On June 2, 2018 Deciphera Pharmaceuticals, Inc. (NASDAQ:DCPH), a clinical-stage biopharmaceutical company focused on addressing key mechanisms of tumor drug resistance, reported the presentation today of updated data from its ongoing Phase 1 clinical trial of DCC-2618, the company’s broad-spectrum KIT and PDGFRα inhibitor, in patients with gastrointestinal stromal tumors (GIST) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2018, in Chicago, Illinois and provided additional clinical and regulatory updates on DCC-2618 (Press release, Deciphera Pharmaceuticals, JUN 2, 2018, View Source [SID1234527070]).

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Suzanne George, M.D. Assistant Professor of Medicine, Harvard Medical School and Clinical Director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute presented the poster titled "Mutational Profile of Drug Resistant GIST Patients Enrolled in the Phase 1 Study of DCC-2618". In addition to describing the mutational profile of KIT in GIST patients, the poster includes details of locally-read Objective Response Rates (ORR) and Disease Control Rates (DCR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) in second, third, and fourth and fourth line plus GIST patients that received DCC-2618 at doses of ≥100mg daily for at least one 28-day cycle prior to February 2, 2018:

The combined 24% ORR and 80% 3-month DCR in second and third line patients receiving DCC-2618 at doses of ≥100mg per day exceeds previously published results of registrational trials for the currently approved therapies for second line (sunitinib) and third line (regorafenib), which have reported ORRs of 7.0% and 4.5%, respectively, and levels of disease control of 60% and 53%, respectively.

"The preliminary data presented today on DCC-2618’s activity in second and third line GIST patients is very encouraging and supports the planned initiation later this year of our Phase 3 trial, INTRIGUE, in second line GIST patients," said Michael D. Taylor, Ph.D., President and Chief Executive Officer of Deciphera. "The mutational profiling data across second, third and fourth line GIST patients observed in the Phase 1 study also demonstrates the need for the broadest spectrum of KIT inhibition in all GIST patients who previously received imatinib."

"We are very pleased with the results presented today demonstrating DCC-2618’s potential to provide improved clinical benefit for not only heavily pre-treated patients, but also for second and third line GIST patients," said Oliver Rosen, M.D. Chief Medical Officer of Deciphera. "Combined with the tolerability data presented at AACR (Free AACR Whitepaper) in April 2018, these results demonstrate the potential of DCC-2618 as an effective and well tolerated therapy for a wide range of GIST patients."

Highlights from the poster presentation include:

Initial Objective Response Rates and Disease Control Rates with DCC-2618 at Doses of ≥100mg Daily in Second and Third Line GIST Patients Exceed Previously Published Results of Registrational Trials for Currently Approved Therapies, as well as the Results Observed in Heavily Pre-Treated GIST Patients Receiving DCC-2618:
24% ORR with DCC-2618 observed to date in second and third line GIST patients is higher than that reported for sunitinib in second line patients (7.0%) or regorafenib in third line patients (4.5%).
These interim results show improved ORR and 3-month DCR in second line GIST patients treated with DCC-2618 compared to fourth and fourth line plus GIST patients treated with DCC-2618.
Mutational Profiling Data Across Second, Third and Fourth Line GIST Patients Demonstrates the Breadth of KIT Mutations in GIST and the Ability of DCC-2618 to Reduce KIT Mutant Allele Frequency (MAF):
Resistance mutations in KIT in exons 13, 14, 17 and 18, or a combination thereof, occurs in second, third and, fourth and fourth line plus patients.
The KIT mutational profile in both tumors and plasma at baseline in GIST patient supports the need for a broad-spectrum KIT inhibitor in all post-imatinib lines of therapy.
57 of 73 patients (78%) receiving DCC-2618 at doses of ≥100 mg daily demonstrated reductions in KIT MAF of more than 50%.
In addition, the company is providing the following clinical and regulatory updates on DCC-2618:

