On April 11, 2021 Checkmate Pharmaceuticals, Inc. (NASDAQ: CMPI) ("Checkmate"), a clinical stage biopharmaceutical company focused on developing its proprietary technology to harness the power of the immune system to combat cancer, reported the presentation of new translational data from Checkmate’s Phase 1b trial of vidutolimod (CMP-001) in combination with pembrolizumab in patients with advanced anti-PD-1 refractory melanoma (Press release, Checkmate Pharmaceuticals, APR 11, 2021, View Source [SID1234577914]).

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Vidutolimod (CMP-001) demonstrates improved response in noninflamed anti–PD-1 refractory melanoma and response is associated with serum CXCL10 (Abstract #: 5231: NCT02680184)

During the 2021 AACR (Free AACR Whitepaper) Virtual Clinical Trials with Novel Immuno-oncology Strategies Session on April 11 from 4:00 – 5:45pm ET, Jason Luke, MD, Director, Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, and Associate Professor of Medicine, University of Pittsburgh School of Medicine, presents new translational data from an ongoing Phase 1b study of vidutolimod in combination with pembrolizumab in patients with PD-1 blockade refractory advanced melanoma.

Key highlights from these clinical data include:

93% of patients had progressive disease as their last response assessment on prior PD-1 blockade therapy, 42% had an elevated LDH, and the median sum of the target lesions longest diameter was 6.7 cm, indicating advanced disease
Response rates to vidutolimod in combination with pembrolizumab were similar across baseline patient characteristics including BRAF mutation, LDH level, number of prior systemic cancer treatments, best response to prior PD-1 blockade therapy, and prior ipilimumab
Responders and non-responders were not distinguished by baseline tumor characteristics including PD-L1 CPS, IFNg transcriptional signature, CD8+ T cells, or nonsynonymous mutations
All patients showed the expected rapid induction of anti-Qb antibodies to the virus-like particle (VLP), which facilitate the pharmacodynamic response to vidutolimod, and the antibody titers were not associated with clinical response
Clinical activity of vidutolimod in combination with pembrolizumab was associated with serum CXCL10 induction magnitude, induction of an inflammatory gene expression profile, and CD8+ T cells in injected and noninjected tumors
"These translational data provide new insights into the rapid pharmacodynamic responses to vidutolimod and support the conclusion that clinical responses to treatment are not associated with the previously-described predictive markers for response to PD-1 blockade such as inflamed tumors," said Dr. Jason Luke.

On April 11, 2021 Taiho Oncology, Inc. reported efficacy and safety results from the Phase 2 FOENIX-CCA2 trial, a single-arm multicenter Phase 2 study evaluating futibatinib (TAS-120) in patients with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene rearrangements including gene fusions who have failed at least one line of therapy (Press release, Taiho, APR 11, 2021, View Source [SID1234577871]). The data were presented online as an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 Week 1 Clinical Trials Plenary from 2:00 – 3:45 PM ET on April 11, 2021.

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In the FOENIX-CCA2 trial, 103 patients with locally advanced or metastatic unresectable iCCA harboring FGFR2 gene rearrangements including fusions who had received one or more prior lines of systemic therapy received futibatinib 20 mg once daily until disease progression or unacceptable toxicity. The study met its primary endpoint of a greater than 20% objective response rate (ORR) assessed by independent central review with an ORR of 41.7%. Secondary endpoints of duration of response (DOR) and disease control rate (DCR) were also reported; responses were durable, with a median DOR of 9.7 months and 72% of responses ≥6 months, and a DCR of 82.5%. Median progression-free survival (PFS) was 9.0 months and median overall survival (OS) was 21.7 months, with 72% of patients alive at 12 months.

Common treatment-related adverse events (TRAEs) were hyperphosphatemia (85%), alopecia (33%) and dry mouth (30%). The most frequent grade 3 TRAE was hyperphosphatemia (30%), which resolved in patients with adequate management. One grade 4 TRAE of increased ALT was reported and there were no treatment related deaths.

