On September 11, 2017 Ionis Pharmaceuticals, Inc. (NASDAQ: IONS) reported that new data from the clinical program for IONIS-STAT3-2.5Rx (AZD9150) were presented at the 2017 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress. The presentation included clinical and safety results from the Phase 1b/2 study evaluating the activity of IONIS-STAT3-2.5Rx in combination with Imfinzi (durvalumab), AstraZeneca’s programmed death ligand (PD-L1) blocking antibody, in patients with advanced solid tumors and recurrent metastatic head and neck cancer (Press release, Ionis Pharmaceuticals, SEP 11, 2017, View Source [SID1234520469]). In the study, the combination treatment resulted in encouraging antitumor activity with a safety and tolerability profile supportive of continued development.

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"Today’s positive data with IONIS-STAT3-2.5Rx are exciting, demonstrating robust activity that is comparable to other promising late-stage checkpoint inhibitor combination therapies for cancer. We continue to be encouraged by the substantial antitumor activity of our Generation 2.5 antisense drugs. Our Generation 2.5 chemistry increases the potency of our antisense drugs, thereby creating opportunities for drugs like IONIS-STAT3-2.5Rx to be effective in targeting more diseases with high unmet need, such as cancers," said Brett Monia, Ph.D., senior vice president of drug discovery and franchise leader for oncology and rare diseases at Ionis Pharmaceuticals. "We are enthusiastic about the broad clinical program AstraZeneca is conducting to evaluate the potential of combining our antisense drugs with immunotherapy approaches to deliver potent and targeted treatment options to patients stricken with various cancers."

"We are encouraged by the anti-tumor activity and safety profile observed in patients with head and neck cancer with AZD9150 in combination with Imfinzi," said Susan Galbraith. M.B., B.Chir., Ph.D. senior vice president and head of oncology innovative medicines unit at AstraZeneca. "We believe this combination therapy supports further study in this group as well as patients with other cancers."

Results from the study were presented at the 2017 ESMO (Free ESMO Whitepaper) Annual Congress in an oral presentation titled, "Phase 1b/2 Study (SCORES) Assessing Safety, Tolerability, and Preliminary Anti-tumor Activity of Durvalumab Plus AZD9150 or AZD5069 in Patients With Advanced Solid Tumors and Refractory and Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (R/M-SCCHN)." In the study, combination therapy with IONIS-STAT3-2.5Rx and Imfinzi in 28 PD-L1 treatment naïve patients with R/M-SCCHN resulted in encouraging antitumor activity and deep responses to treatment. The treatment combination demonstrated a 29% (8/28) objective response rate with four partial responses (PR) and four complete responses (CR), of which one was a CR in target lesions only. An additional eight patients on the treatment combination had stable disease (SD) at 12 weeks, resulting in an overall disease control rate of 57% (16/28). Importantly, a complete response was seen in a patient with R/M-SCCHN that was refractory to previous PD-L1 treatment. Combination therapy with IONIS-STAT3-2.5Rx and Imfinzi demonstrated a manageable safety profile. The most common drug-related adverse events occurred infrequently and were similar to those observed with other drugs targeting the JAK/STAT pathway, including mild liver enzyme increases, mild platelet count decreases and mild anemia.

The Phase 1b/2 study is currently ongoing and enrolling an additional treatment group. AstraZeneca is also currently evaluating IONIS-STAT3-2.5Rx in combination with Imfinzi in patients with diffuse large B cell lymphoma.

About IONIS-STAT3-2.5Rx
IONIS-STAT3-2.5Rx, also referred to as AZD9150, is a Generation 2.5 antisense drug designed to reduce the production of signal transducer and activator of transcription 3, or STAT3, for the treatment of patients with cancer. STAT3 is a protein involved in the translation of key factors critical for tumor cell growth and survival and is an important factor in immune cells of the tumor microenvironment where it contributes to the ability of tumors to evade the host immune system. STAT3 is over-active in a variety of cancers, including brain, lung, breast, bone, liver and multiple myeloma.