Planned Initiation of a Phase 3 Trial in Second Line GIST Patients in 2018
Preliminary efficacy results in second line patients together with recently presented tolerability data at the recommended phase 2 dose (RP2D) of 150mg QD support the planned, randomized Phase 3 trial, INTRIGUE, in second line GIST.
Following discussions with regulatory authorities in the United States and in Europe, the company has designed INTRIGUE as a randomized, multicenter, open-label, Phase 3 trial in second line GIST. This registration study is expected to enroll approximately 350 patients who will be randomized 1:1 to either DCC-2618 or sunitinib, the current standard of care in second line; with median progression free survival as the primary endpoint.
Interim Results with DCC-2618 at Doses of ≥100mg Daily Demonstrate Robust Clinical Activity in Heavily Pretreated GIST Patients, Including Patients Previously Treated with the Investigational Agent avapritinib (BLU-285):
10 patients with KIT-driven GIST who previously received avapritinib were enrolled and treated with DCC-2618 as of January 31, 2018.
6 out of 10 (60%) of these patients achieved stable disease as best response by RECIST during treatment with DCC-2618. In addition, one patient achieved stable disease following intra-patient dose escalation to 150mg BID.
5 out of 10 (50%) of these patients were on study as of April 18, 2018.
3 out of 10 (30%) of these patients received DCC-2618 for more than six months. Two of these patients achieved continued stable disease and remain on study as of April 18, 2018. The third patient with progressive disease was dose escalated and was reported as off study as of April 18, 2018.
A copy of the poster presentation will be available on the Science section of the Deciphera website under "Presentations and Publications" at www.deciphera.com.

About DCC-2618

DCC-2618 is a KIT and PDGFRα kinase switch control inhibitor in clinical development for the treatment of KIT and/or PDGFRα-driven cancers, including gastrointestinal stromal tumors, or GIST, systemic mastocytosis, or SM, and glioblastoma multiforme. DCC-2618 was specifically designed to improve the treatment of GIST patients by inhibiting a broad spectrum of mutations in KIT and PDGFRα. DCC-2618 is a KIT and PDGFRα inhibitor that blocks initiating and secondary KIT mutations in exons 9, 11, 13, 14, 17, and 18, involved in GIST as well as the primary D816V exon 17 mutation involved in SM. DCC-2618 also inhibits primary PDGFRα mutations in exons 12, 14 and 18, including the exon 18 D842V mutation, involved in a subset of GIST.

On June 2, 2018 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that interim results from the Phase Ib/II FB-10 clinical trial of Puma’s investigational drug PB272 (neratinib) given in combination with the antibody drug conjugate T-DM1 (Kadcyla, ado-trastuzumab emtansine) were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting that is currently taking place in Chicago (Press release, Puma Biotechnology, JUN 2, 2018, View Source [SID1234527104]). The presentation entitled, "NSABP FB-10: Phase IB Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) with Neratinib in Women with Metastatic HER2-Positive Breast Cancer" was selected for a poster presentation.

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The FB-10 study is an open-label, single arm study with a dose escalation phase and an expanded cohort phase to evaluate patients with HER2-positive metastatic breast cancer who had previously been treated with chemotherapy and the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta). The primary aim of the Phase Ib portion of the study is to determine the safety and tolerability of the two-drug combination. The primary aim of the Phase II portion of the study is to demonstrate efficacy at the recommended Phase II dose of T-DM1 and neratinib. Study treatment during the Phase Ib portion consisted of the standard dose of T-DM1 at 3.6 mg/kg administered intravenously every 3 weeks and neratinib administered orally at escalating doses of 120, 160, 200 and 240 mg per day continuously. Primary diarrhea prophylaxis with high dose loperamide was administered to all patients. As of the date of the presentation, the study had enrolled 27 patients. Total study enrollment will be a maximum of 63 patients.

For the 20 patients who were evaluable for efficacy, the interim objective response (CR/PR) rate was 60%. More specifically, the efficacy results from the trial demonstrated that 3 patients had a complete response (CR); 9 patients had a partial response (PR); 2 patients had stable disease (SD); and 6 patients had progressive disease (PD). In addition, the poster presentation is available on the Puma Biotechnology website.

