On May 29, 2020 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies, reported long-term interim data from Cohort 2 in the C-144-01 study of lifileucel in advanced melanoma during an oral session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program (Press release, Iovance Biotherapeutics, MAY 29, 2020, View Source [SID1234558709]).

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"We are very pleased to present the long term follow up data for lifileucel in melanoma at the ASCO (Free ASCO Whitepaper) Scientific Program," said Maria Fardis, Ph.D., President and Chief Executive Officer of Iovance Biotherapeutics. "The median duration of response has not been reached at 18.7 months of study follow up supporting potential benefit of the one-time treatment of lifileucel TIL therapy in advanced melanoma patients. The latest data at ASCO (Free ASCO Whitepaper) also demonstrate durable responses with lifileucel across the broad spectrum of our study population, including a wide age range of metastatic melanoma patients who have received prior anti-CTLA-4 and BRAF targeted treatments, and equally in patients with PD-L1 high and low status."

Jason Chesney, MD PhD, Director, James Graham Brown Cancer Center, University of Louisville and C-144-01 study investigator stated, "One of the greatest challenges oncologists face today is the treatment of melanoma patients who have progressed on immune checkpoint and BRAF/MEK inhibitors. The preliminary results of the C-144-01 study demonstrate that autologous tumor infiltrating lymphocytes (TILs; lifileucel) induce durable clinical responses in a significant percentage of this moribund population. Importantly, this new study opens the door for trials of TILs in many other cancer types and in combination with our growing repertoire of immunomodulatory agents."

Updated interim results from Cohort 2 are now available from an oral abstract session titled, "Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies." As of the April 23, 2020 data extract for the oral presentation, lifileucel shows a 36.4% overall response rate (2 complete responses and 22 partial responses) and a disease control rate of 80% (n=66). Median duration of response (DOR) was not reached at 18.7 months of median study follow up (2.2 to 26.9+ months).

The Cohort 2 patients had heavily pretreated metastatic melanoma with high baseline disease burden. They have progressed on multiple prior therapies (3.3 mean prior therapies), including anti-PD-1 and BRAF/MEK inhibitors. The adverse event profile was consistent with the underlying advanced disease, lymphodepletion and IL-2 regimens.

Michael Kaplan, President and CEO of the Melanoma Research Alliance, stated, "While the last decade has brought incredible progress in delivering new treatments for melanoma, we know that more than half of patients with advanced melanoma are still in need of additional options. It is particularly exciting to see a new treatment approach, like lifileucel, that can offer hope and real results for some for whom checkpoint immunotherapy alone has yet to prove successful. The Melanoma Research Alliance is excited that Iovance has taken a significant step forward in ensuring more treatment options for patients who once had very few."

The oral abstract session is available on demand in the ASCO (Free ASCO Whitepaper) Meeting Library at View Source Details of the presentation are as follows:

Title: Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies
Authors: Amod Sarnaik, et al.
Session Title: Melanoma/Skin Cancers
Session Type: Oral Abstract Session
Abstract Number: 10006
Location: ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program at View Source

On May 29, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported follow-up data from the Phase 3 ASPEN trial comparing BRUKINSA (zanubrutinib) to ibrutinib for the treatment of Waldenström’s macroglobulinemia (WM) and long-term follow-up data from a Phase 1/2 study in patients with treatment naïve and relapsed/refractory (R/R) WM, presented at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (Press release, BeiGene, MAY 29, 2020, View Source/news-releases/news-release-details/beigene-presents-updated-head-head-results-phase-3-trial" target="_blank" title="View Source/news-releases/news-release-details/beigene-presents-updated-head-head-results-phase-3-trial" rel="nofollow">View Source [SID1234558708]).

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"The totality of data from the two trials presented at ASCO (Free ASCO Whitepaper) suggests that zanubrutinib may be a preferred treatment option for patients with WM, regardless of whether they have received prior treatment," said Constantine S. Tam, MBBS, M.D., Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at the Peter MacCallum Cancer Center, Australia, and a member of the steering committee and principal investigator for the ASPEN trial. "WM can be a devastating disease for patients and their families. We must offer therapies that are both effective in managing WM and well-tolerated to offer the best quality of life. In the ASPEN trial, zanubrutinib demonstrated a more favorable safety profile and was shown to be a more tolerable option for patients than ibrutinib, especially when considering adverse events of particular interest such as atrial fibrillation, hypertension and diarrhea."

