On May 26, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, reported that it will present data from its broad solid tumor and hematology portfolios in eight presentations at the upcoming American Society of Cancer Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held in Chicago from June 3-7, 2022 (Press release, BeiGene, MAY 26, 2022, View Source [SID1234615125]). Highlights include new clinical data for its BTK-inhibitor zanubrutinib (BRUKINSA):

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Long-term safety and efficacy results from the Phase 3 ASPEN trial of BRUKINSA versus ibrutinib in patients with Waldenström macroglobulinemia, with median follow up of 43 months
Primary analysis from the Phase 2 ROSEWOOD trial of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma
"Waldenström macroglobulinemia is a chronic, indolent condition with median survival of 14 to 16 years, so it is important to understand the long-term profile for treatments. The durable response and continued safety advantage seen in the long-term follow up period of the ASPEN trial supports our confidence in the compelling safety and efficacy profile for BRUKINSA," said Lai Wang, Ph.D., Global Head of R&D at BeiGene. "We continue to explore zanubrutinib in additional indications that may lack tolerable and effective treatment options and we are encouraged by the results from our Phase 2 ROSEWOOD study in a high-risk, relapsed/refractory follicular lymphoma population."

In addition to results from BRUKINSA trials, the company will also present posters from its early development pipeline and results from the Phase 3 RATIONALE-309 trial of tislelizumab in the Rapid Abstract Update session on June 5th. RATIONALE 309 is a Phase 3 trial of tislelizumab, a humanized anti-PD-1 monoclonal antibody, in combination with chemotherapy versus chemotherapy plus placebo as a first-line treatment for patients with recurrent or metastatic nasopharyngeal cancer. These results were initially presented at the virtual ASCO (Free ASCO Whitepaper) Plenary Series on April 19, 2022: BeiGene Presents Updated Results from Phase 3 RATIONALE-309

For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual ASCO (Free ASCO Whitepaper) booth: www.BeiGenevirtualexperience.com

——————-ASPEN and ROSEWOOD details——————-

ASPEN: Long-term follow-up results of a Phase 3 randomized trial of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM)
Abstract Number: 7521

With a median follow-up of 43 months, BRUKINSA continued to demonstrate clinically meaningful efficacy and a tolerable safety profile in patients with WM.

Exploratory analyses showed a consistent trend of deeper, earlier, and more durable responses (CR+VGPR) compared with ibrutinib over time
Median time to CR+VGPR was shorter for zanubrutinib: 6.7 months (range, 1.9-42.0) vs ibrutinib: 16.6 months (range, 2.0-49.9)
Over the follow-up period, patients receiving with zanubrutinib had fewer adverse events leading to death, treatment discontinuation, and dose reduction as compared with ibrutinib
The prevalence of atrial fibrillation, hypertension, and bleeding were lower in the zanubrutinib arm at all time intervals; Neutropenia occurred early, and prevalence decreased over time for patients receiving zanubrutinib
Zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) monotherapy in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): primary analysis of the Phase 2 randomized ROSEWOOD trial
Abstract Number: 7510

The ROSEWOOD trial met its primary endpoint with a 68.3% overall response rate (ORR) in the zanubrutinib plus obinutuzumab arm versus 45.8% in the obinutuzumab arm (p = 0.0017) and median follow-up of 12.5 months. Zanubrutinib plus obinutuzumab was generally well-tolerated, with safety results consistent with previous studies of both medicines.

Zanubrutinib plus obinutuzumab was associated with a deep and durable response, with a complete response (CR) rate of 37.2% compared to 19.4% for obinutuzumab alone; 18-month duration of response rate was 70.9% in the zanubrutinib plus obinutuzumab arm versus 54.6% in the obinutuzumab arm
Time to next anti-lymphoma treatment was significantly prolonged in the zanubrutinib plus obinutuzumab arm (HR 0.37; p ,0.0001)
Median progression-free survival was 27.4 months in the zanubrutinib plus obinutuzumab arm compared to 11.2 months in the obinutuzumab arm (HR: 0.51 [95% CI, 0.32, -0.81],)
The most common any-grade and grade ≥ 3 toxicities in the zanubrutinib plus obinutuzumab arm were hematologic toxicities, and other toxicities were similar between the two arms
Infusion-related reactions were more frequent in the obinutuzumab monotherapy arm
About ASPEN

ASPEN is a randomized, global, open-label, multi-center Phase 3 study comparing BRUKINSA to ibrutinib in patients with relapsed or refractory (R/R) or treatment-naive Waldenström macroglobulinemia. The primary endpoint was proportion of patients achieving complete response or very good partial response (CR+VGPR). Patients with MYD88 mutations were assigned to cohort 1 and randomized 1:1 to receive BRUKINSA 160 mg twice daily or ibrutinib 420 mg once daily. Patients without MYD88 mutations were assigned to cohort 2 and received BRUKINSA160 mg twice daily. A total of 229 patients were enrolled in the trial, with 130 patients receiving BRUKINSA and 99 patients receiving ibrutinib.

