On February 14, 2022 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, reported the presentation of new data showing that bavdegalutamide (also known as ARV-110), a novel PROTAC protein degrader targeting the androgen receptor (AR), continues to provide evidence of anti-tumor activity and patient benefit in metastatic castration-resistant prostate cancer (mCRPC) (Press release, Arvinas, FEB 14, 2022, View Source [SID1234608077]). These data show that bavdegalutamide reduced prostate-specific antigen (PSA) levels greater than or equal to 50% (PSA50) in 46% of patients with tumors harboring AR T878X/H875Y (T878X = T878A or T878S) mutations. Updated Phase 1 and interim Phase 2 ARDENT data will be presented in both a rapid abstract session and a poster session on February 17, 2022, at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (ASCO GU) Cancers Symposium.

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"These results are very encouraging and reinforce our conviction that bavdegalutamide has the potential to provide meaningful clinical benefit to patients with mCRPC who have progressed after treatment with novel hormonal agents and for whom few treatment options exist," said John Houston, Ph.D., president and chief executive officer of Arvinas. "With particularly robust activity in a molecularly defined patient population, we believe there is a clear path forward to developing this novel treatment as a precision medicine and plan to initiate a pivotal trial by year end 2022."

Highlights from the bavdegalutamide abstract (data cut-off date August 26, 2021):

Across 140 biomarker-evaluable patients with ≥1 month of PSA follow-up in the completed Phase 1 dose escalation and ongoing Phase 2 ARDENT expansion cohort:

Evidence of anti-tumor activity and patient benefit, including:
PSA50 rate of 46% in patients with AR T878X/H875Y tumor mutations (n=26)
Two confirmed RECIST (Response Evaluation Criteria in Solid Tumors) partial responses out of seven RECIST-evaluable patients with AR T878X/H875Y tumor mutations
PSA50 rate of 26% (five of 19) in evaluable patients in the subgroup defined as "less pretreated" (having received only one prior novel hormonal agent and no prior chemotherapy). The "less pretreated" subgroup had a similar circulating tumor DNA molecular profile to the more pretreated, biomarker-defined subgroups in the ARDENT trial; a majority of patients with PSA50 declines in this group had tumors with the AR T878X/H875Y mutations
Bavdegalutamide had a manageable tolerability profile at the recommended Phase 2 dose (RP2D) of 420 mg. The majority of treatment-related adverse events (TRAEs) were Grade 1/2 and there were no Grade ≥4 TRAEs in the 113 patients treated at the RP2D.
The most common TRAEs of any grade at the RP2D across Phase 1 and the ongoing phase 2 ARDENT expansion cohort were nausea (Grade 1/2: 42%; Grade 3: 1%), fatigue (Grade 1/2: 27%; Grade 3: 1%), vomiting (Grade 1/2: 23%; Grade 3: 1%), decreased appetite (Grade 1/2: 19%; Grade 3: 0), diarrhea (Grade 1/2: 15%; Grade 3: 2%), and alopecia (Grade 1/2: 11%).
"Novel hormonal agents have become standard of care in castration-sensitive prostate cancer and there is a need for novel AR therapies with the potential to provide benefit for patients with mCRPC and tumors that have developed resistance," said Ron Peck, M.D., chief medical officer at Arvinas. "As an oncologist, I’m particularly excited by a precision medicine approach with the potential to identify patients who are most likely to respond to bavdegalutamide."

Additional data from the completed Phase 1 and interim results from the ongoing Phase 2 ARDENT trial will be presented on Thursday, February 17, 2022. The cut-off date for data in the rapid abstract session and the poster session was December 20, 2021.

Poster presentation:

Poster Title: Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC)
Session: Poster Session A: Prostate Cancer
Date: Thursday, February 17, 2022
Time: 2:30 – 4:00 p.m. ET
Rapid abstract session (7:45 – 8:45 p.m. ET):

Rapid Abstract Title: Rapid Abstract Session A: Prostate Cancer
Date: Thursday, February 17, 2022
Time: 7:55 – 8:00 p.m. ET
The full abstract can be found at the official ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium website here.

Arvinas Webcast Investor Meeting
Arvinas will host a conference call and webcast Thursday, February 17, 2022, at 8:30 a.m. ET, to discuss the completed Phase 1 dose escalation data and interim data from the Phase 2 ARDENT trial presented at ASCO (Free ASCO Whitepaper) GU. Participants are invited to listen by dialing (844) 467-7654 (domestic) or (602) 563-8497 (international) five minutes prior to the start of the call and providing the passcode 1085203.

