On October 1, 2018 InteRNA Technologies reported its results from a set of confirmatory in vitro and in vivo studies further validating the unique mechanism of action (MoA) of InteRNA’s lead microRNA drug candidate, INT-1B3, for the treatment of cancer (Press release, InteRNA Technologies, OCT 1, 2018, View Source [SID1234529688]). Most strikingly, the company was able to demonstrate that INT-1B3’s earlier reported long-term memory immune protection activity against re-challenge with tumor cells is cytotoxic CD8+ T cell-mediated. INT-1B3 is a lipid nanoparticle (LNP) formulated, chemically modified microRNA 193a-3p mimic, a known tumor-suppressor microRNA, that has been shown to induce immune-modulation of the tumor microenvironment, reduction of metastases development leading to improved animal survival, and pronounced long-term immunity with a good safety and tolerability profile. The data were presented in two posters at the 14th Annual Oligonucleotide Therapeutics Society (OTS) Meeting, held in Seattle, WA from September 30 – October 3, 2018.

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"These confirmatory results are consistent with the original preclinical proof-of-concept data we presented at the AACR (Free AACR Whitepaper) Annual Meeting this year and thereby serve as a fundamental validation of INT-1B3’s differentiated mechanism of action," said Dr. Roel Schaapveld, CEO of InteRNA. "It is also very exciting that we were able to demonstrate that the pronounced long-term anti-tumor immunity we have seen is CD8+ T cell-dependent which further clarifies a key aspect of these promising effects. We are convinced that INT-1B3, next to its potential in combination regimens, represents a unique and novel monotherapeutic opportunity in immuno-oncology and we look forward to evaluating its efficacy in cancer patients."

The data presented at the 14th Annual OTS Meeting confirm and expand on the preclinical data presented at AACR (Free AACR Whitepaper) in April 2018 as summarized in the following announcement http://bit.ly/2NnruRI.

In a syngeneic orthotopic mouse model of triple negative breast cancer (TNBC 4T1), systemic administration of INT-1B3 was proven to efficiently modulate the immunosuppressive tumor microenvironment. Upon resection of the primary tumors, this resulted in: 1) the inhibition of tumor re-growth, 2) reduction of distant (lung and intraperitoneal) metastases development with significant impact on animal survival, and 3) long-term immunity to newly injected 4T1 tumor cells in the absence of further drug treatment. Most notably, CD8+ T cell depletion greatly impacted protection of surviving INT-1B3-treated animals against such re-challenge with 4T1 tumor cells, suggesting a CD8+ T cell-dependent long-term immune protection. Furthermore, the results presented in a second poster verify that upon transfection in a wide panel of human tumor cell lines, the microRNA 193a-3p mimic was able to inhibit tumor cell proliferation and survival, modulate the tumor cell cycle, induce apoptosis and/or senescence and decrease tumor cell migration and invasion. In addition, and consistent with results in cell-based assays, significant anti-tumor efficacy of INT-1B3 was demonstrated in several human xenografts and in an extended panel of syngeneic subcutaneous mouse tumor models. Based on these results, INT-1B3 provides a novel and promising therapeutic approach in the immuno-oncology armamentarium.

MicroRNAs are naturally occurring small RNA interfering molecules which represent a part of the body’s arsenal to regulate gene expression, each targeting a specific set of genes that have gained recent attention as a novel therapeutic approach in a variety of disease states. MicroRNA 193a-3p specifically is a known tumor suppressor microRNA that is downregulated in many cancers. InteRNA’s formulated and chemically modified synthetic mimic combines anti-tumor activity with modulation of the immunosuppressive tumor microenvironment, and long-term immunity upon systemic delivery to cancer cells upregulating microRNA 193a-3p’s original function across the pathways involved in the initiation and progression of cancer and the evasion of the immune system in parallel.

The posters entitled "A novel synthetic miR-193a-3p mimic (INT-1B3) targeting multiple hallmarks of cancer reveals potential for therapeutic intervention in oncology" (poster #114) and "INT-1B3, a novel synthetic microRNA mimic and its monotherapy potential in immune-oncology armamentarium" (poster #63) as well as the original proof-of-concept data were presented by InteRNA’s Chief Executive Officer, Dr. Roel Schaapveld and Chief Development Officer, Dr. Michel Janicot and are available on InteRNA’s website through the following link:
View Source