As assessed by an independent review committee based on the modified Sixth International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) response criteria (Treon 2015), the combined rate of CR and VGPR in the overall intent-to-treat population was 28% with BRUKINSA (95% CI: 20, 38), compared to 19% with ibrutinib (95% CI: 12, 28). While this difference was not statistically significant (p=0.09), BRUKINSA did achieve numerically higher VGPR rates and trends towards increased depth of response.

In the ASPEN trial, BRUKINSA demonstrated a more favorable safety profile compared to ibrutinib with lower frequency of certain adverse events, including atrial fibrillation or flutter (2% vs. 15%) and major hemorrhage (6% vs. 9%). Of the 101 patients with WM treated with BRUKINSA, 4% of patients discontinued due to adverse events, and adverse events leading to dose reduction occurred in 14% of patients.

About ROSEWOOD

ROSEWOOD is a randomized, open-label, Phase 2 study comparing BRUKINSA plus obinutuzumab to obinutuzumab alone in patients with R/R FL who have received two or more lines of therapy. The primary endpoint was overall response rate (ORR) assessed by independent central review (ICR) according to the Lugano classification. Select secondary endpoints include: investigator-assessed ORR, ICR-reviewed and investigator-assed duration of response and progression-free survival, overall survival, ICR- and investigator-assessed CR and complete metabolic response rate. A total of 217 patients were enrolled in the trial, with 145 patients receiving BRUKINSA plus obinutuzumab and 72 patients receiving obinutuzumab.

About BRUKINSA

BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

BRUKINSA is supported by a broad clinical program which includes more than 3,900 subjects in 35 trials across 28 markets. To date, BRUKINSA has received more than 20 approvals covering more than 40 countries and regions, including the United States, China, the EU and Great Britain, Canada, Australia and additional international markets. Currently, more than 40 additional regulatory submissions are in review around the world.

About Tislelizumab

Tislelizumab is an anti-programmed death receptor-1 (PD-1) inhibitor designed to help aid the body’s immune cells to detect and fight tumors. Tislelizumab, a humanized monoclonal antibody, is specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

Tislelizumab is the first drug from BeiGene’s immuno-oncology biologics program and is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene has initiated or completed more than 20 potentially registration-enabling clinical trials in 35 countries and regions, including 17 Phase 3 trials and four pivotal Phase 2 trials. More information on the clinical trial program for tislelizumab can be found at: View Source

Tislelizumab is approved by the China National Medical Products Administration (NMPA) as a treatment for eight indications, including multiple approvals in non-small cell lung cancer (NSCLC). Tislelizumab is currently in regulatory review in one additional indication in first line recurrent/metastatic nasopharyngeal cancer in China; as a potential treatment for unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic therapy in the U.S.; and in NSCLC and ESCC in Europe. In January 2021, BeiGene partnered with Novartis to accelerate the clinical development and marketing of tislelizumab in North America, Europe and Japan.

BeiGene Oncology

BeiGene is committed to advancing best- and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D and medical affairs team of approximately 2,900 colleagues dedicated to advancing more than 100 clinical trials that have involved more than 16,000 subjects. Our expansive portfolio is directed predominantly by our internal colleagues supporting clinical trials in more than 45 geographies. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. BeiGene currently has three approved medicines discovered and developed in our own labs: BTK inhibitor BRUKINSA in the U.S., China, the European Union, Great Britain, Canada, Australia, and additional international markets; and the non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab as well as the PARP inhibitor pamiparib in China.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen, Bristol Myers Squibb, EUSA Pharma, and Bio-Thera. We also plan to address greater areas of unmet need globally through our other collaborations including with Mirati Therapeutics, Seagen, and Zymeworks.

In January 2021, BeiGene and Novartis announced a collaboration granting Novartis rights to co-develop, manufacture, and commercialize BeiGene’s anti-PD1 antibody tislelizumab in North America, Europe, and Japan. Building upon this productive collaboration, including a biologics license application (BLA) under U.S. Food and Drug Administration (FDA) review, BeiGene and Novartis announced an option, collaboration, and license agreement in December 2021 for BeiGene’s TIGIT inhibitor ociperlimab that is in Phase 3 development. Novartis and BeiGene also entered into a strategic commercial agreement through which BeiGene is promoting five approved Novartis Oncology products across designated regions of China.