"The results of FOENIX-CCA2 are significant for patients living with refractory intrahepatic cholangiocarcinoma with FGFR2 gene fusions or other rearrangements as futibatinib showed a meaningful ORR of 41.7% and good durability of responses," said medical oncologist Lipika Goyal, MD, MPhil, Massachusetts General Hospital Cancer Center, and lead investigator on the study. "These results represent another example of the promise of precision medicine in cholangiocarcinoma and indicate that futibatinib could be an option for patients with refractory CCA if approved."

The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) for futibatinib for the treatment of patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene rearrangements, including gene fusions in February 2021 based on efficacy and safety results from the FOENIX-CCA2 study. The FDA Office of Orphan Drug Development granted futibatinib orphan drug status for the treatment of cholangiocarcinoma in May 2018.

Additional Data on Futibatinib (TAS-120) in iCCA Presented

Taiho Oncology also presented preclinical and Phase 1 clinical data for futibatinib at AACR (Free AACR Whitepaper) as poster presentations. Presentations include:

Acquired resistance to ATP-competitive and irreversible FGFR inhibitors (FGFRi’s): A library-based approach: Hiroshi Sootome, MS, Manager, Translational Research Planning & Management group, Taiho Pharmaceutical Co., Ltd. (1117). Results were shared online as a poster presentation from 8:30 AM – 11:59 PM ET on April 10, 2021.
Effect of futibatinib on QT/QTc interval: a randomized, controlled, double-blind study: Ikuo Yamamiya, PhD, Associate Director, Bioanalytics & DMPK, Taiho Oncology, Inc. (CT128). Results were shared online as a poster presentation from 8:30 AM – 11:59 PM ET on April 10, 2021.
Evaluation of potential drug-drug interactions (DDIs) between futibatinib and CYP3A inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs): Ikuo Yamamiya, PhD, Associate Director, Bioanalytics & DMPK, Taiho Oncology, Inc. (CT125). Results were shared online as a poster presentation from 8:30 AM – 11:59 PM ET on April 10, 2021.
Please visit Taiho Oncology’s virtual Medical Booth for more information.

"With the low survival rates typically seen in patients with intrahepatic cholangiocarcinoma, the possibility of a new treatment option with demonstrated efficacy and safety is an important development for the oncology community," said Martin J. Birkhofer, MD, Senior Vice President and Chief Medical Officer, Taiho Oncology, Inc. "Taiho Oncology looks forward to sharing these data with regulatory authorities, with the hope of supporting approval for this important investigational therapy."

About Futibatinib (TAS-120)
Futibatinib (TAS-120) is an investigational, oral, potent, selective, and irreversible small-molecule inhibitor of FGFR1, 2, 3 and 4 being studied as a potential treatment for patients with advanced solid tumors with FGFR1-4 genetic aberrations, including cholangiocarcinoma, who were previously treated with chemotherapy or other therapies. Futibatinib selectively and irreversibly binds to the ATP binding pocket of FGFR1-4 resulting in the inhibition of FGFR-mediated signal transduction pathways, reduced tumor cell proliferation and increased tumor cell death in tumors with FGFR1-4 genetic aberrations.

About Cholangiocarcinoma
Cholangiocarcinoma (CCA), also known as bile duct cancer, is not common. About 8,000 people in the U.S. are diagnosed with CCA each year.1 This includes both intrahepatic (inside the liver) and extrahepatic (outside the liver) cancers. CCA can occur at younger ages, but it is seen mainly in older people. The average age of people in the U.S. diagnosed with cancer of the intrahepatic bile ducts is 70, and for cancer of the extrahepatic bile ducts it is 72.1 The five-year survival rate of intrahepatic CCA (all SEER stages combined) is 9%.2

The main treatment for CCA is surgery. Radiation therapy and chemotherapy may be used if the cancer cannot be entirely removed with surgery and in cases where the edges of the tissues removed at the operation show cancer cells (also called a positive margin). Both stage III and stage IV cancers cannot be completely removed surgically. Currently, standard treatment options are limited to radiation, palliative therapy, liver transplantation, surgery, chemotherapy and interventional radiology.3