Ionis licensed IONIS-STAT3-2.5Rx to AstraZeneca for the treatment of cancer. AstraZeneca is currently evaluating IONIS-STAT3-2.5Rx in combination with Imfinzi, AstraZeneca’s programmed death ligand (PDL1) blocking antibody, in multiple Phase 2 studies, including in patients with head and neck cancer in patients with diffuse large B cell lymphoma.

On September 11, 2017 OncoCyte Corporation (NYSE American:OCX), a developer of novel, non-invasive liquid biopsy tests for the early detection of cancer, reported that data from its most recent breast cancer diagnostic study has been selected for presentation in a poster session at the 2017 San Antonio Breast Cancer Symposium (SABCS) (Press release, BioTime, SEP 11, 2017, View Source [SID1234520468]). The SABCS will take place at the Henry B. Gonzalez Convention Center in San Antonio, Texas, from December 5-9, 2017.

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The data to be presented are from the Company’s NICE-BC (Non-Invasive Confirmatory dEtection (of) Breast Cancer follow-on study. The data confirm the findings from OncoCyte’s previous breast cancer study, which were presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2016. In the earlier study, the 15-marker model resulted in an area under the curve (AUC) of 0.92 with a sensitivity of 90% and specificity of 76%. Given this level of accuracy, and subject to successful completion of further R&D and clinical studies, OncoCyte’s novel panel of serum protein biomarkers may become the foundation of a highly accurate, non-invasive breast cancer diagnostic test.

The AUC of a test is a measure that combines sensitivity and specificity to express its total accuracy, with 1.0 being perfect accuracy and 0.50 being a random result. Sensitivity and specificity are statistical measures of test performance, with sensitivity measuring the percentage of malignant lumps or masses that are identified correctly by the test and specificity measuring the percentage of benign lumps or masses correctly identified.

"The presentation of data from our ongoing breast cancer diagnostic studies is another important step in the development of our non-invasive breast cancer diagnostic test," said William Annett, President and Chief Executive Officer. "There is a significant unmet need for a confirmatory breast cancer test that would reduce the number of unnecessary invasive biopsies and lower the financial burden to the healthcare system. We look forward to continued development of this important program."

The data from the NICE-BC study will be presented at SABCS 2017 by Philip McQuary, Ph.D., Director of Product Development at OncoCyte.

Abstract Title: Assessment of an immune response panel of serum protein biomarkers for the non-invasive detection of breast cancer
Poster Session: 4
Session Title: Detection/Diagnosis: Circulating Markers
Session Date: December 7, 2017
Session Time: 7:00 am CT – 9:00 am CT

The current standard of care for breast cancer diagnosis – annual or biannual mammogram screenings – does not meet the needs of large populations of women for whom mammography alone is not sufficient. These populations include women with dense breast tissue, genetic mutations (BRCA), a family history of breast cancer, or those who have suspicious mammogram screening results (BIRADs 3 or 4). The Company’s non-invasive liquid biopsy breast cancer diagnostic is intended to be a confirmatory, post-mammogram test that would address the needs of some of these populations, thereby reducing the number of patients subjected to invasive procedures.

According to published reports, there are about 39 million mammograms performed annually in the U.S., resulting in 1.6 million breast biopsies per year. Of these, only 260,000 (16%) result in a cancer diagnosis. The large number of suspicious findings in diagnostic mammograms leads to a significant amount of unnecessary invasive follow-up procedures. The financial burden to the healthcare system imposed by the follow-up testing of false-positive mammograms and breast cancer over-diagnosis is estimated to be $4 billion a year.

About Breast Cancer

Breast cancer is the second most common cancer among US women. Current screening guidelines set forth by the American Cancer Society recommend screening mammography for the early detection of breast cancer in women at average risk. Specifically, guidelines call for annual mammography for asymptomatic women age 45 to 54 and once every two years for women age 55 and older. Suspicious screening mammograms are generally followed up with a diagnostic mammogram and sometimes by an MRI (Magnetic Resonance Image) or an ultrasound. Ultimately, suspicious findings unresolved by imaging typically result in the recommendation of a breast biopsy.

