On June 4, 2017 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that its BRACAnalysis CDx companion diagnostic test successfully identified BRCA-mutated patients with HER2- metastatic breast cancer in the OlympiAD trial (NCT02000622) who responded better to treatment with olaparib than standard chemotherapy (Press release, Myriad Genetics, JUN 4, 2017, View Source [SID1234519454]).

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OlympiAD compared olaparib (300mg twice daily) to physician’s choice of a standard chemotherapy (capecitabine, vinorelbine or eribulin) in the treatment of 302 patients with HER2-negative metastatic breast cancer harboring germline BRCA1/2 mutations as determined by Myriad’s BRACAnalysis CDx companion diagnostic test. The results showed that BRCA-positive patients treated with olaparib had a statistically-significant and clinically-meaningful PFS benefit of compared to the control group.

"In this study, patients with BRCA mutations experienced significantly prolonged PFS when treated with olaparib versus standard of care chemotherapy," said Johnathan Lancaster, M.D., Ph.D., chief medical officer, Myriad Genetic Laboratories. "Based on these findings, all patients with metastatic breast cancer should know their BRCA status as it will be a critical factor in guiding therapy selection for patients with metastatic breast cancer."

It is estimated there are approximately 60,000 patients per year in the United States who are newly diagnosed with or progress to HER2- metastatic breast cancer. Of these patients, two-thirds are not eligible for BRCA testing based upon current testing criteria. If approved by the FDA as a new indication this would potentially triple the number of patients with metastatic breast cancer who are candidates for BRCA testing.

"We believe the results from the OlympiAD study will expand the population who can benefit from the BRACAnalysis CDx test, and the results will help doctors improve care for their patients with metastatic breast cancer," said Lancaster. "This study further supports the use of advanced biomarkers, like BRACAnalysis CDx, to enable precision medicine, which benefits both patients and the healthcare ecosystem."

The collaboration between Myriad and AstraZeneca to develop a novel companion diagnostic test for olaparib began in 2007. OlympiAD is the first Phase 3 trial to demonstrate the clinical utility of the BRACAnalysis CDx test outside of ovarian cancer for which the test was approved by the U.S. Food and Drug Administration (FDA) in Dec. 2014. Based on the robustness of the OlympiaAD results, Myriad plans to submit a supplementary premarket approval (sPMA) application under its existing PMA for BRACAnalysis CDx to include the HER2- metastatic breast cancer indication.

About BRACAnalysis CDx
BRACAnalysis CDx is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Single nucleotide variants and small insertions and deletions (indels) are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR. Results of the test are used as an aid in identifying ovarian cancer patients with deleterious or suspected deleterious germline BRCA variants, who are or may become eligible for treatment with Lynparza (olaparib). This assay is for professional use only and is to be performed only at 320 Wakara Way, Salt Lake City, UT 84108.

About Lynparza
Lynparza (olaparib) is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that may exploit tumour DNA damage response (DDR) pathway deficiencies to preferentially kill cancer cells. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DNA damage response (DDR) mechanisms in cancer cells. Lynparza is currently approved by regulatory health authorities in the EU for use as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. It is also approved in the US as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Lynparza is currently being investigated in another separate non-metastatic breast cancer Phase III study called OLYMPIA. This study is still open and recruiting patients internationally.

On June 4, 2017 Y-mAbs Therapeutics, Inc. (YmAbs), an immunotherapy company discovering and developing innovative treatments for patients with cancer, reported positive top line results from a pivotal study of 131I-burtomab in Refractory Leptomeningeal Metastasis from Neuroblastoma (Press release, Y-mAbs Therapeutics, JUN 4, 2017, View Source;study-of-burtomab-in-refractory-leptomeningeal–metastasis-from-neuroblastoma/ [SID1234519467]). Results showed a 58 months average survival for the patients treated with 131I-burtomab in the study, compared to an average of 4.7 month and no long term survival or cure, for a contemporary cohort in the Central German Childhood Cancer Registry . After more than a decade of follow-up, data shows more than 40% overall long term survival indicating that the treated children have been cured.