On May 26, 2022 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that new pivotal data on its investigational CD20xCD3 T-cell engaging bispecific antibody, glofitamab, will be presented for the first time at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from June 3-7 and the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Congress from June 9-12 (Press release, Genentech, MAY 26, 2022, View Source [SID1234615124]). Data from the Phase II NP30179 expansion study demonstrated that, after a median follow-up of more than 12 months, fixed-duration glofitamab (given for a fixed amount of time, and not taken until disease progression) induces durable complete responses (CRs) in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who had received a median of three prior therapies.

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"These data bring us one step closer towards our goal of finding solutions for people with heavily pre-treated diffuse large B-cell lymphoma, which often relapses and becomes more aggressive each time it returns," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "The potential of glofitamab as a new fixed-duration, readily available treatment could be instrumental to improving outcomes for people with this difficult-to-treat cancer who otherwise have limited options."

The pivotal Phase II NP30179 expansion study included patients with heavily pre-treated and highly refractory DLBCL, with 58.3% of patients refractory to their initial therapy and about one-third (33.1%) having received prior CAR T-cell therapy. After a median follow-up of 12.6 months, 39.4% of patients (n=61/155) achieved a CR (primary efficacy endpoint) and half of them (51.6%; n=80/155) achieved an overall response (the percentage of patients with a partial or complete response; secondary efficacy endpoint), as assessed by an independent review committee. The majority (77.6%) of complete responses were durable and ongoing at 12 months and the median duration of complete response had not yet been reached (not evaluable [16.8 months, not evaluable]). Cytokine release syndrome (CRS) was the most common adverse event occurring in 63.0% of patients. CRS events were predictable, generally low grade (mainly Grade 1 [47.4%] or 2 [11.7%]), occurred at initial doses, and only one patient discontinued glofitamab due to CRS. Incidence of Grade 3+ CRS was low (3.9%), with no Grade 5 events.

"I’m encouraged by these data as they signify new hope for these patients who otherwise have limited effective treatment options and have faced disappointment from not responding to multiple rounds of treatments," said Associate Professor Michael Dickinson, Hematologist and Lead of the Aggressive Lymphoma Disease Group within Clinical Haematology at Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Australia. "These glofitamab data suggest that patients may be able to achieve durable responses with a set course of treatment that they don’t have to take continuously until disease progression."

Data from the NP30179 study have been submitted for approval to the European Medicines Agency (EMA), and submissions to additional health authorities worldwide, including to the U.S. Food and Drug Administration (FDA), are planned this year. Glofitamab is being investigated in several clinical trials and explored in earlier lines of lymphoma treatment.

Genentech is committed to improving standards of care to enhance the treatment experience and outcomes for people with blood cancers and the scientific data we are sharing at ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper) from our portfolio propels us further towards this goal. Genentech is investigating its CD20xCD3 T-cell engaging bispecific antibodies glofitamab and mosunetuzumab further as subcutaneous formulations and in additional Phase III studies that will expand the understanding of their impact in earlier lines of treatment, with the aim of providing people with different types of lymphomas with robust and durable treatment outcomes. Additionally, the European Commission (EC) recently granted approval of Polivy (polatuzumab vedotin) in combination with Rituxan (rituximab) plus cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL), and the EMA’s Committee for Medicinal Products for Human Use recommended mosunetuzumab for approval for patients with R/R follicular lymphoma, who have received at least two prior systemic therapies.

About Glofitamab

Glofitamab is an investigational CD20xCD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. Glofitamab is based on a novel structural format called ‘2:1’. It is engineered to have two ‘Fab’ regions which bind to CD20, and one ‘Fab’ region which binds to CD3. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. A robust clinical development program for glofitamab is ongoing, investigating the molecule as a monotherapy and in combination with other medicines, for the treatment of people with B-cell non-Hodgkin’s lymphomas, including diffuse large B-cell lymphoma and mantle cell lymphoma, and other blood cancers.

About the NP30179 Study

The NP30179 study [NCT03075696] is a Phase I/II, multicenter, open-label, dose-escalation and expansion study evaluating the safety, efficacy and pharmacokinetics of glofitamab in people with relapsed or refractory diffuse large B-cell lymphoma. Outcome measures include complete response rate by independent review committee (primary endpoint), overall response rate, duration of response, progression-free survival, safety and tolerability (secondary endpoints).

