On June 17, 2019 Veracyte, Inc. (Nasdaq: VCYT) reported that a review article in Cancer Cytopathology, a journal of the American Cancer Society, details how new RNA whole-transcriptome sequencing-based genomic testing is helping physicians overcome a range of challenges in the diagnosis and treatment of thyroid cancer (Press release, Veracyte, JUN 17, 2019, View Source [SID1234537122]). The article describes how the technology behind Veracyte’s Afirma Genomic Sequencing Classifier (GSC) and Xpression Atlas (XA) is helping to reduce unnecessary surgeries in thyroid cancer diagnosis, and also inform surgery and treatment decision-making using the same minimally invasive patient sample. The article is highlighted on the cover of the June print issue, which is scheduled to be available the week of June 17, 2019.

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Challenges involved in the management of thyroid nodules include: Differentiating benign from malignant thyroid nodules when cytopathology results are indeterminate; determining the extent of initial thyroid surgery needed; and identifying targeted treatments for patients with thyroid cancers that do not respond to standard treatment.

"New advances in genomic technology and our understanding of the genomic underpinnings of thyroid disease are changing the landscape for how physicians diagnose and treat patients with thyroid nodules and cancer," said William C. Faquin, M.D., Ph.D., pathologist at Massachusetts General Hospital and Editor-in-Chief of Cancer Cytopathology. "In the last 10 years, physicians have increasingly used genomic testing to help reduce unnecessary thyroid surgeries when the cytopathology sample is indeterminate for cancer. Now, genomic technology can identify gene mutation drivers of disease to inform the type of surgery to be performed. Increasingly, molecular testing may also help guide the use of targeted therapies that are available or in development for patients who do not respond to standard treatment."

The article, titled "Extending Expressed RNA Genomics from Surgical Decision Making for Cytologically Indeterminate Thyroid Nodules to Targeted Therapies for Metastatic Thyroid Cancer," describes the development of and evidence behind the Afirma GSC and XA. Both tests leverage RNA whole-transcriptome sequencing technology to measure gene expression in potentially cancerous thyroid nodules. The authors note that RNA transcriptome technology may provide advantages over DNA-based genomic findings because it reflects a nodule’s current genomic activity, as compared to DNA-based approaches, which may show inactive gene mutations.

Two targeted therapies are now approved by the U.S. Food and Drug Administration for treating thyroid cancer patients: a combination of dabrafenib plus trametinib for BRAF V600E-mutated anaplastic thyroid cancer; and larotrectinib for solid tumors harboring a NTRK gene fusion, regardless of cancer type. Additionally, multiple other recent clinical trials have investigated therapies with specific targets that are relevant for thyroid cancer. These include two compounds targeting RET alterations, which were the subject of new data presentations at the recent American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The Afirma XA identifies these gene alterations, which can help physicians determine which patients could benefit from these cutting-edge new treatments.

"We believe that our novel RNA whole-transcriptome sequencing platform uniquely enables our Afirma offering to answer important clinical questions that can guide various points in a patient’s journey, helping to improve outcomes," said Bonnie Anderson, Veracyte’s chairman and chief executive officer. "Further, by providing this comprehensive information from the original biopsy used in diagnosis, we can streamline workflows and enable patients to get the answers they need faster and more easily."

About Afirma Genomic Testing

The Afirma GSC and Xpression Atlas provide physicians with a comprehensive solution for a complex landscape in thyroid nodule diagnosis and individualization of care. Veracyte developed the Afirma GSC with RNA whole-transcriptome sequencing and machine learning. The test helps identify patients with benign thyroid nodules among those with indeterminate cytopathology results in order to help patients avoid unnecessary diagnostic thyroid surgery. Afirma GSC testing is widely used in thyroid cancer diagnosis and is covered by Medicare and most of the nation’s leading private health insurers. The Afirma XA provides physicians with genomic alteration content from the same fine needle aspiration samples that are used in Afirma GSC testing and may help physicians decide with greater confidence on the surgical or therapeutic pathway for their patients. The Afirma XA includes 761 DNA variants and 130 RNA fusion partners in over 500 genes that are associated with thyroid cancer.

