On June 4, 2018 Dynavax Technologies Corporation (NASDAQ:DVAX) reported data from its ongoing Phase 1b/2 study investigating SD-101, Dynavax’s intratumoral TLR9 agonist, in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy developed by Merck (known as MSD outside the United States and Canada) in patients with advanced melanoma (Press release, Dynavax Technologies, JUN 4, 2018, View Source [SID1234527166]).

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The company reported results on a total of 69 patients comparing two doses of SD-101, £ 2mg (n=30) versus 8mg (n=39) administered by intratumoral injection. These data are being presented in poster and discussion session today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, in Chicago, IL. The primary endpoints of this dose-expansion/dose-finding study are safety and preliminary efficacy. The results of this study showed a 70% overall response rate (ORR) in advanced melanoma patients who received the £ 2 mg dose of SD-101 in up to four lesions versus a 38% ORR in the group receiving the 8 mg dose of SD-101 in one lesion. The combination of SD-101 and KEYTRUDA was well tolerated with adverse events related to SD-101 being transient, mild to moderate flu-like symptoms.

"These data provide further evidence of the potential for SD-101 to improve responses in first-line advanced melanoma patients in combination with an anti-PD-1 therapy," commented Eddie Gray, Chief Executive Officer. "Our studies continue to demonstrate the potential value of SD-101 across multiple tumor types. We plan to build upon this momentum and update our progress with additional data planned for a medical conference later in the year."

Highlights from Poster Presentation (Abstract #9513)

Overall response rate (ORR) of 70% (21 of 30), with a complete response (CR) rate of 17%, for advanced melanoma patients who received the £ 2 mg dose of SD-101 in up to four lesions

ORR of 38% (15 of 39) in patients who received the 8 mg dose of SD-101 in one lesion

Durable response in patients who received £ 2 mg dose of SD-101 with 74% 6-month progression free survival (PFS) rate

Observed responses in injected lesion(s) and distant lesions, including visceral metastases in the liver

Responders included 8 of 10 PD-L1 negative patients in the £ 2 mg dose cohort
AEs related to SD-101 treatment were transient, mild to moderate flu-like symptoms at both the £ 2mg and the 8 mg dosing levels

No increase in the frequency of immune-related adverse events over individual monotherapies reported in other studies1,2 nor evidence of any new safety signals
Additional details on response rates based on patient characteristics including stage of disease, ECOG score, and PD-L1 status are also included in the poster presentation which can be accessed here.

"We are moving forward with the 2mg dose of SD-101 for our Phase 3 trial which we believe is the optimal dose based on these efficacy, safety and biomarker data showing increased immune activation consistent with the biology of TLR9 activation. We continue to collect and analyze data from this trial to finalize details of the Phase 3 study design," stated Rob Janssen, Chief Medical Officer.

The details of the poster presentation and discussion session are as follows:

Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy

Session Title: Melanoma/Skin Cancers

Abstract: 9513

Poster Board: 340

Poster Session Date/Time: Monday, June 4, 2018, 1:15 PM – 4:45 PM CDT

Poster Session Location: McCormick Place South, Hall A, Advanced Disease Poster Section

Discussion Session Date/Time: Monday, June 4, 2018, 4:45 PM – 6:00 PM CDT

Discussion Session Location: McCormick Place Lakeside Center, Level 4 – E451

Analyst/Investor Presentation

Today at 6:30pm CDT, Dynavax will host a presentation for analysts and investors. The presentation will be available via live webcast only and can be accessed in the "Investors and Media" section of the company’s website at www.dynavax.com.

About SYNERGY-001 (KEYNOTE-184)

SYNERGY-001, previously referred to as MEL-01, is the dose-escalation and expansion study of SD-101 in combination with KEYTRUDA which includes patients with histologically or cytologically confirmed unresectable Stage IIIC/IV melanoma. The primary endpoints of the trial are safety and preliminary efficacy of intratumoral SD-101 in combination with KEYTRUDA.

About SD-101

SD-101, the Company’s lead clinical candidate, is a proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. Dynavax is evaluating this intratumoral TLR9 agonist in several clinical studies to assess its safety and activity, including a Phase 2 study in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy, in patients with advanced melanoma and in patients with head and neck squamous cell cancer, in a clinical collaboration with Merck. Dynavax maintains all commercial rights to SD-101.