About Polivy (polatuzumab vedotin-piiq)

Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC). The CD79b protein is expressed specifically in the majority of B cells, an immune cell impacted in some types of non-Hodgkin’s lymphoma (NHL), making it a promising target for the development of new therapies. Polivy binds to CD79b and destroys these B cells through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells. Polivy is being developed by Genentech using Seagen ADC technology and is currently being investigated for the treatment of several types of NHL.

Polivy U.S. Indication

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat diffuse large B-cell lymphoma in adults who have progressed after at least two prior therapies.

The accelerated approval of Polivy is based on a type of response rate. There are ongoing studies to confirm the clinical benefit of Polivy.

Important Safety Information

Possible serious side effects

Everyone reacts differently to Polivy therapy, so it’s important to know what the side effects are. Some people who have been treated with Polivy have experienced serious to fatal side effects. A patient’s doctor may stop or adjust a patient’s treatment if any serious side effects occur. Patients must contact their healthcare team if there are any signs of these side effects.

Nerve problems in arms and legs: This may happen as early as after the first dose and may worsen with every dose. If a patient already has nerve pain, Polivy may make it worse. The patient’s doctor will monitor for signs and symptoms, such as changes in sense of touch, numbness or tingling in hands or feet, nerve pain, burning sensation, any muscle weakness, or changes to walking patterns
Infusion-related reactions: A patient may experience fever, chills, rash, breathing problems, low blood pressure, or hives within 24 hours of the infusion
Infections: Patients should contact their healthcare team if they experience a fever of 100.4°F or higher, chills, cough, or pain during urination. Also, a patient’s doctor may give medication before giving Polivy, which may prevent some infections, and monitor blood counts throughout treatment with Polivy. Treatment with Polivy can cause severe low blood cell counts
Rare and serious brain infections: A patient’s doctor will monitor the patient closely for signs and symptoms of these types of infections. Patients should contact their doctor if they experience confusion, dizziness or loss of balance, trouble talking or walking, or vision changes
Tumor lysis syndrome: Caused by the fast breakdown of cancer cells. Signs include nausea, vomiting, diarrhea, and lack of energy
Potential harm to liver: Some signs include tiredness, weight loss, pain in the abdomen, dark urine, and yellowing of the skin or the white part of the eyes. Patients may be at higher risk if they already have liver problems or are taking other medication
Side effects seen most often

The most common side effects during treatment were:

Low blood cell counts (platelets, red blood cells, white blood cells)
Nerve problems in arms and legs
Tiredness or lack of energy
Diarrhea
Nausea
Fever
Decreased appetite
Infections
Polivy may not be for everyone. A patient should talk to their doctor if they are:

Pregnant or may be pregnant: Data have shown that Polivy may harm an unborn baby
Planning to become pregnant: Women should avoid getting pregnant while taking Polivy. Women should use effective contraception during treatment and for at least 3 months after their last Polivy treatment. Men taking Polivy should use effective contraception during treatment and for at least 5 months after their last Polivy treatment
Breastfeeding: Women should not breastfeed while taking Polivy and for at least 2 months after the last dose
These may not be all the side effects. Patients should talk to their healthcare provider for more information about the benefits and risks of Polivy treatment.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the full Prescribing Information for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit View Source

On May 26, 2022 Oncoinvent AS, a clinical stage company advancing a pipeline of radiopharmaceutical products across a variety of solid cancers, reported that interim safety data from its ongoing Phase 1 RAD-18-002 clinical trial assessing the dose, safety, and tolerability of Radspherin, in patients with peritoneal carcinomatosis from colorectal carcinoma will be presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which will take place in Chicago, IL (both in-person and virtually) from June 3 to 7, 2022 (Press release, Oncoinvent, MAY 26, 2022, View Source [SID1234615123]). The poster, titled "First experience with 224Radium-labelled microparticles (Radspherin) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study)" will be presented by Principle Investigator Stein Gunnar Larsen, MD during the "Gastrointestinal Cancer – Colorectal and Anal" session at 9:00 a.m. EDT on June 4, 2022.

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"We are excited to share these compelling and important interim safety data at ASCO (Free ASCO Whitepaper), which continues to demonstrate that all dose levels of Radspherin are well tolerated with no dose limiting toxicities due to the Radspherin treatment observed to date," said Jan A. Alfheim, Chief Executive Officer of Oncoinvent. "The data to be presented provides strong support as we progress Radspherin through clinical development. In particular, the observed biodistribution of Radspherin in this study is highly encouraging. We look forward to reporting longer-term safety, dosimetry, and first efficacy results of Radspherin later this year."