The interim safety results of the 27 patients with available safety assessments showed that the most frequently observed grade 3 adverse events were diarrhea, nausea, thrombocytopenia and hypertension. More specifically, grade 3 diarrhea was reported in 6 patients (22%), grade 3 nausea was reported in 3 patients (11%), grade 3 thrombocytopenia was reported in 4 patients (15%), and grade 3 hypertension was reported in 3 patients (11%). There was 1 dose limiting toxicity (DLT) at the 120 mg dose (1 of 6 patients), 3 DLTs at the 200 mg dose (3 of 8 patients) and 2 DLTs at the 240 mg dose (2 of 3 patients). There was no DLT for the 10 patients enrolled at the 160 mg dose. The Phase II portion of the trial is being conducted at the recommended Phase II dose of 160 mg of neratinib per day.

Dr. Jame Abraham, Director of the Breast Oncology Program at Taussig Cancer Institute, Professor of Medicine at Cleveland Clinic, and principal investigator of the study, said, "We are encouraged by these initial findings and we look forward to continuing to enroll patients in the Phase II portion of the trial to further evaluate the safety and efficacy of the combination of T-DM1 and neratinib in this patient population."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to see the high interim objective response rate of the combination of T-DM1 and neratinib in this study’s patient population who were previously treated with both pertuzumab and trastuzumab. We look forward to continued enrollment in the Phase II portion of this trial."

IMPORTANT SAFETY INFORMATION

NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information for additional safety information.

The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at www.NERLYNX.com or 1-855-816-5421.

On June 2, 2018 Jounce Therapeutics, Inc. (NASDAQ:JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported that its preliminary data from its ongoing Phase 1/2 ICONIC trial, an adaptive design, open-label trial evaluating JTX-2011 alone and in combination with nivolumab in patients with advanced solid tumors (Press release, Jounce Therapeutics, JUN 2, 2018, View Source;p=RssLanding&cat=news&id=2352867 [SID1234527089]). Safety and preliminary clinical activity data from all evaluable patients across multiple tumor types will be presented in an oral presentation today, Saturday, June 2, 2018 at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

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"We are encouraged by the early signal of clinical activity in heavily pre-treated patients, accompanied by an ICOS pharmacodynamic biomarker. We believe that this biomarker may help guide further development of JTX-2011," said Elizabeth Trehu, M.D., chief medical officer of Jounce Therapeutics. "Importantly, JTX-2011 continues to be safe and well-tolerated both as a single agent and in combination with nivolumab. We look forward to continuing clinical evaluation of JTX-2011, including initiation of new combination dose escalation cohorts within the ICONIC trial of JTX-2011."

The ICONIC study (ICOS AgONist Antibody for Immunotherapy in Cancer Patients) is an open label, dose escalation and expansion clinical study of JTX-2011 alone and in combination with a fixed dose of nivolumab in patients with advanced solid tumors. Patients were heavily pre-treated with approximately 65 percent having received 3 or more prior therapies (i.e. 4th line or greater); approximately 65 percent discontinued during the first three cycles. The adaptive design includes Parts A and B (Phase 1), and C and D (Phase 2), with the Phase 2 cohorts enriched for high ICOS expression. The data presented today include preliminary efficacy data from all evaluable patients as of an April 4, 2018 cut-off date. The Phase 1 portion of ICONIC was a dose escalation study to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). The patients in Phase 2 received JTX-2011 0.3 mg/kg every 3 weeks alone or in combination with nivolumab 240 mg every 3 weeks. Preliminary efficacy evaluation included tumor reductions and RECIST (response evaluation criteria in solid tumors) responses.

Summary of JTX-2011 ICONIC Data

Safety

JTX-2011 was well tolerated alone and in combination with nivolumab 240 mg every 3 weeks. The overall safety profile observed was consistent with previously reported data from the Phase 1 portion of the ICONIC trial.
Clinical Activity

Gastric Cancer

A RECIST partial response (PR) with JTX-2011 monotherapy was observed in 1 of 8 Phase 2 patients (7 PD-1 inhibitor naïve, including PR), ongoing at 8.5+ months.
Two RECIST PRs with JTX-2011 plus nivolumab were observed in 1 of 4 Phase 1 patients (all PD-1 inhibitor naïve) and 1 of 28 Phase 2 patients (22 PD-1 inhibitor naïve, including PR), ongoing at 11+ and 4+ months, respectively.
Disease control(1) was observed in 10 of 28 and tumor reductions were observed in 8 of 28 Phase 2 patients treated with JTX-2011 plus nivolumab, including both PD-1 inhibitor naïve and PD-1 inhibitor failures.
Triple Negative Breast Cancer (TNBC)