On June 4, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the phase 3 ENLIVEN study showed a statistically significant 39 percent overall response rate (ORR) at week 25 based upon central review of MRI scans using Response Evaluation Criteria in Solid Tumors, version 1.1 (the primary endpoint) for patients treated with oral pexidartinib compared to no tumor response among patients who received placebo (P<0.0001) (Press release, Daiichi Sankyo, JUN 4, 2018, View Source [SID1234527165]). Patients enrolled in the trial were those with tenosynovial giant cell tumor (TGCT) for whom surgery would be associated with potentially worse function or severe morbidity. After a median six month follow-up (longest 17 months), no responders in the ENLIVEN study had progressed. The data will be presented during an oral abstract session on Monday, June 4, 2018 between 8:24 AM – 8:36 AM CDT (Abstract 11502) at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

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"Current treatment options for TGCT are largely limited to surgery in order to remove as much of the tumor as possible. Despite the best surgical intervention, the recurrence rate of diffuse TGCT is high and the disease may advance to the point where surgery is no longer an option," said William D. Tap, MD, lead investigator of the study and Chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York City. "Pexidartinib may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended."

Pexidartinib is an investigational, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), a primary growth driver of abnormal cells in the synovium that cause TGCT.

In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib versus placebo (AST or ALT ≥3X ULN: 33 percent, total bilirubin ≥2X ULN: 5 percent, N=61). Eight patients discontinued pexidartinib due to hepatic adverse events (AEs); four were serious nonfatal AEs with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

Other AEs noted in ENLIVEN >10 percent and more common with pexidartinib included hair color changes, pruritus, rash, vomiting, abdominal pain, constipation, fatigue, dysgeusia, facial edema, peripheral edema, periorbital edema, decreased appetite and hypertension.

Secondary efficacy endpoints demonstrated that patients treated with pexidartinib had a 56 percent overall response rate (ORR) by Tumor Volume Score (TVS), compared to no response in patients who received placebo (P<0.0001). Clinically meaningful improvement versus placebo was observed in other secondary efficacy endpoints, including range of motion (+15% vs +6%, P=0.0043), PROMIS physical function (+4.1 vs -0.9, P=0.0019), and worst stiffness (-2.5 vs -0.3, P<0.0001). There was also a nonsignificant improvement in pain response (31% vs 15%).

"We are encouraged by the results from the ENLIVEN study and we look forward to submitting an NDA to the U.S. FDA and engaging European regulators for review of pexidartinib," said Gideon Bollag, PhD, CEO, Plexxikon, a member of the Daiichi Sankyo Group."

About the ENLIVEN Study

ENLIVEN, a double-blind, randomized, global multi-cener, pivotal phase 3 study, evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomized (1:1) to receive either pexidartinib or placebo at 1000 mg/d for 2 weeks followed by 800 mg/d for 22 weeks in order to evaluate the efficacy and safety of pexidartinib versus placebo. The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (Week 25), as assessed with centrally-read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness and measures of pain reduction.

After completing the first part of the study, patients randomized to either pexidartinib or placebo were eligible to take part in the second part of ENLIVEN, a long-term, open-label part where patients could continue to receive or start to receive pexidartinib. In October 2016, following two reported cases of serious, non-fatal liver toxicity in the ENLIVEN study, the data monitoring committee (DMC) recommended that patients receiving placebo in the first part of the study should no longer be eligible to start pexidartinib in the second part of the study. A total of 120 patients who were enrolled prior to the DMC recommendation continued with the study according to the revised protocol.

About TGCT (PVNS/GCT-TS)

Tenosynovial giant cell tumor (TGCT), previously referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a rare, usually non-cancerous tumor that affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb.1,2 It has been estimated that the incidence of TGCT is 11 to 50 cases per million, based on studies from three countries.3-5 Patients are commonly diagnosed in their 20s to 50s,and depending on the type of TGCT, women can be up to twice as likely to develop a tumor as men.6,7

Primary treatment of TGCT includes surgery to remove the tumor. However, in patients with a diffuse form where the tumor can wrap around bone, tendons, ligaments and other parts of the joint, it is more difficult to remove and may require multiple surgeries or joint replacement, eventually advancing to the point where surgical resection is no longer an option and amputation may be considered. It is estimated that the rate of recurrence for diffuse TGCT can be 20 to 55 percent.8

About Pexidartinib

Pexidartinib is an investigational, novel, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib also inhibits c-kit and FLT3-ITD. Pexidartinib was discovered by Plexxikon Inc., the small molecule structure-guided R&D center of Daiichi Sankyo.

