On October 8, 2018 Exelixis, Inc. (Nasdaq: EXEL) reported the initiation of a phase 3 pivotal trial (COSMIC-311) of single-agent cabozantinib in patients with radioiodine-refractory differentiated thyroid cancer (DTC) who have progressed after up to two prior vascular endothelial growth factor receptor (VEGFR)-targeted therapies (Press release, Exelixis, OCT 8, 2018, View Source;p=irol-newsArticle&ID=2370576 [SID1234529814]). The co-primary endpoints for the trial are progression-free survival and objective response rate.

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"Cabozantinib has demonstrated encouraging clinical activity in patients with radioiodine-refractory differentiated thyroid cancer in phase 1 and 2 studies, suggesting it may be a promising treatment option for patients who have progressed after prior VEGFR-targeting therapy," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "We look forward to enrolling patients in this global trial to learn more about the potential of cabozantinib for this intractable form of thyroid cancer."

COSMIC-311 is a multicenter, randomized, double-blind, placebo-controlled phase 3 pivotal trial that aims to enroll approximately 300 patients at approximately 150 sites globally. Patients will be randomized in a 2:1 ratio to receive either cabozantinib 60 mg or placebo once daily.

"With the incidence of thyroid cancer increasing more rapidly than any other type of cancer in the U.S., and limited options available to patients whose disease has progressed following anti-VEGFR therapy, there is an urgent need for new treatments," said Marcia Brose, M.D., Ph.D., Associate Professor of Otorhinolaryngology: Head and Neck Surgery and Director of the Center for Rare Cancers and Personalized Therapy at the Abramson Cancer Center of the University of Pennsylvania, and principal investigator of the trial. "Given the positive results from earlier stage trials, we are eager to learn more from this phase 3 study about cabozantinib’s potential benefit in this patient population."

More information about this trial is available at ClinicalTrials.gov.

About Differentiated Thyroid Carcinoma

Thyroid cancer is commonly diagnosed at a younger age than most other adult cancers and is the most rapidly increasing cancer in the U.S., tripling in incidence in the past three decades.1 Approximately 54,000 new cases of thyroid cancer will be diagnosed in the U.S. in 2018.1 Nearly three out of four of these cases will be in women.1 Cancerous thyroid tumors include differentiated, medullary and anaplastic forms.1

Differentiated thyroid tumors, which make up about 90 percent of all thyroid cancers, are typically treated with surgery followed by ablation of the remaining thyroid with radioiodine.2 Approximately 5 to 15 percent of differentiated thyroid tumors are resistant to radioiodine treatment.3 For these patients, life expectancy is only three to six years from the time metastatic lesions are detected.4,5,6

About CABOMETYX (cabozantinib)

CABOMETYX tablets are approved in the United States for the treatment of patients with advanced RCC. CABOMETYX tablets are also approved in: the European Union, Norway, Iceland, Australia, Switzerland and South Korea for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union for previously untreated intermediate- or poor-risk advanced RCC; and in Canada for adult patients with advanced RCC who have received prior VEGF targeted therapy. In March 2017, the FDA granted orphan drug designation to cabozantinib for the treatment of advanced HCC. In May 2018, the FDA accepted Exelixis’ supplemental New Drug Application for CABOMETYX as a treatment for patients with previously treated HCC and assigned it a Prescription Drug User Fee Act action date of January 14, 2019. On March 28, 2018, Ipsen announced that the European Medicines Agency validated its application for a new indication for cabozantinib as a treatment for previously treated advanced HCC in the European Union; on September 20, 2018 the CHMP provided a positive opinion for CABOMETYX as a monotherapy for the treatment of HCC in adults who have been previously treated with sorafenib. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan.

CABOMETYX is not indicated for radioiodine-refractory DTC.