A RECIST PR with JTX-2011 plus nivolumab was observed in 1 of 17 Phase 2 patients (16 PD-1 inhibitor naïve, including PR), ongoing at 4+ months.
Disease control was observed in 3 of 17 and tumor reductions were observed in 2 of 17 Phase 2 patients treated with JTX-2011 plus nivolumab, all PD-1 inhibitor naïve.
Head and neck squamous cell cancer (HNSCC) PD-1 inhibitor failures

Disease control was observed in 2 of 16 and tumor reductions were observed in 1 of 16 Phase 2 patients treated with JTX-2011 plus nivolumab, all PD-1 inhibitor failures, of whom over 50 percent were refractory(2) to prior PD-1 inhibitors.
Non-small cell lung cancer (NSCLC) PD-1 inhibitor failures

Disease control was observed in 7 of 12 and tumor reductions were observed in 4 of 12 Phase 2 patients treated with JTX-2011 plus nivolumab, all PD-1 inhibitor failures.
(1) Disease control= confirmed PR + SD ≥ 9 weeks
(2) Refractory= best response to prior PD-1 inhibitor was progressive disease

Biomarkers

In a preliminary analysis of evaluable fresh pre-treatment biopsies, rates of disease control and tumor reduction appear higher in subjects with high ICOS scores.
An ICOS pharmacodynamic biomarker (emergence of peripheral blood ICOS high CD4 T cell population) appears to associate with anti-tumor activity.
Present in 7 of 7 subjects with target lesion PRs
Absent in 10 of 10 subjects with progressive disease
Based on preliminary signals of clinical activity associated with an ICOS pharmacodynamic biomarker, Jounce is advancing clinical evaluation of JTX-2011. The next steps for the program include continuing to evaluate the ongoing data and the initiation of two new dose escalation cohorts within the ICONIC trial of JTX-2011, one in combination with ipilimumab and one in combination with pembrolizumab. The new ipilimumab combination cohort may enable Jounce to explore a new combination mechanism that is supported by clinical and pre-clinical research. Exploration with pembrolizumab at its approved q3w dose and schedule may allow the Company to evaluate JTX-2011in combination with a PD-1 inhibitor in earlier lines of therapy.

"We look forward to evaluating the new additional combinations with JTX-2011. From our founding science, the platform we have built, and the team we have in place, we believe we are well positioned to optimize the development of JTX-2011," said Richard Murray, Ph.D., chief executive officer and president of Jounce Therapeutics. "We are grateful to all of the patients who have participated in our trial, their families, our investigators and their study teams. This was a complex biomarker heavy trial that was well executed by the Jounce team."

ICONIC Enrollment Status
Phase 1 has completed enrollment and Phase 2 is nearing completion of enrollment. Given the pace of enrollment of the combination cohorts in gastric cancer, TNBC, HNSCC, NSCLC and the overall quantity of the data collected, Jounce made the decision to stop recruitment of other solid tumors and of the more slowly enrolling monotherapy and melanoma combination cohorts.

Jounce Therapeutics to Host Event and Webcast
Jounce Therapeutics will host an investor and analyst event beginning at 6:30 p.m. CT (7:30 p.m. ET) with a live webcasted presentation beginning at 7:00 p.m. CT (8:00 p.m. ET), on Monday, June 4, 2018. To access the live webcast, please visit the "Events & Presentations" page in the Investors and Media section of the company’s website at www.jouncetx.com. The webcast will be archived and made available for replay on the company’s website approximately two hours after the call and will be available for 30 days thereafter.