About Thyroid Cancer

The American Cancer Society estimates that 52,070 people in the United States will be diagnosed with thyroid cancer this year. Each year in the United States approximately 525,000 patients undergo FNA biopsies to evaluate thyroid nodules for cancer. Up to 30 percent of these patients receive indeterminate results – meaning they are not clearly benign or malignant – and, historically, most were directed to diagnostic surgery even though 70 percent to 80 percent of the time the nodules ultimately proved to be benign.

On June 17, 2019 Resolution Bioscience, Inc., reported the publication of a blinded performance evaluation between two cell-free DNA (cfDNA) next-generation sequencing (NGS) assays (Press release, Resolution Bioscience, JUN 17, 2019, View Source [SID1234537121]). The publication reports that the team of scientists, led by lung cancer researchers and clinicians at Dana-Farber Cancer Institute, found that the Resolution ctDx-Lung assay identified more actionable gene fusion mutations than Guardant Health’s Guardant360 test. The peer-reviewed manuscript, "Sensitivity of next-generation sequencing assays detecting oncogenic fusions in plasma cell-free DNA," was released online ahead of publication in Lung Cancer.

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Plasma genotyping has shown the ability to identify actionable, targetable mutations to drive personalized therapy for patients with advanced non-small cell lung cancer (NSCLC). However, leading commercial platforms have generated variable results when detecting complex variations, such as oncogenic gene fusions or copy number variations. In this comparison study, a cohort of 169 NSCLC patients with Guardant360 plasma results was screened for the presence of gene fusions based on previous tumor tissue analysis. Scientists at Dana-Farber used the Resolution kit in their lab to analyze the plasma of 16 patients who had a rearrangement in their tumor. All personnel involved in sample analysis were blinded to tumor genotype and Guardant360 results.

The Resolution assay detected 13 out of 16 (81.3%) fusions (allele frequency range 0.17-62.8%), while the Guardant360 test detected only seven (43.8%) fusions (allele frequency range 0.3-8.2%). For cases detected by both assays, the Resolution technology identified the mutation at a median of 7% higher allele frequency, which is indicative of a higher capture rate of breakpoint bearing cfDNA that increases overall sensitivity. For the six patients in which a fusion was detected by the Resolution assay but not by Guardant360, the average time to treatment discontinuation was 15.2 months (full range of 3-34 months).

"The Resolution liquid biopsy platform is designed to provide a fast, accurate, and non-invasive solution for mutationally comprehensive tumor genotyping," said Mark Li, CEO of Resolution Bioscience. "While this was a small study, we measure our success one patient at a time. Two patients with a fusion undetected by Guardant360 were on treatment for more than 30 months."

Dana-Farber scientists hypothesized that the Resolution assay offers more efficient hybridization to cfDNA fragments due to its use of tiled, short (˜40 nt) capture probes rather than more common 120 nt probes.

"Our targeted sequencing platform was designed from the ground up for analysis of cfDNA fragments. The shorter probes maintain high specificity while allowing better detection of the low amounts of mutation-bearing fragments often found in plasma," said Li. "Importantly, scientists at the Dana-Farber Cancer Institute performed the assay within their lab, demonstrating the potential of a distributed model."

Scientists presented the early results of this retrospective liquid biopsy comparison study between Resolution’s ctDx-Lung assay and Guardant Health’s Guardant360 test at this year’s American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. To view the full manuscript, please visit View Source

About Resolution Bioscience’s Technology

The Resolution liquid biopsy assays are powered by the company’s patented cfDNA NGS analysis platform, which includes proprietary targeted capture NGS chemistry and tightly coupled, cloud-based bioinformatics. Resolution’s technology has now been recognized as novel by the US Food and Drug Administration and has been cited in several important research publications and presentations. For example:

The Resolution HRD assay was recently granted Breakthrough Device Designation by the US Food and Drug Administration (FDA).
The company was the first to demonstrate detection of all four major types of mutations in a blinded clinical study led by scientists at Dana-Farber Cancer Institute. The team determined the assay has the potential to be implemented broadly for patient care and translational research.
Resolution was also the first company to demonstrate gene deletion detection in cfDNA in a study led by scientists at Vanderbilt University in small cell lung cancer. The team determined that cfDNA sequencing allows for improved monitoring of disease burden, depth of response to treatment, and timely warning of disease relapse in patients.
Resolution recently published 97% clinical response data with Memorial Sloan Kettering Cancer Center for non-small cell lung cancer patients who received plasma-directed therapy selection from Resolution’s assay. With more than 950 patients enrolled, the ongoing study is the largest prospective study of stage II, III, or IV NSCLC aimed at demonstrating clinical response and outcomes based upon plasma-directed therapy selection.
In a recent AstraZeneca publication, Resolution had the highest positive predictive value (PPV) and lowest false positive rate amongst four leading NGS liquid biopsy companies in a blinded comparison study.

On June 17, 2019 T Medical Technologies, Inc., a company dedicated to improving the lives of patients with brain tumors, reported the presentation of clinical data from a prospective study of GammaTile Therapy in patients with previously irradiated intracranial neoplasms (brain tumors) at the American Brachytherapy Society (ABS) 2019 Annual Meeting in Miami (Press release, GT Medical Technologies, JUN 17, 2019, View Source [SID1234537120]). These data reinforce the safety profile of GammaTile Therapy, a surgically targeted radiation therapy (STaRT) that is designed to delay tumor regrowth for patients with recurrent intracranial neoplasms (brain tumors).

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The company also announced that David Brachman, M.D., co-founder and CTO of GT MedTech, received the prestigious Judith Stitt Best Abstract Award for his abstract Surgically Targeted Radiation Therapy: Safety Profile of Collagen Tile Brachytherapy in 79 Recurrent, Previously Irradiated Intracranial Neoplasms on a Prospective Clinical Trial. Only four abstracts every year – out of hundreds of submissions – are selected by the ABS’s scientific committee for this recognition.

GammaTile is an FDA-cleared therapy for patients with recurrent intracranial neoplasms (brain tumors) including primary (benign or malignant) and metastatic tumors. Placed directly at the site of the tumor cavity during the last few minutes of excision surgery, GammaTile Therapy is a new approach that immediately begins targeting residual tumor cells, before they can replicate. Designed to help protect healthy brain tissue and facilitate rapid, accurate placement during the procedure, the therapy features a bioresorbable, conformable, 3D-collagen tile and uniform radiation source.

The prospective, single-arm study evaluated the safety profile of GammaTile Therapy in combination with tumor resection surgery in 79 recurrent brain tumors of various types, including gliomas, meningiomas, and brain metastases. Results from the study showed that GammaTile Therapy improves local tumor control compared to currently available treatments. The study also showed a low rate of adverse events, with wound infection occurring in 2.5% of tumors and radiation-related brain changes occurring in 8% of treated patients during the follow-up period. These findings suggest that GammaTile Therapy is a viable radiation therapy option for the challenging cohort of patients with recurrent brain tumors.

"These data further support the safety profile and efficacy of GammaTile Therapy for patients with brain tumors," said Dr. Brachman. "This therapy is designed to meet a significant unmet need for patients who may not be candidates for other forms of radiation therapy, or for whom surgery is not a viable option without effective adjuvant therapy. We are encouraged by these data, which build on our body of evidence supporting the safety and efficacy of this therapy."

GammaTile Therapy offers advantages over the most common treatment for patients undergoing surgery for recurrent brain tumors: a course of External Beam Radiation Therapy (EBRT), which requires daily treatments for up to six weeks. Some patients may not be candidates for EBRT. Once the disease has returned, many people with recurrent brain tumors have already received levels of radiation therapy that make the risk of additional external beam radiation outweigh the potential benefits. Additionally, those patients who are potentially candidates for EBRT typically have to wait two weeks or more for surgical wound healing before beginning treatment, giving any residual tumor cells a chance to replicate.

