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Astellas’ and Pfizer’s XTANDI® (enzalutamide) Reduced Risk of Death by 34% in Men with Metastatic Hormone-Sensitive Prostate Cancer in Phase 3 ARCHES Study

On September 17, 2021 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Pfizer Inc. (NYSE: PFE) reported ahead of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 that XTANDI (enzalutamide) improved overall survival (OS) in the ARCHES study in men with metastatic hormone-sensitive prostate cancer (mHSPC, also known as metastatic castration-sensitive prostate cancer) (Press release, Astellas, SEP 17, 2021, View Source [SID1234587870]). The Phase 3, randomized, double-blind, placebo-controlled trial compared XTANDI plus androgen deprivation therapy (ADT) versus placebo plus ADT in men with mHSPC and OS was a key secondary endpoint.

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In the study, XTANDI plus ADT reduced the risk of death by 34% (n=1,150; hazard ratio [HR]=0.66; [95% confidence interval [CI]: 0.53-0.81]; p<0.0001) compared to placebo plus ADT. Median OS, which represents the time from randomization to death due to any cause, was not reached in either treatment group. The safety profile in both study arms was consistent with findings from the primary analysis.

Pfizer-Astellas-Logo

Pfizer-Astellas-Logo
Results from the final analysis of the ARCHES trial will be presented virtually at ESMO (Free ESMO Whitepaper) by Andrew Armstrong, M.D., Professor of Medicine, Surgery, Pharmacology and Cancer Biology, and Director of Research in the Duke Cancer Institute’s Center for Prostate and Urologic Cancers in Durham, North Carolina, U.S. (Abstract LBA25; September 18, 14:20 CEST).

"Overall survival benefit has been observed in patients treated with enzalutamide in three stages of advanced prostate cancer – metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, and now in metastatic hormone-sensitive prostate cancer," said Dr. Armstrong. "The results from ARCHES provide valuable data on the clinical profile of enzalutamide in this earlier disease setting."

The primary results from the ARCHES trial were published in the Journal of Clinical Oncology in 2019. The study met its primary endpoint of radiographic progression-free survival (rPFS) as assessed by independent central review, finding that treatment with XTANDI plus ADT demonstrated a 61% reduction in the risk of radiographic disease progression or death compared with ADT alone in men with mHSPC (HR=0.39; [95% CI: 0.30-0.50]; p<0.001).1 The median follow-up time was 14.4 months. Median rPFS was not reached (NR) with XTANDI plus ADT (95% CI: NR to NR) versus 19.0 months (95% CI: 16.6-22.2 months) with placebo plus ADT. At the time of the primary analysis, OS data were not mature.

In the ARCHES primary analysis, Grade 3 or greater adverse events (AEs; defined as severe/disabling or life-threatening) were similar for patients receiving both XTANDI plus ADT and those who received placebo plus ADT (24.3% vs. 25.6%). Common AEs (occurring in at least 5% of patients) that were reported more often in patients treated with XTANDI plus ADT versus those treated with ADT alone included hot flush, fatigue, arthralgia, hypertension, nausea, musculoskeletal pain, diarrhea, asthenia and dizziness.

These data supported global regulatory approvals, including European Commission marketing authorization for mHSPC earlier this year.

About Metastatic Hormone-Sensitive Prostate Cancer
Prostate cancer is considered metastatic once it has spread outside of the prostate gland to other parts of the body, such as the lymph nodes, bones, lungs, and liver.2 Men are considered hormone- (or castration-) sensitive if their disease still responds to medical or surgical treatment to lower testosterone levels.3 Metastatic hormone-sensitive prostate cancer (mHSPC) has a median survival of approximately 3-4 years for men starting treatment with ADT.4

ARCHES Trial
The company-sponsored, Phase 3, randomized, double-blind, placebo-controlled ARCHES trial (NCT02677896) enrolled 1,150 patients with metastatic hormone-sensitive prostate cancer (mHSPC) at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. Patients in the trial were randomized to receive XTANDI 160 mg daily or placebo and continued on a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or had a history of bilateral orchiectomy.