Please see Important Safety Information below and full U.S. prescribing information at View Source

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In two RCC studies, the incidence of Grade ≥ 3 hemorrhagic events was 3% in CABOMETYX-treated patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: In RCC studies, fistulas were reported in 1% of CABOMETYX-treated patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations were reported in 1% of CABOMETYX-treated patients. Monitor patients for symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. In RCC studies, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension, including hypertensive crisis. In RCC studies, hypertension was reported in 44% (18% Grade ≥ 3) of CABOMETYX-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: In RCC studies, diarrhea occurred in 74% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Palmar-Plantar Erythrodysesthesia (PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE) occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-fetal Toxicity may be associated with CABOMETYX. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.
Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment

On October 8, 2018 Perrigo Company plc (NYSE; TASE: PRGO), a leading global provider of Quality Affordable Healthcare Products, reported the appointment of Murray S. Kessler as President, CEO and member of the Board of Directors, effective immediately (Press release, Perrigo Company, OCT 8, 2018, View Source [SID1234529832]).

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Chairman of the Board of Directors, Rolf Classon, stated, "We are excited to have Murray Kessler, a highly successful business executive, join Perrigo as its next CEO. Given the decision to separate the Rx pharmaceuticals business and pursue a consumer-focused strategy, the Board is looking forward to partnering with him to develop Perrigo’s strategic plan. Murray joins Perrigo with more than 30 years of leadership experience in growing consumer products companies and managing businesses in a regulated environment. He has advanced corporate strategy through innovation, inorganic opportunities, and continuous portfolio improvement. We are confident that his track record in driving shareholder value and running highly successful businesses will advance Perrigo’s consumer strategy and help the Company deliver on our commitments to consumers and customers."

Mr. Kessler most recently served as the Chairman of the Board of Directors and CEO of Lorillard Tobacco Company (2010-2015). As a leading innovator in the industry, Mr. Kessler spearheaded the company’s expansion into new and emerging categories, growing Lorillard’s market capitalization from approximately $9 billion to approximately $28 billion during his tenure. Prior to joining Lorillard, Mr. Kessler served as Vice Chair of Altria, Inc. and President and CEO of UST Inc., a wholly owned subsidiary of Altria since 2009. Mr. Kessler originally joined UST in 2000 and was promoted to the role of President of the division within one year. In 2005, Mr. Kessler was appointed COO of UST, and served as CEO from 2007 to 2009. During his tenure, market capitalization grew from approximately $2.5 billion to approximately $12.7 billion.

Before joining UST, Mr. Kessler had more than 18 years of consumer packaged goods experience with several well-known consumer companies, including Vlasic Foods International, Campbell Soup Company and The Clorox Company. He earned a Bachelor of Business Administration degree from Villanova University and a Master of Business Administration degree from the New York University Stern School of Business.

Newly appointed CEO and President of Perrigo, Murray Kessler, commented, "This is a rare opportunity to drive winning results with a passionate and committed team in a high potential, consumer focused company that holds a leadership position in a broad portfolio of sizeable and recognizable categories. My experience in working with highly regulated consumer products reinforces my belief in this opportunity and it is for these reasons that I have chosen to once again take on the deep commitment of being a public company CEO. I look forward to working with the talented Perrigo leadership team and the Board to put a plan in place that delivers long-term sustainable and reliable growth."

Mr. Classon concluded, "The Board and Uwe mutually agreed the transition was in the best interest of the Company and, given the previously announced separation of the Rx business, now is the appropriate time to make this change. The Board determined that Murray is the right CEO for Perrigo’s consumer focused strategy going forward. We are thankful for Uwe’s leadership, including the decision to separate the Rx business. We are grateful for his service and wish him the best in his future endeavours."

Mr. Roehrhoff stepped down as President, CEO and board member and will make himself available to ensure a smooth and successful transition

On October 6, 2018 Blueprint Medicines Corporation (NASDAQ: BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported the presentation of updated data from the ongoing Phase 1 ARROW clinical trial of BLU-667, an investigational precision therapy targeting RET alterations, including resistance mutations (Press release, Blueprint Medicines, OCT 6, 2018, View Source [SID1234529798]). The new results showed that BLU-667 was highly active and well-tolerated in patients with advanced RET-altered medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC), with increased activity observed with higher dose levels and longer treatment durations.