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At ASCO (Free ASCO Whitepaper), Dr. Kim Kramer from Memorial Sloan Kettering Cancer Center (MSK) presented the overall survival data from 80 pediatric patients with CNS and leptomeningeal metastasis from neuroblastoma treated at MSK with 131I-burtomab, and Prof. Dr. med. Frank Berthold from the University of Cologne presented comparable historical data from the Central German Childhood Cancer Registry, thereby demonstrating that the use of 131I-burtomab led to a multi-fold increase of the average survival in this patient population, where no other established therapy exists.

YmAbs Founder, President and Head of Business Development and Strategy, Thomas Gad said, "Having witnessed this out-patient treatment first hand as a parent, these data provide a potential curative treatment addressing an unmet medical need for a life-threatening disease to children suffering from Refractory Leptomeningeal Metastasis from Neuroblastoma. YmAbs is now positioned to seek the most efficient route to approval. This could be a potential game changer for pediatric patients and their families."

Dr. Claus Møller, Chief Executive Officer further notes, "In a setting, where no other therapies are approved, this survival data represents a true breakthrough and hope for these children."

On June 5, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that new data for TECENTRIQ and updates from across its extensive cancer immunotherapy clinical development programme will be presented during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on 2 June – 6 June in Chicago, Illinois, United States (Press release, Hoffmann-La Roche, JUN 3, 2017, View Source [SID1234519439]). Data from phase I, II and Phase III studies presented at ASCO (Free ASCO Whitepaper) 2017 suggest that TECENTRIQ has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

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Data from a study of TECENTRIQ plus Avastin in metastatic Renal Cell Carcinoma (mRCC) supports a scientific rationale for combining TECENTRIQ with Avastin including its potential to increase infiltration (trafficking) of T-cells into tumours and other immune-modulatory properties. New data will also be presented for TECENTRIQ as a monotherapy from the OAK trial, which represent the first treatment-beyond-progression data from a Phase III study of cancer immunotherapy in advanced lung cancer (NSCLC). Updated data will also be presented from the Phase Ib study of TECENTRIQ in combination with chemotherapy for people with advanced NSCLC. Two Phase Ib studies in melanoma combining TECENTRIQ plus Cotellic (cobimetinib) and TECENTRIQ plus Cotellic plus Zelboraf (vemurafenib) showed that the addition of Zelboraf and/or Cotellic may alter the tumour micro environment, enhancing the anti-tumour activity of TECENTRIQ.

"By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with TECENTRIQ to a greater number of people living with cancer," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients, and at ASCO (Free ASCO Whitepaper) 2017 we are presenting data from a range of medicines and combinations that we believe have this potential."
Kidney cancer (Renal Cell Carcinoma RCC)

IMmotion150 is a global, multicentre Phase II study that was designed to evaluate the efficacy and safety of TECENTRIQ plus Avastin, TECENTRIQ alone or sunitinib alone in 305 patients with previously untreated, locally advanced or mRCC. After progression on the sunitinib or TECENTRIQ arms of the study, 77% and 75% of patients crossed over to TECENTRIQ plus Avastin treatment, respectively.

Clinical activity of TECENTRIQ plus Avastin was seen in crossover patients regardless of first line TECENTRIQ or sunitinib therapy or response to first line therapy, further supporting this combination as a potential treatment option. Specifically, TECENTRIQ plus Avastin resulted in an Overall Response Rate (ORR) of 26% in all-crossover patients (28% in crossover post-sunitinib; 24% in crossover post-TECENTRIQ patients) with a median Progression Free Survival (PFS) of 8.8 months in all-crossover patients. There were no new safety signals observed in the crossover treated patients.

A Phase III study, IMmotion151, in a similar population is expected to provide initial results in early 2018.
IMmotion150: A Phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). Oral abstract 4505 Monday 5 June, 08:00 – 11:00 CDT

Lung cancer
In the Phase III OAK trial, which studied the impact of TECENTRIQ treatment beyond radiologic disease progression (PD), showed that a continuation of TECENTRIQ treatment after PD resulted in promising clinical benefit. The study design allowed patients randomised to TECENTRIQ to continue treatment beyond PD, as assessed by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, if the patient was considered to be deriving clinical benefit from treatment. TECENTRIQ could be continued until there was loss of clinical benefit according to the investigator’s clinical judgement.

