On April 16, 2018 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 inhibitor drugs to improve immune cell trafficking to treat cancer and rare diseases, reported data from a presentation at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, X4 Pharmaceuticals, APR 16, 2018, View Source [SID1234525412]) The data, generated from serial tumor biopsies and blood draws taken from melanoma patients, demonstrated dramatic infiltration and activation of cytotoxic CD8+ T cells and increased inflammatory status in the tumor microenvironment (TME) following once-daily oral administration of X4P-001-IO. X4P-001-IO is an investigational CXCR4 allosteric antagonist. Findings highlight single agent X4P-001-IO has the ability to help restore immunity within the TME and has the potential to enhance the anti-tumor activity of agents such as checkpoint inhibitors.

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Results from the tumor biopsies taken from melanoma patients before and after receiving single agent X4P-001-IO treatment for 3 weeks, were analyzed and presented. Single agent X4P-001-IO showed evidence of enhanced immune cell infiltration and activation in the tumor microenvironment, including:

Increases in proliferating CD8+ cells, indicative of cytotoxic T cell activation,
Increases in Granzyme B, a marker of immune-mediated cell killing,
Decreases in distance between CD8+ T cells and the nearest tumor cells, indicative of increased CD8+ T cell infiltration,
Increases in antigen presentation/processing gene expression, suggesting enhanced antigen priming and activation, and
Increases in the Tumor Inflammation Signature (TIS), indicative of increased inflammation status in the TME.
After single agent X4P-001-IO treatment, patients received X4P-001-IO in combination with Keytruda (pembrolizumab) for an additional 6 weeks. Continued signs of positive immune cell changes in the tumor microenvironment were seen. The combination of X4P-001-IO alone and in combination with Keytruda was well tolerated.

"These results demonstrate that CXCR4 inhibition substantially alters the tumor microenvironment in a way that is consistent with the emerging understanding of tumor immunity and inflammatory response," said Robert Andtbacka, MD, CM, a surgeon and investigator with the Huntsman Cancer Institute of the University of Utah, Associate Professor in the Division of Surgical Oncology at the University of Utah School of Medicine, and Principle Investigator of the X4P-001-IO study in melanoma.

In a separate poster presentation, preclinical findings showed that CXCR4 inhibition increases CD8+ T cells in the tumor microenvironment and has potent anti-tumor activity in the syngenic B16-OVA murine melanoma model. The anti-tumor activities were associated with the increase in immunostimulatory CD8+/Perforin+ cells and the reduction of immunosuppressive myeloid derived suppressor cells (MDSCs) and Treg populations in the tumor microenvironment.

"Results from these posters demonstrate the unique mechanism of X4P-001-IO, as it impacts critical aspects of immune cell trafficking, infiltration and activation – playing a positive role in tumor immunity," said Sudha Parasuraman, MD, X4’s Chief Medical Officer. "These data, together with X4P-001-IO’s favorable safety and tolerability profile, support the potential for X4P-001-IO to improve outcomes for patients with tumors that are less responsive to checkpoint inhibitors."

The posters were presented in the Immune Response to Therapy Session at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 14-18, 2018 in Chicago, IL.

About X4P-001-IO in Cancer

X4P-001-IO is an investigational selective, oral, small molecule inhibitor of CXCR4 (C-X-C receptor type 4) that regulates the tumor microenvironment thereby enhancing endogenous anti-tumor responses. CXCR4 is a chemokine receptor that modulates immune function and angiogenesis through the trafficking of key immune cells such as T- cells, dendritic cells, and myeloid derived suppressor cells. CXCR4 signaling is disrupted in a broad range of cancers, facilitating tumor growth by allowing cancer cells to evade immune detection and creating a pro-tumor microenvironment. X4P-001-IO is being investigated in three separate clinical studies in solid tumors.