The primary endpoint of the trial was radiographic progression-free survival (rPFS) assessed by blinded independent central review. Radiographic progression-free survival was defined as the time from randomization to radiographic disease progression at any time or death within 24 weeks after study drug discontinuation. Radiographic disease progression was defined by identification of two or more new bone lesions on a bone scan with confirmation (Prostate Cancer Working Group 2 criteria) and/or progression in soft tissue disease. Patients were stratified by volume of disease (low vs. high) and prior docetaxel therapy for prostate cancer (no prior docetaxel, 1-5 cycles, or 6 prior cycles).

E.U.: About XTANDI (enzalutamide) and Important Safety Information
Enzalutamide is an androgen receptor signaling inhibitor indicated in the European Union for the treatment of adult men with:

Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with ADT.
High-risk non-metastatic castration-resistant prostate cancer (CRPC).
Metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. It is also indicated in adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.
For Important Safety Information for enzalutamide please see the full Summary of Product Characteristics at: View Source

U.S.: About XTANDI (enzalutamide) and Important Safety Information
XTANDI (enzalutamide) is an androgen receptor inhibitor indicated in the U.S. for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Warnings and Precautions

Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in seven randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo.

Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI.

Adverse Reactions (ARs)
In the data from the four randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia.

Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see Full Prescribing Information for additional safety information.

About Pfizer Oncology
At Pfizer Oncology, we are committed to advancing medicines wherever we believe we can make a meaningful difference in the lives of people living with cancer. Today, we have an industry-leading portfolio of 24 approved innovative cancer medicines and biosimilars across more than 30 indications, including breast, genitourinary, colorectal, blood and lung cancers, as well as melanoma.

Company Presentation dated September 2021

On September 17, 2021, AIM ImmunoTech Inc. (the "Company") reported a Company Presentation On September 17, 2021, AIM ImmunoTech Inc. (the "Company") posted a Company Presentation

VBL Therapeutics Announces Independent Data Safety Monitoring Committee Provides Clearance to Continue the OVAL Phase 3 Registration-Enabling Study of VB-111 in Ovarian Cancer

On September 17, 2021 VBL Therapeutics (NASDAQ: VBLT) reported that the independent Data Safety Monitoring Committee (DSMC) of the ongoing OVAL Phase 3 registration-enabling study of VB-111 in ovarian cancer has conducted its fifth pre-planned review and has provided clearance to proceed with further clinical research as planned with no changes to the protocol (Press release, VBL Therapeutics, SEP 17, 2021, View Source [SID1234587867]).

The independent DSMC for the OVAL trial is tasked with setting standards of safety, monitoring these standards’ implementation for the trial participants and treatment efficacy data, and acting on behalf of patients whenever necessary as the committee continues to monitor progress.

"We continue to be very pleased to learn that data collected to date in the OVAL clinical trial has passed independent DSMC review as we progress toward our enrollment goal," said Prof. Dror Harats, M.D., chief executive officer of VBL Therapeutics. "We thank the DSMC for its ongoing diligence, guidance and support."

The OVAL trial is planned to enroll approximately 400 adult patients globally and more than 320 patients (>80 percent) have already been recruited. The trial has two primary endpoints: progression free survival (PFS) and overall survival (OS). Successfully meeting either primary endpoint has the potential to support a biologics license application (BLA). Meeting the PFS endpoint, with a readout anticipated in the second half of 2022, could accelerate BLA submission by approximately one year, subject to discussions with the U.S. Food and Drug Administration (FDA), compared to original projections based on the readout of the OS primary endpoint that remains anticipated in 2023.