Initial data from this study were published this year in the Journal of Neurosurgery (JNS) demonstrating that GammaTile therapy is a safe and effective new option proven to delay tumor progression in patients with previously treated, aggressive meningiomas, the most common type of primary brain tumor. Additional data from this study supporting the safety and efficacy of GammaTile Therapy for various tumor types were presented in April at the American Association of Neurological Surgeons Annual Meeting, affirming that this therapy could help expand options for brain tumors that are challenging to treat.

About GammaTile Therapy

GammaTile Therapy is an FDA-cleared, surgically targeted radiation therapy (STaRT) that is designed to delay tumor regrowth for patients with brain tumors. Featuring a bioresorbable, conformable, 3D-collagen tile and uniform radiation source, GammaTile Therapy is placed at the end of excision surgery so that it immediately begins to target residual tumor cells while limiting the impact of radiation on healthy brain tissue. Because the therapy is implanted at the end of surgery, patients treated with GammaTile Therapy require no additional trips to the hospital or clinic for radiation therapy.

On June 17, 2019 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that it has entered into a mutual agreement with Celgene Corporation to terminate the parties’ global collaboration for tislelizumab, BeiGene’s investigational anti-PD-1 antibody, in advance of the pending acquisition of Celgene by Bristol-Myers Squibb (Press release, BeiGene, JUN 17, 2019, View Source [SID1234537119]). In connection with the termination, Celgene has agreed to pay $150 million to BeiGene.

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"Our collaboration with Celgene was instrumental for the late-stage clinical development of tislelizumab and has provided us with significant resources to continue our broad clinical program," said John V. Oyler, Co-Founder, Chief Executive Officer, and Chairman of BeiGene. "As we have been leading most of the ongoing Phase 3 or potentially registration-enabling trials with a global development organization of over 800 people, we believe that we are well-positioned to continue the development of tislelizumab. I am proud of the work that we have accomplished in collaboration with Celgene and am excited by the tremendous opportunity that we have ahead now that we’ve regained full global rights to tislelizumab."

Tislelizumab has been dosed in over 2,950 patients globally. With two new drug applications under review in China, BeiGene expects tislelizumab to receive its first regulatory approval later this year.

In July 2017, BeiGene and Celgene announced a global strategic collaboration in which Celgene obtained exclusive rights to develop and commercialize tislelizumab in solid tumor cancers in the United States, Europe, Japan and the rest of world outside of Asia. BeiGene retained rights in hematology indications globally and in solid tumor cancers in Asia (ex-Japan). In connection with that agreement, BeiGene also acquired Celgene’s commercial operations in China and an exclusive license to Celgene’s cancer commercial portfolio in China (ABRAXANE, REVLIMID, VIDAZA). BeiGene’s commercial license from Celgene is not affected by the termination of the tislelizumab agreement. In the almost two years since the transaction, BeiGene has grown its commercial organization in China to more than 600 people.

About Tislelizumab

Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug candidate produced from BeiGene’s immuno-oncology biologic program, and is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

Tislelizumab is being studied in a broad clinical program. BeiGene has completed a pivotal Phase 2 clinical trial in patients with relapsed or refractory (R/R) classical Hodgkin’s lymphoma (cHL). Ongoing clinical trials of tislelizumab include a Phase 3 clinical trial in patients with second-line or third-line non-small cell lung cancer (NSCLC); a Phase 3 clinical trial in first-line patients with hepatocellular carcinoma (HCC); a Phase 3 clinical trial in second-line patients with esophageal squamous carcinoma (ESCC); a Phase 3 clinical trial in first-line patients with gastric cancer (GC); a Phase 3 clinical trial in first-line patients with ESCC; a Phase 2 clinical trial in second- or third-line patients with HCC; and a Phase 1 clinical trial in patients with R/R NK/T-cell lymphomas. The aforementioned studies are enrolling patients in multiple countries, including the U.S., Europe, and China.