On April 11, 2021 Antengene Corporation Limited ("Antengene", SEHK: 6996.HK), a leading innovative biopharmaceutical company dedicated to discovering, developing and commercializing global first-in-class and/or best-in-class therapeutics in hematology and oncology, reported that the first patient has been dosed in a phase II trial (BUNCH) in China of ATG-008 (onatasertib), a second-generation mTORC1/2 inhibitor, for the treatment of advanced solid tumors harboring NFE2L2, STK11, RICTOR or other specific genetic alterations (Press release, Antengene, APR 11, 2021, View Source [SID1234577870]). The purpose of the single-arm, open-label trial is to evaluate the safety and efficacy of ATG-008 in patients with such advanced solid tumors that may be predictably sensitive to inhibition of mTORC1/2.

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According to the latest report by the World Health Organization, there were an estimated 19.3 million newly diagnosed cancer cases and 10 million cancer-related mortalities in 2020 globally. Furthermore, the report also projected a 47% increase in cancer-related disease burden in the coming 20 years. China now ranks number one in both cancer incidence and mortality rates[i]. This reminds us of the daunting challenges in cancer treatment and the ever more urgent need for effective novel anti-cancer therapies in China.

There is a close association between the mTOR signaling pathway and genetic mutations in NFE2L2, STK11 and RICTOR. ATG-008, a potent selective inhibitor of mTOR kinase that is currently under clinical development, may induce the cell death of multiple tumor types through the dual-inhibition of mTORC1 and mTORC2. Therefore, mTOR inhibitor ATG-008 has the potential to offer a new treatment option for patients with advanced solid tumors with such genetic alterations. Moreover, preclinical and clinical data also demonstrated the potent antitumor activity of ATG-008 in multiple tumor types.

Dr. Jay Mei, Founder, Chairman and CEO of Antengene, commented: "There are urgent needs for more effective treatment options for patients with various advanced solid tumors. We believe ATG-008 has strong potential to address a serious unmet medical need in a hard-to-treat group of cancers. This trial also marks an important step in the development of our innovative pipeline for the treatment of patients with solid tumors in China. We look forward to producing important clinical data to guide the further development and continue to demonstrate Antengene’s leadership in drug development for mTORC1/2 inhibitors."

Antengene has initiated several clinical trials in China and other Asia Pacific countries and regions with ATG-008 in the treatment of advanced hepatocellular carcinoma (HCC), advanced non-small-cell lung cancer (NSCLC) and in combination with an anti-PD-1 antibody in advanced solid tumors including hepatocellular carcinoma (HCC).

About ATG-008 (onatasertib)

ATG-008 (onatasertib) is a second-generation mTORC1/2 inhibitor, for which development and commercialization rights in Asia Pacific were licensed from Celgene (now Bristol Myers Squibb). ATG-008 is currently being studied in multi-regional clinical trials for the treatment of advanced hepatocellular carcinoma (HCC), as well as non-small-cell lung cancer (NSCLC), advanced solid tumors harboring NFE2L2, STK11, RICTOR or other specific genetic alterations and other cancers as a single agent or in combination with an anti-PD-1 antibody.

On April 11, 2021 Blueprint Medicines Corporation (NASDAQ: BPMC) reported that multiple presentations across the company’s leading systemic mastocytosis (SM) program are being reported at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Blueprint Medicines, APR 11, 2021, View Source [SID1234577847]). The presentations focus on registrational PATHFINDER trial data of AYVAKIT (avapritinib) in advanced SM, PIONEER Part 1 data highlighting the impact of AYVAKIT on skin manifestations of SM, and Phase 1 trial data for BLU-263, a next-generation KIT D816V inhibitor. Blueprint Medicines is developing AYVAKIT for advanced and non-advanced SM, and BLU-263 to further address the range of patient needs in non-advanced SM and other mast cell disorders.

