On September 20, 2021 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM: HCM; HKEX: 13) reported that it has initiated a Japan registration-enabling bridging study for surufatinib to support the registration of surufatinib in the treatment of patients with advanced neuroendocrine tumors ("NETs") (Press release, Hutchison China MediTech, SEP 20, 2021, View Source [SID1234590539]). The first patient was dosed on September 15, 2021.

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Based on dialogue with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), it was agreed that the surufatinib Japanese new drug application ("NDA") for the treatment of advanced NETs include results from a pivotal study to be conducted in Japan, to complement the registration data package supporting the NDA to the U.S. Food and Drug Administration ("FDA") (accepted for review in June 2021) and the Marketing Authorization Application ("MAA") to the European Medicines Agency ("EMA") (validated in July 2021). The basis for the NDA and the MAA includes data from a U.S. Phase I/II study, as well as the completed Phase III SANET-ep and SANET-p studies used to support marketing authorization in China in advanced NETs, where surufatinib is currently marketed under the brand name SULANDA.

This Japan study is a two-stage, open label study of surufatinib where approximately 34 patients are expected to be recruited. In Part 1 of the study, the safety and tolerability of surufatinib 300mg once daily after 28 days of treatment will be assessed in patients with relapsed/refractory non-hematological malignancies; pharmacokinetics ("PK") and anti-tumor activity of surufatinib are secondary endpoints. In Part 2 of the study, efficacy will be assessed in patients with locally advanced or metastatic NETs; the primary outcome measure is objective response rate (ORR). The secondary outcome measures include disease control rate (DCR), progression free survival ("PFS"), duration of response (DoR), safety, and PK.

Surufatinib is the third potential new medicine discovered by HUTCHMED to enter into clinical development in Japan. A global Phase III registration study for fruquintinib, known as the FRESCO-2 study, is ongoing in patients with refractory metastatic colorectal cancer and is expected to enroll over 680 patients from over 150 sites in 14 countries, including Japan. A global single-arm, open-label study, known as the SAVANNAH study, is ongoing for savolitinib (partnered with AstraZeneca PLC) in combination with TAGRISSO in non-small cell lung cancer patients whose disease progressed following TAGRISSO due to MET amplification or overexpression.

About NETs
NETs form in cells that interact with the nervous system or in glands that produce hormones. They can originate in various parts of the body, most often in the gut or the lungs and can be benign or malignant. NETs are typically classified as pancreatic NET ("pNET") or extra-pancreatic (non-pancreatic) NET ("epNET").

According to Frost & Sullivan, there were 19,000 newly diagnosed cases of NET in the U.S. in 2020. Rates across the European Union (E.U.) appear largely similar to the U.S. This is supported by an analysis of global epidemiologic trends, which also show growth in the incidence of NETs worldwide.[i] Importantly, NETs are associated with a relatively long duration of survival compared to other tumors. As a result, there were approximately 140,000 estimated patients living with NET in France, Germany, Italy, Spain, and the United Kingdom in 2020.[ii] In Japan, approximately 6,700 people were diagnosed with gastro-entero-pancreatic neuroendocrine neoplasms in 2016.[iii]

About Surufatinib
Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects.

HUTCHMED currently retains all rights to surufatinib worldwide.

About Surufatinib Development
epNETs in China: On December 29, 2020, surufatinib was granted drug registration approval by the National Medical Products Administration of China ("NMPA") for the treatment of epNET. Surufatinib is marketed in China under the brand name SULANDA. The approval was based on results from the SANET-ep study, a Phase III trial (clinicaltrials.gov identifier: NCT02588170) in patients with advanced epNETs conducted in China. The study met the pre-defined primary endpoint of PFS at a preplanned interim analysis, and was published in The Lancet Oncology[iv]. Median PFS was significantly longer for patients treated with surufatinib at 9.2 months, compared to 3.8 months for patients in the placebo group (HR 0.334; 95% CI: 0.223-0.499; p<0.0001). Surufatinib had an acceptable safety profile, with the most common treatment related adverse events of grade 3 or worse being hypertension (36% of surufatinib patients vs. 13% of placebo patients), proteinuria (19% vs. 0%) and anemia (5% vs. 3%).

pNETs in China: On June 16, 2021, surufatinib was granted drug registration approval by the NMPA for the treatment of pNET. The approval was based on results from the SANET-p study, a Phase III trial (clinicaltrials.gov identifier: NCT02589821) in patients with advanced pNET in China. The pre-defined primary endpoint of PFS was met at a preplanned interim analysis and was published in The Lancet Oncology[v], demonstrating that surufatinib reduces the risk of disease progression or death by 51% in patients, with a median PFS of 10.9 months compared to 3.7 months on placebo (HR 0.491; 95% CI: 0.391-0.755; p=0.0011). The safety profile of surufatinib was manageable and consistent with observations in prior studies.