Patients in the TECENTRIQ arm who continued TECENTRIQ therapy beyond PD had a prolonged clinical benefit, 12.7 months Overall Survival (OS) (95% CI 9.3–14.9) compared with 8.8 months OS (6.0 – 12.1) for those treated with other anti-cancer treatments post PD. Tumour target lesion responses and stabilisation post-PD were seen across all subgroups of programmed death-ligand 1 (PD-L1) expression. These data support the treatment strategy of continuing TECENTRIQ beyond PD until loss of clinical benefit in patients, regardless of the level of PD-L1 expression.
Impact of atezolizumab (atezo) treatment beyond disease progression (TBP) in advanced NSCLC: Results from the randomised phase III OAK study. Oral abstract TPS5090
Tuesday 6 June, 09:45 – 12:45 CDT

The updated efficacy and safety data for Arms C–E of our phase Ib GP28328 study are encouraging for TECENTRIQ in combination with various chemotherapies. The primary endpoint of the study was safety and TECENTRIQ was well tolerated when combined with various chemotherapies.
Updated efficacy and safety data table for TECENTRIQ in combination Arms C–E

The confirmed ORRs and mature OS data provide further evidence for a synergy between the anti-tumour activity of TECENTRIQ and chemotherapy.
Abstract 9092, Poster Board: #418. Lung Cancer—Non-Small Cell Metastatic
Saturday 6 June, 08:00 – 11:30 CDT

Melanoma
Updated study results from two Phase Ib studies combining TECENTRIQ plus Cotellic (cobimetinib) and, TECENTRIQ plus Cotellic plus Zelboraf (vemurafenib) showed improved ORR and PFS after a longer follow up. Both combination studies demonstrated a manageable safety profile.

Based on the results of the Phase 1b studies both combinations are now in Phase III clinical trials. The TECENTRIQ plus Cotellic plus Zelboraf combination will be investigated in people with untreated BRAFV600‑mutant unresectable metastatic melanoma while the TECENTRIQ plus Cotellic combination will be studied in people with untreated, unresectable metastatic BRAF wild-type melanoma.
Atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in BRAFV600-mutant metastatic melanoma (mel): Updated safety and clinical activity. Abstract 3063
Monday 5 June, 08:00 – 11:30 CDT
Atezolizumab (A) + cobimetinib (C) in metastatic melanoma (mel): Updated safety and clinical activity.
Abstract 3057
Monday 5 June, 8:00 – 11:30CDT
Pipeline
Data from two studies will be presented that demonstrate the potential of TECENTRIQ in combination with novel cancer immunotherapies. These studies include a Phase I dose escalation study evaluating the T-cell bispecific (CEA- TCB) antibody as a single agent or in combination with TECENTRIQ in patients with metastatic colorectal cancer and a Phase Ib dose-escalation study evaluating the combined inhibition of TECENTRIQ plus IDO1 (GDC-0919) in patients with locally advanced or metastatic solid tumours and
Monotherapy data will also be presented from a Phase Ia study of TECENTRIQ in advanced/recurrent endometrial cancer (rEC), a patient population for whom the prognosis remains poor. The study is evaluating clinical activity and safety. Results show that TECENTRIQ has a favourable safety profile in rEC, with durable clinical benefit seen in some patients. Clinical benefit appeared to increase with higher PD-L1 expression, suggesting a link between PD-L1 status and response.

Further information on Roche’s contribution to the ASCO (Free ASCO Whitepaper) 2017 scientific programme, the company’s wider progress in cancer care and key data being presented at the conference will be featured at a Roche investor briefing on Monday, 5 June 2017 at 17:15 CDT. This event is independently organised by Roche and is open to analysts attending the ASCO (Free ASCO Whitepaper) 2017 Annual Meeting. To register for the Roche investor briefing, please use the following link: http://roche.cvent.com/d/85qzfy.

To learn more about Roche’s personalised cancer immunotherapy programme and Roche’s contribution to ASCO (Free ASCO Whitepaper) 2017, please follow Roche on Twitter via @Roche. You can keep up to date with ASCO (Free ASCO Whitepaper) 2017 Annual Meeting news and updates by using the hashtag #ASCO17.
Overview of Roche cancer immunotherapy data being presented at ASCO (Free ASCO Whitepaper) 2017

On June 3, 2017 Eli Lilly and Company (NYSE: LLY) reported that results from the Phase 3 MONARCH 2 study showed that abemaciclib, a cyclin-dependent kinase (CDK)4 & 6 inhibitor, in combination with fulvestrant, significantly improved progression-free survival (PFS) compared to treatment with fulvestrant alone in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced breast cancer who have relapsed or progressed after endocrine therapy (median PFS, 16.4 vs. 9.3 months, respectively, HR: 0.553; 95% CI: 0.449, 0.681, P < .0000001) (Press release, Eli Lilly, JUN 3, 2017, View Source [SID1234519366]). The data were presented at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #1000) and simultaneously published online in the Journal of Clinical Oncology.