On September 11, 2017 Inovio Pharmaceuticals, Inc. (NASDAQ:INO), reported that an interim data analysis showed that its INO-5150 cancer immunotherapy product generated antigen-specific CD8+ killer T cell responses measured in peripheral blood from subjects with biochemically recurrent prostate cancer (Press release, Inovio, SEP 11, 2017, View Source;In-Patients-with-Recurrent-Prostate-Cancer/default.aspx [SID1234520467]). The immunology results demonstrate that INO-5150 treatment as a monotherapy generated prostate specific antigen (PSA) and prostate specific membrane antigen (PSMA) specific T cell responses in peripheral blood in 60% (35/58) of the subjects. Moreover, patients with specific CD8+ T cell responses experienced dampening in the rise of PSA and significant increases in PSA Doubling Times (PSADT). PSA is a prostate cancer associated biomarker and positive changes on PSA levels could signal INO-5150’s potential positive impact on the treatment of prostate cancer.

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These results were presented as a poster discussion on September 10th at the 2017 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) meeting in Madrid, Spain.

Dr. Neil Shore, MD, Medical Oncologist at Urologic Associates of North Carolina, and the principal investigator of this study said, "Immunotherapy is an exciting new approach being evaluated for the treatment of many cancers including prostate cancer, where a small subset of patients have been shown to demonstrate clinical benefit from such therapy in the form of checkpoint inhibitors. Our study provides encouraging immunologic and clinical data that Inovio’s immunotherapy product can generate antigen-specific CD8+ killer T cell responses in the blood and link such responses to PSA changes in prostate cancer patients. Our results suggest that further evaluation of this product in prostate cancer patients should be explored."

Dr. J. Joseph Kim, Inovio’s President and CEO, said, "As a leader in active immunotherapy for cancer with its lead program in phase 3, Inovio is pleased to report on promising phase 1b clinical trial data of our prostate cancer therapy INO-5150. The immunotherapy’s ability to generate anti-prostate cancer CD8+ T cell responses in patients dosed is truly exciting. Perhaps even more importantly, we also observed that the treated patients with better T cell responses saw a slower rise of PSA levels compared to those without the T cell responses.

We believe the new clinical data positions INO-5150 as an attractive T cell generating immunotherapy component of a potential combination regimen. In this regard, Inovio already has one the most extensive and dynamic T cell immunotherapy combo portfolio in our field, with three different PD-1/PDL-1 immuno-oncology combo efficacy studies with 3 different collaborators – MedImmune, Regeneron, and Genentech for MEDI0457 and INO-5401."

INO-5150, an active immunotherapy targeting both PSA and PSMA antigens which are present in the majority of prostate cancer cells, is administered with and without INO-9012, Inovio’s DNA-based IL-12 immune activator. INO-5150 is designed to activate patients’ immune responses and to specifically target prostate cancers expressing PSA and PSMA. This open label phase 1b study has fully enrolled 62 subjects with biochemically recurrent (rising PSA) prostate cancer and is intended to assess the safety, tolerability, dosing and immunogenicity of INO-5150 alone or in combination with INO-9012. This multi-centered study is also evaluating changes in PSA levels and kinetics, as PSA is an important biomarker in prostate cancer.

INO-5150 was generated using Inovio’s proprietary technology process to enable significant production of PSA and PSMA antigens with genetic sequences differentiated from native human PSA and PSMA sequences. This patented approach is designed to help the body’s immune system overcome its "self-tolerance" to prostate cancer cells and mount a strong targeted CD8+ killer T cell response to eliminate the cancerous cells displaying these antigens. PSMA is also one of 3 antigens comprising INO-5401, which is being tested as an immunotherapy to treat glioblastoma multiforme and metastatic bladder cancer in combination with Regeneron and Genentech’s checkpoint inhibitors, respectively.