On April 16, 2018 Shire plc (LSE: SHP, NASDAQ: SHPG) the leading global biotechnology company focused on rare diseases reported that it has entered into a definitive agreement with Servier S.A.S. ("Servier") to sell its Oncology business for $2.4 billion. Shire’s Oncology business includes in-market products ONCASPAR (pegaspargase), a component of multi-agent treatment for acute lymphoblastic leukemia (ALL) and ex-U.S. rights to ONIVYDE (irinotecan pegylated liposomal formulation), a component of multi-agent treatment for metastatic pancreatic cancer post gemcitabine-based therapy (Press release, Shire, APR 16, 2018, View Source [SID1234525319]). The portfolio also includes Calaspargase Pegol (Cal-PEG), which is under FDA review for the treatment of ALL and early stage immuno-oncology pipeline collaborations.

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Flemming Ornskov, M.D., M.P.H., Shire Chief Executive Officer, commented:

"This transaction is a key milestone for Shire, demonstrating the clear value embedded in our portfolio. While the Oncology business has delivered high growth and profitability, we have concluded that it is not core to Shire’s longer-term strategy. We will continue to evaluate our portfolio for opportunities to unlock further value and sharpen our focus on rare disease leadership with selective disposals of non-strategic assets.

"We are confident that Servier will continue to invest in this business and our colleagues who are expected to transfer as part of the transaction in order to meet the needs of cancer patients globally.

"The proceeds from the transaction increase optionality and Shire’s Board will consider returning the proceeds of the sale to shareholders through a shareholder-approved share buyback after the current offer period regarding Takeda’s possible offer for Shire concludes."

Olivier Laureau, Servier Group President, commented:

"The acquisition of Shire’s oncology franchise enables Servier to meet its strategic ambitions to become a global key player in oncology. As an essential step in the evolution of the Group, this acquisition allows us to establish a direct commercial presence in the United States, the world’s leading pharmaceuticals market, and to strengthen our portfolio of marketed products in the territories where Servier is already present. Our goal is to bring these treatments to greater numbers of cancer patients around the world. We thoroughly look forward to welcoming Shire’s oncology teams who will join Servier after the closing."

Transaction details

Under the terms of the agreement, Servier has agreed to acquire Shire’s Oncology business for a total consideration of $2.4 billion, in cash, upon completion. In 2017, the Oncology business generated revenues of $262 million. The total consideration represents a revenue multiple of 9.2 times 2017 revenues. The transaction covers the transfer of Shire’s Oncology business including in-market products ONCASPAR (pegaspargase), a component of multi-agent treatment for acute lymphoblastic leukemia (ALL) and ex-U.S. rights to ONIVYDE (irinotecan pegylated liposomal formulation), a component of multi-agent treatment for metastatic pancreatic cancer post gemcitabine-based therapy. The portfolio also includes Calaspargase Pegol (Cal-PEG), which is under FDA review for the treatment of ALL, and early stage immuno-oncology pipeline collaborations.

The gross assets that are the subject of the transaction are approximately $1.6 billion and the profits attributable to the assets being transferred are approximately $140 million, excluding depreciation, amortization and other direct and indirect costs.

Transaction closing

This transaction constitutes a Class 2 transaction for the purposes of the U.K. listing rules and, as such, Shire shareholder approval is not required. The transaction has been approved by the Board of Directors and is expected to close in the second or third quarter of 2018.

Transaction background

Shire’s Board of Directors initiated the potential divestment of the Oncology business in December 2017. The process, which commenced in January 2018, identified multiple potential strategic buyers across the U.S., Europe and Japan.

In the first, Alexander M.M. Eggermont, Director General of the Gustave Roussy Cancer Campus Grand Paris in Villejuif, France, and investigators from 23 countries across the world, found that giving a one-year course of 18 doses of the immunotherapy drug pembrolizumab (Keytruda) significantly reduced the risk of the cancer returning for patients with stage III melanoma who were at high risk of recurrence after surgery (Press release, EORTC, APR 16, 2018, View Source [SID1234525394]). Patients with stage III melanoma have metastatic disease in one or more regional lymph nodes. Giving a dose of 200 milligrams of pembrolizumab every three weeks after surgery for up to a year significantly reduced the risk of recurrence for these patients the investigators found.