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"Metastatic HR+ breast cancer remains a dangerous disease and oncologists are always on the lookout for active new therapies to combat it," said George W. Sledge Jr., M.D., professor of medicine, Stanford University School of Medicine and principal investigator. "I am very impressed with the results from this study. For these patients who progressed on endocrine therapy, there was a significant prolongation of progression-free survival, and more than double the response rate, including an increased rate of complete response."

Patients with measureable disease treated with abemaciclib plus fulvestrant achieved an objective response rate (ORR) of 48.1 percent (3.5% complete response [CR]), compared to 21.3 percent (0% CR) in patients treated with fulvestrant alone. Additionally, abemaciclib plus fulvestrant caused a greater degree of tumor shrinkage than fulvestrant alone.

"One of our goals with the MONARCH clinical development program is not to replicate studies, but rather to further innovate in the field of CDK4 & 6 inhibition and advance potential treatment options for patients wherever they may be in the course of their disease," said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology. "From the single-agent activity seen in MONARCH 1 to the significant MONARCH 2 results shared today, and our ongoing Phase 3 studies, we are committed to working with physicians to evolve treatment expectations for people living with breast cancer."

The global Phase 3, double-blind study was designed to evaluate the efficacy and safety of abemaciclib, in combination with fulvestrant, in patients with advanced (locoregionally recurrent or metastatic) breast cancer. The intent-to-treat population of 669 patients was randomized to receive abemaciclib or placebo orally twice a day on a continuous dosing schedule, given in combination with fulvestrant at its approved dose and schedule, until disease progression. Patients enrolled in the study had experienced disease progression on or within 12 months of receiving endocrine treatment in the neoadjuvant or adjuvant setting or while receiving first-line endocrine therapy for metastatic disease. Patients who had received chemotherapy in the metastatic setting were not eligible for the study. The primary endpoint for MONARCH 2 was PFS.

The most frequent adverse events (AEs) of any grade in the abemaciclib plus fulvestrant arm were diarrhea, neutropenia, nausea, and fatigue. Of these, the reported Grade 3 AEs (abemaciclib vs. placebo arm) were diarrhea (13.4% vs. 0.4%), neutropenia (23.6% vs. 1.3%), nausea (2.7% vs. 0.9%), and fatigue (2.7% vs. 0.4%). No patients in either arm experienced Grade 4 diarrhea, nausea or fatigue, and Grade 4 neutropenia was observed in 2.9 percent versus 0.4 percent of patients in the abemaciclib versus placebo arms, respectively.

Severity and frequency of diarrhea generally decreased following one to two cycles, and was managed with loperamide or dose reduction. The majority (70.1%) of patients in the abemaciclib arm with an AE of diarrhea did not require treatment modification (dose interruption, reduction, or discontinuation), and 2.9 percent of patients discontinued the study drug due to diarrhea.

In addition to the ongoing MONARCH trials, including the newly initiated monarchE adjuvant study, which will assess abemaciclib in patients with high-risk, early breast cancer, Lilly is actively evaluating abemaciclib in lung cancer, pancreatic cancer, and patients with brain metastases.

Notes to Editor

About Advanced Breast Cancer
Breast cancer is the most common cancer in women worldwide with nearly 1.7 million new cases diagnosed in 2012.[1] Advanced breast cancer includes metastatic breast cancer, cancer that has spread from the breast tissue to other parts of the body, and locally or regionally advanced breast cancer, meaning the cancer has grown outside the organ where it started but has not yet spread to other parts of the body.[2] Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic and an estimated six to 10 percent of all new breast cancer cases are initially diagnosed as being metastatic.[3] Survival is lower among women with a more advanced stage at diagnosis: 5-year relative survival is 99 percent for localized disease, 85 percent for regional disease, and 26 percent for metastatic disease. Other factors, such as tumor size, also impact 5-year survival estimates.[4]

