these patients."

Ninety-five percent of patients with relapsed or refractory FL (n=80) who had received at least two prior lines of systemic therapy responded to Yescarta, including 81 percent of patients achieving a CR and 68 percent of patients in an ongoing response after at least nine months of follow-up as per independent review committee assessment. Of patients with relapsed or refractory MZL (n=16), 81 percent responded to Yescarta, with 75 percent achieving a CR after at least one month of follow-up as per independent review committee assessment. With a median follow-up of 15.3 months in all patients, median duration of response (DOR) was 20.8 months, median progression-free survival (PFS) was 23.5 months and median overall survival (OS) was not reached.

In the safety analysis of 140 treated patients with FL or MZL, Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 8 percent and 17 percent of patients, respectively. There were two Grade 5 adverse events in patients with FL, including one patient with multisystem organ failure in the context of CRS related to treatment with Yescarta and one patient with aortic dissection unrelated to Yescarta treatment. The primary analysis with 12 months of follow-up is ongoing.

"Yescarta is substantially improving outcomes for people with certain relapsed and refractory cancers, such as diffuse large B-cell lymphoma," said Ken Takeshita, MD, Kite’s Global Head of Clinical Development. "These results from ZUMA-5 support our assessment that Yescarta has the potential to provide benefit in indolent NHL, and we look forward to sharing results from the primary analysis in patients with relapsed or refractory disease later this year."

Yescarta has not been approved by any regulatory agency for the treatment of indolent non-Hodgkin lymphoma, including follicular lymphoma or marginal zone lymphoma. Its safety and efficacy have not been established in these lymphomas.

Yescarta was the first CAR T cell therapy to be approved by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), and high grade B-cell lymphoma and DLBCL arising from FL. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a risk evaluation and mitigation strategy (REMS) due to these risks; see below for Important Safety Information.

About Indolent Non-Hodgkin Lymphoma

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are both forms of indolent non-Hodgkin lymphoma (NHL) in which malignant tumors slowly grow but can become more aggressive over time.

FL is the most common form of indolent lymphoma and the second most common type of lymphoma globally.It accounts for approximately 22 percent of all lymphomas diagnosed worldwide. MZL is the third most common lymphoma, accounting for 8 to 12 percent of all B-cell NHLs.

Despite advances in management and substantial improvements in long-term survival, patients living with FL have varied outcomes. Currently, there are no standard of care treatments for relapsed and refractory FL after two or more lines of therapy, and there are limited options for the treatment of relapsed or refractory MZL.

About ZUMA-5

ZUMA-5 is a single-arm, multicenter, open-label Phase 2 study that aims to enroll up to 160 adult patients (≥18 years old) with relapsed or refractory iNHL of either follicular lymphoma (FL) or marginal zone lymphoma (MZL) subtypes, who received at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody combined with an alkylating agent. The objectives of the study are to evaluate the efficacy and safety of a single infusion of Yescarta in this patient population. The primary endpoint of the trial is objective response rate (ORR) as assessed by an independent review committee per the 2014 Lugano Classification. Secondary endpoints include CR rate, DOR, PFS, OS, safety and CAR T cell and cytokines levels. The study is ongoing.

U.S. Important Safety Information for Yescarta

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
CYTOKINE RELEASE SYNDROME (CRS) occurred in 94% of patients, with 13% ≥ Grade 3. Among patients who died after receiving Yescarta, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to Yescarta infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES occurred in 87% of patients, 98% of which occurred within the first 8 weeks with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade ≥3 occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%), and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema have occurred. Following Yescarta infusion, monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program called the Yescarta REMS which requires that: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YESCARTAREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients. Grade ≥3 infections occurred in 23% of patients; those due to an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade ≥3 cytopenias not resolved by Day 30 following Yescarta infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common (incidence ≥20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

On May 29, 2020 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported data from the ongoing ARROW clinical trial of pralsetinib in patients with RET fusion-positive non-small cell lung cancer (NSCLC), thyroid cancer and other solid tumors (Press release, Blueprint Medicines, MAY 29, 2020, View Source [SID1234558705]). Registrational data for pralsetinib in patients with RET fusion-positive NSCLC showed deep and durable clinical responses, with a median duration of response (DOR) not reached. Additional results showed the broad clinical activity of pralsetinib across other RET fusion-positive tumors, including thyroid cancer. Pralsetinib was well-tolerated and safety results were consistent with prior data, with no new safety signals observed. These results are being presented during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 (ASCO20) Virtual Scientific Program.