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The reported data showed 90 percent of evaluable patients with MTC and PTC had radiographic tumor reductions, regardless of RET alteration type or prior multi-kinase inhibitor (MKI) therapy. In addition, the response rate was 62 percent in patients with MTC treated once daily (QD) with BLU-667 at doses of 300 to 400 mg for at least 24 weeks. In the MTC and PTC populations, all responders across dose levels and all patients treated at 400 mg QD remain on study. Safety results were consistent with prior data, and the majority of adverse events (AEs) were Grade 1. These results were as of a data cutoff date of September 14, 2018 and were reported today in an oral presentation at The 88th Annual Meeting of the American Thyroid Association (ATA).

"Existing treatment of medullary and papillary thyroid cancer with multi-kinase inhibitors is limited by frequent dose modifications or interruptions due to off-target toxicities, reducing the opportunity for a meaningful or sustained response," said Andy Boral, M.D., Ph.D., Chief Medical Officer of Blueprint Medicines. "These new data showed selectively targeting RET alterations with BLU-667 was well-tolerated and enabled durable responses. Importantly, response rates were high for patients with prolonged time on therapy at higher dose levels, demonstrating that potent and sustained target inhibition leads to improved patient outcomes. We believe these results begin to reveal the potential of BLU-667 to transform the care of patients with RET-altered thyroid cancer, and we look forward to seeing the data continue to mature as additional patients are treated at the recommended phase 2 dose for longer durations."

Based on the encouraging data reported to date, Blueprint Medicines has expanded enrollment targets for the ARROW trial to further evaluate the safety and efficacy of BLU-667 in a broader patient population and, ultimately, to support potential registration.

Data Highlights from the Ongoing Phase 1 ARROW Clinical Trial

The data presented included all patients enrolled in the Phase 1 ARROW clinical trial as of May 9, 2018 and included follow-up on these patients through the data cutoff date of September 14, 2018. Of the 69 patients who had been treated with BLU-667 in the dose escalation and expansion portions of the trial, 42 had RET-altered thyroid cancer, including 37 with MTC and five with PTC. In the dose escalation portion, patients were treated at dose levels ranging from 30 mg to 600 mg QD or up to 300 mg twice daily. In the expansion portion, patients were treated at the recommended phase 2 dose of 400 mg QD.

Clinical Activity Data

As of the data cutoff date, 35 patients with MTC and four patients with PTC were evaluable for response assessment by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Overall, 90 percent of MTC and PTC patients with measurable target lesions had radiographic tumor reductions.

In patients with MTC, response assessments showed increased clinical activity with higher dose levels and longer treatment durations. Across all evaluable MTC patients, the overall response rate (ORR) was 49 percent, including one patient with a confirmed complete response (CR) and 16 patients with a partial response (PR; two pending confirmation). In patients with MTC treated with 300 to 400 mg QD for at least 24 weeks, the response rate was 62 percent, including one patient with a confirmed CR and seven patients with a confirmed PR.

In patients with PTC, two of four evaluable patients had a confirmed PR, and all evaluable patients with PTC had radiographic tumor shrinkage.

The data also showed encouraging evidence of durable activity. All patients with MTC and PTC who responded to BLU-667 remain on treatment as of the data cutoff date. In addition, all patients treated at 400 mg QD are continuing on therapy. Patients with the longest treatment durations remain on therapy for more than 15 months.

Anti-tumor activity was observed regardless of prior MKI therapy or RET alteration. Similar response rates were observed in MTC patients who were MKI-experienced (47 percent; 8/17 patients) and MKI-naïve (50 percent; 9/18 patients). In addition, clinical responses were observed in patients with common activating mutations in MTC (e.g., M918T) and fusion partners in PTC (e.g., NCO4A and CCDC6). A clinical response was also observed in the one evaluable MTC patient with a germline V804M gatekeeper mutation.