While the ASPEN trial did not achieve statistical significance on its primary endpoint of superiority in complete response (CR) and very good partial response (VGPR) rates for zanubrutinib compared to ibrutinib, zanubrutinib demonstrated a numerically higher VGPR rate, as well as clinically meaningful improvements in safety and tolerability compared to ibrutinib. Additional five-month investigator-assessed follow-up data in the overall patient population reinforced the trend toward higher VGPR rates for zanubrutinib and advantages in safety. In a separate presentation of Phase 1/2 long-term follow-up data, rates of VGPR/CR increased with continued zanubrutinib treatment and the therapy was well tolerated.

"These results reinforce that zanubrutinib is a highly effective BTK inhibitor with clinically meaningful improvements in safety and tolerability compared to ibrutinib. Importantly, since WM is typically a disease of older individuals, zanubrutinib appears to have advantages related to cardiovascular safety risks over ibrutinib," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "The choice to evaluate zanubrutinib directly against ibrutinib underscores our bold approach to R&D and our commitment to develop better treatments for patients across the globe."

ASPEN Trial Data
Oral Presentation, Abstract #8007

Data presented from the Phase 3 ASPEN trial (NCT03053440) include the 201 patients in the randomized cohort of patients with WM and a MYD88 mutation.

At data cutoff of August 31, 2019, with 19.4 months median follow-up:
The combined CR+VGPR rate as assessed by independent review committee (IRC) for the overall intent-to-treat population was 28.4% in the zanubrutinib arm and 19.2% in the ibrutinib arm (2-sided descriptive p=0.0921);
The combined CR+VGPR rate as assessed by investigators for the overall intent-to-treat population was 28.4% in the zanubrutinib arm and 17.2% in the ibrutinib arm (2-sided descriptive p=0.0437);
Most common grade ≥ 3 adverse events (≥5% in either arm) for zanubrutinib compared to ibrutinib included hypertension (6% vs. 11%), neutropenia (16% vs. 8%), pneumonia (1% vs. 7%), anemia (5% vs. 5%), and thrombocytopenia (5% vs. 3%);
Categories of AEs of interest for BTK inhibitors for zanubrutinib compared to ibrutinib included atrial fibrillation/flutter of any grade (2.0% vs. 15.3%), bleeding of any grade (48.5% vs. 59.2%), major hemorrhage (5.9% vs. 9.2%), diarrhea (20.8% vs. 31.6%), hypertension (10.9% vs. 17.3%); neutropenia (29.7% vs. 13.3%), infection (66.3% vs. 67.3%), and second malignancy (11.9% vs. 11.2%);
Despite higher rates of grade ≥ 3 neutropenia among AEs of interest in the zanubrutinib arm (19.8% vs. 8.2% for ibrutinib), rates of infection were similar in patients taking zanubrutinib and ibrutinib (all grades: 66.3% vs. 67.3%; grade ≥ 3: 17.8% vs. 19.4%); and
In the zanubrutinib arm, four (4.0%) patients discontinued treatment due to AEs and one (1.0%) patient had an adverse event leading to death; in the ibrutinib arm, nine patients (9.2%) discontinued due to AEs and four (4.1%) patients had an adverse event leading to death.
After an additional five-months of follow-up with a data cutoff of January 31, 2020, with 24.2 months median follow-up:
CR+VGPR as assessed by investigator for zanubrutinib was 30.4% compared to 18.2% for ibrutinib (exploratory analysis; 2-sided descriptive p=0.0302);
Categories of AEs of interest for BTK inhibitors for zanubrutinib compared to ibrutinib included atrial fibrillation/flutter of any grade (3.0% vs. 18.4%), bleeding of any grade (50.5% vs. 60.2%), major hemorrhage (5.9% vs. 10.2%), diarrhea (21.8% vs. 32.7%), hypertension (12.9% vs. 20.4%); and neutropenia (31.7% vs. 15.3%);
Despite higher rates of grade ≥ 3 neutropenia in the zanubrutinib arm (22.8% vs. 8.2% for ibrutinib), rates of infection remained similar in patients taking zanubrutinib and ibrutinib (all grade: 69.3% vs. 71.4%; grade ≥ 3: 18.8% vs. 23.5%); and
No additional patients discontinued treatment due to AEs in the zanubrutinib arm, compared to an additional five patients in the ibrutinib arm (4% vs 14.3%). No additional patients had an adverse event leading to death in both arms (1.0% vs. 4.1%).
ASPEN Data from Non-Randomized Cohort, Patients with MYD88 Wild-Type (MYD88wt) WM
Electronic Abstract #20056

Additional data from the ASPEN trial presented in an abstract included 28 patients who were centrally determined at study entry to have the MYD88WT or mutation unknown genotype. These patients were enrolled into a non-randomized cohort assigned to receive zanubrutinib 160mg twice daily (BID).

