On May 29, 2020 Forma Therapeutics reported that kit has developed a pipeline of small molecules aimed at rare blood disorders and cancers, but it aims to advance two—investigational treatments for sickle cell disease and for advanced prostate cancer—and find partners for the rest of them (Press release, Forma Therapeutics, MAY 29, 2020, View Source [SID1234558743]).

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Now the Watertown, MA-based company is considering tapping the public markets to add enough funds to move one of its pair of core drug candidates further along in the clinic and to start human tests of the other. Forma set a preliminary $150 million goal for its IPO and says it plans to apply for a Nasdaq listing under the stock symbol "FMTX."

The company priorities are its oral, once-daily drug, FT-4202, which it is evaluating in a Phase 1 trial as a treatment for sickle cell disease, and FT-7051, a preclinical-stage treatment for metastatic castration-resistant prostate cancer (mCRPC).

Forma’s sickle cell drug is designed to increase hemoglobin levels and reduce the episodes of acute pain known as vaso-occlusive crises, caused when sickle-shape cells aggregate and block the supply of oxygen to tissues. The drug is intended to activate an enzyme, pyruvate kinase-R, that plays a role in the metabolism, function, and survival of red blood cells.

The biotech is studying the drug in patients age 12 and older who have the blood disorder. About 100,000 people in the US are affected by the inherited condition. A slew of companies are also pursuing new treatments for the disease, including Cambridge, MA-based Imara (NASDAQ: IMRA), which went public in March to raise funds to advance its investigational small molecule; Bluebird Bio (NASDAQ: BLUE), which is developing a gene therapy; and a handful of competitors with experimental gene-editing fixes. Late last year Global Blood Therapeutics (NASDAQ: GBT) won FDA approval for its once-daily sickle cell disease drug.

In its preliminary prospectus, Forma said it also aims to expand clinical development of FT-4202 into beta thalassemia, another rare blood disorder.

Forma’s prostate cancer treatment is designed to inhibit a protein complex, CBP/p300, that plays a role in the activity of the androgen receptor, which drives prostate cancer cell growth. The FDA in April cleared Forma to begin human tests of the drug.

Prostate cancer is the second leading cause of cancer death for men in the US; the type that Forma’s drug is intended to treat is the most advanced form of the disease. The UK’s CellCentric is also aiming to treat mCRPC with a CBP/p300 inhibitor of its own; Cambridge, MA-based Constellation Pharmaceuticals (NASDAQ: CNST) is advancing a clinical-stage drug for the indication, too.

Money raised in an IPO would be deployed to get the sickle cell drug through Phase 1 and, if results are as anticipated, proceed to a pivotal Phase 2/3 clinical trial. The funds would also be used to advance the cancer therapy into a planned Phase I clinical trial.

Some cash would also go toward Forma’s non-core programs—those already partnered and those seeking partners to take them forward. Programs still in search of partners include its most advanced, olutasidenib, which is currently in a pivotal study testing it as a treatment for acute myeloid leukemia. The investigational cancer drug is also being studied in an exploratory Phase I trial for glioma. In addition, Forma is advancing two potential treatments for nonalcoholic steatohepatitis, the liver disease better known as NASH.

Forma previously licensed a molecule it discovered, a potential treatment for non-Hodgkin lymphoma, to Celgene (now a subsidiary Bristol Myers Squibb (NYSE: BMY)) and a KRAS inhibitor, meant to treat solid tumors, to Boehringer Ingelheim.

The company, which was founded in 2007, is headed by president and CEO Frank Lee, who previously ran global development and commercial strategy for Genentech’s immunology, ophthalmology and infectious diseases divisions. Its chief medical officer, Patrick Kelly, who has been with the company since 2016, served previously in the oncology unit at Takeda Pharmaceutical (NYSE: TAK). Forma last month added to its C-suite David Cook, who was most recently at Seres Therapeutics (NASDAQ: MCRB), as its chief scientific officer.

Forma’s founding backers were the investment arms of Eli Lilly (NYSE: LLY) and Novartis (NYSE: NVS. Today, according to the prospectus, RA Capital owns 21.16 percent of the company; Novartis holds 12.63 percent; Baker Bros. Advisors, 10.58 percent; and Lilly, 10.15 percent. Other shareholders include Cormorant Asset Management and Singapore’s Biomedical Sciences Investment Fund.

As of the end of March the company reported about $142 million in cash, cash equivalents, and short-term investments.