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In addition, Blueprint Medicines reported that the U.S. and EU marketing applications for pralsetinib for the treatment of locally advanced or metastatic RET fusion-positive NSCLC have been accepted by the U.S. Food and Drug Administration (FDA) and validated by the European Medicines Agency (EMA), respectively. The FDA granted priority review and set an action date of November 23, 2020 under the Prescription Drug User Fee Act. Blueprint Medicines plans to submit an NDA for pralsetinib for advanced RET mutant and RET fusion-positive thyroid cancers in June 2020, under the FDA’sOncology Center of Excellence Real-Time Oncology Review pilot program.

"The use of targeted therapies for molecularly defined subsets of patients is fundamentally altering the treatment of non-small cell lung cancer and, similar to oncogenes like EGFR and ALK, RET is a proven driver and promising therapeutic target," said Justin Gainor, M.D., Director of the Center for Thoracic Cancers and Targeted Immunotherapy at Massachusetts General Hospital Cancer Center and an investigator on the ARROW trial. "The ARROW trial results presented today during the ASCO (Free ASCO Whitepaper) virtual meeting showed that patients with RET fusion-positive lung cancer treated with the selective RET inhibitor pralsetinib had durable responses. In addition to supporting the development of pralsetinib across a broad population, these data highlight the urgency to test lung cancer patients with next-generation sequencing so that eligible patients may be identified for treatment."

"Building on a unique preclinical profile characterized by selectivity for RET and equipotent activity against predicted resistance mutations, the clinical data for pralsetinib is showing high complete response rates, prolonged durability and a favorable safety profile as a convenient once-daily oral treatment. With this differentiated profile, pralsetinib has the potential to change the standard of care for patients with RET-altered non-small cell lung cancer and thyroid cancer," said Andy Boral, M.D., Ph.D., Chief Medical Officer of Blueprint Medicines. "More broadly, data presented during the ASCO (Free ASCO Whitepaper) virtual meeting highlight the clinical activity of pralsetinib across ten distinct RET-altered tumor types. These results strongly support continued development of pralsetinib across all RET-altered cancers, regardless of a tumor’s tissue of origin, with the goal of delivering transformative benefit to the broadest possible patient population."

Clinical Activity Data

The reported data included response-evaluable populations comprising 116 patients with NSCLC who received a starting dose of 400 mg once daily (QD), including 80 patients with NSCLC previously treated with platinum-based chemotherapy and 26 patients with treatment-naïve NSCLC, 11 patients with RET fusion-positive thyroid cancer, and 12 patients with other RET fusion-positive cancers. Tumor response was assessed by blinded, independent central review using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

RET Fusion-Positive NSCLC

As of a data cutoff of November 18, 2019, pralsetinib demonstrated consistent and robust clinical activity in RET fusion-positive NSCLC, regardless of prior therapy, RET fusion partner or central nervous system (CNS) involvement.

In 80 patients who previously received platinum-based chemotherapy, the ORR was 61 percent (95% CI: 50-72%). Two partial responses (PR) were pending confirmation at the time of the data cut off and were subsequently confirmed. Five percent of patients had a confirmed response (CR) and 14 percent of patients had complete regression of target tumors.

In 26 patients with no prior systemic therapy, the confirmed ORR was 73 percent (95% CI: 52-88%), and the CR rate was 12 percent.

Across all 116 patients, regardless of prior therapy, the median DOR was not reached (95% CI: 11 months, not reached), and the 6-month DOR was 86 percent. Overall, 74 percent of confirmed responders, including all patients with CRs, were on treatment as of the data cutoff.

Robust and durable intracranial activity was shown in nine patients with measurable CNS metastases at baseline. All patients had shrinkage of CNS metastases, with an intracranial CR rate of 33 percent. No CNS responders experienced CNS progressive events. The median CNS DOR was not reached, with ongoing treatment durations up to 12 months in patients with measurable CNS metastases. Among patients without a history of CNS metastases, none have developed new CNS metastases on study as of the data cutoff date.

