On June 1, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported results from the CDX-3379 clinical program at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Celldex Therapeutics, JUN 1, 2019, View Source [SID1234536771]). To date, three studies of CDX-3379 have enrolled patients with head and neck squamous cell carcinoma (HNSCC), including the ongoing Phase 2 exploratory study of CDX-3379 in combination with Erbitux (cetuximab) in patients with cetuximab-resistant, advanced human papillomavirus (HPV) negative HNSCC who have previously been treated with an anti-PD1 checkpoint inhibitor.

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Emerging data from the Phase 2 study and earlier studies of CDX-3379 suggest that antitumor activity may be associated with somatic mutations in certain genes. Based on these observations, Celldex conducted an exploratory biomarker analysis in 18 HNSCC patients across the CDX-3379 clinical development program. These results support the further development of CDX-3379 in biomarker-selected patient populations and were highlighted during a presentation at ASCO (Free ASCO Whitepaper) by Julie E. Bauman, MD, MPH, Professor of Medicine, Chief, Division of Hematology and Oncology, Associate Director, Translational Research, University of Arizona Cancer Center, lead author for the poster and an investigator in the Phase 2 study.

"We have observed intriguing clinical activity across a number of patients with similar gene mutation patterns in a disease that has extremely limited treatment options and a particularly poor prognosis," said Dr. Bauman. "While the data are early, they are provocative and suggest the potential for a biomarker enrichment strategy that could change the standard of care for these patients. I look forward to the opportunity to obtain additional data on CDX-3379 in biomarker selected patient populations."

CDX-3379 is a human monoclonal antibody that uniquely blocks the activity of ErbB3 (HER3). ErbB3 is expressed in many cancers, including head and neck squamous cell cancer (HNSCC) and is believed to be an important receptor regulating cancer cell growth and survival as well as resistance to targeted therapies.

Biomarker analysis

Next-generation sequencing was performed on tumor samples from 18 patients with HNSCC treated with CDX-3379 across the three clinical studies. This data set included four patients with clinical responses, including two durable complete responses (11+ months and 8.3 months), an exceptional partial response (greater than 92% tumor shrinkage) and an unconfirmed partial response; eight patients with stable disease and/or tumor shrinkage; and, six patients with progressive disease.

Across the CDX-3379 program, FAT1 and NOTCH1, NOTCH2, or NOTCH3 mutations and primary tumor site of oral cavity were associated with clinical activity (clinical response, tumor shrinkage and stable disease) in HNSCC
All four clinical responses occurred in patients with FAT1 mutations
All four clinical responses occurred in patients with a primary tumor site of oral cavity
Three of the four clinical responses occurred in patients who also had NOTCH1, NOTCH2 or NOTCH3 mutations
Also, of note, all patients (n=7 of 18) who experienced clinical benefit (objective response or stable disease greater than or equal to 12 weeks) had FAT1 and/or NOTCH1-3 mutations.
Current literature suggests that loss of FAT1 function results in activation of the transcriptional cofactor YAP11; YAP1 has been shown to upregulate components of ErbB signaling pathways2,3, including the ErbB3 ligand NRG14
Inactivating mutations in the FAT1 and NOTCH genes have been identified in 32% and 26% of HPV(-) HNSCC tumors, respectively5
Preclinical studies investigating the association of CDX-3379 sensitivity and inactivating mutations of FAT1 and other genes are ongoing

Phase 2 CDX-3379 Study Results and Next Steps

This multicenter, open-label, Phase 2 study of CDX-3379 in combination with cetuximab is designed to enroll approximately 30 patients with cetuximab-resistant, advanced, HPV negative HNSCC who have previously been treated with an anti-PD1 checkpoint inhibitor, a population with limited options and a particularly poor prognosis. Cetuximab is dosed weekly (initial dose at 400 mg/m2 IV, then 250 mg/m2 IV); CDX-3379 (12 mg/kg IV) is administered once every three weeks. Treatment continues until disease progression or intolerance, and assessments occur every six weeks. Using a Simon two-stage design, the first stage of study was designed to enroll 13 patients, and if at least one patient achieved a partial response or complete response, enrollment could progress to the second stage; this objective was met.

Fifteen patients were enrolled in stage 1 of the study. Patients had a median of 3 (range of 2-6) prior cancer therapy treatments. All patients had received prior checkpoint inhibitor treatment and 14 of 15 patients were cetuximab refractory. Notable clinical activity was observed in this refractory patient population where treatment options are limited.