Safety Data

The reported data showed that across 69 patients, BLU-667 was well-tolerated as of the data cutoff date. Most AEs were Grade 1, and only two patients discontinued therapy due to a treatment-related AE (Grade 3 increased alanine aminotransferase in a patient with liver metastases and Grade 2 pneumonitis). Treatment-emergent AEs (regardless of relationship to BLU-667) reported by investigators (≥15 percent) most commonly were constipation (35 percent), increased aspartate aminotransferase (33 percent), anemia (30 percent), hypertension (30 percent), decreased white blood cell count (29 percent), diarrhea (28 percent), neutropenia (28 percent), increased alanine aminotransferase (25 percent), increased blood creatinine (23 percent), fatigue (19 percent) and headache (17 percent). Grade 3 or higher treatment-related AEs occurring in two or more patients included anemia, hypertension, decreased white blood cell count, diarrhea and neutropenia.

About the Phase 1 ARROW Clinical Trial of BLU-667

ARROW is a Phase 1 clinical trial designed to evaluate the safety, tolerability and efficacy of BLU-667 in multiple ascending doses in adults with RET-altered non-small cell lung cancer (NSCLC), MTC and other advanced solid tumors. The trial consists of two parts: a dose escalation portion and an expansion portion. Enrollment in the dose escalation portion is complete, and the expansion portion has been initiated and is actively enrolling patients in six defined cohorts at the recommended phase 2 dose of 400 mg QD: (1) RET-altered NSCLC patients previously treated with an MKI, (2) RET-altered NSCLC patients who have not previously received any MKI treatment, (3) MTC patients previously treated with an MKI, (4) MTC patients who have not previously received any MKI treatment, (5) patients with other RET-altered solid tumors and (6) RET-altered solid tumor patients with prior selective RET tyrosine kinase inhibitor. Trial objectives include assessing response, pharmacokinetics, pharmacodynamics and safety. The trial is designed to enroll approximately 190 patients across all six expansion cohorts, at multiple sites in the United States, European Union and Asia.

Patients and physicians interested in the ARROW clinical trial can contact the Blueprint Medicines study director at [email protected] or 1-617-714-6707. Additional details are available at www.arrowtrial.com or www.clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03037385).

About RET-Altered Solid Tumors

RET activating fusions and mutations are a key disease driver in many cancer types, including NSCLC and MTC. RET fusions are implicated in approximately 1 to 2 percent of patients with NSCLC and approximately 10 percent of patients with PTC, while RET mutations are implicated in approximately 60 percent of patients with MTC. In addition, oncogenic RET alterations are observed at low frequencies in colorectal, breast, pancreatic and other cancers, and RET fusions have been observed in patients with treatment-resistant, EGFR-mutant NSCLC.

Currently, there are no approved therapies that selectively target RET-driven cancers, though there are several approved MKIs with RET activity being evaluated in clinical trials. Thus far, clinical activity attributable to RET inhibition has been uncertain for these inhibitors, likely due to insufficient inhibition of RET and off-target toxicities. There is a need for precision therapies that provide durable clinical benefit by selectively targeting RET alterations and resistance mutations.

About BLU-667

BLU-667 is an investigational, once-daily oral precision therapy specifically designed for highly potent and selective targeting of oncogenic RET fusions, mutations and resistance mutations. In preclinical studies, BLU-667 consistently demonstrated sub-nanomolar potency against the most common RET fusions, activating mutations and resistance mutations. In addition, BLU-667 demonstrated markedly improved selectivity for RET compared to approved MKIs, including more than 80-fold improved potency for RET versus VEGFR2. By suppressing primary and secondary mutants, BLU-667 has the potential to overcome and prevent the emergence of clinical resistance. This approach is expected to enable durable clinical responses across the range of RET alterations, with a favorable safety profile.

BLU-667 was discovered by Blueprint Medicines’ research team based on its proprietary compound library. The company is developing BLU-667 for the treatment of people with RET-altered NSCLC, MTC and other solid tumors. Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of BLU-667 and certain other drug candidates in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for BLU-667 in the rest of the world.

