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In the Phase III CASPIAN trial Imfinzi at a fixed, convenient dose improved survival with either a cisplatin or carboplatin chemotherapy backbone

On September 9, 2019 AstraZeneca reported detailed results from the Phase III CASPIAN trial, showing Imfinzi (durvalumab) significantly improved overall survival (OS) in patients with previously-untreated extensive-stage small cell lung cancer (SCLC) (Press release, AstraZeneca, SEP 9, 2019, View Source [SID1234539373]).

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Imfinzi in combination with four cycles of standard-of-care (SoC) chemotherapy (etoposide with either cisplatin or carboplatin) demonstrated a statistically-significant and clinically-meaningful improvement in OS vs. SoC consisting of up to six cycles of chemotherapy and optional prophylactic cranial irradiation (PCI).

The risk of death was reduced by 27% (equal to a hazard ratio of 0.73), with median OS of 13.0 months for Imfinzi plus chemotherapy vs. 10.3 months for SoC. Results showed a prolonged OS benefit with an estimated 33.9% of patients alive at 18 months following treatment with Imfinzi plus chemotherapy vs. 24.7% of patients following SoC.

Across all efficacy endpoints, benefits were observed in patients treated with Imfinzi plus chemotherapy vs. SoC. Results showed a significantly higher progression-free survival (PFS) rate at 12 months (17.5% vs. 4.7%), a 10.3% increase in confirmed objective response rate (ORR) (67.9% vs. 57.6%), and improved duration of response (DOR) at 12 months (22.7% vs. 6.3%).

The results were presented at the Presidential Symposium of the IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer in Barcelona, Spain.

José Baselga, Executive Vice President, Oncology R&D said: "We are encouraged to see more than a third of small cell lung cancer patients treated with Imfinzi plus chemotherapy alive at the 18-month landmark, which is remarkable given the aggressive nature of the disease. It is also noteworthy that these results may enable physicians to choose Imfinzi in combination with either cisplatin or carboplatin chemotherapy backbones. We look forward to working with regulatory authorities to bring Imfinzi to patients with small cell lung cancer around the world as soon as possible."

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: "Patients have had limited treatment options for small cell lung cancer, a devastating disease where the five-year survival rate has been as low as 6%. The significant survival benefit demonstrated with Imfinzi combined with only four cycles of a choice of chemotherapy compared to a robust control arm, provides evidence and hope of a new treatment option for these patients."

SCLC is an aggressive, fast-growing cancer that recurs and progresses rapidly despite initial response to platinum-based chemotherapy.1

i Etoposide plus investigator choice of cisplatin or carboplatin chemotherapy.

ii The data cut-off date for analysis of OS, PFS and ORR was 11 March 2019.

iii PFS was not formally tested for statistical significance.

iv Confirmed responses according to investigator assessment per RECIST v1.1.

The safety and tolerability of Imfinzi in combination with SoC etoposide and platinum-based chemotherapy was consistent with previous trials. Results showed that 61.5% of patients experienced a Grade 3 or 4 AE with Imfinzi plus SoC (all causes) vs. 62.4% with SoC, and patients discontinuing treatment due to AEs were similar between arms (9.4% vs. 9.4%).

Imfinzi is also being tested following concurrent chemoradiation therapy in limited-stage SCLC in the Phase III ADRIATIC trial.

Imfinzi is approved in the curative-intent setting of unresectable, Stage III non-small cell lung cancer after chemoradiotherapy in 49 countries, including the US, Japan and across the EU, based on the Phase III PACIFIC trial.

About CASPIAN

The CASPIAN trial is a randomised, open-label, multi-centre, global, Phase III trial in the 1st-line treatment of patients with extensive-stage SCLC. The trial compared Imfinzi in combination with etoposide and either cisplatin or carboplatin chemotherapy, or Imfinzi, tremelimumab and chemotherapy vs. chemotherapy alone. In the experimental arms, patients were treated with up to four cycles of chemotherapy. In comparison, the control arm allowed up to six cycles of chemotherapy and optional PCI. The trial will continue to the final analysis of OS for the combination of Imfinzi, tremelimumab and chemotherapy.

The trial is being conducted in more than 200 centres across 22 countries, including in the US, Europe, South America, Asia and the Middle East. The primary endpoint is OS.

About 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.2 Lung cancer is broadly split into NSCLC and SCLC, with about 15% classified as SCLC.3 About three quarters 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. Prognosis is particularly poor, as only 6% of all SCLC patients will be alive five years after diagnosis.4

About 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 also approved for previously-treated patients with advanced bladder cancer in 10 countries, including the US.