A durable confirmed complete response (11+ months) was observed; this response remains ongoing and the patient continues to receive treatment.
An unconfirmed partial response (uPR) in a patient that had not received cetuximab was also observed.
7 patients experienced stable disease (47%; includes uPR).
A clinical benefit rate of 29% was achieved (objective response or stable disease greater than or equal to 12 weeks).
Dose reductions and/or delays to the combination therapy in the majority of patients may have impacted the magnitude of anti-tumor activity; dose modifications are being considered for future studies.
CDX-3379 in combination with cetuximab was generally associated with the expected target-mediated adverse events of diarrhea and rash.
Celldex intends to incorporate evaluation of biomarkers for patient selection into the CDX-3379 development program, either through amending the existing study or concluding the study and initiating a new clinical trial. The Company, working together with investigators and key opinion leaders in the treatment of HNSCC, anticipates finalizing these plans in the coming weeks.

Erbitux is a registered trademark of Eli Lilly & Co.
1Martin D, Nat Commun 2018. 2Zhang J, Nat Cell Biol 2009. 3Wang C, Cancer Res 2017. 4He C, Oncogene 2015. 5Cancer Genome Atlas Network, Nature 2015.

About CDX-3379
CDX-3379 is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that selectively binds and inhibits ErbB3 activity. ErbB3 may be an important receptor regulating cancer cell growth and survival as well as resistance to targeted therapies, and it is expressed in many cancers, including head and neck, thyroid, breast, lung and gastric cancers, as well as melanoma. The proposed mechanism of action for CDX-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent ErbB3 signaling by binding to a unique epitope. It has a favorable pharmacologic profile, including a longer half-life and slower clearance relative to other drug candidates in this class. CDX-3379 also has potential to enhance anti-tumor activity and/or overcome resistance in combination with other targeted and cytotoxic therapies to directly kill tumor cells.

On June 1, 2019 Five Prime Therapeutics, Inc. (NASDAQ: FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported monotherapy data from the dose escalation portion of the Phase 1a/1b clinical trial of FPA150 in patients with advanced solid tumors (Press release, Five Prime Therapeutics, JUN 1, 2019, View Source [SID1234536770]). These data were presented at the Developmental Immunotherapy and Tumor Immunobiology Poster Session during the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The poster can be found on the Scientific Publications page of the Five Prime Therapeutics website.

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The data are the first presentation of FPA150 results and include safety and pharmacokinetics results from the Phase 1a monotherapy dose escalation portion of the study. The Phase 1a monotherapy portion of the study is being conducted in patients with advanced solid tumors, and the Phase 1b monotherapy expansion is enrolling patients with breast, ovarian and endometrial tumors that overexpress B7-H4.

"FPA150 is a first-in-class B7-H4 antibody that blocks inhibitory signaling to CD8 T cells and promotes the killing of B7-H4 overexpressing tumors through enhanced ADCC," said Jasgit Sachdev, M.D. and Director of Breast and Gynecologic Early Phase Trials at the HonorHealth Research Institute. "It is promising to see in this study that FPA150 was well tolerated at doses as high as 20mg/kg with no dose-limiting toxicities."

The open-label, multi-dose, multi-center Phase 1a dose escalation study was conducted in patients with advanced-stage solid tumors regardless of B7-H4 overexpression at monotherapy doses ranging from 0.01 to 20 mg/kg every three weeks in an accelerated titration followed by 3+3 design and in a separate dose exploration cohort in which patients with tumors that overexpress B7-H4 were treated at doses of 3 or 10 mg/kg every three weeks with mandatory pre- and on-treatment biopsies.

FPA150 monotherapy demonstrated a favorable safety profile with no dose-limiting toxicities or treatment-related serious adverse events. Evaluation of anti-tumor activity is ongoing. A recommended dose of 20 mg/kg every three weeks was selected based on safety and pharmacokinetics.

"Rapid enrollment of this first-in-human study of a novel targeted agent with checkpoint blockade and ADCC activity highlights the significant unmet need in patients with advanced breast and gynecologic cancers," said Helen Collins, Chief Medical Officer of Five Prime Therapeutics. "The preliminary data from the Phase 1a portion of this study, in patients with tumors overexpressing B7-H4, support continued evaluation of FPA150 in the monotherapy and in the anti-PD1 combination therapy setting."