On October 6, 2018 Loxo Oncology, Inc. (Nasdaq: LOXO), a biopharmaceutical company developing highly selective medicines for patients with genomically defined cancers, reported updated interim clinical data for LOXO-292 from the global Phase 1/2 LIBRETTO-001 trial in patients with RET-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancer who were initially included in the LOXO-292 presentation at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Loxo Oncology, OCT 6, 2018, View Source [SID1234529804]). In these 38 patients, approximately 3.5 months of additional patient follow-up were available, as were first follow-up scans for the nine patients most recently enrolled. Sixteen of 17 (94%) responding RET-mutant MTC patients remained on therapy, with median follow-up of 8.4 months. Seven of seven (100%) responding RET fusion-positive thyroid cancer patients remained on therapy, with median follow-up of 8.5 months. Inclusion of new restaging data for the most recently enrolled patients resulted in a 59% overall response rate (56% confirmed overall response rate) in the presented subset of RET-mutant MTC patients, and a 78% confirmed overall response rate in the presented subset of RET fusion-positive thyroid cancer patients. These data are being presented today at the 88th Annual Meeting of the American Thyroid Association.

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"I am very pleased to present the latest LOXO-292 clinical data to colleagues at ATA, demonstrating the activity and safety profile of this promising new agent for RET-altered thyroid cancers," said Lori J. Wirth, M.D., associate professor of medicine at Harvard Medical School and Massachusetts General Hospital. "In the months since ASCO (Free ASCO Whitepaper) we continue to see encouraging early evidence that LOXO-292 has the potential to provide durable responses in heavily pre-treated patients with RET-driven cancers, with a promising safety profile at the Phase 2 dose of 160 mg BID. RET has been a known oncogene in thyroid cancer for many years and I am hopeful that these LOXO-292 data can further increase the awareness of this important target and, with Breakthrough Therapy Designation in hand, that the clinical program will quickly advance to reach our patients in need. "

Trial Background

LIBRETTO-001 is a Phase 1/2 trial of LOXO-292 in advanced cancer patients who primarily have activating RET alterations. LIBRETTO-001 contains a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The primary endpoint of the Phase 1 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. Initial clinical data were first reported at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

Key Data Presented

The data presented today were based on a July 19, 2018 data cut-off date and included the 29 patients with RET-mutant MTC and the nine patients with RET fusion-positive thyroid cancer who were initially included in the LOXO-292 presentation at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting.

Patients were heavily pretreated, having received a median of three prior systemic treatment regimens. Of the patients with RET-mutant MTC, 79% had previously received cabozantinib or vandetanib and 45% had received prior treatment with both agents. Of the patients with RET fusion-positive thyroid cancer, 78% had previously received radioactive iodine and 78% had previously received sorafenib or lenvatinib.

With 3.5 months of additional follow-up since the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting presentation, LOXO-292 demonstrated encouraging, early evidence of durable activity. Sixteen of 17 (94%) responding RET-mutant MTC patients remained on therapy and in response (median follow-up of 7.6 months for all 29 patients; median follow-up of 8.4 months for responding patients). Seven of seven (100%) responding RET fusion-positive thyroid remained on therapy and in response (median follow-up of 7.6 months for all nine patients; median follow-up of 8.5 months for responding patients). The longest treated patient was the first RET-mutant MTC patient enrolled, who had been on therapy for more than 13 months as of the data cut-off date.

The new data cutoff date allowed for the inclusion of first follow-up scans for nine patients (seven with RET-mutant MTC and two with RET fusion-positive thyroid cancer) who had not had any post-baseline response assessment as of the ASCO (Free ASCO Whitepaper) presentation. Of 29 patients with RET-mutant MTC, 17 demonstrated an objective response by RECIST 1.1 (two complete responses and 15 partial responses, including two patients with unconfirmed partial responses awaiting confirmatory response assessments) and seven additional patients demonstrated evidence of tumor regression (-12% to -26%). The overall response rate was 59% (17/29) (95% CI: 39%-77%) and the confirmed overall response rate was 56% (15/27) (95% CI: 35%-75%). Included in this analysis are two patients with non-measurable disease at baseline (1 confirmed complete response, 1 stable disease). Of nine patients with RET fusion-positive thyroid cancer, seven demonstrated an objective response by RECIST 1.1 (all partial responses) and one additional patient demonstrated evidence of tumor regression (-21%). The confirmed overall response rate was 78% (7/9) (95% CI: 40%-97%). Included in the analysis is one patient with non-measurable disease at baseline (stable disease). Response assessments were performed by the local clinical trial sites.

