On December 12, 2019 Gritstone Oncology, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company developing the next generation of cancer immunotherapies to fight multiple cancer types, reported that the company has presented preliminary Phase 1 GRANITE immunogenicity data demonstrating the rapid, robust and consistent induction of large numbers of CD8+ T cells against multiple neoantigens in four solid tumor patients with available IFN-g ELISpot data (up to 3,000 IFN-g spot forming units per 106 PBMCs were generated, as measured by overnight ELISpot) within the first two dosing cohorts (Press release, Gritstone Oncology, DEC 12, 2019, View Source [SID1234552355]). Importantly, these T cells were also able to produce IL-2 and Granzyme B, demonstrating that they have cytotoxic potential. In addition to priming naive CD8+ T cells against encoded neoantigens, the data demonstrate that GRANITE can also stimulate the expansion of pre-existing T-cell populations. Safety data from five patients receiving GRANITE and three patients receiving SLATE across the first two dose levels indicate that the immunotherapies were well-tolerated with no dose-limiting toxicities observed. Dose escalation continues. These results were presented today in an oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno-Oncology Congress in Geneva, Switzerland.

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"We are thrilled to observe very robust, polyfunctional CD8+ T cells against predicted neoantigens even at the first dose level of our phase 1 study," said Andrew Allen, M.D., Ph.D., co-founder, president and chief executive officer of Gritstone Oncology. "We view these preliminary results as important de-risking data, demonstrating the unprecedented immunogenicity of our heterologous prime/boost vaccine platform at its lowest dose, in combination with nivolumab. Pre-clinical data have shown a clear dose response where higher doses of the self-amplifying RNA boost vaccination, as well as the addition of anti-CTLA-4, further increase the number and function of CD8+ T cells. Notably, the starting dose of self-amplifying RNA was conservative since this is the first in-human study with this therapeutic approach. Therefore, we look forward to presenting mature data at higher doses with additional patients receiving the full immunotherapy regimen in several months."

In the GRANITE Phase 1 GO-004 study, the first dosing cohort consisted of three advanced cancer patients, including two gastroesophageal adenocarcinoma patients and one non-small cell lung cancer patient who had previously progressed on prior anti-PD-L1 therapy. From the second GRANITE dosing cohort, early ELISpot data was available from one microsatellite-stable

colorectal cancer patient. Most common adverse events in the GO-004 study were grade 1/2 fever and skin rash, consistent with an inflammatory immune reaction. In the SLATE Phase 1 GO-005 study, patients are still early in their course of treatment, and treatment-related adverse events have been limited to one injection site reaction and one case of grade 1/2 pruritus.

About GRANITE and SLATE Ongoing Phase 1/2 Clinical Studies

Gritstone’s GRANITE personalized immunotherapy delivers a cassette of 20 TSNA identified by the company using its proprietary Gritstone EDGETM artificial intelligence platform and tumor HLA peptide sequencing, representing tumor-specific neoantigens that are derived from the patient’s own tumor. GRANITE is being evaluated in combination with immune checkpoint blockade in a Phase 1/2 clinical study, referred to as GO-004, for the treatment of patients with advanced solid tumors, including microsatellite-stable colorectal cancer (MSS CRC), gastroesophageal cancer, metastatic non-small cell lung cancer, and bladder cancer. In the Phase 1 study, all patients receive a fixed dose of intramuscular adenovirus-based prime with three escalating doses (30, 100 and 300 µg) of intramuscular RNA-based boost vaccinations in combination with intravenous anti-PD-1 therapy. Following dose escalation of the RNA-based boost vaccine to 100 µg, subcutaneous anti-CTLA-4 is added to the treatment regimen in the third dosing cohort. GRANITE was granted Fast Track designation by the U.S. Food and Drug Administration for the treatment of MSS CRC.