On October 1, 2018 Amgen (NASDAQ:AMGN) reported that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) to expand the Prescribing Information for KYPROLIS (carfilzomib) to include a once-weekly dosing option in combination with dexamethasone (once-weekly Kd70) for patients with relapsed or refractory multiple myeloma (Press release, Amgen, OCT 1, 2018, View Source;p=RssLanding&cat=news&id=2369600 [SID1234529745]). The approval is based on data from the Phase 3 A.R.R.O.W. trial, which demonstrated that KYPROLIS administered once-weekly at 70 mg/m2 with dexamethasone achieved superior progression-free survival (PFS) and overall response rates (ORR), with a comparable safety profile, versus twice-weekly KYPROLIS administered at a dose of 27 mg/m2 in combination with dexamethasone (twice-weekly Kd27). KYPROLIS is not approved for twice-weekly 27 mg/m2 administration in combination with dexamethasone alone.

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"In the fight against multiple myeloma, we are committed to continued evidence generation and innovation to serve patients. KYPROLIS now offers patients with relapsed or refractory multiple myeloma the option of a more convenient dosing regimen that provides better outcomes with a comparable safety profile," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We’re pleased that the FDA has recognized the importance of bringing more treatment options to cancer patients more quickly through its pilot programs and proud to participate with this KYPROLIS data."

The FDA reviewed the application under its Oncology Center of Excellence Real-Time Oncology Review and Assessment Aid pilot programs, which aim to explore a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible. The FDA approved the application in just over one month after the final component of the application was submitted.

"While great progress has been made in the last decade, multiple myeloma remains an incurable disease characterized by a recurring pattern of remission and relapse, and it is important that patients have treatment options that meet their individual needs," said David S. Siegel, M.D., Ph.D., chief of the Division of Multiple Myeloma at John Theurer Cancer Center at Hackensack University Medical Center. "The availability of a more convenient once-weekly dosing regimen, with superior efficacy, comparable safety, and longer duration of therapy versus the twice-weekly regimen studied in the trial could allow patients to spend more time outside of the infusion center."

A.R.R.O.W. included 478 patients with relapsed and refractory multiple myeloma who received at least two or three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. Patients in the trial treated with once-weekly Kd70 achieved a statistically significant 3.7 month improvement in PFS compared to the Kd27 twice-weekly regimen (median PFS 11.2 months for once-weekly Kd70 versus 7.6 months for twice-weekly Kd27; HR=0.69; 95 percent CI: 0.54-0.88; one-sided p=0.0014).The ORR in patients treated with once-weekly Kd70 was 62.9 percent versus 40.8 percent for those treated with twice-weekly Kd27 (p<0.0001). In addition, 7.1 percent had complete responses or better in the once-weekly arm versus 1.7 percent in the twice-weekly arm in this refractory patient population.

The overall safety profiles of the two arms in A.R.R.O.W. were comparable, with no new safety risks identified in the once-weekly arm. Discontinuation rates due to adverse events were similar in the two arms. The most frequently reported treatment-emergent adverse events (greater than or equal to 20 percent) in either treatment arm were anemia, diarrhea, fatigue, hypertension, insomnia and pyrexia.

The interim data were presented during an oral session at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and simultaneously published in The Lancet Oncology.

About A.R.R.O.W.
The A.R.R.O.W. (RAndomized, Open-label, Phase 3 Study in Subjects with Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination with Dexamethasone, Comparing Once-Weekly versus Twice-weekly Carfilzomib Dosing) trial evaluated 478 patients with relapsed and refractory multiple myeloma who have received at least two but no more than three prior therapies, including bortezomib and an immunomodulatory drug. Those included in the study were randomized to receive a 30-minute infusion of once-weekly KYPROLIS (20 mg/m2 on day 1 of cycle 1; 70 mg/m2 on days 8 and 15 of cycle 1; and 70 mg/m2 on days 1, 8 and 15 of subsequent cycles) with dexamethasone (40 mg) versus a 10-minute infusion of twice-weekly KYPROLIS (20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m2 on days 1, 2, 8, 9, 15 and 16 of subsequent cycles) with dexamethasone (40 mg). The primary endpoint of the trial was PFS, defined as the time from randomization to disease progression or death. Secondary endpoints included ORR, overall survival, and safety and tolerability.