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, small cell lung cancer, bladder cancer, head and neck cancer, liver cancer, cervical cancer, biliary tract cancer and other solid tumours.

About AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of different forms of lung cancer spanning 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 our approved medicines Iressa (gefitinib) and Tagrisso (osimertinib), and ongoing Phase III trials ADAURA, LAURA, FLAURA and FLAURA2 as well as the Phase II combination trials SAVANNAH and ORCHARD.5-7

Our extensive late-stage Immuno-Oncology programme focuses on lung cancer patients without a targetable genetic mutation which represents approximately three-quarters of all patients with lung cancer.8 Imfinzi (durvalumab), an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON, PEARL, and CASPIAN) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials AEGEAN, PACIFIC-2, ADRIATIC, ADJUVANT BR.31, PACIFIC-4, and PACIFIC-5) both as monotherapy and in combination with tremelimumab and/or chemotherapy.

About AstraZeneca’s approach to Immuno-Oncology (IO)

IO is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. Our IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. We believe that IO-based therapies offer the potential for life-changing cancer treatments for the clear majority of patients.

We are pursuing a comprehensive clinical-trial programme that includes Imfinzi (anti-PDL1) as monotherapy and in combination with tremelimumab (anti-CTLA4) in multiple tumour types, stages of disease, and lines of therapy, 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 our IO portfolio with radiation, chemotherapy, small targeted molecules from across our Oncology pipeline, and from our research partners, may provide new treatment options across a broad range of tumours.

About 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 at least six new medicines to be 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 investments 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.

Kitov Pharma Presents Newly Released Data for NT-219 in Reversing Pancreatic Cancer Drug Resistance

On September 9, 2019 Kitov Pharma Ltd. ("Kitov") (NASDAQ/TASE: KTOV), a clinical-stage company advancing first-in-class therapies to overcome tumor immune evasion and drug resistance, reported newly released proof-of-concept data showing evidence of NT-219 mechanism of action in reversing cancer drug resistance in PDX models (Press release, Kitov Pharmaceuticals , SEP 9, 2019, View Source [SID1234539372]). The data was presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)’s (AACR) (Free AACR Whitepaper) Pancreatic Cancer: Advances in Science and Clinical Care conference in Boston on September 8, 2019.

NT-219 is a first-in-class small molecule bi-specific inhibitor of two key cancer resistance pathways STAT3 and IRS1/2. As previously disclosed, the preclinical study initially evaluated the efficacy of NT-219 in combination with the approved chemotherapy agent gemcitabine on four PDX models of mutated KRAS pancreatic cancer. Data demonstrated reversal of gemcitabine-resistant tumors in all PDX models following treatment with NT-219 and gemcitabine. One of these models demonstrated complete response in about half of the animal group upon addition of NT-219 to gemcitabine. The study was then extended to define an optimal dose regimen and future clinical protocol.

Newly released data from the NT-219 poster showed:

●The combination of NT-219 with the targeted therapies trametinib (MEK inhibitor) or folfirinox (chemotherapy) reversed tumor resistance to the treatments.

●Administering NT-219 prior to chemotherapy suppressed activation of two key cancer survival pathways, STAT3 and IRS. The sequence of administering the therapies had a remarkable impact on the efficacy of NT-219 in reversing resistance.

●Gene expression analysis of the tumors in a PDX model of KRAS mutated pancreatic cancer revealed an average 80% reduction in IRS1 levels compared to the control group following a single treatment with NT-219 and gemcitabine combined therapy. Similar reductions were observed in the expression of STAT3-regulated genes and the proliferation marker Ki67, confirming NT-219 mechanism of action.

●A dose-dependent therapeutic effect of NT-219 was demonstrated on tumor-growth and correlated with NT-219 levels in plasma.

"STAT3 and IRS play an important role in KRAS-induced pancreatic tumorigenesis and drug resistance. Demonstrating efficacy of NT-219 in pancreatic cancer models is in line with previous results in other cancer types. We believe that targeting IRS and STAT3 may be a tumor-agnostic solution to combat resistance to multiple oncology drugs," said Hadas Reuveni, PhD, VP Research and Development of Kitov. "NT-219 is a first-in-class small molecule which suppresses both targets using a unique mechanism of action, and is crucial for overcoming cancer drug resistance."

"We are encouraged by the results of the study which demonstrate the potential of NT-219 to reverse resistance to oncology therapies in a wide range of PDX models. We plan to clinically explore its efficacy in multiple hard-to-treat oncology indications including squamous cell carcinoma of the head and neck in a planned clinical study to be launched soon. We are also exploring its potential in pancreatic cancer," said Isaac Israel, CEO of Kitov. "Resistance to chemotherapy and targeted therapies is a major problem facing oncology patients. Kitov is now strategically focused on developing first-in-class oncology therapies, including such which are targeted to overcome drug resistance and tumor immune evasion, and to ultimately provide patients long-lasting treatment alternatives."