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Pembrolizumab works by blocking a protective mechanism of cancer cells, thus allowing the immune system to destroy them. Of the 1,019 patients recruited to the double-blind trial, 514 were randomised to pembrolizumab, and the others to placebo. For all those randomised to pembrolizumab, the 12-month recurrence-free survival rate was 75.4 percent, compared with 61.0 percent for all those randomised to placebo. The estimated hazard ratio was 0.57, indicating that risk of recurrence or death was reduced by 43 percent in patients randomised to pembrolizumab as compared to those randomised to placebo.

After a median follow-up of 1.25 years, 135 of the 514 patients randomised to pembrolizumab and 216 of the 505 patients randomised to placebo had been diagnosed with recurrent disease or had died. Patients randomised to placebo who had recurrence were offered access to pembrolizumab. "This cross-over design is unique in the world of adjuvant trials in melanoma and will permit us to analyse if adjuvant therapy with pembrolizumab right after surgery is better or not than treating only those who relapse and start treatment at relapse," says Eggermont. "We hope that these data will lead to regulators in the United States and Europe approving pembrolizumab as a new treatment option for these patients."
The trial results are published in the New England Journal of Medicine.
Abstract no CT001 : Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Efficacy and safety results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial

In the second trial, investigators from eight European countries, headed by Patrick Schöffski from KU Leuven, Belgium, found that treatment with a targeted cancer drug achieved complete or partial tumour shrinkage in 50% of patients with inflammatory myofibrobastic tumour (IMFT), a very rare type of soft tissue sarcoma. Soft tissue sarcomas in themselves are very rare, accounting for just 1% of all solid tumour diagnoses, and IMFT so uncommon that there are no reliable statistics for its incidence or for mortality rates.
Many IFMTs have rearrangements of the ALK gene. Recently discovered as a target for cancer therapies, the ALK gene can be oncogenic in three ways – by forming a fusion gene with any of several other genes, by gaining additional copies or through mutations of the actual DNA code for the gene itself.
Schöffski and colleagues therefore set out to see whether the ALK inhibitor crizotinib might be a potential treatment for patients with IMFT. "Inflammatory myofibroblastic tumours are usually resistant to conventional chemotherapy and radiotherapy, so patients with unresectable or locally recurring disease have few treatment options," he says.
Because IMFT is so rare, only 35 patients with a local diagnosis of inflammatory myofibroblastic tumour could be recruited to the trial. Twenty of these patients were confirmed centrally to have the disease and received crizotinib.
Nineteen patients were evaluable for response. The objective response rate among the 12 evaluable patients with ALK-positive IFMTs who received crizotinib was 50 percent (95% confidence interval : 21.1-78.9%); two had a confirmed complete response and four had a confirmed partial response. Among the seven evaluable patients with ALK-negative IFMTs, the rate was 14.3 percent (95% confidence interval: 0.0-57.9%). In the group of patients with ALK-positive IFMT, crizotinib activity met the pre-specified response rate criteria set by the protocol.
« Limitations of the trial include that it is a noncomparative, single-arm study with a relatively small number of patients. Given the disease prevalence, a more definitive, randomised, comparative trial would not be possible, » says Schöffski.
« However, our study highlights how identifying the genetic drivers of a rare type of cancer can be used to find a new precision medicine for patients who otherwise have few treatment options," he adds. "The inclusion in our trial of a group of patients with ALK-negative inflammatory myofibroblastic tumors provides valuable insight into the selectivity of crizotinib and our understanding of this rare disease, even if we cannot formally compare the outcomes for the ALK-positive and -negative groups."
The trial results are published in The Lancet Respiratory Medicine.
Abstract no CT045 :Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 "CREATE"