The trial was conducted in approximately 100 sites worldwide. For more information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT02412878.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.1 It is a rare and life-threatening disease that accounts for approximately one percent of all cancers.2,3 Worldwide, approximately 114,000 people are diagnosed with multiple myeloma each year and 80,000 patient deaths are reported on an annual basis.2

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.4 KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.5 In some cells, KYPROLIS can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.4,5

Since its first approval in 2012, approximately 80,000 patients worldwide have received KYPROLIS. KYPROLIS is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
KYPROLIS is also approved in Argentina, Australia, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Macao, Mexico, Thailand, Colombia, S. Korea, Canada, Qatar, Switzerland, United Arab Emirates, Turkey, Russia, Brazil, India, Oman and additional U.S. regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

Important U.S. KYPROLIS (carfilzomib) Safety Information

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of administration.
Monitor patients for signs or symptoms of cardiac failure or ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate.
For patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment prior to starting treatment with KYPROLIS and remain under close follow-up with fluid management.
Acute Renal Failure

Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency adverse events (including renal failure) have occurred. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred. Patients with a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, and withhold until resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred. Some events have been fatal. In the event of drug‐induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using hormonal contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment.
Infusion Reactions

Infusion reactions, including life‐threatening reactions, have occurred. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms and seek immediate medical attention if they occur.
Hemorrhage

Fatal or serious cases of hemorrhage have been reported. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Monitor platelet counts frequently during treatment. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have occurred. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred. Monitor for signs and symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. If PRES is suspected, discontinue and evaluate with appropriate imaging. The safety of reinitiating KYPROLIS is not known.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.
Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS and for 3 months following the final dose. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse reactions in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.

On October 1, 2018 Adaptive Biotechnologies reported that the U.S. Food and Drug Administration (FDA) has granted De Novo designation for the clonoSEQ Assay to detect and monitor minimal residual disease (MRD) in patients with multiple myeloma (MM) and B-cell acute lymphoblastic leukemia (ALL) using DNA from a patient’s bone marrow sample (Press release, Adaptive Biotechnologies, OCT 1, 2018, View Source [SID1234529689]). The clearance of clonoSEQ marks several "firsts" for patients and for the FDA. The clonoSEQ Assay represents a first-in-class MRD assay that uses next-generation sequencing (NGS) technology to assess disease burden, representing an important additional use of NGS in cancer. clonoSEQ is the first and only assay to be cleared by the FDA for MRD assessment in any lymphoid cancer and the first FDA-cleared diagnostic assay powered by immunosequencing. It is also a major milestone for Adaptive Biotechnologies as the first regulatory clearance for the company’s proprietary (NGS) platform for immune system profiling.

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MRD refers to the small number of cancer cells that can remain in a patient’s body after treatment, which often cause no signs or symptoms but eventually can lead to recurrence of the disease. These residual cells can be present at very low levels and require highly sensitive tests to identify them. Even very small amounts of MRD can have a profound effect on treatment success and patient outcomes. A test that can reliably determine the presence and amount of residual disease at very low levels can be used by physicians in conjunction with other clinical information to predict treatment outcomes, guide management decisions and improve patient care.

"MRD testing provides patients with real-time insights about their response to therapy or the depth of their remission, therefore the MMRF is deeply committed to this important advancement in patient care," said Paul Giusti, president and chief executive officer, Multiple Myeloma Research Foundation (MMRF). "The sensitivity of the test is extremely important, as the number of cells remaining after treatment has been linked to patient outcomes. This clearance provides patients and physicians with access to a highly sensitive, standardized MRD test that can be an important tool in guiding treatment decisions."

There are more than 200,000 MM and ALL patients living in the U.S., and more than 35,000 new cases are diagnosed each year. The clonoSEQ Assay uses NGS to precisely identify and monitor MRD in these patients throughout treatment and remission, with greater sensitivity than other technologies for any given amount of bone marrow sample.1 Detecting MRD with deep sensitivity can be clinically informative for the many patients being treated for these cancers.

"The FDA clearance of clonoSEQ is an important advance for patients with MM and ALL and for the oncologists who care for them. This milestone underscores the importance of MRD as a predictor of patient outcomes," said Aaron Logan, associate professor, Division of Hematology and Blood and Marrow Transplant, UCSF. "Quantification of MRD should be standard practice to assess response to treatment, monitor disease progression and direct patient care. It is thus essential to have an MRD assay that meets regulatory standards and can accurately and reliably measure and track disease burden over time."

For patients who achieve complete response to cancer treatment by traditional response criteria, the presence or absence of MRD has been demonstrated to have a significant relationship with patient outcomes.2 For this reason, many pharmaceutical companies have begun using MRD as a clinically meaningful endpoint to evaluate efficacy and to guide use of their therapies.