Immunotherapy combinations: HUTCHMED entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with anti-PD-1 monoclonal antibodies, including with tislelizumab (BGB-A317), TUOYI (toripalimab) and TYVYT (sintilimab), which are approved as monotherapies in China.

NETs in the U.S. and Europe: A FDA NDA submission was accepted in June 2021, followed by a MAA submission to the EMA validated in July 2021. The basis to support these filings includes the completed SANET-ep and SANET-p studies, along with existing data from surufatinib in U.S. epNET and pNET patients (clinicaltrials.gov identifier: NCT02549937). In the U.S., surufatinib was granted Fast Track Designations for development in pNET and epNET in April 2020, and Orphan Drug Designation for pNET in November 2019.

HUTCHMED has initiated an Expanded Access Protocol (EAP) in the U.S. to ensure patients with NET with limited therapeutic options have access to this treatment. Regulatory clearance of this protocol has been granted by the FDA and this program is open for site activation (clinicaltrials.gov identifier: NCT04814732).

On September 20, 2021 THERADIAG (ISIN: FR0004197747, Ticker: ALTER), a company specializing in in vitro diagnostics and Theranostics, reported its half-year results to June 30, 2021, as approved by the Board of Directors on September 16, 2021 (Press release, Theradiag, SEP 20, 2021, View Source [SID1234587946]).

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Bertrand de Castelnau, CEO of Theradiag, commented: "Over the last year we have been reaping the fruit of the efforts undertaken on controlling our operating costs and on our marketing strategy. Indeed, the effectiveness of our strategic refocus is demonstrated by the considerable improvement in all our financial indicators in the first half despite an economic and public health context that remains uncertain. On the basis of buoyant activity for our innovative solutions and a healthier cost structure, we are intending to accelerate Theradiag’s development by implementing a strategic plan that is in keeping with our growth ambitions on our target markets. Biotherapy monitoring is a vast global market, and the coming semesters look promising for Theradiag".

"The solid improvement in these results demonstrate the success of the Company’s structuring phase initiated some semesters ago. They also materialize the work of Theradiag’s teams, who I would like to congratulate. We now have to accelerate our growth on our markets of choice, and in particular on the Theranostics market", added Chairman of the Board Pierre Morgon.

Revenue up 12.5% despite an uncertain public health situation

Over the six months to June 30, 2021, Theradiag generated revenue of €5.5 million, compared with €4.9 million in the first half of 2020, despite an economic and public health context characterized by persistent difficulties accessing hospital treatment for patients undergoing immunotherapy in all countries.

Theranostics activity continued its growth, increasing by +14.7% in H1, notably driven by dynamic sales of the automated i-Track10. Marked by strong growth for a number of semesters now, for the first time Theranostics activity accounted for the majority of Theradiag’s revenue over the first 6 months of 2021.

Theranostics activity undertaken in the United States in partnership with HalioDX generated revenue of €0.5 million, in line with the Company’s development plan, and was thus up by 33.6%. In its export business, the Company has maintained a buoyant level of activity, with sales increasing by 27.4% to €1.3 million. Penalized by the maintaining of plans blancs emergency plans in hospitals, activity in France slowed slightly, slipping 5.2% compared with the first half of 2020.

IVD (In Vitro Diagnostics) activity generated growth of +10.4%, with revenue totaling €2.7 million over the six months to June 30, 2021.

Substantial improvement in financial indicators thanks to better control over operating costs and a refocusing of Theradiag’s strategy on its fundamentals

Following strong growth in the second half of 2020, the operating loss continued to shrink significantly, by 57.9%, in the first half of 2021. This improvement illustrates Theradiag’s ability to develop commercially while continuing to ensure strict operating cost management. At the same time, as in previous semesters, Theradiag intensified its investments in R&D and in its commercial development in the United States in order to strengthen its leadership position in biotherapy monitoring in France and abroad. Furthermore, the Company has expanded its Quality team to be in a position to comply with the requirements of the new European Union directive with regard to in vitro diagnostic medical devices (IVDR).

In a similar vein, the net result before recurring items improved by a buoyant 84.3% compared with the same period of 2020. It is now close to breakeven, representing -0.4% of revenue.

The overall net loss, including non-recurring items, improved by 59.8% to -€92 thousand at June 30, 2021 versus -€229 thousand at June 30, 2020.