Other RET Fusion-Positive Cancers

As of a data cutoff of February 13, 2020, pralsetinib demonstrated robust clinical activity in a range of additional RET fusion-positive cancers. In 11 patients with RET fusion-positive thyroid cancer (10 previously treated with systemic therapy), the centrally confirmed ORR was 91 percent (95% CI: 59-100%), and the disease control rate was 100 percent (95% CI: 72-100%). Overall, 70 percent of responders remain on therapy with ongoing treatment durations up to 22 months as of the data cutoff. Across 12 patients with other RET fusion-positive cancers previously treated with systemic therapy, the investigator-assessed ORR was 50 percent (95% CI: 21‒79), with one PR pending confirmation. Responses were observed in all evaluable patients with pancreatic adenocarcinoma (n=3) and cholangiocarcinoma (n=2), tumor types with a typically poor prognosis.

Safety Data

As previously reported, as of the data cutoff date of November 18, 2019, a total of 354 patients were enrolled in the ARROW trial at a starting dose of 400 mg QD. Overall, safety results were consistent with previously reported data. Pralsetinib was well-tolerated across tumor types, and most treatment-related adverse events (AEs) were Grade 1 or 2.

The most common treatment-related AEs reported by investigators (≥15 percent) were increased aspartate aminotransferase (AST), anemia, increased alanine aminotransferase (ALT), constipation, hypertension and neutropenia. Investigator-reported Grade 3 or higher treatment-related AEs (≥5 percent) were hypertension, neutropenia and anemia. Only 4 percent of patients discontinued pralsetinib due to treatment-related AEs.

These updated data for pralsetinib are being reported in two presentations at the ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program Annual Meeting, including a poster discussion presentation on trial results in RET fusion-positive NSCLC (Abstract Number: 9515) and an oral presentation on trial results in other RET fusion-positive cancers (Abstract Number: 109). Copies of the data presentations are available in the "Science—Publications and Presentations" section of Blueprint Medicines’ website at www.BlueprintMedicines.com.

Conference Call Information

Blueprint Medicines will host a live webcast today beginning at 8:30 a.m. ET to discuss updated data from the ARROW trial of pralsetinib in RET fusion-positive cancers. To access the live call, please dial (855) 728-4793 (domestic) or (503) 343-6666 (international) and refer to conference ID 8585078. A webcast of the conference call will be available under "Events and Presentations" in the Investors & Media section of Blueprint Medicines’ website at View Source The archived webcast will be available on Blueprint Medicines’ website approximately two hours after the conference call and will be available for 30 days following the call.

About the Clinical Development Program in RET-Altered Cancers

Blueprint Medicines is pursuing a broad development program for pralsetinib in patients with RET fusion-positive NSCLC, RET-mutant medullary thyroid cancer (MTC), RET-fusion thyroid cancer and other advanced solid tumors. The Phase 1/2 ARROW trial and the Phase 3 AcceleRET Lung trial are currently ongoing.

ARROW is designed to evaluate the safety, tolerability and efficacy of pralsetinib in adults with RET-altered cancers. The trial consists of two parts: a dose escalation portion, which is complete, and an expansion portion in patients treated at 400 mg QD. The study’s objectives include assessing response, pharmacokinetics, pharmacodynamics and safety. The trial is enrolling patients at multiple sites in the United States, European Union and Asia.

The primary objective of the AcceleRET Lung trial is to evaluate the potential of pralsetinib to extend progression-free survival compared to platinum-based chemotherapy, with or without pembrolizumab, as a first-line treatment for RET fusion-positive NSCLC. The trial is designed to enroll approximately 250 patients randomized to receive either pralsetinib or the investigator’s choice of platinum-based chemotherapy regimen with or without pembrolizumab. Patients randomized to the control arm may crossover upon progression to receive pralsetinib. Additional endpoints include overall survival, ORR and DOR. Multiple trial sites are active or planned in North America, Europe and Asia.

Patients and physicians interested in the ARROW or AcceleRET Lung trial can contact the Blueprint Medicines study director at [email protected] or 1-617-714-6707. Additional information is available at www.BlueprintClinicalTrials.com/ARROW and www.clinicaltrials.gov.

About RET-Altered Solid Tumors

RET activating fusions and mutations are key disease drivers in many cancer types, including NSCLC and MTC. RET fusions are implicated in approximately 1 to 2 percent of patients with NSCLC and approximately 10 to 20 percent of patients with papillary thyroid cancer, while RET mutations are implicated in approximately 90 percent of patients with advanced MTC. In addition, oncogenic RET alterations are observed at low frequencies in colorectal, breast, pancreatic and other cancers, and RET fusions have been observed in patients with treatment-resistant EGFR-mutant NSCLC.