Pexidartinib has been granted Breakthrough Therapy Designation for the treatment of patients with pigmented villonodular synovitis (PVNS) or giant cell tumor of tendon sheath (GCT-TS), where surgical resection may result in potentially worsening functional limitation or severe morbidity and Orphan Drug Designation for PVNS/GCT-TS by the U.S. Food and Drug Administration (FDA). Pexidartinib also has received Orphan Designation from the European Commission for the treatment of TGCT. Pexidartinib is not approved by the FDA or any other regulatory agency worldwide as a treatment for any indication. Safety and efficacy have not been established.

On June 4, 2018 Rgenix, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported it is presenting data on the safety, pharmacodynamics, and clinical activity from the dose escalation stage of the ongoing Phase Ia/b trial of RGX-104, an oral small molecule immunotherapy that targets the liver X receptor (LXR) (Press release, Rgenix, JUN 4, 2018, View Source [SID1234527164]).

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In a poster presentation of an abstract accepted for the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), "Pharmacodynamic and clinical activity of RGX-104, a first-in-class immunotherapy targeting the liver-X nuclear hormone receptor (LXR), in patients with refractory malignancies", Rgenix showed the first-in-class compound to be capable of generating immunologic and anti-tumor activity.

RGX-104 is a small-molecule LXR agonist that modulates innate immunity by activating the ApoE gene. In murine models, the small molecule depletes myeloid derived suppressor cells (MDSCs) and stimulates dendritic cells (DCs), activating anti-tumor immunity as a single agent as well as in combination with adoptive T cell therapy or checkpoint inhibitors. The Phase 1a/b trial in progress is studying the therapy with regards to safety, efficacy, pharmacokinetics and pharmacodynamics. A total of 26 patients with a broad array of tumors have received RGX-104 at a range of dose levels and frequency as part of the dose escalation stage of the study.

RGX-104 was well tolerated across dose cohorts, with hyperlipidemia – an on target effect of LXR agonism – representing the most common adverse event. Robust ApoE target gene engagement was observed in patients, along with substantial MDSC depletion and DC stimulation in 12 of 17 evaluable patients. Activation of circulating PD-1+ T cells was observed in 11 of the 12 patients that experienced MDSC depletion.

One patient with a high-grade neuroendocrine malignancy with small cell features had a confirmed radiographic partial response with a 53% reduction in index hepatic metastases at the 160 mg BID dose. This response was associated with a greater than 12-fold increase in activated PD-1+ T cells. Additionally, seven patients had stable disease for durations of 8-16 weeks. The dose of 160 mg BID was chosen as the Recommended Phase 2 Dose, with robust pharmacodynamic effects on ApoE expression and relevant immune cell populations.

Masoud Tavazoie, MD, PhD, and Chief Executive Officer of Rgenix, said, "Today’s presentation illustrates the promise of our lead clinical candidate RGX-104. It enables us to move forward with our plans to study the compound in expansion cohorts as a single agent as well as in combination with a PD-1 inhibitor in patients with both checkpoint-inhibitor refractory and naïve tumors." Escalation and Expansion cohorts in the Phase 1b stage of the clinical trial are currently enrolling patients with epithelial ovarian carcinoma (EOC), melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), renal cell cancer (RCC), bladder cancer (BLC), and triple negative breast cancer (TNBC).

On June 4, 2018 Pierre Fabre and its partner Array BioPharma Inc. reported updated results from the Phase 3 COLUMBUS trial in BRAF-mutant advanced melanoma (Press release, Array BioPharma, JUN 4, 2018, View Source [SID1234527163]). The results showed median overall survival (mOS) was 33.6 months for patients treated with the combination of encorafenib and binimetinib compared with 16.9 months for patients treated with vemurafenib as a monotherapy. The combination reduced the risk of death compared with vemurafenib monotherapy (hazard ratio [HR] of 0.61 [95% CI: 0.47–0.79], p<0.0001]. The observed efficacy of vemurafenib in the control arm is also consistent with historical data, providing an additional benchmark for validating the patient population and results observed in COLUMBUS.1,2 Further, the two-year OS with the combination therapy was 58%. These results will be part of an oral presentation today at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in Chicago, Illinois, and have been selected for the "Best of ASCO (Free ASCO Whitepaper)" program.

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"These data indicate that regardless of treatment group, the use of subsequent immunotherapies was similar, and therefore indicate that post-trial treatments are unlikely to have contributed to the OS results we’ve seen"

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Importantly, the presentation included data showing limited use of post-trial immunotherapy, which is consistent with other published pivotal trials of BRAF and MEK inhibitors in BRAF-mutant advanced melanoma.1,3

"These data indicate that regardless of treatment group, the use of subsequent immunotherapies was similar, and therefore indicate that post-trial treatments are unlikely to have contributed to the OS results we’ve seen," said Professor Reinhard Dummer, University of Zurich, lead author and Vice-Chairman of the Department of Dermatology in the University Hospital of Zürich, Switzerland. "We’re pleased to present this data at ASCO (Free ASCO Whitepaper) which builds upon previous analyses of the COLUMBUS data and further support our belief that encorafenib and binimetinib could be a promising new treatment option for patients with BRAF-mutant advanced melanoma."