Gritstone’s SLATE "off-the-shelf" immunotherapy delivers a cassette of 20 TSNA identified by the company using its proprietary EDGE artificial intelligence platform and tumor HLA peptide sequencing, representing mutated gene sequences that are shared across patients (such as K-RAS mutations). SLATE is being evaluated in combination with immune checkpoint blockade in a Phase 1/2 clinical study called GO-005 for the treatment of patients with advanced solid tumors, including metastatic non-small cell lung cancer, pancreatic ductal adenocarcinoma and microsatellite-stable colorectal cancer, as well as in patients with other solid tumor types who have relevant mutation/HLA (human leukocyte antigen) combinations. In the Phase 1 study, all patients receive a fixed dose of intramuscular adenovirus-based prime with three escalating doses (30, 100 and 300 µg) of intramuscular RNA-based boost vaccinations in combination with intravenous anti-PD-1 therapy. Following dose escalation of the RNA-based boost vaccine to 30 µg, subcutaneous anti-CTLA-4 is added to the treatment regimen in the second dosing cohort.

Investor Teleconference and Webcast

The company will host a conference call today, December 12, 2019 at 8:00 am ET to review its clinical programs, including the clinical data presented at ESMO (Free ESMO Whitepaper)-IO. The conference call can be accessed by dialing (866) 866-1333 or (404) 260-1421 and referencing conference ID number 49260042. A webcast of the call and accompanying slides will be available within the Investors & Media section of the Gritstone Oncology website at View Source An archived replay will be accessible for 30 days following the event.

On December 12, 2019 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that its collaborators at The Institute of Cancer Research, London, presented results from the cohort of patients in the plasmaMATCH trial treated with Puma’s drug neratinib at the 2019 San Antonio Breast Cancer Symposium (SABCS) in San Antonio, Texas (Press release, Puma Biotechnology, DEC 12, 2019, View Source [SID1234552317]). The oral presentation entitled, "Results from the plasmaMATCH trial: A multiple parallel cohort, multi-centre clinical trial of circulating tumour DNA testing to direct targeted therapies in patients with advanced breast cancer (CRUK/15/010)," and the poster presentation entitled, "Results from plasmaMATCH trial treatment Cohort B: A phase II trial of neratinib plus fulvestrant in ER positive breast cancer or neratinib alone in ER negative breast cancer in patients with a ERBB2 (HER2) mutation identified via ctDNA screening (CRUK/15/010)" were presented by Professor Nicholas Turner, M.D., Ph.D., Professor of Molecular Oncology at The Institute of Cancer Research (ICR) and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, who is the principal investigator of the plasmaMATCH trial, and Andrew M. Wardley, M.D., consultant medical oncologist at The Christie NHS Foundation Trust in Manchester, England and Medical Director of the National Institute for Health Research (NIHR) Manchester Clinical Research Facility at The Christie, respectively. The plasmaMATCH trial was funded by Cancer Research UK.

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The plasma-based Molecular profiling of Advanced breast cancer to inform Therapeutic Choices (plasmaMATCH) trial is a phase IIa, multiple parallel cohort, open-label, multicentre trial in patients with advanced breast cancer, which aims to assess whether analyzing a blood sample for circulating tumor DNA (ctDNA) could provide an alternative to biopsies for identifying the genetic mutations present in advanced breast cancer and whether subgroups of patients with advanced breast cancer, identified through ctDNA screening, may benefit from a treatment targeting their type of cancer.

Approximately 1,044 patients with advanced breast cancer from approximately 20 sites in the United Kingdom registered for the trial and ctDNA results were available for 1,033 (98.9%) of the patients. Depending on the results of the ctDNA screening, patients were enrolled in one of five treatment cohorts and received therapy to target their type of breast cancer. Patients with HER2 mutations were enrolled in the cohort of patients who received either neratinib monotherapy (for patients with hormone receptor negative disease) or neratinib in combination with fulvestrant (for patients with hormone receptor positive disease). Twenty-one patients with HER2 mutations were enrolled in the cohort and 20 patients were evaluable for the primary endpoint of the trial, which was confirmed objective response rate as determined by RECIST 1.1 assessed by the investigator.

In the HER2-mutant cohort, 18 (86%) of the 21 patients had hormone receptor positive breast cancer, 18 patients (86%) had visceral disease, 18 patients (86%) had received prior chemotherapy for metastatic disease, and 11 patients (52%) had received two or more prior lines of chemotherapy for metastatic disease.

The efficacy results from the trial showed that for the 20 efficacy evaluable patients, 5 patients (25%) experienced a confirmed objective response, and three further patients had unconfirmed responses. The median duration of response was 5.7 months, and the median progression free survival in this cohort of patients was 5.4 months.