There are several approved multi-kinase inhibitors (MKIs) with RET activity being evaluated in clinical trials. To date, clinical activity attributable to RET inhibition has been uncertain for these approved MKIs, likely due to insufficient inhibition of RET and off-target toxicities. There is a need for precision therapies that provide durable clinical benefit by selectively targeting RET alterations and anticipated resistance mutations.

About Pralsetinib

Pralsetinib is an investigational, once-daily oral precision therapy specifically designed for highly potent and selective targeting of oncogenic RET alterations. Blueprint Medicines is developing pralsetinib for the treatment of patients with RET-altered NSCLC, thyroid cancer and other solid tumors. The FDA has granted Breakthrough Therapy Designation to pralsetinib for the treatment of RET fusion-positive NSCLC that has progressed following platinum-based chemotherapy, and RET mutation-positive MTC that requires systemic treatment and for which there are no acceptable alternative treatments.

Pralsetinib was designed by Blueprint Medicines’ research team, leveraging the company’s proprietary compound library. In preclinical studies, pralsetinib consistently demonstrated sub-nanomolar potency against the most common RET fusions, activating mutations and predicted resistance mutations. In addition, pralsetinib demonstrated markedly improved selectivity for RET compared to pharmacologically relevant kinases, including approximately 80-fold improved potency for RET versus VEGFR2. By suppressing primary and secondary mutants, pralsetinib has the potential to overcome and prevent the emergence of clinical resistance. Blueprint Medicines believes this approach will enable durable clinical responses across a diverse range of RET alterations, with a favorable safety profile.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of pralsetinib and certain other drug candidates in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for pralsetinib in the rest of the world.

On May 29, 2020 Gilead Sciences, Inc. (Nasdaq: GILD) reported updated results from a single-arm, open-label Phase 1b trial of magrolimab, an investigational anti-CD47 monoclonal antibody, in combination with azacitidine in previously untreated patients with higher-risk myelodysplastic syndrome (MDS) and previously untreated patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, including patients with TP53-mutant AML, a high unmet need population (Press release, Gilead Sciences, MAY 29, 2020, View Source [SID1234558703]). Results continue to support the clinical activity of magrolimab and azacitidine. The data were presented during an oral session at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting held from May 29-31 (Abstract #7057).

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At the time of the data cut-off, 68 patients had been treated with magrolimab plus azacitidine, including 39 patients with previously untreated higher-risk MDS and 29 patients with previously untreated AML. Of 33 MDS patients who were evaluable for efficacy, 91 percent (n=30/33) achieved an objective response (response assessments per 2006 IWG MDS criteria) including 42 percent (n=14/33) with a complete response (CR). Responses to magrolimab and azacitidine also deepened over time, as the CR rate with at least six months of follow-up was 56 percent in MDS patients.

In AML, 64 percent (n=16/25) of patients evaluable for efficacy achieved an objective response (response assessments per 2017 AML ELN criteria), including 56 percent (n=14/25) with a CR or a CR with incomplete blood count recovery (CRi). Notably in TP53-mutant AML (n=12), a treatment refractory and poor prognosis population, 75 percent achieved a CR or CRi.

Median duration of response and median overall survival have not yet been reached in MDS, AML or TP53-mutant AML, with a median follow-up of 5.8 (range: 2.0-15.0 months), 9.4 (range: 1.9-16.9 months) and 8.8 months (range: 1.9-16.9 months), respectively.

The safety profile of the combination of magrolimab plus azacitidine was generally consistent with prior reports with no maximum tolerated dose reached. Common all-grade treatment-related adverse events (AEs) among 68 patients with MDS or AML were anemia (38 percent), fatigue (21 percent), neutropenia (19 percent), thrombocytopenia (18 percent) and infusion reaction (16 percent). Treatment-related febrile neutropenia occurred in 1.5 percent of patients. Only one patient (1.5 percent) discontinued the trial due to a treatment-related AE.

"We continue to be encouraged by the response rates observed with magrolimab and azacitidine in first-line, high-risk MDS and AML," said David Sallman, MD, H. Lee Moffitt Cancer Center and Research Institute, an investigator for the clinical trial. "Particularly impressive are the responses in some of the most difficult-to-treat patients, including AML patients with a TP53 mutation. This patient group suffers from a lack of effective treatment options. These results support further study in these patients and provide hope for a potentially meaningful clinical advance."