Cash position and financial structure

At June 30, 2021, Theradiag had €1.4 million in net available cash, compared with €3.5 million at December 31, 2020. This difference is the result of cash lags, now resolved, totaling €0.5 million, while investments in R&D and international development are in line with Theradiag’s strategic plan.

To finance its growth strategy on the biotherapy monitoring market while maintaining a solid financial structure, Theradiag is not ruling out the possibility of raising additional funds depending on market conditions and the progress of its strategic plan.

Reminder of the main H1 2021 highlights

· January 2021: CE marking for the four new i-Tracker test kits: i-Tracker Vedolizumab, i-Tracker Anti-Vedolizumab, i-Tracker Ustekinumab and i-Tracker Anti-Ustekinumab, on originator and biosimilar molecules

· January 2021: Signing of a contract to supply quality control reagents to Orgentec, a specialist in in vitro diagnostics notably in the field of autoimmunity, infectious diseases and molecular biology

May 2021: Participation in Humabdiag, a large-scale research project undertaken with the University of Tours targeting the bioproduction of monoclonal antibodies dedicated in particular to Theradiag and the entire biotherapy market.

On September 20, 2021 Exelixis, Inc. (Nasdaq: EXEL) reported final results from the phase 3 COSMIC-311 pivotal trial of CABOMETYX (cabozantinib) in patients with previously treated radioactive iodine-refractory differentiated thyroid cancer (DTC) (Press release, Exelixis, SEP 20, 2021, View Source [SID1234587962]). Following a previous announcement that the trial met one of the two primary endpoints of significant improvement versus placebo in progression-free survival (PFS) assessed by blinded independent radiology committee (BIRC; p<0.0001), the results of the final analysis are being presented during the Mini Oral Session – NETs and Endocrine Tumours at 5:30 p.m. CEST on Monday, September 20 at the 2021 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (LBA67). At a median follow-up of 10.1 months, the significant improvement in PFS with CABOMETYX was maintained, with consistent benefit in subgroups based on prior treatment.

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"Given the urgent need for new treatments for differentiated thyroid cancer, I’m encouraged to see that cabozantinib benefited patients in COSMIC-311 both at a longer follow-up and across prior therapy subgroups," said Jaume Capdevila, M.D., Ph.D., Medical Oncologist at Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, and a COSMIC-311 study investigator. "These strong findings, which formed the basis for the recent U.S. FDA approval, further support cabozantinib as an important new treatment option for patients with radioactive iodine-refractory differentiated thyroid cancer who previously had no standard of care following disease progression on anti-VEGFR therapy."

At a median follow-up of 10.1 months, CABOMETYX reduced the risk of disease progression or death versus placebo (hazard ratio [HR]: 0.22; 96% confidence interval [CI]: 0.15–0.32) in the intent-to-treat (ITT) population. Median PFS as assessed by BIRC was 11.0 months for patients treated with CABOMETYX (n=170) compared with 1.9 months for patients treated with placebo (n=88). Subgroup analyses demonstrated that CABOMETYX improved PFS versus placebo irrespective of prior exposure to lenvatinib and/or sorafenib:

Prior sorafenib/no lenvatinib: median PFS was 16.6 months for patients treated with CABOMETYX (n=63) compared with 3.2 months for placebo (n=33) (HR: 0.13; 95% CI: 0.06–0.26).
Prior lenvatinib/no sorafenib: median PFS was 5.8 months for patients treated with CABOMETYX (n=68) compared with 1.9 months for placebo (n=34) (HR: 0.28; 95% CI: 0.16–0.48).
Prior sorafenib and lenvatinib: median PFS was 7.6 months for patients treated with CABOMETYX (n=39) compared with 1.9 months for placebo (n=21) (HR: 0.27; 95% CI: 0.13–0.54).
An updated analysis for the primary endpoint of objective response rate (ORR) as assessed by BIRC in the ITT population favored CABOMETYX at 11%, including one complete response, versus 0% for placebo. Median overall survival, an additional endpoint, was 19.4 months for patients treated with CABOMETYX and not estimable for patients treated with placebo (HR: 0.76; 95% CI: 0.45–1.31).

The safety profile was consistent with that previously observed for CABOMETYX, and adverse events (AEs) were managed with dose modifications. The discontinuation rate due to treatment-emergent AEs was 8.8% for CABOMETYX versus 0% for placebo. Rates of grade 3/4 treatment-emergent AEs were 62% for CABOMETYX versus 28% for placebo, with no treatment-related deaths. Dose reductions due to AEs were required in 67% of patients treated with CABOMETYX versus 5% for placebo.