On May 29, 2020 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage oncology therapeutics company developing drugs to treat cancers with the greatest medical need for new treatment options, including KRAS-mutated colorectal cancer, Zytiga-resistant prostate cancer and leukemia, reported additional positive efficacy and favorable safety data were featured in a virtual oral poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) conference (Press release, Cardiff Oncology, MAY 29, 2020, View Source [SID1234558760]).

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The new data from Cardiff Oncology’s ongoing Phase 1b/2 clinical trial of onvansertib in combination with FOLFIRI and Avastin (bevacizumab) for second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC) continues to demonstrate that primary efficacy endpoint of overall objective response (ORR), as measured by tumor regression, is ten-fold greater than current standard-of-care of 4%. To-date, 89% of evaluable patients in the onvansertib trial have achieved a clinical response and the response appears durable with patients having progression-free survival (PFS) of at least 6 months. Onvansertib has also shown its effectiveness in targeting the most prevalent KRAS mutation subtypes associated with colorectal cancer, which until recently have been considered to be undruggable.

"We are pleased to be participating in this clinical trial and importantly, our patients are not only tolerating the combination of onvansertib plus standard-of-care FOLFIRI and bevacizumab, but we are very encouraged by the efficacy we are seeing," said Dr. Daniel Ahn, lead investigator and medical oncologist, Mayo Clinic Cancer Center, Arizona. "Being able to effectively treat patients with KRAS-mutated mCRC has been a challenge and their prognosis is poor. Onvansertib is showing great potential as a new second-line treatment option, in combination with standard-of-care, for these patients."

"Our trial is achieving critical milestones and gaining momentum," said Dr. Mark Erlander, Chief Executive Officer of Cardiff Oncology. "We continue to see safety and efficacy demonstrated and this, coupled with the FDA granting of Fast Track Designation, is further validation of the potential value of onvansertib to tackle the once undruggable KRAS-mutations that drive aggressive growth of CRC tumors."

Highlights of the ASCO (Free ASCO Whitepaper) Presentation – Onvansertib in KRAS-Mutated mCRC Phase 1b/2 Trial

In the Phase 1b dose escalation, the 1st two dose levels (onvansertib 12 mg/m2 and 15 mg/m2) have been cleared for safety; the 3rd dose level (onvansertib 18 mg/m2) is enrolling; the maximum tolerated dose has not been reached to-date
As of the data cutoff date, clinical response was observed in 8 (89%) of the 9 evaluable patients and post the data cutoff 1 additional patient achieved an objective response:
As of the ASCO (Free ASCO Whitepaper) cutoff date, 4 patients had experienced an objective response, and another 4 patients had stable disease
One patient proceeded to have successful curative surgery; an unprecedented event in this patient population
Progression-free survival (PFS) is >6 months, with 6 patients remaining on treatment
Decreases in plasma KRAS mutation level during the first cycle of treatment are highly predictive of tumor regression and subsequent therapeutic response:
Onvansertib effectively targets all prevalent KRAS mutation subtypes associated with CRC
8 of the 9 patients had a KRAS mutation detected by ctDNA analysis at baseline (ddPCR and NGS)
Changes in KRAS mutant during cycle 1 of treatment were highly predictive of tumor regression:
5 patients had a decrease in KRAS mutant to non-detectable level in cycle 1 (28 days) and subsequent tumor regression at 8 weeks
The Phase 2 continuation trial will further assess the safety and efficacy of onvansertib at the recommended Phase 2 dose (RP2D) in combination with FOLFIRI + bevacizumab, as well as the value of KRAS liquid biopsy to predict treatment response
About the Phase 1b/2 Clinical Trial of Onvansertib in KRAS-Mutated mCRC

The ongoing trial, A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with FOLFIRI and Bevacizumab for Second‑Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS Mutation (NCT03829410) is evaluating the safety and efficacy of onvansertib in combination with standard-of-care FOLFIRI and Avastin (bevacizumab). Up to 44 patients, with a confirmed KRAS mutation, metastatic and unresectable disease, who have failed or are intolerant of treatment with FOLFOX (fluoropyrimidine and oxaliplatin) with or without Avastin (bevacizumab), will be enrolled. The trial is being conducted at two prestigious cancer centers: USC Norris Comprehensive Cancer Center and the Mayo Clinic Cancer Center.

About Onvansertib

Onvansertib is a first-in-class, third-generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK1) enzyme, which is over-expressed in multiple cancers including leukemias, lymphomas and solid tumors. Onvansertib targets the PLK1 isoform only (not PLK2 or PLK3), is orally administered and has a 24-hour half-life with only mild-to-moderate side effects reported. Cardiff Oncology believes that targeting only PLK1 and having a favorable safety and tolerability profile, along with an improved dose/scheduling regimen will significantly improve on the outcome observed in previous studies with a former panPLK inhibitor in AML.