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"Data reported at AACR (Free AACR Whitepaper) reflect our commitment to transform treatment for patients living with systemic mastocytosis," said Becker Hewes, M.D., Chief Medical Officer at Blueprint Medicines. "In the PATHFINDER trial, AYVAKIT had high response rates consistent with EXPLORER trial data, reinforcing the profound clinical benefits that can be achieved by precisely targeting the underlying driver of disease. For BLU-263, data in healthy volunteers showed a well-tolerated safety profile and support our plans to initiate the Phase 2/3 HARBOR study, which expands our development efforts into a broader population of patients with non-advanced SM. We are currently on the precipice of our first potential approval in advanced SM, and we are committed to working closely with the SM community so we may meet the needs of patients as quickly as possible."

AYVAKIT – Highlights from the Registrational Phase 2 PATHFINDER Trial

In a pre-specified interim analysis from the PATHFINDER trial, 32 patients who primarily received a starting dose of 200 mg once daily were evaluable for response, as of a data cutoff date of June 23, 2020. Combined with Phase 1 EXPLORER trial results, these data support Blueprint Medicines’ marketing applications in advanced SM under review in the U.S. and Europe. Overall, 75 percent (95% CI: 57%, 89%) of patients had a confirmed response, which was defined as complete remission with full or partial recovery of peripheral blood counts (CR/CRh), partial remission or clinical improvement. The median time to response was two months, and all responses were ongoing at a median follow-up of 10.4 months. The CRh rate was 19 percent, with a median time to CRh of 5.6 months. These results show that responses deepened over time at a rate consistent with the EXPLORER trial.

AYVAKIT led to robust and durable benefits across a number of additional clinical activity measures. In new patient-reported outcomes data, AYVAKIT showed a statistically significant reduction in total symptom score after 40 weeks (p<0.001), as measured by the Advanced Systemic Mastocytosis Symptom Assessment Form. Treatment with AYVAKIT resulted in robust improvements in patient-reported quality of life, based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Across multiple measures of mast cell burden, AYVAKIT showed profound reductions in serum tryptase, bone marrow mast cells, KIT D816V allele burden and spleen volume.

Consistent with previously disclosed data, AYVAKIT was generally well-tolerated in 62 patients enrolled in the PATHFINDER trial, and most adverse events (AEs) were reported as Grade 1 or 2. The most common AEs (≥15 percent) were peripheral edema, periorbital edema, thrombocytopenia, anemia, neutropenia, diarrhea, nausea, vomiting and fatigue. Three patients (5 percent) discontinued AYVAKIT due to treatment-related AEs, and most patients (84 percent) have remained on treatment as of the data cutoff date.

"These data reinforce the potential of avapritinib to improve the standard of care for patients with advanced systemic mastocytosis, a disease characterized by organ damage due to mast cell infiltration," said Daniel DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at Dana-Farber Cancer Institute. "I am highly encouraged by the rapid and durable responses shown across multiple measures of mast cell burden, patient-reported symptoms as well as quality of life. Furthermore, avapritinib was generally well-tolerated, with 5 percent of patients discontinuing due to treatment-related adverse events. Since avapritinib is able to selectively target the primary driver of the disease, it has the potential to fundamentally change the outlook for patients with advanced SM."

AYVAKIT – Statistically Significant Reductions of Aberrant CD30-Positive Mast Cells in Skin Lesions Shown in Phase 2 PIONEER Trial

In non-advanced SM, skin symptoms frequently persist and can severely impact quality of life. To assess the effects of AYVAKIT on mast cell burden in skin lesions, skin biopsies were obtained at baseline and week 12 in Part 1 of the PIONEER trial. Immunohistochemistry tests were performed to determine the proportion of aberrant mast cells in skin tissue, based on expression of CD25, CD30 and other transmembrane receptors observed in SM. Skin lesional tissue at baseline had more CD30-positive than CD25-positive mast cells. Following 12 weeks of treatment, AYVAKIT significantly reduced the proportion of aberrant CD30-positive mast cells in skin lesions compared to placebo (p=0.0082), as of a data cutoff date of December 4, 2020. These data expand on previously reported results showing the impact of AYVAKIT on skin manifestations of SM, and suggest that CD30 may be an important biomarker of aberrant mast cells in SM-related skin lesions.