Supporting materials for the conference call and webcast will be available on the Arvinas’ website at www.arvinas.com under Events + Presentations. A replay of the webcast will be archived on the Arvinas website following the presentation.

About Bavdegalutamide (ARV-110)

Bavdegalutamide is an investigational orally bioavailable PROTAC protein degrader designed to selectively target and degrade the androgen receptor (AR). Bavdegalutamide is being developed as a potential treatment for men with metastatic castration-resistant prostate cancer.

Bavdegalutamide has demonstrated activity in preclinical models of AR mutation or overexpression, both common mechanisms of resistance to currently available AR-targeted therapies.

On February 14, 2022 ImmunityBio, Inc. (NASDAQ: IBRX), a clinical-stage immunotherapy company, reported positive data from the company’s late-stage bladder cancer trial (QUILT-3.032) (Press release, ImmunityBio, FEB 14, 2022, View Source [SID1234608075]). The data showed sustained complete response rates in patients with BCG-unresponsive non-muscle invasive carcinoma in situ (NMIBC CIS) bladder cancer (Cohort A) and with papillary disease (Cohort B). Of the 83 patients with BCG-unresponsive NMIBC CIS, 59 (71%) had a complete response with a median duration of response of 24.1 months—exceeding historical complete response rates of 41% and 18% for FDA-approved therapies pembrolizumab and valrubicin, respectively. In the papillary disease arm of the study (Cohort B), 57% of patients are disease free at 12 months and 53% at 18 months.

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"We are excited with these promising results," said Sam Chang, M.D., Urologic Surgery Chief Surgical Officer, Vanderbilt Ingram Cancer Center and trial investigator. "This study suggests that BCG induces trained immunity as the prime, while N-803 serves as a vital boost for innate immune memory. These results of high efficacy activity and excellent safety profile set a new bar for NMIBC treatment, and together with the familiar and favorable mode of administration, will advance our current standards of care for patients with bladder cancer."

The latest data from this trial exceeds AUA-FDA workshop benchmarks for both the magnitude of complete remission and the duration of complete response for new therapies for BCG-unresponsive bladder cancer. Indeed, the benchmark of 30% durable response at 18 to 24 months for a clinically meaningful therapy "is likely too high and may not be realistically achievable,"3 according to recommendations published in the Journal of Clinical Oncology. This "realistically unachievable" endpoint of 30% durable response at 18 months has in fact now been achieved and exceeded with the combination of Anktiva and BCG in this trial reported today. Taken together, the high rates of complete response, cystectomy avoidance, avoidance of progression to muscle invasive disease in the patients that responded, and the prolonged duration of complete response, as well as the favorable safety profile, places this novel immunotherapy combination at the forefront of both existing approved and potential treatments for bladder cancer patients.

"Trained immunity is a recently discovered immune system response triggered by BCG. Natural Killer (NK) and T cells are activated by BCG resulting in bladder cancer cell death. When an appropriate secondary stimulus is administered along with BCG, that trained immune response is enhanced to induce immune memory resulting in a prolonged duration of immunological response," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer of ImmunityBio. "N-803, our IL-15 superagonist which proliferates NK and T cells, serves as this enhancing secondary boost and augments the immunological response when given in combination with BCG. This mechanism of action of inducing trained innate immune memory, through the combination of N-803 and BCG, accounts for the prolonged 24-month durable complete response reported in this trial."

"These results support our hypothesis that immunogenic cell death can induce long-term memory and that N-803 increases the immunologic potential of BCG, even in patients who become unresponsive to BCG alone," Soon-Shiong said. "N-803 does this by stimulating proliferation and enhancing activity of tumor-killing Natural Killer (NK) cells and T cells, acting as a secondary stimulus or boost to the prime trained immunity induced by BCG."

The study results presented at ASCO (Free ASCO Whitepaper) GU are summarized below:

Cohort A (CIS)
Excellent safety and tolerability profile of N-803 + BCG for CIS

0% treatment-related SAEs
0% immune-related AE
0% grade 4 and 5 AE
71% Complete remission (CR) rate at anytime
24.1 Months median durable complete remission
96% Avoidance of bladder cancer progression at 24 months in responders
91% Avoidance of cystectomy at 24 months in responders
100% Bladder cancer specific overall survival at 24 months
Favorable & familiar dosing schedule with activity localized to the bladder
Cohort B (Papillary Disease)
Excellent safety and tolerability profile of N-803 + BCG for papillary disease

0% treatment-related SAEs
0% immune-related AE
0% grade 4 and 5 AE
57% Disease free survival rate at 12 months
99% Overall bladder cancer specific survival
95% Cystectomy avoidance rate
Favorable & familiar dosing schedule with activity localized to the bladder
"When we began the QUILT trials across multiple tumor types, initiating our Cancer Moonshot program, the goal was to achieve a new paradigm in cancer care by activating the patient’s own immune system to induce NK and T cell memory with long-term complete remission in patients who have failed all current therapies," Soon-Shiong said. "With these results in bladder cancer, as well as our recently reported results in pancreatic cancer, we are one step closer to proving our hypothesis that delivering therapies that harness the patient’s own immune system is what will truly transform current standards of care."