This poster presentation provided immune response and clinical correlation across all four cohorts. In addition to immune responses, clinical correlative analyses evaluating PSA kinetics showed that patients with specific CD8+ T cell responses experienced dampening in the rise of PSA and significant increases in PSADT. Additional prostate cancer tissue analyses are ongoing to further investigate immunological correlation.

About Prostate Cancer and Biochemically Recurrent Prostate Cancer (BRPC)

Prostate cancer is the second most frequently diagnosed cancer in men. Nearly three-quarters of the registered cases occur in developed countries. Accounting for nearly 300,000 deaths each year, prostate cancer is the sixth leading cause of death from cancer in men. There are about 60,000 patients each year in the US that develop biochemically recurrent prostate cancer (BRPC). The development of a new treatment for prostate cancer would be a significant medical advance given that current standard-of-care treatment options (surgery, radiation and hormone deprivation), while somewhat effective, all carry deleterious side effects and are often not a long-term cure.

On September 11, 2017 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that new preclinical data for its first-in-class clinical stage antibodies IPH5401 and monalizumab, were presented at the 3rd CRI-CIMT-EATI-AACR International Cancer Immunotherapy conference, September 6 – 9, 2017, in Frankfurt, Germany (Press release, Innate Pharma, SEP 11, 2017, View Source [SID1234520466]).

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Poster #B184 shows the selective expression of C5aR on myeloid-derived suppressor cells (MDSC) and neutrophils. These cells accumulate within the tumor microenvironment and secrete pro-angiogenic factors which promote tumor progression. They also inhibit NK and T cells and suppress anti-tumor immunity.

In this poster, the data demonstrate that IPH5401 selectively inhibits the activation of neutrophils. Moreover, the data show that the combined administration of anti-C5aR with anti-PD-1 reduced tumor growth. Taken together, these data suggest that C5aR blockade may result in a more permissive environment for immune-mediated tumor killing and treatment with checkpoint inhibitors.

Poster #A130 demonstrates that blocking both NKG2A/HLA-E and PD-1/PD-L1 pathways enhance anti-tumor efficacy of CD8+ T cells. The data show that the deletion of either NKG2A (Qa-1b) or PD-L1 significantly delays tumor growth, suggesting that both receptors are involved in the immune-escape of tumors. Combined PD-L1 and NKG2A blockade achieved a complete response of 82%, compared to 54% for anti-PD-L1 and 36% for anti-NKG2A alone. CD8+ tumor infiltrated lymphocytes (TILs) expressing high levels of PD-1 co-expressed high levels of NKG2A, raising the possibility that NKG2A blockade may potentiate PD-1/PD-L1 blockers by directly enhancing CD8+ T cell-mediated killing of tumors.

Yannis Morel, Executive Vice President Products Portfolio Strategy of Innate Pharma, said: "We are encouraged by the preclinical data for IPH5401, which further support the development of this first-in-class anti-C5aR antibody especially in combination with PD‑1/PD‑L1 checkpoint inhibitors. We look forward to start clinical trials in oncology with IPH5401 in 2018.

In addition, preclinical data indicate that NKG2A blockade in conjunction with PD-L1 blockade enhances anti-tumor efficacy of CD8+ T cells and provide further evidence to support the ongoing clinical trial evaluating monalizumab, Innate’s first-in-class NKG2A checkpoint inhibitor, in combination with durvalumab, AstraZeneca/Medimmune’s PD-L1 checkpoint inhibitor."

Poster #B184 and Poster A#130 are available on Innate Pharma’s website.

On September 11, 2017 Ignyta, Inc. (Nasdaq:RXDX), a biotechnology company focused on precision medicine in oncology, provided an update on entrectinib—an orally bioavailable, CNS-active tyrosine kinase inhibitor being developed in tumors that harbor NTRK fusions or ROS1 fusions, currently being studied in a registration-enabling Phase 2 clinical trial known as STARTRK-2—and RXDX-105—an investigational, VEGFR-sparing, potent RET inhibitor (Press release, Ignyta, SEP 11, 2017, View Source [SID1234520465]).