Kitov plans to submit an Investigational New Drug Application (IND) to the U.S Food and Drug Authority (FDA) for a clinical study on NT-219 in combination with cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck before the end of 2019, and to initiate the trial immediately following FDA’s clearance.

The poster is available on the "Investor Relations" section on the Kitov website: View Source

Genmab and Tempus Enter into Strategic Collaboration Agreement

On September 9, 2019 Genmab A/S (Nasdaq: GMAB) reported that it has entered into a strategic collaboration agreement with Tempus, a privately-owned technology company advancing precision medicine through the practical application of artificial intelligence in healthcare (Press release, Genmab, SEP 9, 2019, View Source [SID1234539371]). The multi-year collaboration will combine Tempus’ sequencing capabilities and industry-leading platform of integrated clinical and molecular data with Genmab’s state-of-the-art translational, biomarker and target discovery expertise. The companies will work together, based upon novel insights identified by Genmab, to advance new disease targets and biomarkers that may have the potential to generate new treatments in oncology.

This new strategic collaboration builds upon existing service agreements between the companies. Under the terms of the collaboration agreement, the companies will jointly work on research projects that are identified by Genmab to explore novel product concepts and biomarkers. For any resulting products, Genmab will lead all development and commercial activities. Tempus will be eligible for undisclosed milestones and royalties from Genmab and will also have the option to fund part of product development programs in exchange for increased royalty payments due to Tempus under the agreement.

"Tempus has built the world’s largest library of clinical and molecular data, is a leader in the field of personalized medicine and like Genmab, Tempus has a mission to improve the lives of cancer patients. We are looking forward to expanding our exciting partnership with them and to the possibility of discovering important new oncology targets and biomarkers," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Today’s news does not impact Genmab’s 2019 Financial Guidance.

Lilly Announces Positive Results for Selpercatinib (LOXO-292), Demonstrating a 68 Percent Objective Response Rate and Sustained Durability in Heavily Pretreated RET Fusion-Positive Non-Small Cell Lung Cancer

On September 9, 2019 Eli Lilly and Company (NYSE: LLY) reported data from the LIBRETTO-001 clinical trial intended to support the registration of oral selpercatinib[1] monotherapy, also known as LOXO-292, for the treatment of RET fusion-positive non-small cell lung cancer (NSCLC) (Press release, Eli Lilly, SEP 9, 2019, View Source [SID1234539370]). In the registration dataset consisting of the first 105 enrolled RET fusion-positive NSCLC patients with prior platinum-based chemotherapy, selpercatinib treatment resulted in a 68 percent objective response rate (ORR) (95% CI: 58-76%). This population was heavily pretreated (median of three prior systemic regimens; 55 percent previously treated with an anti-PD-1/PD-L1 antibody and 48 percent previously treated with at least one multikinase inhibitor) and ORR was similar regardless of prior therapy. Up to 50 percent of RET fusion-positive NSCLCs can metastasize to the brain, and in the subset of patients with brain metastases in the registrational dataset, selpercatinib treatment demonstrated a CNS (Central Nervous System) ORR of 91 percent (95% CI: 59-100%).

As of the data cut-off date of June 17, 2019, median duration of response (DOR) was 20.3 months (95% CI: 13.8-24.0) and median progression-free survival (PFS) was 18.4 months (95% CI: 12.9-24.9). Since the majority of patients remain in response or progression-free as of the data cut-off date, these medians will continue to mature over time. In a safety analysis of all 531 patients enrolled to LIBRETTO-001, selpercatinib was well-tolerated, with only 9 patients (1.7%) discontinuing therapy due to treatment-related toxicity. The most commonly observed adverse events, regardless of attribution, were dry mouth, diarrhea, hypertension, increased liver enzymes, fatigue, constipation, and headache. These results were presented in the Presidential Symposium Session at the 2019 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, hosted by the International Association for the Study of Lung Cancer (IASLC). Selpercatinib has received breakthrough therapy designation from the U.S. Food and Drug Administration.

"In this large cohort, selpercatinib’s response rate, durability, robust CNS activity, and safety show promise. Furthermore, this continues to confirm that RET fusions are clinically targetable alterations, placing them in the company of activating EGFR/ALK/ROS1 alterations. We are encouraged by these data as there is currently an unmet need to provide genomically-tailored therapy to patients with RET fusion-positive NSCLCs," said Alexander Drilon, M.D., lead investigator, Memorial Sloan Kettering Cancer Center in New York City.