Anti-tumor activity was observed regardless of RET mutation, RET fusion partner, and prior multikinase inhibitor treatment. One patient, with RET fusion-positive thyroid cancer, had RECIST target lesions in the central nervous system (CNS) and exhibited an intracranial partial response by RECIST 1.1, pending confirmation.

Of the 82 patients in the safety analysis, most treatment-emergent adverse events were Grade 1 in severity and judged by the investigator as not related to LOXO-292. The treatment-emergent adverse events observed in ≥10% of patients, regardless of relationship to LOXO-292, were diarrhea (15% Grade 1, 7% Grade 2, 1% Grade 3), fatigue (9% Grade 1, 13% Grade 2, 0% ≥Grade 3), dry mouth (21% Grade 1, 0% ≥Grade 2), constipation (17% Grade 1, 2% Grade 2, 0% ≥Grade 3), hypomagnesemia (12% Grade 1, 1% Grade 2, 0% ≥Grade 3), cough (11% Grade 1, 1% Grade 2, 0% ≥Grade 3), headache (10% Grade 1, 1% Grade 2, 1% Grade 3) and nausea (9% Grade 1, 4% Grade 2, 0% ≥Grade 3). Four patients experienced adverse events ≥Grade 3 that were attributed to LOXO-292 (all Grade 3): tumor lysis syndrome, increased ALT/AST, diarrhea, and thrombocytopenia. All resolved with dose interruption. 160mg BID has been advanced as the Phase 2 dose, with dose exploration at 200mg BID ongoing to further characterize LOXO-292 safety and efficacy.

The presentation will be available online at View Source

About LOXO-292
LOXO-292 is an oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach. LOXO-292 has been granted Breakthrough Therapy Designation by the U.S. FDA.

LOXO-292 is currently being studied in the global LIBRETTO-001 Phase 1/2 trial. For additional information about the LOXO-292 clinical trial, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient RET Clinical Trial Hotline at 1-855-RET-4-292 or email [email protected].

About RET-Altered Cancers
Genomic alterations in RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 2% of non-small cell lung cancer, 10-20% of papillary and other thyroid cancers, and a subset of other cancers. Activating RET point mutations account for approximately 60% of medullary thyroid cancer (MTC). Both RET fusion cancers and RET-mutant MTC are primarily dependent on this single activated kinase for their proliferation and survival. This dependency, often referred to as "oncogene addiction," renders such tumors highly susceptible to small molecule inhibitors targeting RET.

On October 6, 2018 Veracyte, Inc. (Nasdaq: VCYT) reported that new findings from six studies reinforcing the "real world" performance of the next-generation Afirma Genomic Sequencing Classifier (GSC) and the Afirma Xpression Atlas in thyroid cancer diagnosis were presented at the 88th Annual Meeting of the American Thyroid Association (ATA) (Press release, Veracyte, OCT 6, 2018, View Source [SID1234529797]). The meeting is being held October 3-7 in Washington, D.C.

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Researchers from leading institutions presented posters showing that use of the Afirma GSC at their respective centers significantly increased the identification of benign thyroid nodules among those deemed indeterminate – not clearly benign or malignant – following cytopathology review, compared to the original Afirma test.