"This year has been historic for the field of hematology, with a paradigm-shifting FDA decision to approve the first therapy, BLINCYTO, based on the MRD status of a patient with ALL, validating the clinical relevance of MRD in ALL as a clinically meaningful endpoint," said Greg Friberg, M.D., vice president, Global Development, Oncology at Amgen. "Now, physicians and patients will have access to the first FDA-cleared MRD assay, providing them with another important tool to make informed decisions about treatments to help achieve MRD negativity. We look forward to continuing our collaboration with Adaptive Biotechnologies to further explore MRD and deliver on our mission to serve patients through transformative science."

The recent FDA review and approval of drugs with MRD included as a clinical endpoint, as well as the agency’s inclusion of MRD on the recently released list of surrogate endpoints that can serve as the basis of drug approvals, demonstrate the clinical actionability of MRD and reinforce the need for an accurate and standardized, FDA-cleared method like clonoSEQ.3,4

"The clearance of the clonoSEQ Assay is an exciting advance for MM and ALL patients and physicians; as MRD is increasingly used to inform treatment decisions, the importance of having an accurate and standardized assessment method becomes paramount," said Chad Robins, chief executive officer and co-founder of Adaptive Biotechnologies. "NGS MRD testing is already part of National Comprehensive Cancer Network (NCCN) treatment guidelines for patients with MM, ALL, and CLL, and clonoSEQ is already in use for patient management in the majority of NCCN cancer centers, further demonstrating the clinical importance of MRD and acceptance of NGS MRD testing by the oncology community. Adaptive is working diligently with public and private payers to make clonoSEQ broadly available to patients in need."

About Minimal Residual Disease

Minimal residual disease (MRD), also referred to as measurable residual disease, refers to cancer cells that remain in the body after treatment for patients with lymphoid cancers. These cells can be present at levels undetectable by traditional morphologic methods, microscopic examination of blood, or a bone marrow or a lymph node biopsy.

MRD is used by physicians to detect and monitor disease burden in patients and to inform their treatment decisions. Clinical practice guidelines recommend assessing MRD at multiple time points during treatment and maintenance in MM and ALL, and guidelines for both diseases include NGS as a recommended testing method.5,6 The prognostic value of MRD assessment has been demonstrated in multiple lymphoid cancers.7,8 Controlled trials have shown that even small amounts of disease are profoundly significant for predicting a patient’s long-term clinical outcomes.1,9,10,11,12 Therefore, highly sensitive, standardized molecular technologies are needed for reliable detection of MRD.

Measurement of MRD is currently being evaluated as a way to measure efficacy in drug trials, with the potential to expedite the approval of emerging therapies.13

About the clonoSEQ Assay

The Adaptive Biotechnologies clonoSEQ Assay has been granted De Novo designation by the FDA as an in vitro diagnostic (IVD) to detect and monitor minimal residual disease (MRD) in patients with multiple myeloma (MM) and B-cell acute lymphoblastic leukemia (ALL) using DNA from bone marrow samples. It identifies and quantifies specific DNA sequences found in malignant cells, allowing clinicians to monitor patients for changes in disease burden during and after treatment. This robust assay provides sensitive and accurate measurement of residual disease that allows physicians to predict patient outcomes, assess response to therapy over time, monitor patients during remission and detect potential relapse. The clonoSEQ Assay is a single-site assay performed at Adaptive Biotechnologies. It is also available as a CLIA-regulated laboratory developed test (LDT) service for use in other lymphoid cancers.

clonoSEQ was reviewed under the FDA’s De Novo premarket review pathway, a regulatory pathway for some low- to moderate-risk novel devices for which there is no legally marketed predicate device.

For important information about the FDA-cleared uses of clonoSEQ, including the full intended use, limitations, and detailed performance characteristics, please visit www.clonoSEQ.com/technical-summary.

On October 1, 2018 AVEO Oncology (NASDAQ: AVEO) reported that it has initiated topline analysis of the phase 3 TIVO-3 clinical trial on the unanimous recommendation of the independent TIVO-3 Study Steering Committee, and after notice to the FDA (Press release, AVEO, OCT 1, 2018, View Source [SID1234529690]). The TIVO-3 trial is the Company’s randomized, controlled, multi-center, open-label study to compare FOTIVDA (tivozanib) to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). The Company expects to complete data analysis and report topline results from the study in approximately 6 weeks.

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The Steering Committee recommendation was preceded by a slowing in the rate of progression free survival (PFS) events in the trial over the last 4-6 months. The reasons given by the Steering Committee for the unanimous recommendation were that current patients have been on study for at least one year and may not progress for some time, and that the small reduction in events at the time of final analysis was unlikely to materially affect the clinical interpretation of the results. As of September 26, 2018, the last review of events, a total of 242 PFS events had occurred in the trial. The Company plans to set the data cutoff date for the primary analysis at October 4, 2018. Performing the primary analysis at 242 events reduces the power of the study from 90% (based on the prior target of 255 PFS events) to 88%.