Additional Data in Treatment-Naïve RET Fusion-Positive NSCLC Patients
Investigators also presented the results of selpercatinib in treatment-naïve RET fusion-positive NSCLC patients. In this analysis of 34 patients, selpercatinib treatment resulted in an 85 percent ORR (95% CI: 69-95%). Median DOR and PFS were not reached in this treatment-naïve population, as the majority of patients remain in response or progression-free.

"We’re seeing the importance of precision medicines, designed for specific patients, grow in oncology," said Anne White, president of Lilly Oncology. "The data from LIBRETTO-001 show that selpercatinib, also known as LOXO-292, represents an important new advance for patients with RET fusion-positive non-small cell lung cancer, emblematic of the kinds of new oncology medicines we hope to continue to bring forward at Lilly Oncology. We’re very excited to partner with Loxo Oncology to continue to accelerate this important medicine. In two and half years, Loxo Oncology advanced this molecule from first human dose to submission ready data, demonstrating the power of precision oncology to rapidly translate scientific discovery into treatments for patients."

"When we first started the selpercatinib discovery program, we hoped to build a RET inhibitor that would deliver for patients with RET-altered cancers in the way that medicines such as osimertinib and alectinib have delivered for EGFR-mutated and ALK-fusion patients, respectively. We believe that the selpercatinib data presented at World Lung validate these efforts," said Josh Bilenker, M.D., interim senior vice president of oncology research and early phase development at Lilly, and CEO of Loxo Oncology, a wholly owned subsidiary of Lilly. "We look forward to submitting the NDA later this year, and should selpercatinib receive regulatory approval, patients with RET fusion-positive NSCLC will finally have their first genomically-guided medicine."

Trial Background
The LIBRETTO-001 Phase 1/2 trial is the largest clinical trial of patients with RET-altered cancers treated with a RET inhibitor. The trial includes a dose escalation phase (Phase 1) and a dose expansion phase (Phase 2). The Phase 2 portion of the trial had a primary endpoint of objective response rate (ORR) and secondary endpoints of duration of response, progression free survival and safety. The primary analysis set for NSCLC regulatory submissions, as defined with the U.S. Food and Drug Administration, consists of the first 105 enrolled patients with RET fusion-positive non-small cell lung cancer who have experienced prior platinum-based chemotherapy. All data presented at WCLC were as of a data cut-off date of June 17, 2019, and all efficacy measures utilized investigator assessments.

About Selpercatinib (LOXO-292)
Selpercatinib, also known as LOXO-292, is a highly selective and potent, oral investigational new medicine 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. Selpercatinib was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms.

Selpercatinib has received breakthrough designation for the treatment of patients with:

Metastatic RET fusion-positive non-small cell lung cancer who require systemic therapy and have progressed following platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 therapy;
RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options; and for
Advanced RET-fusion-positive thyroid cancer who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options.
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 percent of non-small cell lung cancer, 10-20 percent of papillary and other thyroid cancers and a subset of other cancers. Activating RET point mutations account for approximately 60 percent of MTC. RET fusion-positive 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.

Avelas Biosciences to Present at Upcoming Conferences in September

On September 9, 2019 Avelas Biosciences, Inc., a clinical-stage oncology company developing AVB-620 for real-time cancer detection, reported that it will be presenting at two upcoming conferences in the month of September (Press release, Athenex, SEP 9, 2019, View Source [SID1234539369]).

Plastic Surgery The Meeting, September 19-23, 2019

Dr. Steven Chen, Avelas’ Chief Medical Officer, will be participating in a "Hot Topics" session at the 88th Annual Plastic Surgery The Meeting on Thursday, September 19, 2019, in San Diego, CA. The session will discuss the latest cutting-edge research and applied technology of interest to plastic surgeons.

The MedTech Conference, September 23-25, 2019

On Tuesday, September 24, 2019, Jay Lichter, Avelas’ Chief Executive Officer, will be participating in the MedTech Innovator Showcase (Oncology) panel session at The MedTech Conference in Boston, MA. The session will be held in Hall B, 500 Aisle from 10:30-11:00am.

As part of its participation in the MedTech Showcase program, Avelas has also submitted a pitch video to the MedTech Innovator Best Video Competition. Avelas’ video can be viewed below.

Throughout the three-day conference, Avelas will be available for partnering. Interested parties may reach out to the company through The MedTech Connect networking platform or directly contact Will Stratton, Avelas’ Head of Business Development ([email protected]).