Prof. Nicholas Turner, Professor of Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said, "Somatic HER2 mutations can be readily and accurately identified from ctDNA blood samples and are clinically actionable for targeted therapy in metastatic breast cancers. The combination of neratinib plus fulvestrant therapy demonstrates encouraging clinical activity with durable responses in this heavily pretreated metastatic breast cancer patient population with HER2-mutated disease."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, added, "We are very pleased with the activity seen in this cohort of patients with HER2-mutated breast cancer with neratinib in plasmaMATCH. This data correlates with the data observed in the neratinib plus fulvestrant arm of the SUMMIT trial, and we look forward to the further development of the combination of neratinib plus trastuzumab plus fulvestrant in this patient population."

On December 12, 2019 CStone Pharmaceuticals ("CStone" or the "Company", HKEX: 2616) reported that the Company has recently received the approval from the Human Research Ethics Committee (HREC) in Australia, and the acknowledgement from Australia’s Therapeutic Goods Administration (TGA) on the Phase I clinical trial of CS3005 (Press release, CStone Pharmaceauticals, DEC 12, 2019, View Source [SID1234552336]). This Phase I trial is an open-label, multicenter, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of CS3005 in patients with advanced solid tumors.

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The tumor microenvironment (TME) is a cellular space in which the tumor dynamically interacts with the surrounding blood vessels, immune cells, stromal components, signaling molecules, and the extracellular matrix. Studies showed that multiple compensatory immunosuppressive mechanisms exist in the TME not only contribute to the development of tumors but also affect the response to immunotherapies. The adenosine signaling pathway plays a critical role in immune modulation and is an important compensatory resistance mechanism against immune checkpoint inhibitors.

Discovered by CStone, CS3005 is an adenosine A2a receptor antagonist that modulates the tumor immune microenvironment. CS3005 could potentially activate antitumor immunity and improve the response to immune checkpoint inhibitors by blocking the binding of adenosine with adenosine A2a receptors and thereby reversing the immunosuppressive mechanism. At present, no adenosine A2a receptor antagonist has been approved for cancer treatment anywhere in the world.

"I am pleased that the clinical trial of CS3005 has been approved in Australia. This drug candidate is the Company’s first tumor immune microenvironment modulator entering clinical development as we have begun to roll out CStone’s Pipeline 2.0," said Dr. Frank Jiang, Chairman and CEO of CStone. "Immuno-oncology therapy has brought new hope to cancer patients in recent years, yet many patients fail to respond to those treatments. We are hopeful that the research and development of tumor microenvironment modulators will allow immunotherapies to benefit more patients."

CStone’s Chief Scientific Officer, Dr. Jon Wang, noted: "Early studies on adenosine A2a receptor antagonists have shown good safety profiles and antitumor activities, either as monotherapies or in combination with immune checkpoint inhibitors, in patients with advanced solid tumors. Interestingly, adenosine A2a receptor antagonists have also demonstrated antitumor activities in patients with low PD-L1 expressing tumors or who are resistant/refractory to anti-PD-(L)1. These observations implicate possible benefits to patients with solid tumors. CS3005 also adds to the depth and flexibility of CStone’s strategy in immuno-oncology combination therapy."

On December 12, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported new data from the phase III FeDeriCa study which showed the investigational fixed-dose combination (FDC) of Perjeta (pertuzumab) and Herceptin (trastuzumab), administered by subcutaneous (SC) injection in combination with intravenous (IV) chemotherapy, demonstrated non-inferior levels of Perjeta in the blood (pharmacokinetics) and comparable efficacy and safety to standard IV infusions of Perjeta plus Herceptin and chemotherapy in eligible people with HER2-positive early breast cancer (eBC) (Press release, Hoffmann-La Roche, DEC 12, 2019, View Source [SID1234552293]). 1

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These new data, from a primary analysis of the FeDeriCa study, will be presented in a spotlight session at 07.00 CST today at the 2019 San Antonio Breast Cancer Symposium (SABCS) in Texas, US (Abstract #PD4-07).