"Following the recent U.S. FDA approval, we are pleased to share these detailed results at this year’s ESMO (Free ESMO Whitepaper) which show CABOMETYX continued to benefit these patients with advanced differentiated thyroid cancer in the trial at a longer follow-up," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer, Exelixis. "This patient population faces a poor prognosis and previously had very limited treatment options. We are thrilled that eligible patients in the U.S. now have CABOMETYX as an approved treatment option and will continue to work with our partners on their efforts to bring CABOMETYX to even more patients worldwide."

Results from COSMIC-311 served as the basis for the September 17, 2021 U.S. Food and Drug Administration (FDA) approval of CABOMETYX for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible. The application was approved well ahead of the Prescription Drug User Fee Act (PDUFA) target action date of December 4, 2021.

About COSMIC-311
COSMIC-311 was a multicenter, randomized, double-blind, placebo-controlled phase 3 pivotal trial that enrolled 258 patients at 164 sites globally. Patients were randomized in a 2:1 ratio to receive either CABOMETYX 60 mg or placebo once daily. The primary endpoints were PFS and ORR. Exelixis is sponsoring COSMIC-311, and Ipsen is co-funding the trial. More information about this trial is available at ClinicalTrials.gov.

About DTC
Approximately 44,000 new cases of thyroid cancer will be diagnosed in the U.S. in 2021.1 Nearly three out of four of these cases will be in women, and the disease is more commonly diagnosed at a younger age compared to most other adult cancers.2 While cancerous thyroid tumors include differentiated, medullary and anaplastic forms, differentiated thyroid tumors make up about 90% of cases.2 These include papillary, follicular and Hürthle cell cancer.2 DTC is typically treated with surgery followed by ablation of the remaining thyroid tissue with radioiodine, but approximately 5% to 15% of cases are resistant to radioiodine treatment. 2,3 For these patients, life expectancy is only three to five years from the time metastatic lesions are detected.4,5,6

About CABOMETYX (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (RCC); for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information
View Source

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

On September 20, 2021 Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, reported that Brian M. Culley, the Company’s Chief Executive Officer, will be presenting at the 2021 Cantor Fitzgerald Virtual Global Healthcare Conference in a fireside chat hosted by Kristen Kluska, Director, Equity Research on September 27th, 2021 at 4pm ET / 1pm PT (Press release, Lineage Cell Therapeutics, SEP 20, 2021, View Source [SID1234587999]).

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Interested parties can register to view both the on-demand and live industry presentations on the Events and Presentations section of Lineage’s website. Additional videos are available on the Media page of the Lineage website.

On September 20, 2021 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported new data from the dose-escalation portion of the Phase 1 clinical trial of SY-5609, its highly selective and potent oral cyclin-dependent kinase 7 (CDK7) inhibitor, demonstrating clinical activity at tolerable doses as a single agent across multiple tumor types (Press release, Syros Pharmaceuticals, SEP 20, 2021, View Source [SID1234588030]). The data is being presented today in an oral presentation at the 2021 ESMO (Free ESMO Whitepaper) Congress.

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"I am encouraged by the results from this dose-escalation study," said Manish R. Sharma, M.D., Associate Director of Clinical Research at START Midwest in Grand Rapids, Michigan, and an investigator in the Phase 1 study of SY-5609. "This trial enrolled heavily pretreated patients with some of the most difficult-to-treat malignancies. Notably, the prolonged stable disease and tumor shrinkage seen in pancreatic cancer patients is distinct from what you would expect to see in this highly refractory patient population – particularly when treated with a single agent. Based on these results, together with preclinical data supporting combination strategies, I believe SY-5609 has the potential to provide a meaningful benefit for patients with cancers that have largely eluded treatment to date."

"The new data presented today demonstrate proof-of-activity for SY-5609 and point to an optimal dosing regimen with a tolerability profile that is amenable to multiple combination approaches," said David A. Roth, M.D., Chief Medical Officer of Syros. "As we move into this next stage of development, we are introducing a three-pronged strategy to maximize the potential of SY-5609 and drive to proof-of-concept in combination with chemotherapy, a targeted therapy and an immunotherapy in both solid tumors and blood cancer. We believe this approach could unlock significant opportunities for SY-5609 and achieve the transformative potential of CDK7 inhibition for people with difficult-to-treat cancers."