Details of the poster presentation are as follows:

Poster Presentation Title: First experience with 224Radium-labelled microparticles (radspherin) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study).
Session Title: Gastrointestinal Cancer – Colorectal and Anal
Date/Time: June 4, 2022 at 9:00 a.m. EDT
Presenting Author: Stein G Larsen
Abstract Number: 3599

This first-in-human Phase 1 study is designed to evaluate the safety and tolerability of Radspherin after dose escalation at increasing levels of 1-2-4-7 MBq and explore the highest tolerated dose and biodistribution. In this planned safety interim analysis, conducted 21 days following administration at two specialized cytoreductive surgery-hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) centers (Norwegian Radium Hospital and Uppsala University Hospital), a total of 23 patients were enrolled; 14 in the dose escalation cohort, 3 in the repeated cohort, and 6 in an expansion cohort. Radspherin was injected in the abdominal cavity through an in-dwelling catheter 2 days after completion of CRS-HIPEC. The maximal tolerated dose and biodistribution were evaluated by single photo-emission computed tomography and computed tomography (SPECT/CT) imaging.

Key results:

The biodistribution of Radspherin showed a relatively even peritoneal distribution, and no patients had compartments of the abdominal cavity without radioactivity, and the number of hot spots were low.
No serious adverse events were observed related to treatment with Radspherin.
The 7Mbq dose was selected as recommended dose as no dose limiting toxicity (DLT) was observed at this level.
Radspherin is also being evaluated at the 7Mbq dose in a Phase 1 open-label, dose-escalation clinical trial in subjects with peritoneal carcinomatosis from ovarian cancer following complete cytoreductive surgery.

About the RAD-18-002 Study

The phase 1 open-label, dose-escalation clinical trial is designed to assess the dose, safety, and tolerability of Radspherin, an α-emitting radionuclide therapy, administered into the intraperitoneal cavity in subjects with peritoneal carcinomatosis from colorectal carcinoma following complete cytoreductive surgery and HIPEC. Key objectives in the study include determining maximum tolerated dose, abdominal biodistribution, and preliminary anti-tumor activity. Please refer to www.clinicaltrials.gov for additional clinical trial details.

On May 26, 2022 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported initial dose-escalation data from the Phase 1 study evaluating XmAb104, a PD-1 x ICOS bispecific antibody, in patients with advanced solid tumors (DUET-3) (Press release, Xencor, MAY 26, 2022, View Source [SID1234615122]). These results will be presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), during the poster session "Developmental Therapeutics—Immunotherapy" on Sunday, June 5, 2022, from 8:00 a.m. to 11 a.m. CDT in Hall A at McCormick Place in Chicago.

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DUET-3 is an ongoing Phase 1 study of XmAb104 to assess the candidate’s safety and tolerability profile in patients with advanced solid tumors and to determine the maximum tolerated dose (MTD). The expansion portion of the study is currently enrolling patients with colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), non-squamous non-small cell lung cancer (NSCLC), sarcoma, melanoma and clear-cell renal cell carcinoma (RCC) and is randomizing patients 1:1 to receive 10 mg/kg intravenous XmAb104 every two weeks as monotherapy or in combination with ipilimumab.

"XmAb104 is engineered to selectively engage T cells that express both PD-1 and ICOS, important regulators of T cell activity, and we have observed biomarker activity consistent with engagement of both receptors. XmAb104 has been well tolerated and is exhibiting a distinct safety profile compared to other clinical ICOS programs, which, along with early anti-tumor activity in patients, supports its evaluation in expansion cohorts," said Allen Yang, M.D., Ph.D., senior vice president and chief medical officer at Xencor. "The ongoing expansion portion of the study is testing XmAb104, with or without the anti-CTLA-4 antibody ipilimumab, as CTLA-4 blockade has been found to increase the frequency of ICOS-expressing T cells in multiple solid tumor types."

Additionally, a trial-in-progress poster, "A phase 2, multicenter, parallel-group, open-label study of vudalimab (XmAb20717), a PD-1 x CTLA-4 bispecific antibody, alone or in combination with chemotherapy or targeted therapy in patients with molecularly defined subtypes of metastatic castration-resistant prostate cancer," will be presented during the session "Genitourinary Cancer—Prostate, Testicular, and Penile" on Monday, June 6, 2022, from 1:15 p.m. to 4:15 p.m. CDT in Hall A.

Posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com, at the time of the formal presentations at ASCO (Free ASCO Whitepaper).