SC administration of the FDC takes approximately eight minutes for the initial loading dose and approximately five minutes for each subsequent maintenance dose. This is compared to approximately 150 minutes for infusion of a loading dose of Perjeta and Herceptin using the standard IV formulations, and between 60 to150 minutes for subsequent maintenance infusions of the two medicines.2,3,4

"This fixed-dose subcutaneous combination has the potential to provide a quicker and less invasive method of administration for people with HER2-positive breast cancer being treated with Perjeta and Herceptin," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "This is the first time that we have brought together two of our targeted antibodies as a single subcutaneous injection that can be administered in just minutes."

The FeDeriCa study met its primary endpoint, with SC administration of the FDC showing non-inferior levels of Perjeta in the blood during a given dosing interval (Ctrough) when compared to IV administration of Perjeta. The geometric mean ratio (GMR; a type of average used when assessing pharmacokinetics) for the primary endpoint was 1.22 (90% CI: 1.14 to 1.31), with the lower limit of the 90% CI of the GMR=1.14≥0.80 (the pre-specified non-inferiority margin). A secondary endpoint of non-inferior Ctrough of Herceptin was also met, with blood concentrations for people receiving the FDC non-inferior to those receiving IV Herceptin (GMR=1.33 [90% CI: 1.24 to 1.43]; lower limit of 90% CI of GMR=1.24≥0.80). A non-inferiority endpoint was chosen for the study to ensure that people were receiving sufficient dosing with Perjeta and Herceptin as compared to the established IV doses at the same treatment intervals. In addition, rates of total pathological complete response (pCR), a secondary endpoint, were comparable between the treatment arms, with 59.7% of patients receiving the FDC and 59.5% of patients treated with IV Perjeta and Herceptin achieving a total pCR – a difference of 0.15% (95% CI: -8.67 to 8.97).1

The safety profile of the FDC in combination with chemotherapy was comparable to that of IV administration of Perjeta plus Herceptin and chemotherapy and no new safety signals were identified, including no meaningful difference in cardiac toxicity. The most common adverse events in both arms were alopecia, nausea, diarrhoea and anaemia.1

In previous studies, SC administration has been shown to be strongly preferred by the majority of patients compared to IV administration of the same medicine, with the most common reason being that administration required less time in the clinic.5 Roche is currently investigating patient preference for SC administration of the FDC compared to standard IV administration of Perjeta and Herceptin in people with HER2-positive eBC in the PHranceSCa study. Interim results of this phase II study will be presented at a future medical meeting.

About the FeDeriCa study 6
FeDeriCa is an international, multi-centre, two-arm, randomised, open-label, phase III study evaluating the pharmacokinetics, efficacy and safety of SC injection of the FDC of Perjeta and Herceptin in combination with chemotherapy, compared with standard IV infusions of Perjeta and Herceptin in combination with chemotherapy in 500 people with HER2-positive eBC who are being treated in the neoadjuvant (before surgery) and adjuvant (after surgery) settings. The primary endpoint of the study is minimum levels of Perjeta in the blood during a given dosing interval (Ctrough). Secondary endpoints include safety; minimum levels of Herceptin in the blood during a given dosing interval (Ctrough); and total pCR, meaning there is no tumour tissue detectable in the tissue removed at the time of surgery.

About the FDC of Perjeta and Herceptin
The FDC of Perjeta and Herceptin is a new SC formulation that combines Perjeta and Herceptin with Halozyme Therapeutics’ Enhanze drug delivery technology.

Trastuzumab in the FDC is the same monoclonal antibody as in IV Herceptin and pertuzumab in the FDC is the same monoclonal antibody as in IV Perjeta. The mechanisms of action of Perjeta and Herceptin are believed to complement each other as both bind to the HER2 receptor, but in different locations. The combination of Perjeta and Herceptin is thought to provide a more comprehensive, dual blockade of the HER signaling pathways.7,8

The standard IV formulation of Perjeta in combination with IV Herceptin and chemotherapy (the Perjeta-based regimen) is approved in over 100 countries for the treatment of both early and metastatic HER2-positive breast cancer. In the neoadjuvant eBC setting, the Perjeta-based regimen has been shown to almost double the rate of pCR compared to Herceptin and chemotherapy.9 Additionally, the combination has been shown to significantly reduce the risk of recurrence of invasive disease or death in the adjuvant eBC setting.10 In the metastatic setting, the combination has shown an unprecedented survival benefit in previously untreated (first-line) patients with HER2-positive metastatic breast cancer.11