BLU-263 – Safety and Pharmacokinetics Profile from Phase 1 Trial in Healthy Volunteers

A placebo-controlled, Phase 1 trial evaluated the safety, tolerability and pharmacokinetics of BLU-263 in healthy volunteers. This AACR (Free AACR Whitepaper) presentation reported on single ascending dose cohorts (15 to 200 mg doses) and multiple ascending dose cohorts (25 to 100 mg once-daily doses for ten consecutive days), as of a data cutoff date of November 9, 2020. BLU-263 was well-tolerated across all doses studied, and all AEs were reported as Grade 1. Pharmacokinetic data showed dose-dependent increases in systemic exposure of BLU-263, with the half-life of BLU-263 supporting once-daily dosing. Based on these results, the company plans to evaluate BLU-263 at doses ranging from 25 to 100 mg once daily in Part 1 of the Phase 2/3 HARBOR trial in patients with non-advanced SM, which the company plans to initiate in mid-2021.

Copies of Blueprint Medicines data presentations from the AACR (Free AACR Whitepaper) annual meeting are available in the "Science—Publications and Presentations" section of the company’s website at www.BlueprintMedicines.com.

Conference Call Information

Blueprint Medicines will host a live webcast on Monday, April 12, 2021 beginning at 8:00 a.m. ET to review data for multiple research- and clinical-stage programs presented at the AACR (Free AACR Whitepaper) annual meeting. To access the live call, please dial (855) 728-4793 (domestic) or (503) 343-6666 (international) and refer to conference ID 5548976. A webcast of the conference call will be available under "Events and Presentations" in the Investors & Media section of Blueprint Medicines’ website at View Source The archived webcast will be available on Blueprint Medicines’ website approximately two hours after the conference call and will be available for 30 days following the call.

About SM

SM is a rare disease driven by the KIT D816V mutation. Uncontrolled proliferation and activation of mast cells result in chronic, severe and often unpredictable symptoms for patients across the spectrum of SM. The vast majority of those affected have non-advanced (indolent or smoldering) SM, with debilitating symptoms that lead to a profound, negative impact on quality of life. A minority of patients have advanced SM, which encompasses a group of high-risk SM subtypes including aggressive SM, SM with an associated hematological neoplasm and mast cell leukemia. In addition to mast cell activation symptoms, advanced SM is associated with organ damage due to mast cell infiltration and poor survival.

Debilitating symptoms, including anaphylaxis, maculopapular rash, pruritis, diarrhea, brain fog, fatigue and bone pain, often persist across all forms of SM despite treatment with a number of symptomatic therapies. Patients often live in fear of severe, unexpected symptoms, have limited ability to work or perform daily activities, and isolate themselves to protect against unpredictable triggers. Currently, there are no approved therapies for the treatment of SM that selectively inhibit D816V mutant KIT.

About AYVAKIT (avapritinib)

AYVAKIT (avapritinib) is a kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. For more information, visit www.AYVAKIT.com. This medicine is approved in Europe under the brand name AYVAKYT for the treatment of adults with unresectable or metastatic GIST harboring the PDGFRA D842V mutation, and in China for the treatment of adults with unresectable or metastatic PDGFRA exon 18 mutant GIST.

AYVAKIT/AYVAKYT is not approved for the treatment of any other indication, including SM, in the U.S. by the FDA, in Europe by the European Commission or in China by the National Medical Products Administration, or for any indication in any other jurisdiction by any other health authority.

Blueprint Medicines is developing AYVAKIT globally for the treatment of advanced and non-advanced SM. The FDA granted breakthrough therapy designation to AYVAKIT for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematological neoplasm and mast cell leukemia, and for the treatment of moderate to severe indolent SM.