Dose-Escalation Data Demonstrate Clinical Activity Across Multiple Tumor Types
The Phase 1 multi-center, open-label dose-escalation study of SY-5609 enrolled patients with advanced breast, colorectal, lung, ovarian and pancreatic cancers, as well as patients with solid tumors of any histology harboring Rb pathway alterations. Patients were treated in cohorts exploring continuous daily dosing as well as intermittent dosing regimens, including seven days on treatment and seven days off (7d on/7d off) and five days on treatment and two days off (5d on/2d off).

As of July 6, 54 patients treated with single-agent SY-5609 in the study were eligible for a safety analysis and 45 patients were evaluable for clinical response. The median age of patients enrolled in the study was 65.5. Patients had been heavily pre-treated with as many as eight prior therapies and a median of four prior therapies.

Safety, Tolerability, Dose and Schedule

Across all doses and schedules, the majority of adverse events (AEs) were low-grade and reversible. The most common treatment-emergent AEs were nausea, diarrhea, thrombocytopenia, fatigue and anemia.
Low rate of discontinuations due to AEs.
Tolerability was optimized with 7d on/7d off schedule, which had lowest rates of treatment-emergent AEs, while demonstrating comparable rates of stable disease (SD) as seen with more dose-intense regimens, supporting the selection of this schedule for further development of SY-5609.
The maximum tolerated dose (MTD) of the 7d on/7d off schedule has not yet been reached.
Changes in POLR2A mRNA expression, a pharmacodynamic (PD) marker for CDK7 inhibition, were associated with anti-tumor activity and were sustained for at least three days following drug cessation, supporting intermittent dosing.
Early Clinical Activity Data

Thirteen patients (28.9%) achieved SD, with tumor regressions of up to 20% in six of those patients, across multiple tumor types.
The most substantial clinical activity was observed in heavily pre-treated patients with advanced pancreatic cancer.
Five of 13 (38.5%) evaluable patients achieved SD, with tumor reductions in two of those patients.
Reductions in the CA 19-9 tumor marker, which is used in clinical practice to monitor tumor progression, were observed in three of four pancreatic cancer patients with serial CA 19-9 data. These reductions ranged from 32% to 72%.
Notably, one metastatic pancreatic cancer patient who had failed two prior lines of therapy and relapsed after a third line of treatment experienced prolonged SD of up to 10 months.
Analysis of clinical activity by tumor type and mutational status supports the mechanistic rationale for SY-5609 in Rb-altered and KRAS-mutant cancers.
Clinical Development Plans for SY-5609 in Solid Tumors and Blood Cancer
Further development of SY-5609 will explore three combination regimens, focusing initially on indications with compelling clinical and/or preclinical activity, as well as a strong mechanistic rationale and high unmet need.

Syros plans to initiate an expansion cohort evaluating SY-5609 in combination with chemotherapy for the treatment of pancreatic cancer in the fourth quarter of 2021. Syros also plans to initiate a Phase 1b trial evaluating SY-5609 in combination with a Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of mantle cell lymphoma in the first half of 2022. Syros plans to employ a 7d on/7d off dosing schedule in both of these trials. In addition, as announced in August 2021, Syros entered into an agreement with Roche to explore SY-5609 in combination with atezolizumab in patients with BRAF-mutant colorectal cancer in Roche’s ongoing Phase 1/1b INTRINSIC trial.

New Preclinical Data Further Support Planned Expansion Strategy
Syros also presented new preclinical data at ESMO (Free ESMO Whitepaper) evaluating the anti-tumor and PD activity of intermittent dosing regimens for SY-5609, as well as new preclinical data evaluating SY-5609 as a single agent and in combination with chemotherapy in pancreatic cancer models. Taken together, these data further support Syros’ dose expansion strategy, including the decision to use a 7d on/7d off dosing schedule and combine with chemotherapy in patients with pancreatic cancer. The data showed that SY-5609:

Induced robust anti-tumor activity as a single agent in ovarian cancer models that was maintained at higher doses on intermittent schedules, including a 7d on/7d off schedule. POLR2A PD effects were sustained in tumor tissue through 72 hours post-dosing, consistent with what was observed in patients in the dose-escalation study.
Induced regressions as a single agent in half (4/8) of the pancreatic cancer models that were studied, including models derived from heavily pre-treated patients.
Resulted in deeper responses when combined on 7d on/7d off schedule with gemcitabine in KRAS-mutant pancreatic models than either agent alone.
Conference Call Information
Syros will host a conference call at 4:00 p.m. ET today to discuss these data, as well as the design of its dose expansion study. To access the live conference call, please dial 866-595-4538 (domestic) or 636-812-6496 (international), and refer to conference ID 4648345. A webcast of the call will also be available on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available for approximately 30 days following the conference call.