Following the last review of events, 42 patients remain on treatment in the TIVO-3 study with 28 of the remaining patients yet to have a PFS event as determined by the independent radiology committee. All patients still enrolled in the study will continue to receive treatment per study protocol. The Company will remain blinded to study data until data analysis is complete.

"Initiation of the topline analysis of the TIVO-3 trial brings us one step closer to potentially realizing the strategy we laid out in 2015, which included commercialization of tivozanib in the United States and Europe, and exploration of tivozanib’s clinical potential in immunotherapy combinations," said Michael Bailey, president and chief executive officer of AVEO. "With the introduction of immunotherapy as a treatment for earlier-line RCC, survival among patients is extending well beyond disease progression on first- and second-line treatment, which we believe may substantially increase the third-plus-line opportunity for tivozanib. TIVO-3 has the potential to serve as the first prospective Phase 3 randomized dataset in this setting, creating an evidence-based guidepost for sequencing therapies in refractory disease. We look forward to announcing the topline results of TIVO-3 in the coming weeks."

The TIVO-3 trial was designed to enroll patients with RCC who have failed at least two prior regimens, including VEGFR-TKI therapy. Eligible patients may also have received checkpoint inhibitor therapy in earlier lines of treatment. Patients are randomized 1:1 to receive either tivozanib or sorafenib, with no crossover between arms. The primary endpoint of the study is PFS. Secondary endpoints include overall survival (OS), overall response rate, and safety and tolerability. TIVO-3, together with the previously completed TIVO-1 trial of tivozanib in the first-line treatment of RCC, is designed to support a regulatory submission of tivozanib in the U.S. as a treatment for RCC, if the data are positive. TIVO-3 patients were exclusively enrolled in North America, Western Europe, and Central Europe.

About Tivozanib (FOTIVDA)

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Hakko Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.1,2 Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models, enabling potentially enhanced activity when used in combination with immune modulating therapy.3 As part of a North American registration plan, tivozanib is currently being studied in the Phase 3 TIVO-3 trial, a randomized, controlled, multi-center, open-label study to compare tivozanib to sorafenib in subjects with refractory RCC. Tivozanib has been investigated in several tumors types, including renal cell, hepatocellular, colorectal and breast cancers.

On October 1, 2018 Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) reported that it earned a $22 million payment from Verastem Oncology under the license agreement between the Company and Verastem for COPIKTRA (duvelisib) (Press release, Infinity Pharmaceuticals, OCT 1, 2018, View Source [SID1234530645]). The payment was earned upon the approval by the U.S. Food and Drug Administration (FDA) on September 24, 2018 of duvelisib for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies, as well as accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies.

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"We are really pleased that duvelisib is now available for patients with CLL/SLL and follicular lymphoma and are proud of the role Infinity played in its development," said Adelene Perkins, Chief Executive Officer and Chair of Infinity. "This $22 million FDA approval payment from Verastem supports Infinity’s continued expansion of the development of IPI-549, our first-in-class, oral, immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase-gamma (PI3K-gamma), including in doublet and triplet combination trials to identify the best combination regimens to treat patients with specific types of cancer."

In 2016, Infinity entered into a license agreement granting Verastem an exclusive worldwide license for the research, development, commercialization, and manufacture of duvelisib and products containing duvelisib in oncology. Pursuant to the terms of the license agreement, Verastem has notified Infinity of its election to make the $22 million payment in cash, which Infinity expects to receive later this year. Infinity also is eligible for royalties on worldwide net sales of duvelisib ranging from the mid-to-high single digits, shared equally with Takeda.

Infinity’s updated 2018 financial guidance is:

Net Loss: Infinity expects net loss for 2018 to range from $10 million to $20 million.

Cash and Investments: Infinity expects to end 2018 with a year-end cash, cash equivalents and available-for-sale securities balance ranging from $50 million to $60 million.

Cash Runway: Based on its current operational plans, Infinity expects that its existing cash, cash equivalents and available-for-sale securities will be adequate to satisfy the company’s capital needs into 2020. Infinity’s financial guidance excludes additional funding or business development activities and does not include a potential $2 million payment from PellePharm, a private company, upon initiation of a Phase 3 study for the hedgehog inhibitor program, which Infinity licensed to PellePharm in 2013.