Onvansertib has demonstrated synergy in preclinical studies with numerous chemotherapies and targeted therapeutics used to treat leukemias, lymphomas and solid tumor cancers, including irinotecan, FLT3 and HDAC inhibitors, taxanes and cytotoxins. Cardiff Oncology believes the combination of onvansertib with other compounds has the potential to improve clinical efficacy in acute myeloid leukemia (AML), metastatic castration-resistant prostate cancer (mCRPC), non-Hodgkin lymphoma (NHL), colorectal cancer and triple-negative breast cancer (TNBC), as well as other types of cancer.

Cardiff Oncology has three ongoing clinical trials of onvansertib: A Phase 2 trial of onvansertib in combination with Zytiga (abiraterone acetate)/prednisone in patients with mCRPC who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving Zytiga (NCT03414034); a Phase 1b/2 Study of onvansertib in combination with FOLFIRI and Avastin for second-line treatment in patients with mCRC with a KRAS mutation (NCT03829410); and a Phase 2 clinical trial of onvansertib in combination with decitabine in patients with relapsed or refractory AML (NCT03303339).

Cardiff Oncology licensed onvansertib (also known as NMS-1286937 and PCM-075) from Nerviano Medical Sciences (NMS), the largest oncology-focused research and development company in Italy, and a leader in protein kinase drug development. NMS has an excellent track record of licensing innovative drugs to pharma/biotech companies, including Array (recently acquired by Pfizer), Ignyta (acquired by Roche) and Genentech.

On May 29, 2020 BridgeBio Pharma, Inc. (Nasdaq: BBIO) affiliate QED Therapeutics reported that it will present data at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Virtual Scientific Program showing clinical advancement for infigratinib, QED’s oral FGFR1-3 inhibitor, in both urothelial carcinoma and cholangiocarcinoma (CCA) (Press release, BridgeBio, MAY 29, 2020, View Source [SID1234576229]).

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Title: Infigratinib (BGJ398) in advanced/unresectable or metastatic urothelial carcinoma demonstrates consistent treatment response in both first-line and later-line treatment settings

Abstract: 5038

Presenter: Yung Lyou, City of Hope Comprehensive Cancer Center

An analysis of response rates in patients with advanced/unresectable or metastatic urothelial carcinoma based on the amount of prior lines of treatment showed consistent response to infigratinib. The objective response rate (ORR) for all patients (n=67) was 25% (95% CI 15.5-37.5), while the ORR for patients receiving infigratinib as first-line treatment (n=13) saw a response rate of 31% (95% CI 9.1-61.4) compared to 24% (95% CI 13.5-37.6) for patients receiving infigratinib as a second-line or later treatment (n=54). All eight patients in the study with upper tract urothelial carcinoma (UTUC) received infigratinib as second-line or later therapy. The response rates were higher for patients with UTUC, with an ORR of 50% (95% CI 15.7–84.3) and a disease control rate of 100%. In the study, treatment emergent adverse events occurring in >30% of patients were: hyperphosphatemia (46%), elevated creatinine (42%), fatigue (37%), constipation (37%), anemia (36%), decreased appetite (33%), dry mouth (31%), and alopecia (31%).

"These findings support the design of the ongoing, placebo-controlled PROOF 302 study to evaluate the efficacy of infigratinib in adjuvant urothelial carcinoma," said author and PROOF 302 trial lead Sumanta Pal, MD, professor of medical oncology and therapeutics research at City of Hope Comprehensive Cancer Center. "The results in upper tract urothelial cancer (UTUC) build upon earlier research that the disease has a different genetic profile than urothelial carcinoma of the bladder, particularly with respect to FGFR3 alterations, and warrants further investigation in an even earlier setting."

Title: A retrospective analysis of post second-line chemotherapy treatment outcomes for patients with advanced or metastatic cholangiocarcinoma and FGFR2 fusions

Abstract: 4591

Presenter: Milind M. Javle, MD Anderson Cancer Center

In a retrospective analysis of a subset of a single-arm Phase 2 study of infigratinib (n=37), outcomes from patients with FGFR-fusion-positive bile duct cancer receiving infigratinib as third- and later-line therapy were compared with the tumor response when those same patients received second-line therapy with chemotherapy. Treatment with infigratinib resulted in progression free survival (PFS) improvements. The median PFS was 6.8 months (95% CI 3.9-7.8 months) for third- and later-line infigratinib treatment compared to 4.6 months (95% CI 2.7-7.2 months) for second-line chemotherapy.