Additionally, the updated median progression-free survival (mPFS) results for patients treated with the combination of encorafenib and binimetinib remained consistent with what was previously reported: 14.9 months versus 7.3 months for patients treated with vemurafenib (HR=0.51 [95% CI 0.39–0.67]; p<0.0001).

As previously reported, the combination of encorafenib and binimetinib was generally well-tolerated. Grade 3–4 adverse events (AEs) that occurred in more than 5% of patients receiving the combination were increased gamma-glutamyltransferase (GGT; 9%), increased blood creatine phosphokinase (CK; 7%) and hypertension (6%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available BRAF+MEK inhibitor treatments, for patients receiving the combination of encorafenib and binimetinib included: rash (22%), serous retinopathy including retinal pigment epithelial detachment (20%), pyrexia (18%) and photosensitivity (5%). Full safety results of COLOMBUS Part 1 were published in The Lancet Oncology.

About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates.4,5 There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma.4,6,7,8

About COLUMBUS
The COLUMBUS trial (NCT01909453) is a two-part, international, randomized, open-label Phase 3 trial evaluating the efficacy and safety of the combination of encorafenib and binimetinib compared with vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial. Patients were randomized into two parts:

In Part 1, 577 patients were randomized 1:1:1 to receive encorafenib 450 mg daily + binimetinib 45 mg twice daily (COMBO450); encorafenib 300 mg daily (ENCO 300); or vemurafenib 960 mg twice daily as a monotherapy. The dose of encorafenib in the combination arm is 50% higher than the single-agent maximum tolerated dose of 300 mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was a median progression-free survival (mPFS) comparison of the COMBO450 arm versus vemurafenib. mPFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Central Review (BICR). Secondary endpoints include a comparison of the mPFS of COMBO450 arm to that of ENCO300 and a comparison of overall survival (OS) in patients treated in the COMBO450 arm to that of vemurafenib alone. Results from Part 1 of the COLUMBUS trial previously published in The Lancet Oncology earlier this year (online March 2018, print May 2018), showed that COMBO450 more than doubled mPFS in patients with advanced BRAF-mutant melanoma, with a mPFS of 14.9 months compared with 7.3 months observed with vemurafenib (HR 0.54 [95% CI 0.41-0.71], p<0.0001). In the secondary mPFS comparison of COMBO450 to ENCO300, ENCO300 demonstrated a mPFS of 9.6 months (HR 0.75 [95% CI 0.56-1.00], p=0.051).
In Part 2, 344 patients were randomized 3:1 to receive encorafenib 300 mg daily plus binimetinib 45 mg twice daily (COMBO300) or ENCO300. Part 2 was designed to provide additional data to help evaluate the contribution of binimetinib to the combination of encorafenib and binimetinib.
As the secondary endpoint comparison of mPFS between the COMBO450 arm and ENCO300 arm in Part 1 did not achieve statistical significance, the protocol-specified analysis of OS is descriptive.

About Encorafenib and Binimetinib
BRAF and MEK are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities, including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 COLUMBUS trial and the Phase 3 BEACON CRC trial.

Pierre Fabre has exclusive rights to commercialize encorafenib and binimetinib in Europe, Asia, Latin America and Australia. Pierre Fabre’s development partner, Array BioPharma, has exclusive rights in the U.S. and Canada, and has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea. Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

On May 4, 2018 Kite, a Gilead Company (Nasdaq: GILD), reported new analyses from the ZUMA chimeric antigen receptor T (CAR T) cell therapy development program that are being presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Kite Pharma, MAY 4, 2018, View Source [SID1234527162]). The results include analyses of the ZUMA-1 study of Yescarta (axicabtagene ciloleucel) in adult patients with refractory large B-cell lymphoma showing that response status may predict rates of progression-free survival (PFS) (Abstract #3003) and that treatment responses were consistent across prior lines of therapy (Abstract #3039). Additionally, an analysis of the ZUMA-3 study evaluating investigational KTE-C19 for the treatment of adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) showed that patients experienced manageable safety and encouraging efficacy irrespective of prior blinatumomab use (Abstract #7006).