Key Highlights from DUET-3 (Abstract #2604)

At the data cut off on April 15, 2022, 62 patients had been treated in nine dose-escalation cohorts escalating from 0.002 to 15 mg/kg of XmAb104 administered every other week in four-week cycles. Patients were a median age of 63 years and had a median of three prior systemic therapies. 62.9% of patients had received at least one prior checkpoint therapy, and 91.9% of patients had Stage IV disease.

Patients presented with the following primary tumor types: CRC (n=14), pancreatic adenocarcinoma (n=8), soft tissue sarcoma (n=8), melanoma (n=6), HNSCC (n=5), RCC (n=4), endometrial cancer (n=2), NSCLC (n=2) and other solid tumor types (n=8). Of the patients with CRC, eight were microsatellite stable (MSS), three were microsatellite instable (MSI) and three were not defined. Most patients had tumors generally not considered to be sensitive to checkpoint inhibition.

Safety and Tolerability

Safety was evaluated in all 62 patients. XmAb104 was well tolerated through the highest tested dose cohort, and treatment-related adverse events (TRAE) were mostly mild. The most common TRAEs (>5 patients) were decreased appetite (9.7%), diarrhea (9.7%), fatigue (9.7%) and maculopapular rash (8.1%). Immune-related adverse events were reported for a limited number of patients, were predominantly Grade 1 or 2, and showed no relationship to dose level. Two patients (3.2%) experienced serious TRAEs, including a Grade 3 hyperbilirubinemia and a Grade 4 asymptomatic lipase increase; both events resolved with prednisone. Four patients (6.5%) discontinued from the study due to an adverse event.

No dose-limiting toxicities were observed, and the MTD was not reached. The recommended dose for continued study, based on feasibility of administration at higher dose levels and a review of safety data with investigators, was determined to be 10 mg/kg.

Clinical Activity Highlights

The efficacy analysis included 51 evaluable patients who received any amount of XmAb104 and had at least one post-baseline assessment by RECIST 1.1. At the data cut off, two confirmed partial responses (PR), one unconfirmed PR, and stable disease have been observed:

A patient with undifferentiated pleomorphic sarcoma, who was immunotherapy naïve, presented with two target lesions in the lung and a subpleural lingular nodule. The patient was enrolled into the 0.2 mg/kg cohort and dose escalated to 0.6 mg/kg. The nodule completely resolved, and a single non-target lesion remained in the lung. The confirmed partial response continued at the time of the data cut (28 months).
A patient with clear cell RCC, who had previously received treatment with pembrolizumab/axitinib, presented with two target lesions in the ribs, one target lesion in a lymph node, and a non-target lesion in bone. The patient was treated at the 10 mg/kg dose. A partial response was observed at the end of Cycle 2, and the patient remained in response at the time of the data cut (8 months).
A patient with HNSCC, who had recently received treatment with pembrolizumab, was enrolled into the 1.8 mg/kg dose cohort. Prior therapies also included neo-adjuvant nivolumab, cisplatin, nivolumab and a GAL-3 inhibitor, and the patient experienced disease progression on all prior therapies. Two target lesions in the lung were identified, and the patient experienced a partial response at the end of Cycle 2.
Two patients with CRC have experienced durable stable disease for over 20 months, both ongoing at the time of data cut. A patient with microsatellite instability high (MSI-H)-CRC was treated at an initial dose of 1.8 mg/kg and dose escalated to 10 mg/kg. Laboratory results indicated a decrease in the tumor marker CEA over time. A second patient, with MSI-H CRC, was treated at the 10 mg/kg dose, and at the time of the data cut, continued to experience stable disease in Cycle 22.
Pharmacokinetics/Pharmacokinetics Assessments

Data from assessments of pharmacokinetics (PK) and pharmacodynamics (PD) will not be shown in the poster presentation. The PK analysis indicated a linear and dose-proportional profile. Biomarker analyses indicated complete receptor saturation on peripheral T cells beginning at the 0.6 mg/kg dose level.

About XmAb104

XmAb104 is an investigational XmAb bispecific antibody designed to promote tumor-selective T-cell activation by simultaneously targeting immune checkpoint receptor PD-1 and the immune co-stimulatory receptor ICOS. Xencor’s approach to dual checkpoint inhibition and co-stimulation reduces the need for multiple antibodies and allows for more selective targeting of T cells with high target expression, which may potentially improve the therapeutic index of combination immunotherapies. In preclinical studies, dual blockade of PD-1 and ICOS with XmAb104 significantly enhanced T cell proliferation and activation, and anti-tumor activity in vivo. XmAb104 is currently being evaluated, as a monotherapy and in combination with ipilimumab, in the expansion portion of a Phase 1 clinical study for the treatment of patients with advanced solid tumors.