The Ohio State University – Researchers compared results of 113 indeterminate samples that were tested with the Afirma GSC to those of 403 samples using the earlier version of the test (the Afirma Gene Expression Classifier, or GEC). The Afirma GSC identified 74.1 percent of the nodules as benign, compared to 48.4 percent with the GEC, an increase of 53 percent. The overall surgery rate among all patients who underwent genomic testing decreased by more than half – from 42.2 percent with the GEC to 20.2 percent with the GSC.
Cleveland Clinic – Comparing results of 46 samples tested with the Afirma GSC between July 2017 and December 2017 with 182 samples tested with the original test between December 2011 and July 2017, researchers found that the GSC identified 67.4 percent as benign, compared to 41.8 percent with the GEC – an increase of 61 percent. The overall surgery rate for nodules tested with the GSC was 32.6 percent, compared to 47.3 percent with the original test, a decrease of 31 percent.
Brigham and Women’s Hospital – Researchers evaluated results for 583 thyroid nodules tested with either the Afirma GSC (n=97) or GEC (n=486) between 2011 and 2018. They found that the Afirma GSC identified 64.9 percent of nodules as benign, compared to 47.9 percent with the GEC, an increase of 35 percent.
"Our results show that with the improved testing, we sent significantly fewer patients to surgery," said Dr. Christian Nasr, medical director of the Thyroid Center in the Endocrinology & Metabolism Institute at Cleveland Clinic in Cleveland, Ohio. "Additionally, when patients went to surgery following ‘suspicious’ results, we were more likely to find cancer. Our findings suggest that the next-generation test can help more patients avoid unnecessary thyroid surgery, while focusing healthcare resources on the patients who are more likely to need them."

Additionally, in two oral presentations, researchers shared the first "real world" Afirma Xpression Atlas data, providing insights into the distribution of a wide range of gene variants and fusions across key categories of indeterminate thyroid nodules and Afirma GSC results. For example, among 13,549 indeterminate thyroid nodules evaluated using the Afirma GSC and Xpression Atlas, more than a quarter (25.9 percent) of GSC-suspicious nodules (in primary risk categories known as Bethesda III/IV) contained RAS variants. Additionally, RET, NTRK, BRAF and ALK fusions were only found in GSC-suspicious, versus GSC-benign, cases (in all Bethesda categories).

"Having detailed genomic information about thyroid nodules that are malignant or suspicious for cancer may in some cases help inform surgical decision-making for these patients," said Dr. Allan C. Golding of Memorial Healthcare System in Hollywood, Fla. "Additionally, the wide range of gene alterations detected by the Xpression Atlas may provide further insights into pathway activation and potential cancer treatment targets for patients with thyroid cancer."

The field of precision medicine is progressing rapidly, and multiple targeted therapies are in clinical trials or have been approved for treatment of advanced cancers that harbor specific genomic alterations. In the new data presented at the ATA conference, genomic changes (or alterations) targeted by these new therapies were identified in Afirma GSC-suspicious cases by the Xpression Atlas.

"The new data shared at the ATA annual meeting add to the growing library of real-world evidence demonstrating the Afirma GSC’s performance across multiple institutions in reducing unnecessary surgeries in thyroid cancer diagnosis," said Bonnie Anderson, Veracyte’s chairman and chief executive officer. "Additionally, these new study data for the Afirma Xpression Atlas demonstrate the ability of our robust RNA sequencing platform to provide rich genomic content that may help inform surgery decisions and treatment options for patients with suspected or confirmed thyroid cancer. The extensive gene alteration data that it provides becomes increasingly important in the era of targeted therapies."

For more information, please visit the Veracyte Booth #201 or www.afirma.com/ATA2018.

About Afirma

Veracyte’s Afirma solution provides a comprehensive offering in thyroid cancer diagnosis for physicians evaluating patients with thyroid nodules. The Afirma Genomic Sequencing Classifier combines RNA sequencing data with machine learning to identify patients with benign thyroid nodules among those with indeterminate cytopathology results in order to avoid unnecessary surgery and preserve the thyroid. Since the commercial introduction of Afirma in 2011, Veracyte has performed over 100,000 genomic tests, and estimates it has saved more than 40,000 patients from unnecessary thyroid surgery and removed an estimated $800 million in surgery costs from the healthcare system. The Afirma classifier is proven in over 20 published clinical studies, is included in most leading clinical guidelines and is covered as medically necessary by Medicare and all major U.S. health plans. The company’s Afirma Xpression Atlas platform, introduced in May 2018, provides extensive genomic data that may inform surgery strategy and treatment options for patients with thyroid nodules that are suspicious for cancer or cancerous. The RNA sequencing-based platform measures 761 DNA variants and 130 RNA fusions in over 500 genes shown to be associated with thyroid cancer on thyroid nodule fine needle aspiration samples.