"Results presented at ASCO (Free ASCO Whitepaper) reinforce the clinical potential of CD47 inhibition with magrolimab in high risk, difficult-to-treat hematologic malignancies," said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. "We look forward to initiating additional trials in MDS and TP53-mutant AML, which will be a significant step forward for this exciting next-generation cancer immunotherapy."

Magrolimab is investigational and not approved anywhere globally. Its efficacy and safety have not been established. More information about clinical trials with magrolimab is available at www.clinicaltrials.gov (NCT03248479).

About Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Myelodysplastic syndromes (MDS) are a type of cancer caused by poorly formed or dysfunctional blood cells in the bone marrow. Approximately 15,000 people are diagnosed with MDS in the U.S. each year, and no new treatments have been approved in 14 years.

Acute myeloid leukemia (AML) is a type of cancer which begins in the bone marrow and can quickly move to the blood and other parts of the body. AML most often develops from cells that would turn into white blood cells, but can also develop from other types of blood-forming cells. Cancers such as MDS can also develop into AML. Approximately 20,000 Americans will be diagnosed with AML each year.

About the Phase 1b Trial

The Phase 1b trial, which is being funded in part by the California Institute of Regenerative Medicine (CIRM), is designed to evaluate the safety, tolerability and efficacy of magrolimab in combination with azacitidine in untreated patients with higher-risk MDS or with AML who are ineligible for induction chemotherapy. All patients in the trial received a 1 mg/kg priming dose of magrolimab, coupled with intrapatient dose escalation, to mitigate on-target anemia. Patients were then treated with full doses of azacitidine and a magrolimab maintenance dose of 30 mg/kg once weekly (QW) or every two weeks (Q2W). Based on pharmacokinetics and CD47 receptor occupancy data in the bone marrow from the ongoing trial, Q2W dosing has been selected to optimize patient convenience.

This trial, which is ongoing, aims to enroll up to a total of 257 patients.

About Magrolimab

Magrolimab is an investigational monoclonal antibody against CD47 that is designed to interfere with recognition of CD47 by the SIRPα receptor on macrophages, thus blocking the "don’t eat me" signal used by cancer cells to avoid being ingested by macrophages. Forty Seven, Inc. developed magrolimab and was recently acquired by Gilead. Magrolimab is initially being studied in patients with MDS and AML, and additional studies are ongoing in non-Hodgkin lymphoma (NHL) and solid tumors. Magrolimab has been granted Fast Track designation by the FDA for the treatment of MDS and AML, and for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma, two forms of B-cell non-Hodgkin’s lymphoma. Magrolimab has also been granted Orphan Drug designation by the U.S. Food and Drug Administration for AML and MDS and by the European Medicines Agency for the treatment of AML.

On May 29, 2020 Seattle Genetics, Inc. reported positive results from exploratory analyses of intracranial efficacy, including survival, in patients with HER2-positive metastatic breast cancer (MBC) who had stable or active brain metastases in the HER2CLIMB pivotal trial of TUKYSA (tucatinib) (Press release, Seattle Genetics, MAY 29, 2020, View Source [SID1234558702]). HER2CLIMB compared TUKYSA in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with unresectable, locally advanced or metastatic HER2-positive breast cancer with or without brain metastases. Of the patients enrolled in the trial, 48 percent had a presence or history of brain metastases. Results demonstrated that the addition of TUKYSA to trastuzumab and capecitabine in patients with brain metastases delayed progression in the brain, doubled the intracranial response rate (tumor shrinkage in the brain) and reduced the overall risk of death by nearly half. The data were consistent across patients who had either stable or active brain metastases. Results were presented in an oral presentation in the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and simultaneously published in the Journal of Clinical Oncology.

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TUKYSA in combination with trastuzumab and capecitabine was approved by the U.S. Food and Drug Administration (FDA) in April 2020 for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. Primary results from HER2CLIMB were first presented at the San Antonio Breast Cancer Symposium in December 2019 and published in the New England Journal of Medicine.