Additionally, BeiGene is conducting a Phase 3 clinical trial in first-line patients with non-squamous NSCLC; a Phase 3 clinical trial in first-line patients with squamous NSCLC; a Phase 3 clinical trial in patients with nasopharyngeal cancer (NPC); a Phase 3 clinical trial in first-line patients with urothelial carcinoma (UC); a pivotal Phase 2 clinical trial in patients with locally advanced or metastatic urothelial cancer; and a pivotal Phase 2 trial in patients with MSI-H or dMMR solid tumors. These studies are enrolling patients in China.

New drug applications (NDA) for tislelizumab in patients with R/R cHL and in patients with locally advanced or metastatic UC have been accepted by the China National Medical Products Administration (NMPA, formerly known as CFDA) and the R/R cHL filing has been granted priority review.

On June 17, 2019 Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company), a biopharmaceutical company focused on developing and commercializing medicines seeking to improve the survival and quality of life of cancer patients, reported that two posters highlighting clinical data for COPIKTRA (duvelisib) in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2019 Annual Meeting which took place June 13-16, 2019, in Amsterdam (Press release, Verastem, JUN 17, 2019, View Source;p=irol-newsArticle&ID=2401532 [SID1234537118]). One poster describes results from a post-hoc analysis evaluating the effect of COPIKTRA on lymphocytosis in patients with relapsed or refractory CLL/SLL from the Phase 3 DUO study, including patients with high-risk factors. The other poster describes dose modification data from patients with relapsed or refractory CLL/SLL in the DUO study.

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COPIKTRA, a targeted oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, received approval as monotherapy from the U.S. Food and Drug Administration (FDA) in September 2018 for the treatment of patients with relapsed or refractory CLL/SLL after at least two prior therapies.

"Duvelisib is a potent oral dual inhibitor of PI3K-delta and -gamma with clinical activity in patients with CLL/SLL after at least two prior therapies," said Hagop Youssoufian, MSc, M.D., Head of Medical Strategy at Verastem Oncology. "In a post-hoc analysis authored by Dr. Barrientos and colleagues, duvelisib induced rapid and transient lymphocytosis that was associated with a reduction in lymphadenopathy, including in high-risk patients. Notably, duvelisib also resulted in resolution of lymphocytosis at up to 21 weeks, and the majority of patients achieved a lymph node response and also achieved rapid shrinkage of their lymph nodes."

Patterns of Duvelisib-Induced Lymphocytosis in Patients with Relapsed/Refractory CLL/SLL, Including Those with High-Risk Factors

In this study, researchers aimed to characterize the clinical profile and kinetics associated with duvelisib-related lymphocytosis. Lymphocytosis is an increase in the number of lymphocytes (white blood cells) in the blood and is a recognized biological marker of treatment with B-cell receptor pathway inhibitors. Similar to ibrutinib and idelalisib, duvelisib treatment induces lymphocytosis in patients with CLL. This post hoc analysis defined response in patients (n=158) with relapsed or refractory CLL/SLL, including high-risk subgroups, which were characterized by unmutated IGHV (n=110), 17p deletion/TP53 mutation (n=48), 11q deletion (n=38), and bulky disease (n=74).

Of 158 patients treated with duvelisib, 78% experienced lymphocytosis. Median time to onset of lymphocytosis was one week across all patients, including patients in the high-risk subgroups. Median time to resolution of lymphocytosis was 14 weeks, with a 50% reduction from baseline at 21 weeks. Similar results were observed regardless of high-risk status. Rapid shrinkage of lymph nodes was noted, with 86% of patients achieving lymph node response. Among patients who achieved a response with duvelisib at first or second assessment, 78% and 86%, respectively, experienced lymphocytosis; median time to resolution of lymphocytosis in these patients was 12 and 18 weeks, respectively. Prolonged lymphocytosis (for >12 months) occurred in 12 patients (8%). The overall response rate in patients with prolonged lymphocytosis was 83%. Of note, the median PFS was similar among patients with and without prolonged lymphocytosis; 22.1 months (95% CI, 12.9-27.6), compared to 24 months (95% CI, 20.5-NE), respectively. Overall, there were low rates of tumor lysis syndrome (1 patient; 0.6%). These results showed that duvelisib monotherapy induced rapid and transient lymphocytosis temporally associated with a reduction in lymphadenopathy in patients with relapsed or refractory CLL/SLL.