"Through this retrospective analysis, we can see that infigratinib may have potential for patients whose tumors progress after second-line chemotherapy," said Susan Moran, MD, MSCE, chief medical officer for QED. "These data support continued investigation of infigratinib in patients with FGFR-driven cholangiocarcinoma."

On May 29, 2020 AstraZeneca reported Detailed results from an updated analysis of the Phase III CASPIAN trial showed Imfinzi (durvalumab) in combination with a choice of chemotherapies, etoposide plus either carboplatin or cisplatin, demonstrated a sustained, clinically meaningful overall survival (OS) benefit for adults with extensive-stage small cell lung cancer (ES-SCLC) treated in the 1st-line setting (Press release, AstraZeneca, MAY 29, 2020, View Source [SID1234558677]).

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The CASPIAN trial met the primary endpoint of OS in June 2019, reducing the risk of death by 27% (based on a hazard ratio [HR] of 0.73; 95% confidence interval [CI] 0.59-0.91; p=0.0047) which formed the basis of the US FDA approval in March 2020.

After a median follow up of more than two years, the latest results for Imfinzi plus chemotherapy showed sustained efficacy, maintaining a 25% reduction in the risk of death versus chemotherapy alone (based on an HR of 0.75; 95% CI 0.62, 0.91; nominal p=0.0032). Updated median OS was 12.9 months versus 10.5 for chemotherapy. In a post-hoc analysis, an estimated 22.2% of patients treated with Imfinzi plus chemotherapy were alive at 24 months versus 14.4% for chemotherapy.

For Imfinzi plus chemotherapy, 11% of patients were alive and progression-free at 24 months versus 2.9% for chemotherapy alone (post-hoc). Imfinzi plus chemotherapy maintained a high confirmed objective response rate (ORR) (68% versus 58%) and in a post-hoc analysis, duration of response (DoR) for Imfinzi at 24 months was 13.5% versus 3.9% for chemotherapy. At 24 months, 12% of patients in the Imfinzi plus chemotherapy arm remained on Imfinzi treatment.

Luis Paz-Ares MD, Ph.D., Chair, Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain and principal investigator in the Phase III CASPIAN trial said: "These updated results from the CASPIAN trial show a remarkable 22% of patients still alive at 24 months, supporting the sustained benefits of treatment with Imfinzi plus chemotherapy. This is an effective 1st-line treatment in the extensive-stage setting, where improving outcomes has been a challenge and so few patients survive five years."

José Baselga, Executive Vice President, Oncology R&D, said: "After two years median follow-up, Imfinzi continues to show sustained and meaningful improvements in survival and prolonged treatment response for patients facing this devastating and aggressive disease. These data reinforce Imfinzi plus chemotherapy as an important new standard of care for extensive-stage small cell lung cancer patients, and this regimen offers patients convenient dosing every four weeks during maintenance. We look forward to bringing the benefits of Imfinzi to patients around the world."

The second experimental arm in the CASPIAN trial testing tremelimumab, an anti-CTLA4 monoclonal antibody, added to Imfinzi and chemotherapy showed a trend towards OS, but did not reach statistical significance compared to chemotherapy alone.

Summary of updated results:

Data cut-off date was 27 January 2020. Formal statistical analysis was completed at the time of the interim analysis per trial protocol. Therefore, no formal testing for statistical significance could be performed in this updated analysis.

i. Etoposide plus investigator choice of carboplatin or cisplatin chemotherapy.
ii. OS rate is an estimated proportion of patients alive at 24 months.
iii. Post-hoc analysis.
iv. Confirmed responses according to investigator assessment per RECIST v1.1.
v. Unconfirmed ORR was a prespecified secondary endpoint per protocol.

The safety and tolerability for Imfinzi plus chemotherapy was consistent with the known safety profile of these medicines. Results showed 62.3% of patients experienced a Grade 3 or 4 adverse event with Imfinzi plus chemotherapy (all causes) versus 62.8% with chemotherapy alone. The percentage of patients discontinuing treatment (all causes) was 10.2% for Imfinzi plus chemotherapy and 9.4% for chemotherapy alone.

Imfinzi in combination with etoposide and either carboplatin or cisplatin is currently under regulatory review for the treatment of ES-SCLC in the 1st-line setting in the EU and Japan.