Of the 29 patients in the Phase 1a portion of the study,18 had B7-H4 positive tumors based on medium or high immunohistochemistry (IHC) scores, including 11 patients with advanced ovarian cancer. Of these, one patient with ovarian cancer, who had been treated with seven prior lines of therapy including anti-PD1 therapy, achieved a confirmed partial response with a duration of 6.2 months.

Monotherapy Phase 1b expansion began in February 2019 and is enrolling cohorts of patients with B7-H4 positive breast, ovarian and endometrial cancers at a dose of 20 mg/kg every three weeks. A safety lead-in of the combination of Keytruda (pembrolizumab), a PD1 antibody, and FPA150 has also begun enrolling patients with B7-H4 positive ovarian cancer. The company expects to present preliminary efficacy results from the monotherapy expansion cohorts and early safety results from the FPA150-Keytruda combination at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) in September 2019.

About FPA150
FPA150 is a novel, fully human, afucosylated monoclonal antibody targeting B7-H4. B7-H4 overexpression is observed in multiple solid tumors, including breast and gynecologic cancers. FPA150 is designed with a dual mechanism of action: blocking the T cell checkpoint activity of B7-H4 as well as promoting enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells expressing B7-H4.

About Five Prime Therapeutics
Five Prime Therapeutics, Inc. discovers and develops innovative protein therapeutics to improve the lives of patients with serious diseases. Five Prime’s product candidates have innovative mechanisms of action and address patient populations in need of better therapies. The company focuses on researching and developing immuno-oncology and targeted cancer therapies paired with companion diagnostics to identify patients who are most likely to benefit from treatment with Five Prime’s product candidates. Five Prime has entered into strategic collaborations with leading global pharmaceutical companies and has promising product candidates in clinical and preclinical developm

On June 1, 2019 Moderna, Inc., (Nasdaq: MRNA) a clinical-stage biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients, reported interim data from an ongoing Phase 1 clinical study in patients with both resected (adjuvant) and unresected (advanced) solid tumors (Press release, Moderna Therapeutics, JUN 1, 2019, View Source [SID1234536769]). The data showed that the Company’s mRNA personalized cancer vaccine (PCV) mRNA-4157, given alone or in combination with Merck’s pembrolizumab (KEYTRUDA), was well-tolerated at all doses tested and elicited neoantigen-specific T-cell responses. There were no vaccine-related serious adverse events (SAEs) reported for the PCV when administered to patients as a monotherapy or in combination with pembrolizumab.

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Presented today at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, the study demonstrates the immunogenicity of Moderna’s mRNA platform for developing PCVs. In addition, clinical activity was observed in some patients receiving mRNA-4157 in combination with pembrolizumab. These safety, tolerability and immunogenicity data and the initial clinical activity observed support Moderna’s randomized Phase 2 study investigating pembrolizumab in combination with a 1 mg dose of mRNA-4157, compared to pembrolizumab alone, for the treatment of high-risk adjuvant melanoma.

"We are encouraged by these interim data from our personalized cancer vaccine program, which involves designing and manufacturing a unique vaccine for each patient based on their specific tumor," said Tal Zaks, M.D., Ph.D., chief medical officer at Moderna. "This study demonstrates the ability of Moderna’s mRNA personalized cancer vaccine to elicit T-cells that are specific to the cancer mutations. We also observed early signs of clinical activity of our personalized cancer vaccine in combination with pembrolizumab, including in two patients previously treated with checkpoint inhibitors. We look forward to building on these learnings about tolerability and immunogenicity by assessing activity in a randomized Phase 2 study for the treatment of adjuvant melanoma."

"For decades, the cancer community has been working on the concept of developing medicines that can be personalized down to the individual patient level," said Howard A. "Skip" Burris III, M.D., president, clinical operations & chief medical officer at Sarah Cannon Research Institute, and a principal investigator of the mRNA-4157 Phase 1 study. "We know that cancer mutations are rarely shared between patients, so it’s encouraging to see individualized, personalized cancer vaccines like mRNA-4157 eliciting immune responses. We’re pleased to be a part of a study that aims to advance the science of immunotherapy through mRNA vaccines, and deliver a novel approach that is customized for each patient."

About the Data

Abstract 2523: A phase 1 multicenter study to assess the safety, tolerability and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.