As of August 31, 2019, the median follow-up was 17.9 months and 17 patients remained on study treatment. Updated results included:

In the 26 centrally confirmed MYD88WT patients, the overall response rate (ORR) assessed by IRC was 80.8%, with a major response rate of 50.0%, including a VGPR rate of 26.9%;

Progression-free survival (PFS) event-free rate at 12 months was 72.4%;

In this cohort of 28 patients with MYD88WT or mutation unknown genotype, the most frequently reported AEs (≥ 20%) were diarrhea, anemia, contusion, pyrexia, and upper respiratory tract infection. Major hemorrhage was reported in 2 patients, and atrial fibrillation was reported in 1 patient. There were no fatal AEs; and

Two patients (7.1%) discontinued zanubrutinib due to adverse events, and 6 patients (14.3%) discontinued due to disease progression.
Phase 1/2 Trial Data
Poster Presentation, Abstract #8051

Data presented from the Phase 1/2 trial (NCT02343120) evaluating zanubrutinib in patients with treatment-naïve or relapsed/refractory WM include:

As of January 29, 2020, with a median follow-up of 35.3 months, 73% remained on treatment;

The ORR was 96% and the VGPR/CR rate was 46%;

The proportion of patients achieving a best response of VGPR or CR increased with treatment duration;

Three-year PFS event-free rate was 80%, and overall survival was 83%;

Reasons for treatment discontinuation included AEs in 13% of patients, disease progression in 10%, and other in 4%;

The most commonly reported AEs (≥ 20%) were upper respiratory tract infection (55%), contusion (33%, all grade 1), cough (23%), and diarrhea (21%);

62.3% of patients (48/77) experienced at least one grade ≥3 AE and five patients experienced AEs leading to death;

AEs of interest included minor bleeding (35%), hypertension (18%), major hemorrhage (5%), and atrial fibrillation/flutter (5%).
Investor Conference Call

The Company will host an investor conference call and webcast on Friday, May 29, 2020 at 8:00 p.m. ET to discuss results presented at the ASCO (Free ASCO Whitepaper) Virtual Scientific Program.

A live webcast of the conference call can be accessed from the investors section of BeiGene’s website at View Source or View Source An archived replay will be available for 90 days following the event.

To learn more about BeiGene’s pipeline and data presented during the ASCO (Free ASCO Whitepaper)2020 Virtual Scientific Program, visit BeiGeneVirtualCongress.com.

About Waldenström’s Macroglobulinemia

WM is a rare lymphoma representing approximately 1% of all non-Hodgkin lymphomas and typically progresses slowly after diagnosis.1 In the United States, approximately 3,000 people are diagnosed with WM each year.1

About the ASPENTrial

The Phase 3 randomized, open-label, multicenter ASPEN clinical trial (NCT03053440) evaluated zanubrutinib versus ibrutinib in patients with relapsed/refractory (R/R) or treatment-naïve (TN) Waldenström’s macroglobulinemia. The primary objective was to establish superiority of zanubrutinib compared to ibrutinib as demonstrated by the proportion of patients achieving complete response (CR) or very good partial response (VGPR). Secondary endpoints included major response rate, duration of response and progression-free survival, and safety, measured by incidence, timing and severity of treatment-emergent adverse events. The pre-specified analysis populations for the trial included the overall population (n=201) and R/R patients (n=164). Exploratory endpoints included quality of life measures.

The study included two cohorts, a randomized cohort (cohort 1) consisting of 201 patients with a MYD88 mutation and a non-randomized cohort (cohort 2) in which 28 patients with MYD88 wild-type (MYD88WT) received zanubrutinib because they have historically responded poorly to ibrutinib therapy.