About Abemaciclib
In many cancers, uncontrolled cell growth arises from a loss of cell cycle regulation due to increased signaling from CDK4 and CDK6. Abemaciclib (LY2835219) is an investigational, oral cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting cyclin-dependent kinases, CDK4 and CDK6, and was most active against Cyclin D1 and CDK4 in cell-free enzymatic assays. In breast cancer, Cyclin D1/CDK4 has been shown to promote phosphorylation of the retinoblastoma protein (Rb), cell proliferation and tumor growth. In hormone receptor-positive breast cancer cell lines, sustained target inhibition by abemaciclib reduced phosphorylation of Rb, inducing cell cycle arrest.

In 2015, the U.S. Food and Drug Administration granted abemaciclib Breakthrough Therapy Designation based on data from the breast cancer cohort expansion of the company’s Phase 1 trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. In addition to its current MONARCH clinical trials evaluating abemaciclib in breast cancer, a Phase 3 trial of abemaciclib in lung cancer is also underway.

For more information on additional abemaciclib trials, a complete listing can be found on ClinicalTrials.gov (in the search box on the home page, type in "abemaciclib").

About the MONARCH Clinical Trial Program
Lilly is evaluating abemaciclib in the comprehensive MONARCH clinical program, which includes the following studies:

MONARCH 1: a global Phase 2 study evaluating the efficacy and safety of abemaciclib monotherapy in patients with HR+, HER2- advanced breast cancer who had prior endocrine therapy and chemotherapy for metastatic disease.

MONARCH 2: a global Phase 3 study evaluating the efficacy and safety of abemaciclib, in combination with fulvestrant, in patients with HR+, HER2- advanced breast cancer who progressed on endocrine therapy.

MONARCH 3: a global Phase 3 study evaluating the efficacy and safety of abemaciclib, in combination with an aromatase inhibitor, as initial endocrine-based therapy for postmenopausal women with HR+, HER2- advanced breast cancer who have had no prior systemic treatment for advanced disease.

monarcHER: a global Phase 2 study evaluating abemaciclib plus trastuzumab (with or without fulvestrant) in women with HR+, HER2+ advanced breast cancer.

MONARCH plus: a Phase 3 study evaluating the efficacy and safety of abemaciclib, in combination with endocrine therapies, to support registration in China.

neoMONARCH: a Phase 2 study evaluating abemaciclib in the neoadjuvant setting, alone or in combination with the non-steroidal aromatase-inhibitor anastrozole, in postmenopausal women with previously untreated early stage HR+, HER2- breast cancer.

monarchE: a global Phase 3 study evaluating the efficacy and safety of abemaciclib in the adjuvant setting in patients with high-risk, early breast cancer.

On June 3, 2017 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the fields of cancer metabolism and rare genetic diseases, reported updated data from the dose-escalation and expansion cohorts of the Phase 1 study evaluating single agent AG-120 (ivosidenib) in isocitrate dehydrogenase-1 (IDH1) mutant positive cholangiocarcinoma at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 2-6, 2017 in Chicago (Press release, Five Prime Therapeutics, JUN 3, 2017, View Source [SID1234519368]).

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"The durable disease control signal seen with the Phase 1 data, combined with AG-120’s favorable safety profile, are encouraging for patients with advanced IDH1 mutant cholangiocarcinoma who have received multiple prior therapies," said Maeve Lowery, M.D., Memorial Sloan Kettering Cancer Center who presented the study results. "With no approved treatments and few effective options beyond the first line setting in this challenging disease, we look forward to continuing to characterize AG-120’s activity in the Phase 3 ClarIDHy study."

"Consistent with AG-120’s unique mechanism of action and in the context of this heavily pre-treated patient population, we believe durable stable disease is a meaningful measure of clinical benefit," said Chris Bowden, M.D., chief medical officer at Agios. "These data support further development of AG-120 in our ongoing Phase 3 registration-enabling ClarIDHy study, where we aim to confirm the early efficacy signal and evaluate the potential to impact tumor biology."