"It is immensely gratifying to see for the first time, results for patients with stable or active brain metastases who are not typically included in clinical trials, especially when you consider that nearly half of patients with HER2-positive metastatic breast cancer experience disease progression to the brain," said Nancy U. Lin, M.D., director of the Metastatic Breast Cancer Program in the Susan F. Smith Center for Women’s Cancers at Dana-Farber in Boston, MA. "These additional analyses provide further evidence that TUKYSA improves survival and delays cancer progression in the brain for patients with HER2-positive metastatic breast cancer who have brain metastases."

"These additional analyses, together with the primary analysis of HER2CLIMB, show TUKYSA is active for patients with and without disease that has spread to the brain," said Roger Dansey, M.D., Chief Medical Officer of Seattle Genetics. "We continue to be encouraged by the remarkable clinical activity of TUKYSA in combination with trastuzumab and capecitabine and look forward to evaluating its potential in additional treatment settings and tumor types through our ongoing clinical program."

The new data that further examine TUKYSA’s effect in the brain include exploratory analyses for central nervous system progression-free survival (CNS-PFS), overall survival (OS), intracranial objective response rate (ORR-IC) and duration of response in HER2-positive metastatic breast cancer patients whose disease had spread to the brain.

The exploratory analyses demonstrated that patients with brain metastases who received the TUKYSA combination versus trastuzumab and capecitabine alone had:

a 42 percent reduction in the risk of death
a 68 percent reduction in the risk of CNS disease progression (a delay in progression in the brain) or death
a more than doubling of intracranial response rate (47 percent vs. 20 percent) for patients who had active measurable intracranial lesions at baseline
Endpoint

TUKYSA Arm (TUKYSA + trastuzumab + capecitabine)

Control Arm (Placebo + trastuzumab + capecitabine)

OS Benefit in All Patients with Brain Metastases

N=198

N=93

Risk Reduction

42% (Hazard Ratio [HR]=0.58 [95% Confidence Interval (CI): 0.40, 0.85]; p=0.005)

One-Year OS

70.1% (95% CI: 62.1, 76.7)

46.7% (95% CI: 33.9, 58.4)

Median OS

18.1 months (95% CI: 15.5, not estimable)

12 months (95% CI: 11.2, 15.2)

CNS-PFS Benefit in All Patients with Brain Metastases

N=198

N=93

Risk Reduction

68% (HR=0.32 [95% CI: 0.22, 0.48]; p<0.0001)

One-year CNS-PFS

40.2% (95% CI: 29.5, 50.6)

0%

Median CNS-PFS

9.9 months (95% CI: 8.0, 13.9)

4.2 months (95% CI: 3.6, 5.7)

Intracranial Objective Response Rate (ORR-IC) in Patients with Active Brain Metastases and Measurable Intracranial Lesions at Baseline

N=55

N=20

Complete Response (CR)

3 (5.5%)

1 (5.0%)

Partial Response (PR)

23 (41.8%)

3 (15.0%)

Stable Disease

24 (43.6%)

16 (80.0%)

Progressive Disease

2 (3.6%)

0

Not Available

3 (5.5%)

0

ORR-IC (CR+PR)

26 (47%) (95% CI: 34, 61)

4 (20%) (95% CI: 6, 44)

Duration of Response-IC

6.8 months (95% CI: 5.5, 16.4)

3 months (95% CI: 3.0, 10.3)

About HER2CLIMB

HER2CLIMB is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing TUKYSA in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab and T-DM1. The primary endpoint of the trial was PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including OS, PFS per BICR in patients with brain metastases at baseline and confirmed ORR.1

Results of Primary Analysis of HER2CLIMB

Endpoint TUKYSA Arm (TUKYSA + trastuzumab + capecitabine)
Control Arm (Placebo + trastuzumab + capecitabine)

PFS by BICR in the first 480 patients

46% reduction in risk of progression or death (HR=0.54 [95% CI: 0.42, 0.71]; p<0.00001; N=480)

OS

34% reduction in risk of death (HR=0.66 [95% CI: 0.50, 0.87]; p=0.0048; N=612)

PFS* by BICR in patients with brain metastases

52% reduction in risk of progression or death (HR=0.48 [95% CI: 0.34, 0.69]; p<.0.00001; N=291)

One-Year PFS

25% (95% CI: 17, 34)

0%

Median PFS

7.6 months (95% CI: 6.2, 9.5)

5.4 months (95% CI: 4.1, 5.7)