About VB-111 (ofranergene obadenovec; `ofra-vec`)
VB-111 is an investigational anti-cancer, gene-therapy agent in development to treat a wide range of solid tumors. VB-111 is a unique biologic agent designed to use a dual mechanism to target solid tumors. Its mechanism combines the blockade of tumor vasculature with an anti-tumor immune response. VB-111 is administered as an IV infusion once every 6-8 weeks. It has been observed in past clinical research to be generally well-tolerated in >300 cancer patients and demonstrated activity signals in an "all comers" Phase 1 trial as well as in three tumor-specific Phase 2 studies. VB-111 has received orphan designation for the treatment of ovarian cancer by the European Commission. VB-111 has also received orphan drug designation in both the United States and Europe, and fast track designation in the United States, for prolongation of survival in patients with recurrent glioblastoma. VB-111 demonstrated proof-of-concept and survival benefit in Phase 2 clinical trials in radioiodine-refractory thyroid cancer (NCT01229865) and platinum-resistant ovarian cancer (NCT01711970).

About the OVAL Trial (NCT03398655)
OVAL (VB-111-701/GOG-3018) is an international Phase 3 randomized, pivotal registration-enabling clinical trial comparing a combination of VB-111 and paclitaxel to placebo plus paclitaxel, in adult patients with recurrent platinum-resistant ovarian cancer. OVAL is conducted in collaboration with the GOG Foundation, Inc., an independent international non-profit organization with the purpose of promoting excellence in the field of gynecologic malignancies.

Deciphera Pharmaceuticals Presents New Clinical Study Results Across Pipeline at the European Society for Medical Oncology (ESMO) Congress 2021

On September 17, 2021 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a commercial-stage biopharmaceutical company developing innovative medicines to improve the lives of people with cancer, reported four e-poster presentations at the ESMO (Free ESMO Whitepaper) Congress 2021 (Press release, Deciphera Pharmaceuticals, SEP 17, 2021, View Source [SID1234587866]). The presentations include updated preliminary results from the ongoing Phase 1b/2 study of rebastinib in combination with paclitaxel in patients with PROC and updated preliminary results from the ongoing Phase 1/2 study of vimseltinib in patients with TGCT. A long-term update on the Phase 3 INVICTUS study of QINLOCK (ripretinib) in patients with advanced gastrointestinal stromal tumors (GIST), and results from the expansion phase of the Phase 1 study of ripretinib in patients with KIT-altered metastatic melanoma will also be presented.

All e-poster presentations are now available on-demand via the ESMO (Free ESMO Whitepaper) website and on the Company’s website at www.deciphera.com/presentations-publications. Deciphera will also host an investor event featuring key opinion leaders to discuss the rebastinib and vimseltinib data today, September 17, 2021, at 10 AM ET. A live webcast of the event may be accessed through the "Investors" section of Deciphera’s website at www.deciphera.com. A replay of the webcast will be available following the event.

"We are excited to present strong results at this year’s ESMO (Free ESMO Whitepaper) Congress, which support both our plans to initiate a Phase 3 pivotal study for rebastinib pending regulatory feedback, and our plans to initiate a Phase 3 pivotal study for vimseltinib. The updated safety and efficacy results for rebastinib in combination with paclitaxel show highly encouraging results, including a median progression free survival of 9.1 months, in heavily pretreated patients with PROC where additional treatment is heterogeneous and single agent paclitaxel retreatment has historically shown only 3-4 months of PFS. Based on these impressive results in patients with a significant unmet medical need, we have begun planning for a pivotal Phase 3 study that we plan to initiate in 2022 following regulatory feedback," said Matthew L. Sherman, MD, Executive Vice President and Chief Medical Officer of Deciphera. "We are equally encouraged by the tolerability and efficacy data presented today from the Phase 1/2 study of vimseltinib in TGCT. The data presented today with vimseltinib in TGCT reinforce its potential to be a best-in-class treatment for this disease. We are rapidly moving forward with this program and we expect to initiate our Phase 3 study, MOTION, in the fourth quarter of this year."

Dr. Sherman continued, "In addition to rebastinib and vimseltinib, we presented positive results from the Phase 1 study of ripretinib in patients with KIT-altered metastatic melanoma, and a long-term update from the Phase 3 INVICTUS study of QINLOCK, which shows further prolonged clinically meaningful median overall survival among patients receiving QINLOCK. Finally, we look forward to our Phase 3 INTRIGUE readout later this year in patients with second-line GIST."