The ongoing Phase 1 trial is assessing the safety and tolerability of AG-120 in advanced solid tumors, including glioma, cholangiocarcinoma and chondrosarcomas with an IDH1 mutation. Enrollment is now complete for the dose-escalation and expansion cohorts. As of March 10, 2017, 73 patients with IDH1 mutant positive cholangiocarcinoma have been treated with single agent AG-120 in the dose escalation (n=24) and expansion cohorts (n=49). Thirteen patients remain on treatment. AG-120 was administered at the following dose levels and schedules in the dose-escalation cohort: 100 mg twice daily, and 300, 400, 500, 800 and 1200 mg once a day over a 28 day cycle length. In the dose expansion cohort, patients received 500 mg once a day, which was the selected dose for the ongoing Phase 3 ClarIDHy trial. Among the Phase 1 cholangiocarcinoma population, the median age is 60 (ranging from 32-81). Sixty-five patients had intrahepatic cholangiocarcinoma and eight had extrahepatic disease. The median number of prior systemic therapies was two (ranging from one to five) and 97% of patients received a prior gemcitabine-based chemotherapy regimen.

Safety Data

A safety analysis conducted for all 73 treated patients as of the data cut-off demonstrated that AG-120 was well-tolerated with a favorable safety profile in IDH1 mutant positive cholangiocarcinoma patients.

No dose limiting toxicities or treatment-related deaths have been observed.
The majority of adverse events (AEs) reported were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhea and decreased appetite.
Four patients experienced drug-related AEs ≥ grade 3: two at the 500 mg dose level, fatigue (n=1) and blood alkaline phosphatase increases (n=1) and two at the 1200 mg dose level, fatigue (n=1) and blood phosphorous decreases (n=1).
One patient had a dose reduction for a grade 2 AE of worsening leg cramps that was considered to be possibly drug-related.
Efficacy Data

Efficacy data from all 73 treated patients as of the data cut-off showed:

Four patients (5%) experienced a confirmed partial response (one at 300 mg QD and three at 500 mg QD). A partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
Forty-one patients (56%) experienced stable disease.
Landmark analyses of progression free survival at six (PFS6) and 12 months (PFS12) were 38.5% and 20.7% respectively. The median progression free survival (PFS) was 3.8 months (95% CI 3.6, 7.3).
AG-120 treatment inhibited plasma 2-hydroxyglutarate (2-HG) to within levels found in healthy volunteers, and also reduced 2-HG in tumor biopsies, with 2-HG levels in plasma and tumor biopsies showing a positive correlation.
Pathology review of on-study tumor biopsies were conducted in a patient achieving a partial response, which showed morphologic changes suggestive of cellular differentiation which is consistent with the proposed mechanism of action of AG-120.
ClarIDHy Phase 3 Trial

AG-120 (ivosidenib) is currently being evaluated in an ongoing, global, registration-enabling randomized Phase 3 trial known as ClarIDHy, enrolling 186 previously treated IDH1m positive cholangiocarcinoma patients who have documented disease progression following one or two systemic therapies in the advanced setting.

Patients will be randomized 2:1 to receive either single-agent AG-120 500 mg once daily or placebo with crossover to AG-120 permitted at the time of progression.
The primary endpoint of the trial is PFS with secondary endpoints including safety and tolerability, overall response rate, overall survival, duration of response, PK/PD and quality of life assessments.
Assuming a median PFS of 3 months for the control group, the study was designed with 96% power to detect a hazard ratio of 0.5 for PFS (AG-120 vs placebo), with a one-sided alpha of 0.025.
Thermo Fisher Scientific is providing next-generation sequencing to detect IDH1m for all tumor samples as inclusion criteria for enrollment in the study and will develop and commercialize the validated companion diagnostic.
About Cholangiocarcinoma

Cholangiocarcinoma (CC) is a rare cancer of the bile ducts within and outside of the liver. Cases that occur within the liver are known as intrahepatic cholangiocarcinoma (IHCC) and those that occur outside the liver are considered extrahepatic. Mutations in IDH1 occur in 13–15% of CC cases overall and in up to 25% of IHCC cases. Current treatment options for localized disease include surgery, radiation and/or other ablative treatments. There are no approved systemic therapies for cholangiocarcinoma and limited chemotherapy options are available in the advanced setting. Gemcitabine-based chemotherapy is often recommended for newly diagnosed metastatic disease. Progression-free survival (PFS) in patients with advanced biliary cancer receiving second-line chemotherapy is 2–3 months.