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"Building on last week’s announcement of the completion of enrollment of the entrectinib efficacy data set for NDA submission in ROS1 fusion-positive non-small cell lung cancer, we are equally excited to also have completed enrollment of the efficacy data set for NDA submission in the NTRK tissue-agnostic indication," said Jonathan Lim, M.D., chairman and CEO of Ignyta. "We look forward to dual registration submissions in 2018 for these two independent, high unmet need, molecularly defined populations."

Entrectinib program updates:

Based on written feedback from the FDA, Ignyta confirms completion of enrollment of the efficacy data sets for both the NTRK tissue-agnostic (i.e., fusion-positive solid tumor) cohort and the ROS1 NSCLC cohort to support dual NDA submissions in 2018.
No additional studies were requested for these submissions.
Entrectinib was intentionally designed to cross the blood-brain barrier and has demonstrated CNS activity. Specific guidance was provided by FDA on inclusion of entrectinib CNS efficacy data in future prescribing information for both NTRK and ROS1.
An update on data from STARTRK-2 on entrectinib in ROS1 NSCLC, including an additional six months of follow-up, will be presented at the International Association for the Study of Lung Cancer (IASLC) 18th World Conference on Lung Cancer (WCLC) in Yokohama, Japan October 18, 2017. Previous interim data were shared in an investor update call in April 2017.
Additionally, a recent joint meeting with the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation Research (CDER) on companion diagnostic strategy for entrectinib confirms the premarket approval submission plan and timeline for Trailblaze Pharos are tracking with the dual NDA submissions in NTRK and ROS1.
RXDX-105 program updates:

New Phase 1b clinical data on RXDX-105 presented this week at the ESMO (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain demonstrated clinical activity in RET fusions and compelling response rate in an ultra-rare lung cancer population.

Safety –

A total of 152 patients, with a range of solid tumors, have been treated in the Phase 1/1b clinical trial, including 74 patients treated at the recommended Phase 2 dose of 275mg daily in the fed state, and 43 patients treated at a dose of 350mg daily in the fed state.
RXDX-105 continues to be well tolerated, with the most common treatment-related adverse events Grade 1 or 2 and reversible with dose modifications. The most common Grade 3 treatment-related adverse events ( > 5 percent) were rash (10 percent), hypophosphatemia (7 percent) and elevated ALT (7 percent).
Importantly, toxicities commonly associated with VEGFR inhibition, such as hypertension, hypothyroidism, proteinuria and neurotoxicity were rarely observed ( < 5 percent); and RXDX-105 was not associated with Qt/QTc prolongation.
Efficacy –

Of those treated, 22 patients had NSCLC harboring RET fusions and were RET inhibitor naïve, making them evaluable for response.
A preliminary objective response rate of 75 percent was observed in patients with non-KIF5B-RET fusions, with six of eight patients achieving a confirmed partial response. In contrast, those with KIF5B-RET fusions (14 patients) did not demonstrate a RECIST response. These data are consistent with previous studies that suggest that KIF5B-RET fusions may be less susceptible to RET inhibition.
The longest duration of response (DOR) in a responding patient with non-KIF5B-RET fusion was 10.2 months and ongoing; two-thirds of responding patients currently continue on treatment in active response; median DOR therefore has not yet been reached.
Development plan –

This robust clinical trial design has employed next generation sequencing to identify the precise patient populations most likely to benefit from RXDX-105 – those with non-KIF5B-RET fusions – which is estimated to be approximately 800 new patients per year in the United States.
The RXDX-105 Phase 1b study will be concluded with no further enrollment. Those currently receiving treatment will remain on study.
Ignyta will continue discussing RXDX-105 with potential partners and will provide an update on this program in the first half of 2018.