Updated results from the CASPIAN trial were presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program on 29 to 31 May 2020. Several presentations featured during the meeting will showcase AstraZeneca’s leadership in lung cancer across early and late-stage disease and reinforce the Company’s biomarker-driven approach.

Small cell lung cancer

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and SCLC, with about 15% classified as SCLC.2 SCLC is a highly aggressive, fast-growing form of lung cancer that typically recurs and progresses rapidly despite initial response to chemotherapy.3,4 About two thirds of SCLC patients are diagnosed with extensive-stage disease, in which the cancer has spread widely through the lung or to other parts of the body.5 Prognosis is particularly poor, as only 6% of all SCLC patients will be alive five years after diagnosis.5

CASPIAN

CASPIAN was a randomised, open-label, multi-centre, global, Phase III trial in the 1st-line treatment of 805 patients with ES-SCLC. The trial compared Imfinzi in combination with etoposide and either carboplatin or cisplatin chemotherapy, or Imfinzi and chemotherapy with the addition of a second immunotherapy, tremelimumab, versus chemotherapy alone. In the experimental arms, patients were treated with four cycles of chemotherapy. In comparison, the control arm allowed up to six cycles of chemotherapy and optional prophylactic cranial irradiation. The trial was conducted in more than 200 centres across 23 countries, including the US, in Europe, South America, Asia and the Middle East. The primary endpoint was OS in each of the two experimental arms.

Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after chemoradiation therapy in the US, Japan, China, across the EU and in many other countries, based on the Phase III PACIFIC trial. Imfinzi is approved for the 1st-line treatment of ES-SCLC in combination with chemotherapy in the US and Singapore. Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and a small number of other countries.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, SCLC, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, cervical cancer and other solid tumours.

Tremelimumab

Tremelimumab is a human monoclonal antibody and potential new medicine that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death. Tremelimumab is being tested in a clinical trial programme in combination with Imfinzi in NSCLC, SCLC, bladder cancer, head and neck cancer and liver cancer.

AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines Iressa (gefitinib) and Tagrisso and its ongoing Phase III trials LAURA, and FLAURA2.6-8 We are also committed to addressing tumour mechanisms of resistance through the ongoing Phase II trials SAVANNAH and ORCHARD which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines. Enhertu a HER2-directed antibody drug conjugate is in development for metastatic non-squamous HER2-overexpressing or HER2-mutated NSCLC including trials in combination with other anticancer treatments.

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.9 Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON and PEARL) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials MERMAID-1, AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Imfinzi is also in development in the Phase II trials NeoCOAST, COAST and HUDSON in combination with potential new medicines from the early-stage pipeline including Enhertu.

AstraZeneca’s approach to Immuno-Oncology

Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine the IO portfolio with radiation, chemotherapy, small targeted molecules from across AstraZeneca’s Oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On May 29, 2020 Incyte (Nasdaq:INCY) reported that data from the interim analysis of the Phase 2 OPTIC (Optimizing Ponatinib Treatment In CML) trial, which was sponsored by Takeda and co-funded by Incyte, will be presented during an oral session at the upcoming 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Meeting (ASCO20; May 29 – May 31) (Abstract #7502)1; and at the virtual 25thCongress of the European Hematology Association (EHA) (Free EHA Whitepaper) (EHA25; June 11 – 14) (Abstract #S172)2 (Press release, Incyte, MAY 29, 2020, View Source [SID1234558693]).

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The OPTIC trial is an ongoing randomized, open-label study prospectively evaluating response-based dosing regimens of Iclusig (ponatinib) over a range of three starting doses (45 mg, 30 mg, 15 mg) with the aim of optimizing its efficacy and safety in patients with chronic-phase chronic myeloid leukemia (CP-CML), who are resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. With a median follow up of approximately 21 months, data from the interim analysis of the OPTIC trial show that the optimal benefit-risk profile for Iclusig in patients with CP-CML is achieved with a daily starting dose of 45 mg followed by a dose reduction to 15 mg upon achieving ≤1% BCR-ABL1. This dosing regimen resulted in an adjudicated arterial occlusive event (AOE) rate of 5.3%.

"As a physician, my focus is on treating CP-CML patients in a manner that will provide the best possible outcome by achieving desirable efficacy, while maintaining a manageable safety profile," said Dr. Gianantonio Rosti, M.D., Institute of Haematology and Oncology, St Orsola University Hospital, Bologne. "I believe that patient selection, good management of comorbidities, close monitoring and appropriate dose adjustments are key factors in the management of CP-CML. I am encouraged by these data on the benefit-risk profile that is emerging from the interim OPTIC data of the Iclusig regimen starting at 45 mg, followed by a dose reduction to 15 mg."