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"With the U.S. approval of Yescarta last year, we aim to transform the treatment of patients with refractory large B-cell lymphoma," said Alessandro Riva, MD, Gilead’s Executive Vice President, Oncology Therapeutics & Head, Cell Therapy. "We are also committed to studying Yescarta and other CD19-directed CAR T therapies for people with other relapsed or refractory blood cancers. Based on the strength of the ZUMA-1 data, we are now evaluating the potential of Yescarta in the second-line treatment setting in a Phase 3 study, ZUMA-7, and we continue to evaluate KTE-C19 in Phase 1/2 studies in ALL and other hematologic cancers."

Yescarta was the first CAR T cell therapy to be approved by the U.S. Food and Drug Administration (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, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

Yescarta has a Boxed Warning in its product label and an associated Risk Evaluation and Mitigation Strategy (REMS) regarding the risks of CRS and neurologic toxicities. Please see below for Important Safety Information.

A Marketing Authorization Application (MAA) for axicabtagene ciloleucel is currently under review with the European Medicines Agency (EMA).

Ongoing Responses, Response by Prior Lines of Therapy in ZUMA-1 (Abstracts #3003 and #3039)

Long-term ZUMA-1 follow-up data have shown an overall response rate (ORR) of 83 percent (n=84/101), including 58 percent (n=59/101) of patients with a complete response at a median follow-up of 15.1 months. In this long-term follow-up, Grade 3 or higher cytokine release syndrome (CRS) and neurologic events were seen in 12 percent and 29 percent of patients, respectively.

A new analysis of ZUMA-1 suggests that response status three months after infusion of Yescarta may be predictive of longer-term disease control. Of the 42 patients with complete response and nine with partial response at three months, the 12-month PFS rates were 79 percent and 78 percent, respectively. This abstract has also been selected for inclusion in the 2018 Best of ASCO (Free ASCO Whitepaper) program.

"We are encouraged by the strong long-term complete response rates in ZUMA-1, which represents a patient population that previously had few if any remaining treatment options," said Frederick L. Locke, MD, ZUMA-1 Co-Lead Investigator and Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. "Importantly, this new study analysis indicates that response status at three months is potentially predictive of prolonged PFS."

An additional ZUMA-1 analysis evaluated outcomes based on prior therapy the patients had received. The results indicate long-term clinical benefit for patients with refractory large B cell lymphoma, irrespective of the number of prior lines of therapy.

Rates of Response with Prior Blinatumomab Treatment in ZUMA-3 (Abstract #7006)

Phase 1 data for KTE-C19, an investigational CD19 CAR T cell therapy, presented at the 2017 Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) demonstrated high rates of complete response in adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL). A new analysis of data from the ZUMA-3 study shows patients responded to KTE-C19 regardless of prior treatment with blinatumomab, an FDA-approved treatment for relapsed or refractory ALL. After eight or more weeks of follow-up, 63 percent (n=5/8) of patients with prior blinatumomab treatment and 80 percent (n=8/10) of patients without prior blinatumomab treatment had achieved a complete response or complete response with incomplete hematological recovery. Overall, 94 percent (n=17/18) of patients had minimal residual disease (MRD)-negative remission. KTE-C19 was also manufactured successfully in both groups, with similar product characteristics in terms of CD4/CD8 ratio and other measures.

"As a CD19/CD3 bispecific T cell antibody, the possible impact of prior blinatumomab use on the efficacy of KTE-C19 – a CD19-directed CAR T therapy – was an important question for exploration," said Bijal Shah, MD, ZUMA-3 investigator and medical oncologist, Moffitt Cancer Center. "We observed that prior blinatumomab use did not affect the manufacturing of efficacious product, and that high response rates were seen regardless of previous treatment with blinatumomab."

Grade 3 or higher CRS was seen in 27 percent of patients with prior blinatumomab and in 17 percent of patients without prior blinatumomab. Grade 3 or higher neurologic events were seen in 36 percent of patients with prior blinatumomab and 67 percent of patients without prior blinatumomab. A greater number of subjects in the blinatumomab-naïve group received the higher 1 × 106 cells/kg dose.

KTE-C19 for ALL is investigational and has not been proven safe or efficacious.

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): CRS occurred in 94% of patients, including 13% with ≥ 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 infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. 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: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities 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 or higher 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 occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available 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 may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with 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 Yescarta 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 or higher 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 Yescarta infusion.

HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia 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: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy 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 adverse reactions (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.

Please see accompanying full Prescribing Information, including BOXED WARNING and Medication Guide.