Effect of Dose Modification on Response to COPIKTRA in Patients with Relapsed or Refractory CLL/SLL in the Phase 3 DUO Study

The randomized, multicenter, open-label, Phase 3 DUO study, compared COPIKTRA versus ofatumumab in 319 adult patients with CLL (n=312) or SLL (n=7) after at least one prior therapy. The study randomized patients with a 1:1 ratio to receive either COPIKTRA 25mg twice daily until disease progression or unacceptable toxicity, or ofatumumab, an approved standard of care treatment for use in CLL/SLL, for 7 cycles. This analysis examined dose modification patterns and their impact on response to COPIKTRA. Dose interruptions or dose reductions to 15mg, 10mg or 5mg twice daily were permitted per study protocol to manage treatment-emergent adverse events (TEAEs). Responses were assessed per an Independent Review Committee.

Among the 158 COPIKTRA-treated patients in the DUO study, the median duration of exposure was 11.6 months, versus 5.3 months for patients treated with ofatumumab. The most common cause of dose interruption was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n=118), median time to first response on COPIKTRA was 1.9 months and the estimated median duration of response was 11.1 months. Median time to first dose interruption was 3.9 months and median duration of dose interruption was 15 days (range 1 to 133 days). Response to COPIKTRA was improved or maintained in most patients evaluated for response who had at least one dose interruption for >1 week (84%) or >2 weeks (82%) followed by at least 3 weeks on COPIKTRA. In a landmark analysis, median PFS was similar in patients with dose interruptions and those without dose interruptions for >1 week (17.8 versus 16.3 months) or >2 weeks (17.8 versus 16.3 months) within the first 3 months. The median time to dose reduction after a complete response or partial response was 5.6 months (n=25) and median duration was 3.4 months. Median time to onset across adverse events of special interest (AESIs) after starting COPIKTRA ranged from 2.2 to 4.3 months. Median time to resolution was within 4 weeks across AESIs. Proportions of patients experiencing AESIs were stable or decreased over time after 3-6 months: 0-3 months, 64%; >3-6 months, 63%; >6-9 months, 47%; >9-12 months, 52%, and seldom led to discontinuation of COPIKTRA (≤10%). These findings support the thesis that dose interruptions or dose reductions may be useful in managing TEAEs with COPIKTRA and that dose interruptions of >1-2 weeks or more did not appear to significantly impact response to COPIKTRA or PFS.

PDF copies of these poster presentations are available here.

Details for the EHA (Free EHA Whitepaper) 2019 poster presentations are as follows:

Title: Effect of dose modifications on response to duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial
Lead author: Paolo Ghia, Università Vita-Salute San Raffaele
Session: 6. Chronic lymphocytic leukemia and related disorders – Clinical
Abstract #: PS1157
Title: Patterns of duvelisib-induced lymphocytosis in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia including those with high-risk factors treated in the DUO trial
Lead author: Jacqueline Barrientos, Zucker School of Medicine at Hofstra/Northwell
Session: 6. Chronic lymphocytic leukemia and related disorders – Clinical
Abstract #: PS1160
Important Safety Information

WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS

•Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.

•Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.

•Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA.

•Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.

WARNINGS AND PRECAUTIONS

Infections: Serious, including fatal (4%), infections occurred in 31% of patients receiving COPIKTRA (N=442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months, with 75% of cases occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise patients to report new or worsening signs and symptoms of infection. Cases of Pneumocystis jirovecii pneumonia (PJP) (1%) and cytomegalovirus (CMV) reactivation/infection (1%) occurred in patients taking COPIKTRA. Provide prophylaxis for PJP during treatment and following completion of treatment until the absolute CD4+ T cell count is greater than 200 cells/µL. Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV infection including CMV reactivation.