To learn about ongoing or planned clinical trials, contact Blueprint Medicines at [email protected] or 1-888-BLU-PRNT (1-888-258-7768). Additional information is available at www.pioneertrial.com or www.clinicaltrials.gov.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of AYVAKIT in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for AYVAKIT in the rest of the world.

About BLU-263

BLU-263, a next-generation KIT D816V inhibitor, has the potential to expand the reach of KIT D816V-targeted therapy to a broad population of patients with non-advanced SM and related mast cell disorders. BLU-263 was designed to target D816V mutant KIT with similar sub-nanomolar potency as AYVAKIT, enhanced selectivity and minimal central nervous system penetration. BLU-263 was developed based on learnings from the AYVAKIT clinical program. The initial focus of the BLU-263 development program is non-advanced SM.

On April 11, 2021 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative medicines worldwide, reported that clinical data on its anti-PD-1 antibody tislelizumab, in combination with the investigational spectrum-selective kinase inhibitor sitravatinib being jointly developed with Mirati Therapeutics, Inc. (Mirati), were presented in two oral presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, BeiGene, APR 11, 2021, View Source [SID1234577843]). Data presented at the meeting were from two cohorts of a Phase 1b trial (NCT03666143), in patients with unresectable or metastatic melanoma who were refractory or resistant to PD-1/L1 inhibitors and in patients with advanced platinum-resistant ovarian cancer (PROC).

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BeiGene has an exclusive collaboration and license agreement with Mirati for the development, manufacturing and commercialization of sitravatinib in Asia (excluding Japan), Australia, and New Zealand.

"From the results presented today, we believe that sitravatinib in combination with tislelizumab could potentially provide clinical benefit to patients with advanced solid tumors, which supports our plan to further evaluate this innovative combination in our ongoing clinical trials. In addition, we are excited about the preliminary antitumor activity observed in patients with PD-1/L1 resistant or refractory melanoma," commented Yong (Ben) Ben, M.D., Chief Medical Officer, Immuno-Oncology at BeiGene. "As we continue to follow these patients and complete enrollment in this trial, we are excited to expand our knowledge of this novel combination in the hope that it will lead to a combination therapy that can help more patients around the world in the fight against cancer."

This open-label, multicohort, Phase 1b trial was designed to evaluate safety/tolerability and preliminary antitumor activity of sitravatinib in combination with tislelizumab in advanced solid tumors. The primary endpoint of the trial was safety/tolerability of the combination; key secondary endpoints include investigator-assessed objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) per RECIST v1.1; overall survival (OS) was also assessed.

Results in Patients with Unresectable or Metastatic Melanoma Refractory or Resistant to PD-1/L1 Inhibitors

"Checkpoint inhibitors have changed the treatment of advanced melanoma, but a significant proportion of patients do not benefit from PD-1 inhibitors due to primary or innate resistance. In this Phase 1b trial, we’re glad to see that the combination of sitravatinib and tislelizumab was generally well-tolerated and demonstrated encouraging preliminary antitumor activity in patients with PD-1/L1 resistant melanoma," commented Chuanliang Cui, Professor at Beijing Cancer Hospital in China.

At the time of data cutoff on October 13, 2020, a total of 25 patients with unresectable or metastatic melanoma who were refractory or resistant to anti-PD-1/L1 antibodies and had not received other prior immunotherapy had been enrolled in cohort G of the Phase 1b trial, including 12 with cutaneous subtype, seven with acral subtype, and four with mucosal subtype. At the time of data cutoff, 16 patients (64%) remained on study treatment. With a median follow-up time of 5.5 months, results included:

All 25 patients (100%) experienced at least one treatment-emergent adverse event (TEAE) of any grade, with the most common (≥20%) being increased alanine transaminase (ALT; 76%), increased aspartate aminotransferase (AST; 68%), increased blood cholesterol (56%), hypertriglyceridemia (52%), hypothyroidism (48%), weight decreased (48%), increased blood creatine kinase (BCK; 40%), diarrhea (40%), increased gamma-glutamyltransferase (GGT; 40%), proteinuria (40%), increased blood bilirubin (BB; 36%), abnormal electrocardiogram T wave (36%), hypertension (36%), palmar-plantar erythrodysesthesia syndrome (32%), increased CK-myocardial band isozyme (CK-MB; 28%), hyperuricemia (28%), upper abdominal pain (24%), vomiting (24%), and hypokalemia (20%);
Twelve patients (48%) experienced at least one Grade ≥3 TEAE, with the most common (≥5%) being hypertension (12%), increased ALT (8%), and increased GGT (8%);
One patient (4%) experienced a serious TEAE of anal abscess, associated with sitravatinib;
Treatment discontinuation due to TEAEs occurred in two patients (8%), with one discontinuing tislelizumab due to vaginal hemorrhage (unrelated to tislelizumab) and the other sitravatinib due to increased BCK (related to sitravatinib);
Dose interruptions and reductions of sitravatinib occurred in 18 patients (72%) and 13 patients (52%), respectively;
All 25 patients were evaluable for efficacy and the confirmed ORR was 24% (95% CI: 9.4, 45.1), including six partial responses (PRs), and the disease control rate (DCR) was 88% (95% CI: 68.8, 97.5); and
The media duration of response (DoR) was not reached, and the investigator-assessed median PFS was 6.7 months (95% CI: 4.07, not evaluable).
Results in Patients with Advanced PROC

"It’s common to see patients with ovarian cancer become refractory or resistant to platinum-based therapy after receiving the current standard of care. The combination of sitravatinib and tislelizumab was generally well tolerated and showed promising antitumor activity among patients with advanced PROC, including those who were heavily pretreated. While the sample size is relatively small, we look forward to further evaluating this novel combination in PROC," said Jeffrey Goh, MBBS, FRACP, Medical Oncologist at Icon Cancer Centre in Australia.

At the time of data cutoff on October 13, 2020, a total of 60 patients with recurrent PROC who had no prior exposure to anti-PD-1/L1 antibodies had been enrolled in cohort E of the Phase 1b trial and 13 of them (22%) remained on study treatment. These patients received a median of four (range: 1, 11) prior regimens. With a median follow-up time of six months, results included:

Fifty-eight patients (97%) experienced at least one TEAE of any grade, with the most common (≥20%) being diarrhea (67%), nausea (57%), fatigue (48%), hypertension (40%), decreased appetite (37%), vomiting (37%), abdominal pain (35%), constipation (33%), increased ALT (30%), urinary tract infection (27%), increased AST (20%), dysphonia (20%), headache (20%), and palmar-plantar erythrodysesthesia syndrome (20%);
Forty-one patients (68%) experienced at least one Grade ≥3 TEAE, with the most common (≥10%) being hypertension (18%) and abdominal pain (12%);
Forty-two patients (70%) experienced at least one serious TEAE;
Treatment discontinuation due to TEAEs occurred in 23 patients (38%), with nine patients (15%) discontinuing tislelizumab and 14 (23%) sitravatinib;
Dose interruptions and reductions of sitravatinib occurred in 50 patients (83%) and 30 patients (50%), respectively, and dose interruption of tislelizumab occurred in one patient (2%);
Four fatal TEAEs were reported, with none considered related to study treatment;
Among the 53 patients who were evaluable for efficacy, the confirmed ORR was 26% (95% CI: 15.3, 40.3), including 14 PRs, and the DCR was 77% (95% CI: 63.8, 87.7);
The median DoR was 4.7 months (95% CI: 2.8, not estimable); and
The median PFS and OS was 4.1 months (95% CI: 4.0, 5.1) and 12.9 months (95% CI: 6.3, 17.2), respectively.
About Sitravatinib