About JTX-2011
Jounce’s lead product candidate, JTX-2011, is a monoclonal antibody that binds to and activates ICOS, the Inducible T cell CO­Stimulator, a protein on the surface of certain T cells. Preclinical data support that JTX-2011 may have a dual mechanism of action that stimulates anti-tumor T effector cells, and also reduces the immunosuppressive T regulatory cells in the tumor microenvironment. The company is developing JTX-2011 to treat solid tumors as a single agent and in combination with other therapies.

On June 2, 2018 Odonate Therapeutics, Inc. (NASDAQ: ODT), a pharmaceutical company dedicated to the development of best-in-class therapeutics that improve and extend the lives of patients with cancer, reported that results from a multicenter Phase 2 study of tesetaxel, administered orally as a single agent to patients with HER2 negative, hormone receptor (HR) positive, metastatic breast cancer (MBC), were presented at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois(Poster Board #123; Abstract #1042) (Press release, Odonate Therapeutics, JUN 2, 2018, View Source [SID1234527106]).

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In this Phase 2 study (Study TOB203), 38 patients with HER2 negative, HR positive, MBC received tesetaxel orally as a single agent once every 3 weeks (Q3W) at a starting dose of 27 mg/m2. Eighty-seven percent (87%) had visceral disease, 74% previously received at least one endocrine therapy, 68% previously received neoadjuvant or adjuvant chemotherapy and 53% previously received a taxane-containing regimen. Objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with confirmation no less than 4 weeks after initial response was the primary endpoint.

In all 38 patients, the confirmed response rate was 45%. The confirmed response rate was consistent across subgroups. Forty-four percent (44%) of patients who did not previously receive a taxane-containing regimen achieved a confirmed response, compared to 45% of patients who previously received a taxane-containing regimen. Median duration of response was 10.9 months, and median progression-free survival was 5.4 months.

Neutropenia was the most common Grade ≥3 adverse event and occurred in 25% of the 24 patients who were not dose-escalated beyond the 27 mg/m2 starting dose (the dose selected for CONTESSA, our ongoing Phase 3 study (Poster Board #184a; Abstract #TPS1106); in these patients, febrile neutropenia occurred in 1 patient (4%) and Grade ≥3 neuropathy occurred in 1 patient (4%). There were no hypersensitivity reactions or drug-related deaths, and the rate of Grade 2 alopecia (hair loss) was 18%.

"Despite recent advances in the treatment of advanced breast cancer, there remains a significant need for new therapies that allow patients to maintain a better quality of life," said Joyce O’Shaughnessy, M.D., Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, Texas Oncology and Chair, Breast Cancer Research, US Oncology.

"Tesetaxel’s significant single-agent activity, once-every-three-week oral dosing and low rates of neuropathy and hair loss could make this investigational agent a unique treatment option for patients, if approved," said Andrew Seidman, M.D., Attending Physician and Associate Chair, Academic Administration, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC) and Professor of Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College. "We look forward to further characterizing tesetaxel’s therapeutic profile in CONTESSA, an ongoing Phase 3 study."

About Tesetaxel

Tesetaxel is an investigational, orally administered chemotherapy agent that belongs to a class of drugs known as taxanes, which are widely used in the treatment of cancer. Tesetaxel has several potential therapeutic advantages over currently available taxanes, including: oral administration with a low pill burden and a patient-friendly dosing regimen; no history of hypersensitivity (allergic) reactions; and significant activity against chemotherapy-resistant tumors. More than 500 patients have been treated with tesetaxel in clinical studies. In patients with metastatic breast cancer, tesetaxel was shown to have significant, single-agent antitumor activity in two, multicenter, Phase 2 studies.

About CONTESSA

CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel, an investigational, orally administered taxane, in patients with locally advanced or metastatic breast cancer (LA/MBC). CONTESSA is comparing tesetaxel dosed orally at 27 mg/m2 on the first day of a 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally on days 1-14 of a 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day dosed orally on days 1-14 of a 21-day cycle) in approximately 600 patients randomized 1:1 with HER2 negative, hormone receptor (HR) positive LA/MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in LA/MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. The primary endpoint is progression-free survival (PFS) assessed by an Independent Radiologic Review Committee (IRC). CONTESSA’s secondary efficacy endpoints are overall survival, objective response rate (ORR) assessed by IRC and disease control rate assessed by IRC. To learn more, please visit www.contessastudy.com.