On April 16, 2018 VBL Therapeutics (NASDAQ:VBLT) reported that its presented a late-breaking study demonstrating a novel bi-specific antibody that induces immune-cell mediated killing of cancer cells through binding to a tumor membrane receptor, MOSPD2 (Press release, VBL Therapeutics, APR 16, 2018, View Source [SID1234525364]). Data are presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting in Chicago, Illinois

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.
"Selective targeting of tumor cells is challenging, as it requires a tumor-specific receptor, or process, that can be attacked without compromising safety. Our new data demonstrate that different solid tumors show high expression of MOSPD2 as it likely supports their ability to invade and metastasize. Our bi-specific antibody is taking advantage of this tumor-specificity to induce killing of tumor cells. We continue to advance our exciting VB-600 series of antibodies as drug candidates for oncology and inflammatory indications," said Dror Harats, M.D., Chief Executive Officer of VBL Therapeutics.

VBL research has identified MOSPD2 (Motile Sperm Domain-containing Protein 2) as a protein involved in cell motility. Previously, the Company published data on the involvement of MOSPD2 in immune cell migration, and new data presented today at AACR (Free AACR Whitepaper) show high and selective MOSPD2 expression by multiple tumor types along with involvement of MOSPD2 in tumor cell invasiveness. In addition, a novel bi-specific antibody that was engineered to bridge interaction of T-cells with tumor cells, via binding to the T-cell protein CD3 and the tumor receptor MOSPD2, induced T-cell activation and resulted in the killing of cancer cells in a pre-clinical setting.
These data provide proof-of-concept for the use of antibody-mediated killing of MOSPD2-expressing cancer cells, with potential applicability to solid tumors and myeloid malignancies. VBL is developing its VB-600 series of antibodies targeting MOSPD2 for oncology and inflammatory applications.
For VBL’s poster presentation at AACR (Free AACR Whitepaper) kindly see the following link.

On April 16, 2018 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported that initial data from the Phase 1 GARNET trial of TSR-042 (anti-PD-1 antibody) in patients with microsatellite instability high (MSI-H) endometrial cancer and non-small cell lung cancer (NSCLC) presented during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, TESARO, APR 16, 2018, View Source [SID1234525363]).

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"Preliminary results from GARNET presented today at AACR (Free AACR Whitepaper) are the first clinical data from expansion cohorts for TSR-042, our anti-PD-1 antibody," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "These results demonstrate the clinical activity of TSR-042 and support our unique patient-centric dosing regimen that includes dosing every 6 weeks. We expect to complete enrollment in the MSI-H endometrial cohort of the GARNET trial by the end of the year. A regulatory submission for TSR-042 is planned in 2019. The breadth of TESARO’s immuno-oncology portfolio, which also includes antibodies targeting TIM-3 and LAG-3, enables us to evaluate both monotherapy and novel combination approaches with a goal of providing transformative therapies for people living with cancer."

Preliminary Activity in MSI-H Endometrial Cancer and Non-Small Cell Lung Cancer
GARNET is a multicenter, open-label, Phase 1 dose-escalation study designed to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TSR-042 in patients with advanced solid tumors. Part 1, a weight-based dose escalation study, and part 2A, a fixed-dose safety study, of GARNET have been completed. The ongoing part 2B expansion portion of GARNET is evaluating TSR-042 at a dose of 500 milligrams every 3 weeks for the first 4 cycles, and 1000 milligrams every 6 weeks thereafter in four open cohorts: MSI-H endometrial cancer, MSI-high non-endometrial cancer, MSS endometrial cancer and NSCLC. Data presented at AACR (Free AACR Whitepaper) included efficacy data from the cohorts of patients with MSI-H endometrial cancer and NSCLC from part 2B of the trial.