Presented by: Howard A. Burris, M.D., FACP, FASCO, Sarah Cannon Research Institute
(Poster Session, Saturday, June 1, 8:00 a.m. – 11:00 a.m. CT followed by a Poster Discussion at 1:15 p.m. – 2:45 p.m. CT)

The ASCO (Free ASCO Whitepaper) poster is now available on the "Events and Presentations" section of our website.

In this dose-escalation study, 13 patients with resected solid tumors (melanoma, colon and lung cancers) received mRNA-4157 as adjuvant monotherapy after resection of their primary tumor. An additional 20 patients with metastatic, unresected solid tumors (melanoma, bladder, lung, colon, prostate, head and neck and endometrial cancers) received at least one dose of mRNA-4157 in combination with pembrolizumab.

Results:

mRNA-4157 was well-tolerated at all dose levels studied with no dose-limiting toxicities or grade 3/4 adverse events (AEs) or SAEs reported when administered as a monotherapy or in combination with pembrolizumab. The most common grade 2 adverse events were fatigue, soreness at the injection site, colitis and myalgias.
A cohort of patients at the top dose level (1 mg) are undergoing apheresis and deeper characterization of immunogenicity responses. Data from one such patient was available at the data cutoff and showed neoantigen-specific CD8 T-cell responses were detected to 10 out of 18 class I neoantigens after the 4th dose of the vaccine (compared to 0/18 at baseline).
Clinical responses (one complete response + five partial responses) at doses ranging from 0.04-1.0 mg were observed in 6 out of 20 patients receiving at least one dose of mRNA-4157 in combination with pembrolizumab. The complete response occurred to pembrolizumab monotherapy before mRNA-4157 was administered. Of the five partial responses, two were seen in patients previously treated with a checkpoint inhibitor.
Of the 13 patients who received adjuvant mRNA-4157 monotherapy, all patients have completed a full course of vaccination per the study protocol. Eleven patients remained disease free up to 75 weeks on study.
Additionally, the National Cancer Institute (NCI) presented early data today from its Phase 1 study of PCV mRNA-4650 as a monotherapy for patients with advanced metastatic cancers. The NCI program uses Moderna’s mRNA technology but uses a different neoantigen selection process and study design than Moderna’s Phase 1 mRNA-4157 study.

Abstract 2643: A Phase 1/2 study to assess the immunogenicity and tolerability of personalized mRNA vaccine mRNA-4650 encoding defined neoantigens expressed by the autologous cancer.

Presented by: Gal Cafri, Ph.D., Postdoctoral Fellow, National Cancer Institute Surgery Branch
(Poster Session, Saturday, June 1, 8:00 a.m. – 11:00 a.m. CT)

Conference Call

Moderna will host a conference call and webcast on Monday, June 3 at 8:00 a.m. ET to discuss these mRNA-4157 data. Participants are invited to listen by dialing (866) 922-5184 (domestic) or (409) 937-8950 (international) and providing conference ID 3016438 or join the live webcast by going to the "Events and Presentations" area on the Investors page of the Company’s website, www.modernatx.com. An archived webcast of the conference call can also be accessed through the Company’s website and a replay of the call will be available there for four weeks after the call.

About Moderna’s Immuno-Oncology Programs

Moderna’s oncology programs are currently focused on two main areas: cancer vaccines and intratumoral immuno-oncology (I/O) therapies. Moderna is developing these potential mRNA treatments as monotherapies and/or in combination with checkpoint inhibitors from our strategic collaborators Merck and AstraZeneca. The company currently has five I/O programs in development, including two programs advancing into Phase 2 trials.

An advantage of Moderna’s mRNA platform is that it allows for investigational medicines that combine in a single mRNA therapy several different approaches to activate the immune system to attack cancer, either with mRNA encoding for common tumor proteins found across cancer types or multiple mRNAs encoding for various immunomodulatory proteins.

Moderna’s investigational PCVs are designed to use neoantigens identified from an individual’s tumor to program the body’s immune system to elicit a more effective anti-tumor response. Upon sequencing the tumor, Moderna’s proprietary algorithms predict the neoantigens (antigens encoded by tumor-specific mutated genes) most likely to trigger the immune system to attack a particular cancer. Today, mRNA encoding up to 34 unique neoantigens can be delivered in a single vaccine. Moderna develops and manufactures these investigational PCVs at its personalized vaccines unit within its Norwood, Mass. manufacturing facility.