On June 2, 2018 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company developing highly selective medicines for patients with genomically defined cancers, reported interim clinical data from the LOXO-292 global Phase 1 LIBRETTO-001 (LOXO-292 Investigated to Block RET-altered Tumors) dose escalation trial (Press release, Loxo Oncology, JUN 2, 2018, View Source [SID1234527090]). LOXO-292 is an investigational, highly potent and selective RET inhibitor. These data are being presented today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (abstract 102).

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"The LOXO-292 Phase 1 data are striking," said Alexander Drilon, M.D., clinical director in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and presenting author. "The activity we reported is impressive and I am thrilled to see this promising efficacy with limited adverse events, especially in this heavily pre-treated patient population of RET fusion cancers, including those with brain metastases, and RET mutated MTC."

"We are very excited to share the initial LOXO-292 clinical experience with the oncology community at ASCO (Free ASCO Whitepaper)," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "We have long believed that patients with RET fusion cancers and RET mutated MTC needed a purpose-built medicine tailored to their tumors. We hope that LOXO-292 continues to deliver on that premise. Thank you to the patients, investigators and clinical trial teams who made possible today’s presentation."

Trial Background

The LIBRETTO-001 Phase 1 trial contains a dose escalation phase and a dose expansion phase. The dose escalation phase follows a "3+3" design. LOXO-292 is dosed orally in 28-day cycles. As dose cohorts are cleared, additional patients can enroll in these cleared cohorts. Intra-patient dose escalation is also permitted as dose cohorts are cleared. The primary endpoint of the trial is the determination of the maximum tolerated dose (MTD) or recommended dose for further study. Secondary endpoints include safety, overall response rate (by RECIST 1.1) and duration of response. The dose expansion phase is designed to further characterize the overall response rate, durability of response, and safety of LOXO-292 in predefined groups of patients with activating RET alterations.

Key Data Presented at ASCO (Free ASCO Whitepaper)

The data presented at ASCO (Free ASCO Whitepaper) were based on an April 2, 2018 data cut-off date. Eighty-two total patients had been enrolled to eight dose escalation cohorts: 20 mg QD (n=6), 20 mg BID (n=10), 40 mg BID (n=16), 60 mg BID (n=10), 80 mg BID (n=18), 120 mg BID (n=4), 160 mg BID (n=12) and 240 mg BID (n=6). RET alterations were identified by local laboratories either in tumor or plasma and included the following primary diagnoses:

38 patients with RET fusion-positive non-small cell lung cancer (NSCLC) (21 with prior MKI treatment, 17 without)
9 patients with RET fusion-positive thyroid cancer (8 with prior MKI treatment, 1 without)
2 patients with RET fusion-positive pancreatic cancer (1 with prior MKI treatment, 1 without)
29 patients with RET-mutated medullary thyroid cancer (MTC) (23 with prior MKI treatment, 6 without)
4 patients with no known activating RET alterations
In addition to many patients with prior MKI treatment, 46% of patients had received prior chemotherapy and 24% had received prior immunotherapy (47% of those with NSCLC).

Pharmacokinetic analyses during the dose escalation demonstrated dose-dependent increases in LOXO-292 exposure with increasing dose. Starting at the 40 mg BID dose and the 80 mg BID dose, respectively, LOXO-292 delivered sustained >IC90 RET fusion and >IC90 RET M918T-mutant target coverage, based on cell-based potencies.

The data presented at ASCO (Free ASCO Whitepaper), summarized below, are based on response assessments performed by each respective clinical trial site (local, investigator-assessed radiology).

1. Patients eligible for response evaluation include thyroid cancer (n=7), pancreatic cancer (n=2).
2. Excludes patients recently enrolled that remain on treatment, but have not had a first post-baseline response assessment.
3. Response status per RECIST 1.1. Overall response rate = CR+uCR+PR+uPR. Overall response rate, Confirmed overall response rate: all RET fusion-positive (30/39, 25/34), RET fusion-positive NSCLC (23/30, 20/27), RET fusion-positive other (7/9, 5/7), RET-mutant MTC (10/22, 6/18).
4. Excludes patients with unconfirmed CR/PR pending confirmation at time of data cut-off.
5. Unconfirmed responses in patients that remain on treatment awaiting a confirmatory response assessment.
6. Patients that discontinued treatment prior to a first post-baseline response assessment.