*standard RECIST, includes brain and body

In HER2CLIMB, serious adverse reactions occurred in 26 percent of patients who received TUKYSA. Serious adverse reactions occurring in 2 percent or more of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea, abdominal pain, and seizure (2% each). The most common adverse reactions occurring in 20 percent or more of patients who received TUKYSA were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Adverse reactions leading to treatment discontinuation occurred in 6 percent of patients who received TUKYSA; adverse reactions leading to treatment discontinuation of TUKYSA (in 1 percent or more of patients) were hepatotoxicity (1.5%) and diarrhea (1%).1

About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. An estimated 279,100 new cases of breast cancer will be diagnosed in the U.S. in 2020.2 Between 15 and 20 percent of breast cancer cases are HER2-positive.3 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.3,4,5 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time. 6,7,8

About TUKYSA (tucatinib)

TUKYSA is an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth.1,9 In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.1

Important Safety Information

Warnings and Precautions

Diarrhea – TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Hepatotoxicity – TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 5% had an AST increase >5 × ULN, and 1.5% had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Embryo-Fetal Toxicity – TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for at least 1 week after the last dose.
Adverse Reactions

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Lab Abnormalities

In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.
Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.
P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicity.
Use in Specific Populations

Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 1 week after the last dose.
Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.
Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.

On May 29, 2020 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, reported new data highlighting progress on AUTO3, the company’s CAR T cell therapy being investigated in the ALEXANDER study, a Phase 1/2 study in relapsed/refractory diffuse large B cell lymphoma (DLBCL), during the Annual Society of Clinical Oncology 2020 (ASCO20) Virtual Scientific Program beginning May 29 (Press release, Autolus, MAY 29, 2020, View Source [SID1234558701]).

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"Data from the ALEXANDER trial of AUTO3, a CD19/CD22 dual-targeting CAR T product candidate in DLBCL have shown a complete response rate of 63% at the recommended Phase 2 dose range with an excellent safety profile," said Dr. Aravind Ramakrishnan, Medical Director, Bone Marrow Transplant and Cellular Therapy Program, Sarah Cannon Blood Cancer Center at St. David’s South Austin Medical Center. "We are encouraged by the current study results and have begun enrollment in an outpatient cohort to assess how this approach may benefit a greater population of DLBCL patients."

As of the data cut-off date of April 27, 2020, 23 patients in the ALEXANDER Phase 1/2 clinical trial of AUTO3 were evaluable for safety and efficacy with a minimum of 28-days follow-up. AUTO3 was well tolerated, with no patients experiencing dose limiting toxicity, and there were no treatment-related deaths. At a dose of ≥ 150 x 106 cells across the 2 dosing regimens for pembrolizumab, a single dose of pembrolizumab on day minus 1 (D-1) or three doses of pembrolizumab starting on day 14 (D14), no patient experienced Grade 3 or higher Cytokine Release Syndrome (CRS) and no patient experienced neurotoxicity of any grade. At these doses, 11 out of 16 patients achieved a complete or partial response (ORR=69%), and 9 out of 16 achieved a complete response (CRR=56%) with all 9 complete responses ongoing at a median follow-up of 3 months (range 1-12 months). Additionally, at the recommended Phase 2 dose range of 150 – 450 x 106 cells with pembrolizumab D-1, 6 out of 8 patients achieved a complete response or partial response (ORR=75%), and 5 out of 8 patients achieved a complete response (CRR=63%).

"We are very pleased with the progression of AUTO3 in DLBCL, combining a high level of complete remissions with a safety profile supportive of outpatient use. We have not seen early relapses from complete remissions and are in the process of confirming the profile at the recommended Phase 2 regimen. Our 20 patient outpatient cohort has started, and the results are expected for the second half of 2020 and will further inform the design of the Phase 2 study," said Dr. Christian Itin, chairman and chief executive officer of Autolus.

Investor call on Monday June 1, 2020
Management will host a conference call and webcast at 8:30 am EDT/1:30 pm BST to discuss the ASCO (Free ASCO Whitepaper) data. To listen to the webcast and view the accompanying slide presentation, please go to: View Source

The call may also be accessed by dialing (866) 679-5407 for U.S. and Canada callers or (409) 217-8320 for international callers. Please reference conference ID 4880556. After the conference call, a replay will be available for one week. To access the replay, please dial (855) 859-2056 for U.S. and Canada callers or (404) 537-3406 for international callers. Please reference conference ID 4880556.