Diarrhea or Colitis: Serious, including fatal (<1%), diarrhea or colitis occurred in 18% of patients receiving COPIKTRA (N=442). Median time to onset of any grade diarrhea or colitis was 4 months, with 75% of cases occurring by 8 months. The median event duration was 0.5 months. Advise patients to report any new or worsening diarrhea.

Cutaneous Reactions: Serious, including fatal (<1%), cutaneous reactions occurred in 5% of patients receiving COPIKTRA (N=442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months with a median event duration of 1 month. Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report new or worsening cutaneous reactions.

Pneumonitis: Serious, including fatal (<1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving COPIKTRA (N=442). Median time to onset of any grade pneumonitis was 4 months with 75% of cases occurring within 9 months. The median event duration was 1 month with 75% of cases resolving by 2 months.

Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, of patients receiving COPIKTRA (N=442). Two percent of patients had both an ALT or AST > 3 X ULN and total bilirubin > 2 X ULN. Median time to onset of any grade transaminase elevation was 2 months with a median event duration of 1 month. Monitor hepatic function during treatment with COPIKTRA.

Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of patients receiving COPIKTRA (N=442), with Grade 4 neutropenia occurring in 24% of all patients. Median time to onset of grade ≥3 neutropenia was 2 months. Monitor neutrophil counts at least every 2 weeks for the first 2 months of COPIKTRA therapy, and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4).

Embryo-Fetal Toxicity: COPIKTRA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus and conduct pregnancy testing before initiating COPIKTRA treatment. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.

ADVERSE REACTIONS

B-cell Malignancies Summary

Fatal adverse reactions within 30 days of the last dose occurred in 8% (36/442) of patients treated with COPIKTRA 25 mg BID. Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%). The most common adverse reactions (reported in ≥20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain and anemia.

CLL/SLL

Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155) of patients treated with ofatumumab. Serious adverse reactions were reported in 73% (115/158) of patients treated with COPIKTRA and most often involved infection (38%; 60/158) and diarrhea or colitis (23%; 36/158). The most common adverse reactions with COPIKTRA (≥20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.

For specific information on the management of the adverse reactions above, please review Dose Modifications for Adverse Reactions within the full Prescribing Information.

DRUG INTERACTIONS

CYP3A Inducers: Coadministration with a strong CYP3A inducer may reduce COPIKTRA efficacy. Avoid coadministration with strong CYP3A4 inducers.

CYP3A Inhibitors: Coadministration with a strong CYP3A inhibitor may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dose to 15 mg BID when coadministered with a strong CYP3A4 inhibitor.

CYP3A Substrates: Coadministration of COPIKTRA with sensitive CYP3A4 substrates may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.

To report Adverse Reactions, contact FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch and Verastem Oncology at 1-877-7RXVSTM (1-877-779-8786).

Please see accompanying full Prescribing Information, including Boxed Warning.

About Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers that affect lymphocytes and are essentially the same disease, with the only difference being the location where the cancer primarily occurs. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL. The symptoms of CLL/SLL include a tender, swollen abdomen and feeling full even after eating only a small amount. Other symptoms can include fatigue, shortness of breath, anemia, bruising easily, night sweats, weight loss, and frequent infections. However, many patients with CLL/SLL will live for years without symptoms. There are approximately 200,000 patients in the US affected by CLL/SLL with nearly 20,000 new diagnoses this year alone. While there are therapies currently available, real-world data reveals that a significant number of patients either relapse following treatment, become refractory to current agents, or are unable to tolerate treatment, representing a significant medical need. The potential of additional oral agents, particularly as a monotherapy that can be used in the general community physician’s armamentarium, may hold significant value in the treatment of patients with CLL/SLL.

About COPIKTRA (duvelisib)

COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status, and is being investigated in combination with other agents through investigator-sponsored studies.4 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.