On May 26, 2022 Merck, a leading science and technology company, reported the latest research representing the Company’s innovative oncology portfolio has been accepted for presentation at this year’s American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, June 3-7, 2022 (Press release, Merck & Co, MAY 26, 2022, View Source [SID1234615121]). Data encompass Company-sponsored, investigator-sponsored, and external collaboration studies.

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Abstracts to be shared at the meeting include data for the Company’s licensed medicines BAVENCIO (avelumab), TEPMETKO (tepotinib) and ERBITUX (cetuximab), and its oncology pipeline. The presentations span key tumor types including advanced urothelial carcinoma (UC), advanced renal cell carcinoma (RCC), metastatic non-small cell lung cancer (NSCLC), metastatic colorectal cancer (CRC), and head and neck cancer (SCCHN).

"We look forward to coming together with the scientific community at ASCO (Free ASCO Whitepaper) 2022, where we will share the latest data from our portfolio, which demonstrate our determination to make a real difference in the lives of patients with some of the most challenging cancers," said Victoria Zazulina, Head of Development Unit, Oncology, for the Healthcare business of Merck.

Select presentations include:

BAVENCIO (avelumab): New analyses of long-term data from the Phase III JAVELIN Bladder 100 study of BAVENCIO as first-line maintenance treatment in advanced UC, including data from subgroups defined by best response to first-line chemotherapy and in patients who did or did not receive second-line treatment after BAVENCIO maintenance.
TEPMETKO (tepotinib): Data for the oral MET inhibitor TEPMETKO include two poster presentations from the VISION trial reporting efficacy, safety and quality-of-life results of TEPMETKO in Asian patients with METex14 skipping NSCLC, and updated efficacy and safety results of TEPMETKO and exploratory biomarker analyses in patients with NSCLC with high-level MET amplification enrolled into Cohort B of the VISION trial based on liquid biopsy.
ERBITUX (cetuximab): Abstracts from key investigator-sponsored studies (ISS) exploring ERBITUX-based combinations, including the Phase III FIRE-4 study of early switch-maintenance from ERBITUX/FOLFIRI to bevacizumab/5-FU and rechallenge in later lines for RAS wild-type mCRC patients, and the Phase II AVETUXIRI study evaluating BAVENCIO combined with ERBITUX and irinotecan for refractory microsatellite stable metastatic colorectal cancer.
Berzosertib: Results from research collaborations assessing the intravenous ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor berzosertib, including the National Cancer Institute’s (NCI) Cancer Therapy Evaluation Program 9938 Phase I study of berzosertib plus irinotecan in patients with advanced solid tumors and NCI single-arm Phase II data of berzosertib plus topotecan in patients with relapsed extra-pulmonary small cell neuroendocrine carcinomas.
Below is a selection of key Merck-related abstracts accepted for presentation at ASCO (Free ASCO Whitepaper) 2022:

Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): long-term outcomes from JAVELIN Bladder 100 in subgroups defined by response to 1L chemotherapy

Randomized study to investigate a switch maintenance concept with 5-FU plus Bevacizumab after FOLFIRI plus Cetuximab induction treatment versus continued treatment with FOLFIRI plus cetuximab: report of a secondary endpoint of the phase-III FIRE-4 study (AIO KRK-0114)

*These studies are sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, under its Cooperative Research and Development Agreement with Merck for M6620.

All Merck press releases are distributed by e-mail at the same time they become available on the Merck website. Please go to www.merckgroup.com/subscribe to register online, change your selection or discontinue this service.

Commitment to Cancer
Merck is a science-led organization dedicated to delivering transformative medicines with the goal of making a meaningful difference in the lives of people affected by cancer. Our oncology research efforts aim to leverage our synergistic portfolio in oncogenic pathways, immuno-oncology, and DNA Damage Response (DDR) to tackle challenging tumor types in gastrointestinal, genitourinary, and thoracic cancers. Our curiosity drives our pursuit of treatments for even the most complex cancers, as we work to illuminate a path to scientific breakthroughs that transform patient outcomes. Learn more at www.merckgrouponcology.com.

About BAVENCIO (avelumab)
BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.7-9 In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications
The European Commission (EC) has authorized the use of BAVENCIO as monotherapy for the first-line maintenance treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) who are progression-free following platinum-based chemotherapy. BAVENCIO in combination with axitinib is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). BAVENCIO is also authorized by the EC for use as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (MCC).