Updated Preliminary Data from the Ongoing Phase 1b/2 Study of Rebastinib in Combination with Paclitaxel in PROC

The Phase 1b/2 study of rebastinib in combination with paclitaxel is a two-part, open-label, multicenter study assessing the safety, tolerability, anti-tumor activity, and pharmacokinetics of rebastinib in patients with advanced or metastatic solid tumors. The data presented today is from the second stage of Part 2 of the Simon two-stage design in PROC.

As of the June 22, 2021 cutoff date, 38 patients with PROC initiated treatment with rebastinib and paclitaxel and are included in the safety population and 34 patients that met the criteria for the modified intent-to-treat population (mITT) are included in the efficacy analysis.

The median progression-free survival (PFS) was 9.1 months.
There were 13 patients with objective responses (10 confirmed) for an objective response rate (ORR) of 38% (confirmed and unconfirmed) and 29% (confirmed only) with a median duration response of 5.5 months.
The clinical benefit rate at 16 weeks was 76%.
A CA-125 response occurred in 19 of 26 patients (73%).
Rebastinib in combination with paclitaxel was generally well tolerated at 50 mg BID, and most common (≥15%) treatment-emergent adverse events (TEAEs) were Grade 1 or 2.
Four patients experienced serious adverse events (SAEs) at least possibly related to rebastinib including reversible muscular weakness (n=2), constipation (n=1), fatigue (n=1), and urinary tract infection (n=1).
Based on the strength of these findings, the Company has begun planning for a pivotal study in PROC that is anticipated to start in 2022, subject to feedback from regulators.

Updated Preliminary Data from the Ongoing Phase 1/2 Study of Vimseltinib in TGCT

The Phase 1/2 study of vimseltinib is an open-label, multicenter study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of vimseltinib in patients with solid tumors and TGCT. The data today is from patients with TGCT in both the Phase 1 dose escalation portion of the study and from cohort A in the Phase 2 expansion portion of the study. Cohort A includes TGCT patients with no prior anti-CSF1/CSF1R (previous therapy with imatinib or nilotinib is allowed) and cohort B includes patients with prior anti-CSF1/CSF1R (previous therapy with imatinib or nilotinib are not eligible).

As of the June 7, 2021 cutoff date, 68 TGCT patients were treated with vimseltinib and included in the safety population, including 32 TGCT patients enrolled in the Phase 1 dose escalation portion of the study and 36 TGCT patients enrolled in cohort A in the Phase 2 portion of the study. Efficacy data presented today is from 51 TGCT patients, including all 32 TGCT patients enrolled in the Phase 1 dose escalation portion of the study and 19 TGCT patients enrolled in cohort A in the Phase 2 portion of the study that were evaluable for efficacy as of the cutoff date.

Dose Cohorts and Demographics:

32 patients enrolled in Phase 1 (dose escalation) and 36 patients enrolled in Phase 2 cohort A (expansion):
Phase 1 cohort 5 (n=8): 30 mg loading dose daily for five days followed by a maintenance dose of 30 mg twice a week.
Phase 1 cohort 8 (n=12): 30 mg loading dose daily for three days followed by a maintenance dose of 10 mg daily.
Phase 1 cohort 9 (n=12): 20 mg loading dose daily for three days followed by a maintenance dose of 6 mg daily.
Phase 2 cohort A (n=36): 30 mg twice weekly (no loading dose).
12 out of 32 patients (38%) in Phase 1 and 32 out of 36 patients (89%) in Phase 2 cohort A had at least one prior surgery; five patients (16%) in Phase 1 and two patients (6%) in Phase 2 cohort A had received at least one prior systematic therapy.
51 patients were evaluable for efficacy by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 at the data cutoff in Phase 1 across all dose cohorts and in Phase 2 cohort A; response data is based on independent central radiologic review with the exception of one patient who had a local assessment, and for whom no central assessment was performed.
Updated Preliminary Efficacy and Duration of Treatment:

Of the 51 efficacy-evaluable patients in Phase 1 across all dose cohorts and in the Phase 2 cohort A, 24 patients had a response resulting in an ORR of 47%.
Of the 32 patients in Phase 1, 16 patients achieved an objective response for an ORR of 50% with durable responses observed across all dose cohorts, including one complete response in cohort 5. The median duration of treatment for all patients was 10.1 months. 72% of patients remain active in the study as of the data cutoff date.
Of the 36 patients enrolled in Phase 2 cohort A, 19 patients were evaluable for efficacy, of which there were eight patients with an objective response for an ORR of 42%. Of the 19 patients, 10 had more than one follow-up imaging assessment and two responses occurred at later scans. The median duration of treatment for all patients was 1.9 months. The study is ongoing and follow-up evaluation is continuing with 83% of patients remaining active as of the data cutoff date.
Safety and Tolerability:

In both Phase 1 and Phase 2 cohort A, treatment with vimseltinib was generally well tolerated in patients with TGCT. Two patients (6%) discontinued treatment due to a TEAE in Phase 1 and one patient (3%) discontinued treatment due to an TEAE in Phase 2 cohort A.
Two patients experienced SAEs at least possibly related to vimseltinib, including metabolic encephalopathy and vaginal hemorrhage in Phase 1; no treatment-related SAEs were reported in Phase 2 cohort A.
The majority of the common (≥15%) TEAEs were Grade 2 or lower.
Observed transaminase, pancreatic, and creatine phosphokinase enzyme elevations were mostly low grade, asymptomatic, and consistent with mechanism of action of CSF1R inhibitors.
No abnormalities in bilirubin levels were reported.
Phase 3 MOTION Study

Based on the positive results of the ongoing Phase 1/2 study, the Company plans to advance vimseltinib into a pivotal Phase 3 study in patients with TGCT. The MOTION study is two-part, randomized, double-blind, placebo-controlled study of vimseltinib to assess the efficacy and safety in patients with symptomatic TGCT who are not amenable to surgery. In Part 1 of the study, eligible study participants will be assigned to receive either vimseltinib or matching placebo for 24 weeks. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib for Part 2 of the study. Part 2 is a long-term treatment phase in which all participants receive open-label vimseltinib. The primary endpoint of the study is ORR at 25 weeks as measured by RECIST v1.1 by blinded independent central review. The Company expects to initiate the MOTION study in the fourth quarter of this year.

Long-term Update from Phase 3 INVICTUS Study of QINLOCK in Patients with Advanced GIST

The INVICTUS Phase 3 clinical study is a randomized (2:1), double-blind, placebo-controlled, international, multicenter study to evaluate the safety, tolerability, and efficacy of QINLOCK compared to placebo in patients with advanced GIST whose previous therapies have included at least imatinib, sunitinib, and regorafenib. The Company previously reported primary results from the randomized portion of the INVICTUS study, in which QINLOCK significantly improved PFS and showed a clinically meaningful overall survival (OS) benefit.

An exploratory evaluation of primary and secondary endpoints in the Phase 3 INVICTUS study, with a cutoff date of January 15, 2021, an additional 19 months after the primary analysis, demonstrates consistent PFS with no change since the primary data cut off, and improved median OS among patients receiving ripretinib.

Median PFS was 6.3 months with QINLOCK compared to 1.0 month with placebo.
Median OS was 18.2 months with QINLOCK compared to 6.3 months with placebo.
Median OS was 10 months in placebo patients who crossed over to QINLOCK.
Median ORR was 11.8% with QINLOCK compared to 0% with placebo.
Median duration of response with QINLOCK was 14.5 months.
Safety findings were consistent with the primary analysis results and most TEAEs were Grade 1 or 2. Increases in TEAEs and TEAEs leading to dose modifications in the additional 19 months of follow up were minimal.

These more mature results continue to support the clinically meaningful benefit in PFS and OS for QINLOCK with an acceptable safety profile in patients with advanced GIST treated with three or more prior lines of therapy.