Sitravatinib is an investigational, spectrum-selective receptor tyrosine kinase (RTK) inhibitor that can potentially stimulate the body’s immune response to fight cancer. Sitravatinib targets the VEGFR and TAM (TYRO3, AXL, MERTK) receptor families, which are implicated in orchestrating an immunosuppressive tumor microenvironment (TME). Inhibiting these receptors has been shown to stimulate an anti-tumor immune response and potentially re-sensitize patients to checkpoint inhibitor (CPI) therapy in patients who previously developed resistance to CPI therapy. By targeting specific RTKs with sitravatinib, the immunosuppressive TME is converted to an immune-supportive TME, and combining with CPI therapy may help regain an immune response potentially overcoming resistance to CPI therapy. Sitravatinib is being evaluated in multiple clinical trials, including the Phase 3 SAPPHIRE study, in patients with advanced non-small cell lung cancer who are resistant to CPI therapy, and certain patients who are naïve to CPI therapy.

For more information visit www.mirati.com/science.

About Tislelizumab

Tislelizumab (BGB-A317) is a humanized IgG4 anti-PD-1 monoclonal antibody 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.

The China National Medical Products Administration (NMPA) has granted tislelizumab full approval for first-line treatment of patients with advanced squamous non-small cell lung cancer (NSCLC) in combination with chemotherapy. Tislelizumab has also received conditional approval from the NMPA for the treatment of patients with classical Hodgkin’s lymphoma (cHL) who received at least two prior therapies, and for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) with PD-L1 high expression whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Full approval for these indications is contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

In addition, three supplemental Biologics License Applications for tislelizumab have been accepted by the Center for Drug Evaluation (CDE) of the NMPA and are under review for first-line treatment of patients with advanced non-squamous NSCLC in combination with chemotherapy, for the second- or third-line treatment of patients with locally advanced or metastatic NSCLC who progressed on prior platinum-based chemotherapy, and for previously treated unresectable hepatocellular carcinoma.

Currently, 16 potentially registration-enabling clinical trials are being conducted in China and globally, including 13 Phase 3 trials and three pivotal Phase 2 trials.

In January 2021, BeiGene and Novartis entered into a collaboration and license agreement granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

Tislelizumab is not approved for use outside of China.

About the Tislelizumab Clinical Program

Clinical trials of tislelizumab include:

Phase 3 trial comparing tislelizumab with docetaxel in the second- or third-line setting in patients with NSCLC (NCT03358875);
Phase 3 trial comparing tislelizumab to salvage chemotherapy in patients with relapsed/refractory classical Hodgkin Lymphoma (NCT04486391);
Phase 3 trial in patients with locally advanced or metastatic urothelial carcinoma (NCT03967977);
Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced squamous NSCLC (NCT03594747);
Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced non-squamous NSCLC (NCT03663205);
Phase 3 trial of tislelizumab in combination with platinum-based doublet chemotherapy as neoadjuvant treatment for patients with NSCLC (NCT04379635);
Phase 3 trial of tislelizumab combined with platinum and etoposide versus placebo combined with platinum and etoposide in patients with extensive-stage small cell lung cancer (NCT04005716);
Phase 3 trial comparing tislelizumab with sorafenib as first-line treatment for patients with hepatocellular carcinoma (HCC; NCT03412773);
Phase 2 trial in patients with previously treated unresectable HCC (NCT03419897);
Phase 2 trial in patients with locally advanced or metastatic urothelial bladder cancer (NCT04004221);
Phase 3 trial comparing tislelizumab with chemotherapy as second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC; NCT03430843);
Phase 3 trial of tislelizumab in combination with chemotherapy as first-line treatment for patients with ESCC (NCT03783442);
Phase 3 trial of tislelizumab versus placebo in combination with chemoradiotherapy in patients with localized ESCC (NCT03957590);
Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment for patients with gastric cancer (NCT03777657);
Phase 2 trial in patients with MSI-H/dMMR solid tumors (NCT03736889); and
Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment in patients with nasopharyngeal cancer (NCT03924986).