On June 1, 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 preliminary results of tislelizumab, its investigational anti-PD-1 inhibitor, in Chinese patients with nasopharyngeal cancer (NPC) that were presented in a poster at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, being held in ChicagoMay 31 – June 4, 2019 (Press release, BeiGene, JUN 1, 2019, View Source [SID1234536768]).

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"We believe that these data further support the broad development program for tislelizumab, including the global Phase 3 double-blind trial of tislelizumab in combination with chemotherapy in comparison to placebo with chemotherapy as a first-line treatment for patients with recurrent or metastatic NPC," said Yong (Ben) Ben, M.D., Chief Medical Officer, Immuno-Oncology, at BeiGene. "We see tislelizumab as a potentially differentiated anti-PD1 antibody and are committed to improving outcomes for patients globally."

"This is the first presentation of tislelizumab data in a population of patients with NPC, and we are encouraged by the objective response rate of 43 percent in Chinese patients with locally advanced or metastatic NPC. Tislelizumab was also generally well-tolerated in these patients," said Siyang Wang, M.D., Chief Physician, Department of Head and Neck Oncology at The Fifth Affiliated Hospital, Sun Yat-Sen University, in Zhuhai, China, and lead author on the study. "We hope that further study of tislelizumab may lead to a new treatment for the large number of patients with these tumors in need."

Preliminary Results with Tislelizumab in Chinese Patients with NPC
Phase 1/2 Poster Data (Abstract number 2556, board number #200)

The multi-center, open-label Phase 1/2 trial of tislelizumab as monotherapy in advanced solid tumors in China (Chinadrugtrials.org registration number: CTR20160872) consists of a Phase 1 dose verification and pharmacokinetics component and a Phase 2 component of indication expansion in disease-specific cohorts, including patients with NPC solid tumors.

Data presented at ASCO (Free ASCO Whitepaper) today are from 21 patients with NPC, of whom 20 were enrolled in the Phase 2 indication-expansion portion of the trial. Patients were treated with tislelizumab at a dose of 200 mg every three weeks. Ninety-five percent of the study population received one or more prior regimens of systemic therapy. At the time of the data cutoff on December 1, 2018, median treatment duration was 7.5 months (2.1-15.8 months), median follow-up time was 11.7 months (4.9-15.7 months), and nine patients (43%) remained on treatment.

Adverse events (AEs) assessed by the investigator to be related to treatment occurred in 14 patients. Of those, the most common treatment-related AEs (TRAEs) (occurring in ≥ 10% of patients) were hypothyroidism (24%), anemia (14%), increased AST (10%), and hemoptysis (10%). There was one grade 4 cutaneous reaction TRAE that led to discontinuation. Of the eight patients (38%) who experienced immune-related AEs (irAEs), two patients experienced three grade ≥3 irAEs (drug interruption, n=1; rash, n=1; increased γ-glutamyltransferase, n=1). No patients experienced fatal TRAEs.

As of the data cutoff, all 21 patients were evaluable for antitumor activity. A total of nine patients achieved a confirmed partial response and nine patients achieved stable disease. Clinical benefit was observed regardless of PD-L1 expression. The confirmed objective response rate (ORR) was 43 percent. Median duration of response (DOR) was estimated as 8.3 months and median progression-free survival (PFS) was 10.4 months; however, data were not yet mature enough to estimate overall survival (OS).

About Nasopharyngeal Cancer
Nasopharyngeal cancer (NPC) is a type of head and neck cancer, starting in the nasopharynx, the upper part of the throat behind the nose and near the base of skull.i The estimated five-year survival rate for people with NPC is 60 percent.ii Although NPC is rare in most parts of the world, it is one of the most common malignancies in Asia. There were an estimated 60,558 new cases of NPC in China in 2018, accounting for 46.9 percent of the worldwide incidence.iii In addition to geography, sex and age are epidemiological characteristics of NPC that affect incidence and mortalityiv,[v], including Epstein-Barr virus which has also been reported to be strongly linked with NPC in epidemic areas.vi The risk of NPC increases slowly throughout life, but it can occur in people of any age, including children.

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 3 trial in patients with Stage III NSCLC; 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 UC; 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 previously treated 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. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumor cancers outside of Asia (except Japan).

On June 1, 2019 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported data from the registration-enabling NAVIGATOR trial of avapritinib in patients with PDGFRA Exon 18 mutant gastrointestinal stromal tumors (GIST) and fourth-line GIST (Press release, Blueprint Medicines, JUN 1, 2019, View Source [SID1234536767]). These results were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019 Annual Meeting and will form the basis for planned worldwide marketing applications for avapritinib, an investigational, highly selective KIT and PDGFRA inhibitor for patients with advanced GIST. The data demonstrate clinical activity and favorable tolerability in patients with PDGFRA Exon 18 mutant and fourth-line GIST, two populations with no effective therapies.