Phase 1 Study of Ripretinib in Patients with KIT-altered Metastatic Melanoma

As part of the expansion phase of the Phase 1 study, 26 patients with KIT-altered metastatic melanoma were treated with ripretinib at the recommended Phase 2 dose of 150 mg daily in repeated 28-day cycles. Tumor progression was assessed by the investigator using computed tomography/magnetic resonance imaging according to RECIST v1.1 on day 1 of cycles 3, 5, 7, and every three cycles thereafter, and a final study visit. ORR was confirmed with follow-up imaging approximately 28 days later. Patients who had disease progression at ripretinib 150 mg daily were allowed to dose escalate to 150 mg twice daily.

Ripretinib demonstrated encouraging efficacy in patients with KIT-altered metastatic melanoma with a confirmed ORR of 23%, median duration of response of 9.1 months, and median PFS of 7.3 months. In addition, there were two unconfirmed partial responses resulting in an ORR of 31% (confirmed and unconfirmed).
Tyrosine kinase inhibitor (TKI)-naïve patients had a greater response (confirmed ORR of 29% and median PFS of 10.2 months) to ripretinib than those with prior TKI treatment (confirmed ORR of 11% and median PFS of 2.9 months).
Ripretinib had an acceptable safety profile in KIT-altered metastatic melanoma consistent with the approved indication in GIST.

Roche presents first phase II data on giredestrant, a next generation selective oestrogen receptor degrader, in untreated oestrogen receptor (ER)-positive, early breast cancer

On September 17, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported interim data from the randomised phase II coopERA Breast Cancer trial evaluating neoadjuvant treatment with giredestrant (formerly known as GDC-9545), an investigational next generation oral selective oestrogen receptor degrader (SERD), in post-menopausal women with ER-positive, HER2-negative early breast cancer (Press release, Hoffmann-La Roche, SEP 17, 2021, View Source [SID1234587865]). In the window of opportunity phase, after 14 days of treatment, giredestrant showed a reduction in Ki67, a prognostic marker that measures tumour proliferation, compared to anastrozole (80% versus 67% respectively, p=0.0222). The safety profile of giredestrant remained consistent with previous trials and fewer patients experienced side effects assessed as related to giredestrant versus anastrozole.1 Interim analysis results from the coopERA Breast Cancer study will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 and the primary analysis data will be presented at an upcoming medical meeting.

"We are pleased to share the first randomised phase II data for giredestrant, which shows encouraging activity and safety in early HR-positive, HER2-negative breast cancer," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "Our ongoing comprehensive programme in HR-positive breast cancer aims to address significant unmet needs for people who still experience a profound impact on their quality of life, including the risk of treatment resistance and disease recurrence."

The interim analysis data from 83/202 patients enrolled in the coopERA Breast Cancer study demonstrated superior anti-proliferative activity of giredestrant compared with anastrozole and a favourable safety profile in HR-positive, HER2-negative breast cancer1:

During the window of opportunity phase (1-14 days) in this neoadjuvant (pre-operative) study, the pharmacodynamic effect of giredestrant was assessed using the relative Ki67 reduction as proliferation biomarker, which indicates the ability of a therapy to suppress tumour growth:
Giredestrant showed a mean Ki67 reduction of 80% (95% CI: –85%, –72%) versus 67% for anastrozole (95% CI; 95% CI: –75%, –56%) p=0.0222.
Consistent Ki67 suppression was observed in patients with baseline Ki67 ≥20% (83% reduction for giredestrant versus 71% for anastrozole) or baseline Ki67 <20% (65% vs 24% respectively).
After 14 days of treatment, 25% of tumours exhibited Complete Cell Cycle Arrest Rate (CCCA) with giredestrant versus 5% with anastrozole (Δ 20%; 95% CI: -37%, -3%).
The safety profile of giredestrant was consistent with its mechanism of action, with fewer patients experiencing side effects assessed as related to giredestrant (28%) versus anastrozole (38%) by the reporting investigators. No Grade ≥3 adverse events (AEs) or serious AEs were giredestrant-related.