The randomized cohort 1 enrolled 102 patients (including 83 relapsed or refractory (R/R) patients and 19 treatment-naïve (TN) patients) in the zanubrutinib arm and 99 patients (including 81 R/R patients and 18 TN patients) in the ibrutinib arm. Patients in the zanubrutinib arm were assigned to receive zanubrutinib 160 mg twice daily (BID) and patients in the ibrutinib arm received 420 mg of ibrutinib once daily (QD).

About the Zanubrutinib Clinical Trial Program

Clinical trials of zanubrutinib include:

Fully-enrolled Phase 3 ASPEN clinical trial in patients with Waldenström’s macroglobulinemia (WM) comparing zanubrutinib to ibrutinib (NCT03053440), currently the only approved BTK inhibitor for WM;

Phase 3 SEQUOIA trial comparing zanubrutinib with bendamustine plus rituximab in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (NCT03336333);

Phase 3 ALPINE trial comparing zanubrutinib to ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL (NCT03734016);

Phase 2 trial in combination with GAZYVA (obinutuzumab) in patients with R/R follicular lymphoma (FL) (NCT03332017);

Phase 3 trial comparing zanubrutinib and rituximab to bendamustine and rituximab in patients with untreated MCL (NCT04002297);

Phase 2 MAGNOLIA trial in patients with R/R marginal zone lymphoma (MZL) (NCT03846427);

Phase 2 ROSEWOOD trial (NCT03332017) in China comparing obinutuzumab and zanubrutinib vs obinutuzumab alone in treating patients with R/R FL;

Phase 2 trial (NCT04382586) in the U.S. comparing zanubrutinib plus supportive care to placebo plus supportive care for the treatment of patients with COVID-19 disease and pulmonary distress;

Phase 2 trial (NCT03332173) in China in patients with R/R WM; and

Completed Phase 2 trials in China in patients with R/R MCL (NCT03206970) and R/R CLL/SLL (NCT03206918).
About BRUKINSA (zanubrutinib)

BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK), discovered by BeiGene scientists, that is currently being evaluated globally in a broad pivotal clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

BRUKINSA was approved by the U.S. FDA to treat adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy on November 14, 2019. This indication was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

New Drug Applications (NDAs) in China for relapsed refractory (R/R) MCL and R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have been accepted by the China National Medical Products Administration (NMPA) and granted priority review and are pending approval.

BRUKINSA is not approved for use outside the United States. BRUKINSA is not approved for the treatment of Waldenström’s macroglobulinemia.

IMPORTANT SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%), and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For co-administration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

On May 29, 2020 Affimed N.V. (Nasdaq: AFMD), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported details of its AFM13 REDIRECT clinical trial design and rationale at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Annual Meeting, being held in virtual format on May 29-31, 2020 (Press release, Affimed, MAY 29, 2020, View Source [SID1234558707]).

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AFM13 is a first-in-class innate cell engager that induces specific and selective killing of CD30-positive tumor cells by engaging and activating NK cells and macrophages thereby leveraging the power of the innate immune system. As detailed in the poster at ASCO (Free ASCO Whitepaper), REDIRECT is a registration-directed trial with AFM13 as monotherapy in patients with relapsed/refractory peripheral T cell lymphoma or transformed mycosis fungoides. The study is actively recruiting.

"We recognize that we target difficult to treat malignancies and we are committed to advancing AFM13 in the clinic for patients who currently have limited treatment options," said Dr. Andreas Harstrick, Affimed’s Chief Medical Officer. "Having received the U.S. FDA orphan drug designation for AFM13 last month further reinforced our commitment to this area with high unmet medical need and the importance of developing new therapies."

The REDIRECT poster presented at ASCO (Free ASCO Whitepaper) is available online at View Source

About AFM13

AFM13 is a first-in-class tetravalent, bispecific innate cell engager that specifically binds to CD30 on tumor cells and to CD16A on NK cells and macrophages. AFM13 is being developed in peripheral T cell lymphoma (pTCL) and in other CD30-positive lymphomas. AFM13 has shown a favorable safety profile and signs of therapeutic efficacy as a monotherapy in CD30-positive non-Hodgkin lymphoma with cutaneous manifestation. In addition, data from a combination study of AFM13 with Merck’s anti-PD-1 antibody Keytruda (pembrolizumab) in Hodgkin lymphoma (HL) supports proof of principle for the combination of NK cell engagement with checkpoint inhibition. AFM13 has been granted orphan drug designation by the U.S. Food and Drug Administration for HL.

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.