Halozyme’s Enhanze drug delivery technology may enable and optimise SC drug delivery for appropriate co-administered therapeutics. The technology is based on a proprietary recombinant human hyaluronidase PH20 (rHuPH20), an enzyme that temporarily degrades hyaluronan – a glycosaminoglycan or chain of natural sugars in the body to aid in the dispersion and absorption of other injected therapeutic drugs.12

About Roche’s medicines for HER2-positive breast cancer
Roche has been leading research into the HER2 pathway for over 30 years and is committed to improving the health, quality of life and survival of people with both early and metastatic HER2-positive disease. HER2-positive breast cancer is a particularly aggressive form of the disease that affects approximately 15-20% of patients.13 Roche has developed three innovative medicines that have helped transform the treatment of HER2-positive breast cancer: Herceptin (trastuzumab), Perjeta (pertuzumab) and Kadcyla (trastuzumab emtansine). Eligibility for treatment with Roche’s HER2-targeted medicines is determined via a diagnostic test which identifies people who will likely benefit from these medicines at the onset of their disease.

On December 12, 2019 Transgene (Paris:TNG) (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported that the primary endpoint (overall response rate) of the Phase 2 trial evaluating TG4010 in combination with chemotherapy and Opdivo (nivolumab) was not reached (Press release, Transgene, DEC 12, 2019, View Source [SID1234552318]). This combination regimen was assessed as a first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC) with low-to-no expression of PD-L1 by the tumor cells (PD-L1<50%). Transgene has taken the decision to stop further development of TG4010.
This multi-center single-arm Phase 2 trial enrolled 40 evaluable patients in the USA and Europe. It was conducted under a clinical collaboration agreement with Bristol-Myers Squibb, which is supplying nivolumab.

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Philippe Archinard, PhD, Chairman and CEO of Transgene, added:
"We are obviously very disappointed with the outcome of this Phase 2 trial which showed that the triple combination regimen of TG4010, chemotherapy and nivolumab did not sufficiently increase the response rate in this patient population with advanced NSCLC whose tumor express low or undetectable levels of PD-L1. Additional data analyses are still ongoing and the complete study results will be presented at an upcoming scientific conference.
With funding until 2022 and a diversified portfolio of novel immunotherapies targeting solid tumors, our strategy remains clear and unchanged. The Phase 2 combination trial of TG4001 in HPV-positive cancers is recruiting well and we expect to report the next clinical readout as planned in H1 2020. We are also advancing our two novel technology platforms myvac and Invir.IO. Clinical sites have been initiated and the first two trials evaluating TG4050, the first myvac candidate, will soon be enrolling patients. These trials will be jointly funded with NEC. A trial with TG6002 administered via the intrahepatic artery is also about to enroll its first patient. In addition, we expect to submit a clinical trial application in the first half of 2020 for BT-001, the first Invir.IO oncolytic virus encoding for an anti-CTLA4 antibody. Finally, our collaboration with AstraZeneca focused on generating novel multi-armed Invir.IO oncolytic viruses is making excellent progress.
These multiple advances give me great confidence that Transgene is well placed to demonstrate and deliver the potential of its novel therapeutic vaccines and oncolytic viruses designed to improve the treatment of solid tumors."

A conference call in English is scheduled on December 12, 2019, at 6:30 p.m. CET.

Webcast link to conference call: https://channel.royalcast.com/webcast/transgene/20191212_1/

Participant telephone numbers:

France: +33 (0) 1 7037 7166

United Kingdom: +44 (0) 20 3003 2666

United States: +1 212 999 6659

Confirmation code: Transgene

A replay of the call will be available on the Transgene website (www.transgene.fr) following the live event.

About TG4010
TG4010 is an immunotherapy that has been designed to express the coding sequences of the MUC1 tumor-associated antigen and the cytokine, Interleukin-2 (IL2). It is based on a modified Vaccinia virus (MVA) and has been shown to induce an immune response against MUC1 expressing tumors, such as non-small cell lung cancer (NSCLC). Its mechanism of action and safety profile make TG4010 a very suitable candidate for combinations with other therapies. The combination of TG4010 immunotherapy and chemotherapy has demonstrated significant efficacy in terms of progression-free survival and overall survival in patients with advanced stage NSCLC in a Phase 2b trial (Quoix et al. Lancet Oncol. 2015).