In the US, BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

BAVENCIO in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced RCC. Additionally, the US Food and Drug Administration (FDA) granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic MCC. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

BAVENCIO is currently approved for at least one indication for patients in more than 50 countries.

BAVENCIO Safety Profile from the EU Summary of Product Characteristics (SmPC)
The special warnings and precautions for use for BAVENCIO monotherapy include infusion-related reactions, as well as immune-related adverse reactions that include pneumonitis and hepatitis (including fatal cases), colitis, pancreatitis (including fatal cases), myocarditis (including fatal cases), endocrinopathies, nephritis and renal dysfunction, and other immune-related adverse reactions. The special warnings and precautions for use for BAVENCIO in combination with axitinib include hepatotoxicity.

The SmPC list of the most common adverse reactions with BAVENCIO monotherapy in patients with solid tumors includes fatigue, nausea, diarrhea, decreased appetite, constipation, infusion-related reactions, weight decreased and vomiting. The list of most common adverse reactions with BAVENCIO in combination with axitinib includes diarrhea, hypertension, fatigue, nausea, dysphonia, decreased appetite, hypothyroidism, cough, headache, dyspnea, and arthralgia.

About TEPMETKO (tepotinib)
TEPMETKO is a once-daily oral MET inhibitor that inhibits the oncogenic MET receptor signaling caused by MET (gene) alterations. Discovered and developed in-house at Merck, TEPMETKO has a highly selective mechanism of action, with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations.

TEPMETKO was the first oral MET inhibitor to receive a regulatory approval anywhere in the world for the treatment of advanced NSCLC harboring MET gene alterations, with its approval in Japan in March 2020. In February 2021, the U.S. Food and Drug Administration granted accelerated approval to TEPMETKO, making it the first and only once-daily oral MET inhibitor approved for patients in the U.S. with metastatic NSCLC with METex14 skipping alterations. Tepotinib is available in a number of countries, and under review by various other regulatory authorities globally. To meet an urgent clinical need, tepotinib is also available in a pilot zone of China in line with the government policy to drive early access for innovative medicines approved outside of China.

Merck is also investigating the potential role of tepotinib in treating patients with NSCLC and acquired resistance due to MET amplification in the Phase II INSIGHT 2 study of tepotinib in combination with osimertinib in MET amplified, advanced or metastatic NSCLC harboring activating EGFR mutations that has progressed following first-line treatment with osimertinib.

TEPMETKO Safety Profile from the EU Summary of Product Characteristics (SmPC)
The special warnings and precautions for use for TEPMETKO monotherapy include Interstitial lung disease (ILD) or ILD-like adverse reactions including pneumonitis, increase of Liver enzymes (ALT and AST), QTc prolongation, and embryo-foetal toxicity.

The most common adverse reactions in ≥ 20% of exposed to tepotinib at the recommended dose in the target indication are oedema, mainly peripheral oedema, nausea, hypoalbuminaemia, diarrhoea and increase in creatinine. The most common serious adverse reactions in ≥ 1% of patients are peripheral oedema, generalised oedema and ILD.

About Berzosertib (M6620)
Berzosertib is an investigational, intravenous, potent and selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) protein that blocks ATR activity in cells. Berzosertib is the first ATR inhibitor evaluated in a randomized clinical trial in any tumor type, and it is the lead candidate in Merck’s DNA Damage Response (DDR) inhibitor portfolio. It is currently being investigated in a number of internal and external studies with early phase I/II data in small cell lung cancer, ovarian cancer, and various solid tumors. Berzosertib, formerly known as VX-970, was licensed from Vertex Pharmaceuticals in 2017. Berzosertib is not approved for any use anywhere in the world.

About ERBITUX (cetuximab)
ERBITUX is an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of ERBITUX is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumor cells and the spread of tumors to new sites. It is also believed to inhibit the ability of tumor cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumors, which appears to lead to an overall suppression of tumor growth. Based on in vitro evidence, ERBITUX also targets cytotoxic immune effector cells towards EGFR-expressing tumor cells (antibody-dependent cell-mediated cytotoxicity [ADCC]).

ERBITUX has already obtained market authorization in over 100 countries worldwide for the treatment of RAS wild-type metastatic colorectal cancer and for the treatment of squamous cell carcinoma of the head and neck. Merck licensed the right to market ERBITUX, a registered trademark of ImClone LLC, outside the U.S. and Canada from ImClone LLC, a wholly owned subsidiary of Eli Lilly and Company, in 1998.