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Data from the ongoing NAVIGATOR trial in patients with PDGFRA Exon 18 mutant GIST, which primarily includes the D842V mutation, and fourth-line GIST support Blueprint Medicines’ plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in June 2019 and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in the third quarter of 2019. Avapritinib has received FDA Breakthrough Therapy Designation for the treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation.

In patients with PDGFRA Exon 18 mutant GIST, the objective response rate (ORR) was 86 percent and the median duration of response (DOR) was not reached. In patients with fourth-line GIST, the ORR was 22 percent and the median DOR was 10.2 months. ORR and DOR per central radiographic review will be the primary registrational endpoints. Avapritinib was well-tolerated with most adverse events (AEs) reported by investigators as Grade 1 or 2. These results were as of a data cutoff date of November 16, 2018.

"These data highlight the potential of avapritinib to shift the treatment paradigm for GIST toward a precision medicine approach based on the genomic driver of disease," said Michael Heinrich, M.D., Professor of Medicine at Oregon Health & Science University and an investigator on the NAVIGATOR trial. "In the PDGFRα D842V population where we currently have no effective agents, avapritinib demonstrated remarkable activity regardless of line of therapy. I believe these results will further catalyze the use of mutational testing in GIST patients prior to starting therapy, which is currently recommended by treatment guidelines. Importantly, avapritinib has also demonstrated the potential to suppress complex and heterogenous mutational profiles associated with treatment-resistant fourth-line GIST. Combined with the well-tolerated safety profile of avapritinib, I believe these data show the broad potential of avapritinib to advance care across the GIST treatment landscape."

"These results further demonstrate the activity and favorable tolerability of avapritinib, a potent and highly selective PDGFRA and KIT inhibitor, in two patient populations with tumor mutations resistant to currently available therapies," said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. "Based on the strength of these data and the clear medical needs in PDGFRA Exon 18 mutant and fourth-line GIST, we look forward to working closely with global regulatory authorities to bring this important advance in treatment to patients as expeditiously as possible. In addition, the previously reported preliminary data in third-line and second-line GIST support our broad clinical development program and highlight the potential of avapritinib to become a foundational GIST treatment."

Highlights from ASCO (Free ASCO Whitepaper) Presentation of NAVIGATOR Trial Data

As of the data cutoff date of November 16, 2018, 204 patients were treated with avapritinib at a starting dose of 300 or 400 mg once daily (QD). Patients with PDGFRA Exon 18 mutant GIST were treated across all lines of therapy. Patients with fourth-line or later GIST had a median of four prior lines of therapy (ranging from three to 11) prior to receiving avapritinib.

Clinical Activity Data

As of the data cutoff date, 43 patients with PDGFRA Exon 18 mutant GIST (including 38 patients with PDGFRα D842V-driven GIST) and 111 patients with fourth-line GIST were treated at a starting dose of 300 or 400 mg QD and evaluable for response assessments. Patients were evaluable if they had at least one centrally reviewed radiographic scan, and data are based on modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1 criteria) for GIST.

In evaluable patients with PDGFRA Exon 18 mutant GIST:

The ORR was 86 percent, with three confirmed complete responses (CR) and 34 partial responses (PR; one pending confirmation1).
The ORR was 100 percent (two CRs and three PRs; all responses were confirmed) in the first-line treatment setting.
The median DOR was not reached.
28 patients (78 percent) remained in response as of the data cutoff date.
Median follow-up was 10.9 months.
In evaluable patients with fourth-line GIST:

The ORR was 22 percent, with one confirmed CR and 23 PRs (one pending confirmation1).
The median DOR was 10.2 months.
Median follow-up was 10.8 months.
Safety Data

Avapritinib had a favorable safety profile in patients treated at a starting dose of 300 or 400 mg QD, with most AEs determined by investigators to be Grade 1 or 2 as of the data cutoff date. Across all patients, 8 percent of patients discontinued treatment with avapritinib due to treatment-related AEs. A lower incidence of commonly reported AEs was reported at 300 mg QD dosing compared to 400 mg QD dosing.