Further data from the primary analysis of this study are expected to be presented at an upcoming medical meeting and will include results from the full population of the window of opportunity phase and early results from the neoadjuvant phase of the study, which evaluates giredestrant plus palbociclib versus anastrozole plus palbociclib.

Roche is currently enrolling patients into a second phase II study (acelERA Breast Cancer) evaluating giredestrant in second/third-line oestrogen receptor (ER)-positive early breast cancer, as well as two phase III studies: persevERA Breast Cancer, evaluating giredestrant plus palbociclib against letrozole plus palbociclib in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer and lidERA Breast Cancer, evaluating adjuvant giredestrant versus endocrine therapy of physician’s choice in patients with medium- and high-risk ER-positive and HER2-negative early breast cancer.3,4,5 In August 2021, the first patient was enrolled in the lidERA study, the first study to evaluate an oral SERD in the adjuvant setting.6 Data was also recently published in the Journal of Medicinal Chemistry; with giredestrant shown to be a potent SERD and a full antagonist, with best in class potential due to its better anti-proliferative activity than other known SERDs. Among the various SERDs reported so far, giredestrant ‘stands out in its overall preclinical package’.2,7

Giredestrant received U.S. Food and Drug Administration (FDA) Fast Track Designation (FTD) for ER-positive, HER2-negative, second and third-line metastatic breast cancer on 15 December 2020. FTD is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.8

About giredestrant
Giredestrant is a next generation investigational SERD, designed to fully block ER signalling with robust receptor occupancy and demonstrates an exceptional preclinical profile. Oestrogen encourages HR-positive breast cancer cells to grow by attaching to the ER. Giredestrant works by blocking this receptor to prevent the action of oestrogen, and in the process causes the receptor to be degraded. This investigational medicine has also shown efficacy regardless of ESR1 mutation status (mutations in the ESR1 gene are important mechanisms of resistance to hormone therapy).9.10,11,12

Orally given, giredestrant delivers an encouraging clinical efficacy and safety profile and has shown superior pre-clinical potency over other SERDs in development.2,11,13 The oral administration of giredestrant has the potential to transform the treatment experience for patients, offering greater convenience and a less painful option compared to therapies administered via intramuscular injection.

Giredestrant has a comprehensive development programme across a broad range of settings and treatment combinations for patients with HR-positive, HER2-negative breast cancer. A standardised once-daily 30 mg dose has been selected for the giredestrant development programme, both as a monotherapy and in combination studies.

About coopERA (NCT04436744)14
An open-label, two-arm, phase II study to evaluate the efficacy, safety, and pharmacokinetics of giredestrant versus anastrozole (in the window of opportunity phase) and giredestrant plus palbociclib compared with anastrozole plus palbociclib (in the neoadjuvant phase) in postmenopausal women with untreated, ER-positive, HER2-negative early breast cancer. The primary endpoint of the study is the geometric change in Ki67 scores (a measure of how quickly cancer cells are proliferating) from baseline to week 2 during the window of opportunity phase. Secondary endpoints include overall response rate, CCCA, safety outcomes and plasma concentration of giredestrant.

About Roche in breast cancer
Roche has been advancing breast cancer research for more than 30 years with the goal of helping as many people with the disease as possible. Our medicines, along with companion diagnostic tests, have contributed to bringing breakthrough innovations in HER2-positive and triple-negative breast cancers. As our understanding of breast cancer biology rapidly improves, we are working to identify new biomarkers and approaches to treatment for all forms of early and advanced breast cancer, including triple-negative and hormone receptor-positive.

Our targeted medicines Herceptin (trastuzumab), Perjeta (pertuzumab), Phesgo, Kadcyla (trastuzumab emtansine) and Tecentriq (atezolizumab) are continuing to transform the treatment of early and advanced HER2-positive and triple-negative breast cancers and, through our clinical programmes, we hope to bring new treatment combinations to people with breast cancer, ultimately improving outcomes.