"The interim data from OPTIC provide important additional context around the safety profile of Iclusig in appropriate patients with CP-CML." said Luca Marini, M.D., Regional VP, Head of European Medical Affairs, Incyte. "We believe that they may offer additional guidance to healthcare providers on how to optimize treatment with the goal of maintaining efficacy while reducing the risk of arterial occlusive events."

Key findings from the OPTIC interim analysis (IA; cutoff date of July 2019) include:

With median follow-up time of approximately 21 months, 77% (n/N=216/282) of patients in the OPTIC trial were evaluable for the primary endpoint.
The OPTIC IA shows benefit of ponatinib in all three starting doses in a largely resistant population where the majority of patients (>60%) demonstrated less than a complete hematologic response (CHR) to immediate prior therapy.
The maximum rates of ≤1% BCR-ABL1IS at 12 months were achieved in the 45 mg/day starting dose cohort (38.7%), and responses were maintained with the dose reduction to 15 mg/day.
With the protocol-mandated dose reduction for response in the higher dose cohorts, 75% patients in 45 mg cohort and 88% patients in 30 mg cohort were able to maintain ≤1% BCR-ABL1IS response for as long as up to two years.
Safety data as of the IA cutoff date include:
Among all patients (N=282), the most common treatment-emergent adverse events (TEAEs) of any grade (occurring in ≥10% of all patients) were thrombocytopenia (39.4%), neutropenia (25.2%), hypertension (24.1%), anemia (17.4%), headache (17.0%), increased lipase (16.0%), arthralgia (14.2%), constipation (12.4%), platelet count decrease (10.6%) and ALT increase (10.3%).
There was a dose-dependent trend in arterial occlusive event (AOE) rates:
Pre-adjudicated AOEs were reported in (45 mg, 30 mg, 15 mg/day starting dose cohorts) 8.5% (n/N = 8/94), 4.3% (n/N = 4/94), and 2.1% (n/N = 2/94).
Prospective adjudication of AOEs by independent experts resulted in (45 mg, 30 mg, 15 mg/day starting dose cohorts) 5.3% (n/N = 5/94), 4.3% (n/N = 4/94), and 1.1% (n/N = 1/94).
At the IA, there were no AOE-related deaths reported.
The complete primary analysis of the OPTIC trial will be conducted after all patients have at least 12 months of follow-up and will be presented at a later date.
Incyte has an exclusive license from Takeda Pharmaceuticals International AG to commercialize Iclusig in the European Union and 29 other countries, including Switzerland, UK, Norway, Turkey, Israel and Russia. Iclusig is marketed by Takeda Pharmaceuticals International AG in the U.S.

About the OPTIC Trial

OPTIC (Optimizing Ponatinib Treatment In CML) is a randomized, dose-ranging Phase 2 trial designed to evaluate three starting doses (15 mg, 30 mg, 45 mg) of Iclusig (ponatinib) in patients with resistant chronic-phase chronic myeloid leukemia (CP-CML) or who had documented history of presence of T315I mutation after receiving any number of prior tyrosine kinase inhibitors (TKIs). Dose reduction at response occurred per study protocol. The trial is expected to inform the optimal use of Iclusig in these patients. The primary endpoint of the trial is achieving ≤1% BCR-ABL1 at 12 months. Approximately 283 patients were enrolled at clinical sites around the world. Dose reduction at response occurred per study protocol.

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About CML and Ph+ ALL

CML – a rare malignancy – is one of four main types of leukemia; it is a result of a genetic mutation that takes place in early, immature versions of myeloid cells, which form red blood cells, platelets and most types of white blood cells. Subsequently, an abnormal gene called BCR-ABL1 forms, turning the damaged cell into a CML cell. CML typically progresses slowly, but it can change into a fast-growing acute leukemia that is hard to treat.

Ph+ ALL is a rare form of ALL that accounts for one quarter of adult ALL cases. and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome positive (Ph+), an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR-ABL1 and is associated with Ph+ ALL.

About Iclusig (ponatinib) Tablets

Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

Iclusig is approved in the U.S., EU, UK, Australia, Switzerland, Israel and Canada.

In the EU, Iclusig is approved for the treatment of adult patients with chronic phase, accelerated phase or blast phase chronic myeloid leukemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation, or the treatment of adult patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.