At the time of data cutoff, 15 patients with MSI-H endometrial cancer and 24 patients with NSCLC had at least 1 tumor assessment. Among the 15 patients with MSI-H endometrial cancer, 7 had partial responses by immune related RECIST (irRECIST) criteria (ORR 47%). Eleven patients continue on therapy, including one patient with a partial response who has thus far received over 42 weeks of TSR-042. Three additional patients (20%) had stable disease.

Among the 24 patients with NSCLC, 7 had partial responses by irRECIST criteria (ORR 29%). Twelve patients continue on therapy, including one patient with a partial response who has thus far received over 36 weeks of TSR-042. Ten additional patients had stable disease (42%), one of whom has continued treatment for over 36 weeks.
Preliminary safety findings among the 120 evaluable patients (including patients with MSI-H endometrial, NSCLC, and other tumor types) indicate TSR-042 is well-tolerated. Grade ≥3 treatment-related treatment-emergent adverse events (TEAEs) were reported in 9 of 120 patients (7%).
Serum concentrations of TSR-042 observed 6 weeks after the 1000 milligram dose were comparable to those observed 3 weeks after the 500 milligram dose, and maximal receptor occupancy was maintained throughout the 6-week dosing interval.

The GARNET study is intended to support a Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) for patients with MSI-H cancers in 2019.
TESARO Poster Presentations at AACR (Free AACR Whitepaper) (all times local)

Immuno-oncology
Monday, April 16, 2018, 8:00 AM to 12:00 PM
Preliminary safety, efficacy and PK/PD characterization from GARNET, a phase I clinical trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced NSCLC or MSI-H endometrial cancer
Poster Session, Abstract: CT053, Location: Exhibit Hall A, Poster Section 42, Poster Board 6
Monday, April 16, 2018, 8:00 AM to 12:00 PM
Checkpoint inhibitor signatures across endometrial cancer histologies
Poster Session, Abstract: 1687, Location: Exhibit Hall A, Poster Section 31, Poster Board 12
Monday, April 16, 2018, 8:00 AM to 12:00 PM
Simultaneous measurement and significance of PD-1, LAG-3 and TIM-3 expression in human solid tumors
Poster Session, Abstract: 1681, Location: Exhibit Hall A, Poster Section 31, Poster Board 6
Monday, April 16, 2018, 1:00 PM to 5:00 PM
Investigation of the expression profile and functional role of PD-1, TIM-3 and LAG-3 in human tumors
Poster Session, Abstract: 2722, Location: Exhibit Hall A, Poster Section 32, Poster Board 14
Wednesday, April 18, 2018, 8:00 AM to 12:00 PM
Characterization of tumor growth and immune microenvironment in humanized NOG-EXL mice implanted with A549, MDA-MB-436 and A375 cells
Poster Session, Abstract: 5690, Location: Exhibit Hall A, Poster Section 31, Poster Board 26

About GARNET
The ongoing Phase I GARNET trial is evaluating TSR-042 as monotherapy in patients with advanced solid tumors. GARNET included a weight-based dose escalation study (Part 1) and a fixed-dose safety study (Part 2A), both of which have been completed. Results of these studies were used to determine the recommended Phase 2 dose (RP2D; 500 mg Q3W for the first 4 cycles then 1000 mg Q6W). The study is now enrolling patients with MSI-H endometrial cancer, MSI-H non-endometrial cancer, MSS endometrial cancer, and NSCLC into four large expansion cohorts.

About TSR-042
TSR-042 is an investigational humanized anti-programmed death (PD)-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. TSR-042 is the only anti-PD-1 therapy administered as monotherapy every 3 weeks for 4 doses then every 6 weeks thereafter. TSR-042 was developed as part of the collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drugs targeting PD-1, TIM-3 (TSR-022), and LAG-3 (TSR-033), in addition to a bi-specific antibody drug candidate targeting PD-1/LAG-3 (TSR-075).