Anti-tumor activity was observed regardless of RET fusion partner (including KIF5B), RET mutation (including M918T and V804M gatekeeper mutations), and prior MKI treatment. Twelve patients with RET fusion cancers had central nervous system (CNS) metastases at enrollment and all remained on study without progression. Three of these patients had RECIST target lesions in the CNS, and all three exhibited intracranial partial responses. In patients with RET-mutant MTC, LOXO-292 treatment resulted in significant reductions in the serum tumor markers calcitonin and carcinoembryonic antigen (CEA).

As of the data cutoff, LOXO-292 demonstrated early evidence of durable activity, with 90% of RET fusion-positive cancer patients and 93% of RET-mutant MTC patients remaining on therapy. All responding patients across all tumor types remained on therapy. The longest responding patient on therapy was the first RET fusion-positive NSCLC patient enrolled, who had been on therapy for more than ten months as of the data cut-off date.

Most treatment-emergent adverse events were Grade 1 in severity. The treatment-emergent adverse events observed in ≥10% of patients, regardless of relationship to LOXO-292, were fatigue (12% Grade 1, 7% Grade 2, 0% ≥Grade 3), diarrhea (10% Grade 1, 6% Grade 2, 0% ≥Grade 3), constipation (13% Grade 1, 1% Grade 2, 0% ≥Grade 3), dry mouth (12% Grade 1, 0% ≥Grade 2), nausea (9% Grade 1, 4% Grade 2, 0% ≥Grade 3), and dyspnea (7% Grade 1, 2% Grade 2, 1% ≥Grade 3). Only two adverse events ≥Grade 3 were attributed to LOXO-292 (Grade 3 tumor lysis syndrome, Grade 3 increased ALT). An MTD had not been reached. At the 240 mg BID dose level, one dose limiting toxicity (DLT) was reported (aforementioned Grade 3 tumor lysis syndrome).

LOXO-292 also demonstrated robust reduction and clearance of RET alterations as detected in patients’ plasma cell free DNA (cfDNA). These data will be presented in a separate poster presentation on June 3, 2018.

LIBRETTO-001 Trial Update

The expansion cohorts of the LIBRETTO-001 trial are now open and enrolling at the 160 mg BID dose. This dose was selected for initial expansion based on its promising activity and tolerability profile. Additional dose exploration above 160 mg BID is ongoing and patients enrolled to the expansion cohorts may dose escalate should a higher dose be advanced.

About the ASCO (Free ASCO Whitepaper) Presentations

LOXO-292 data are being presented in two presentations at ASCO (Free ASCO Whitepaper):

"A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers." This abstract is being presented in an oral presentation by Dr. Alexander Drilon, Memorial Sloan Kettering Cancer Center, during a Clinical Science Symposium session entitled, "Tumor Genomics: Finding the Target, Hitting the Target" from 8:00 – 9:30AM CT on Saturday, June 2, 2018 (Abstract 102).
"Detection and clearance of RET variants in plasma cell free DNA (cfDNA) from patients (pts) treated with LOXO-292." This abstract is being presented as a poster by Dr. Geoff Oxnard, Dana Farber Cancer Institute, during the Lung Cancer—Non-Small Cell Metastatic poster session from 8:00 – 11:30AM CT on Sunday, June 3, 2018 (Abstract 9048).
The presentations will be available online at View Source at the time of their scheduled presentation at ASCO (Free ASCO Whitepaper).

Conference Call and Webcast Information
Loxo Oncology management will host a conference call and live webcast with slides and Q&A today at 4:00 p.m. CT to discuss the LOXO-292 data. To participate in the conference call, please dial (877) 930-8065 (domestic) or (253) 336-8041 (international) and refer to conference ID 3597058. A live webcast of the presentation will be available at View Source A replay of the webcast will be available shortly after the conclusion of the call and archived on the company’s website for 30 days following the call.