Across all grades, the most common treatment-emergent AEs (regardless of relationship to avapritinib) reported by investigators (≥25 percent) were nausea, fatigue, anemia, cognitive effects, periorbital edema, vomiting, decreased appetite, diarrhea, increased lacrimation and peripheral edema. Investigator-reported Grade 3 or 4 treatment-related AEs (≥2 percent) included anemia, fatigue, cognitive effects, increased blood bilirubin, diarrhea, hypophosphatemia, decreased neutrophil count, neutropenia and lymphopenia.

These data on avapritinib were presented at the ASCO (Free ASCO Whitepaper) 2019 Annual Meeting in a poster presentation on Saturday, June 1 (Abstract Number: 11022). A copy of the poster is available in the "Science—Publications and Presentations" section of Blueprint Medicines’ website at www.BlueprintMedicines.com.

About the Avapritinib Clinical Development Program in GIST

Blueprint Medicines is pursuing a broad clinical development program for avapritinib across all lines of GIST. Avapritinib is currently being evaluated in two global registration-enabling clinical trials for GIST: the Phase 1 NAVIGATOR trial and the Phase 3 VOYAGER trial.

The NAVIGATOR trial is designed to evaluate the safety, tolerability and clinical activity of avapritinib in patients with unresectable or metastatic GIST. The trial consists of two parts, a dose escalation portion and an expansion portion. Trial objectives include assessing response using blinded central radiology review, as well as pharmacokinetics and pharmacodynamic measures. The expansion cohorts of the trial enrolled patients at multiple sites in the United States, European Union and Asia.

The VOYAGER trial is a global, open-label, randomized, Phase 3 trial designed to evaluate the safety and efficacy of avapritinib versus regorafenib in patients with third- or fourth-line GIST. The trial is designed to enroll approximately 460 patients randomized 1:1 to receive either avapritinib or regorafenib at multiple sites in the United States, Canada, European Union, Australia and Asia.

In the second half of 2019, Blueprint Medicines plans to initiate COMPASS-2L, a global, randomized, Phase 3 precision medicine trial. The trial will evaluate the safety and efficacy of avapritinib versus sunitinib in second-line GIST patients with pre-specified disease genotypes.

Patients and physicians interested in the Phase 3 VOYAGER trial can contact the Blueprint Medicines study director at [email protected] or 1-617-714-6707. For more information about the VOYAGER trial, please visit www.BlueprintClinicalTrials.com/VOYAGER. Additional details are available on www.clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03465722).

About GIST

GIST is a sarcoma, or tumor of bone or connective tissue, of the gastrointestinal (GI) tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50 to 80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction.

Most GIST cases are caused by a spectrum of clinically relevant mutations that force the KIT or PDGFRA protein kinases into an increasingly active state. Because currently available therapies primarily bind to the inactive protein conformations, certain primary and secondary mutations typically lead to treatment resistance and disease progression.

Treatment options for KIT-driven GIST patients who progress beyond imatinib are currently limited. There are no effective treatment options for patients with metastatic PDGFRα D842V-driven GIST, and progression occurs in a median of approximately three to four months with available therapy. In unresectable or metastatic GIST, clinical benefits from existing treatments can vary by mutation type. Mutational testing is critical to tailor therapy to the underlying disease driver and is recommended in expert guidelines.

About Avapritinib

Avapritinib is an investigational, oral precision therapy that selectively and potently inhibits KIT and PDGFRA mutant kinases. It is a type 1 inhibitor designed to target the active kinase conformation; all oncogenic kinases signal via this conformation. Avapritinib has demonstrated broad inhibition of KIT and PDGFRA mutations associated with GIST, including potent activity against activation loop mutations that are associated with resistance to currently approved therapies. In contrast to approved multi-kinase inhibitors, avapritinib has shown marked selectivity for KIT and PDGFRA over other kinases. In addition, avapritinib is uniquely designed to selectively bind and inhibit D816V mutant KIT, the common driver of disease in approximately 95 percent of all systemic mastocytosis (SM) patients. Preclinical studies have shown avapritinib potently inhibited KIT D816V at sub-nanomolar potencies with minimal off-target activity.

Blueprint Medicines is initially developing avapritinib for the treatment of advanced GIST, advanced SM, and indolent and smoldering SM. The FDA has granted avapritinib two Breakthrough Therapy Designations, one for the treatment of unresectable or metastatic GIST harboring the PDGFRα D842V mutation and one for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia.

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