The data will be announced on Friday, February 18 during an oral presentation at the 2022 ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium titled Phase II/III clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC)

Incidence of Bladder Cancer

Bladder cancer has a high incidence worldwide; in 2020, an estimated 573,278 new cases were diagnosed and caused 212,536 deaths.4 In the United States, bladder cancer is the fourth most commonly-diagnosed solid malignancy in men and the twelfth for women; the American Cancer Society estimates there will be 83,730 new cases and 17,200 deaths from bladder cancer in 2021.5 Approximately 75–85% of bladder cancer patients present with a disease confined to the mucosa (stage Ta, carcinoma in situ) or submucosa (stage T1); these categories are grouped as non-muscle-invasive bladder cancer (NMIBC). Of these, approximately 70% present as stage Ta, 20% as T1, and 10% as CIS.6

For the last 30 years, BCG immunotherapy has been the standard for treating NMIBC. However, disease recurrence and progression rates remain unacceptably high. Standard-of-care recommendations include lifetime invasive surveillance and rapid treatment of recurrences, creating a substantial financial burden and drastic impact on quality of life. Of those patients who experience recurrence, approximately 30% will succumb to their disease over a 15-year period, and another 50% will undergo radical cystectomy of the bladder (surgical removal of the bladder that may require removing surrounding organs) in an attempt to control the disease.7

There is an urgent, unmet need to treat NMIBC and avoid cystectomy. Despite the advent of minimally-invasive procedures and robotic techniques, the 90-day mortality and morbidity rates in cystectomy patients remain unacceptably high at 3-6% and 28-64%, respectively.8&9 Based on this urgent need, the FDA published guidance in February 2018 to address BCG unresponsive NMIBC, stating that the goal of therapy in patients with BCG-unresponsive NMIBC is to avoid cystectomy.

About the Study and Breakthrough Designation

QUILT 3.032 is an open-label, three cohort, multicenter Phase 2/3 study of intravesical BCG plus Anktiva (N-803) in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) and was opened in 2017. The primary endpoint for Cohort A of this Phase 2/3 study is incidence of complete response (CR) of CIS at any time. The FDA had granted Fast Track Designation to the pivotal trial based on Phase I data. In December 2019, the FDA granted ImmunityBio Breakthrough Therapy Designation based on interim Phase 2 data indicating the primary endpoint of the trial was already met.

ImmunityBio’s IL-15 superagonist Anktiva (N-803)

The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of the natural killer (NK) and T cells. N-803 is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. Its mechanism of action is direct specific stimulation of CD8+ T cells and NK cells through beta gamma T-cell receptor binding (not alpha) while avoiding T-reg stimulation. N-803 has improved pharmacokinetic properties, longer persistence in lymphoid tissues and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.

N-803 is currently being evaluated for adult patients in two clinical NMIBC trials. QUILT 2.005 is investigating use of N-803 in combination with BCG for patients with BCG-naïve NMIBC; QUILT 3.032 is studying N-803 in combination with BCG in patients with BCG-unresponsive NMIBC.

Mechanism of Action & Contribution of N-803 (Anktiva) and BCG for Bladder Cancer

Trained immunity10 is a recently discovered immune system response triggered by BCG. Natural Killer (NK) and T cells11 are activated by BCG resulting in bladder cancer cell death. When an appropriate secondary stimulus is administered along with BCG, that trained immune response is enhanced to induce immune memory resulting in a prolonged duration12 of immunological response. N-803, an IL-15 superagonist which proliferates NK and T cells13, serves as this enhancing secondary boost and augments the immunological response when given in combination with BCG. This mechanism of action of inducing trained innate immune memory, through the combination of N-803 and BCG, accounts for the prolonged 24-month durable complete response reported in this trial.

On February 14, 2022 AVEO Oncology (Nasdaq: AVEO), a commercial stage, oncology-focused biopharmaceutical company, reported that new long-term progression free survival (PFS) data from the Phase 3 TIVO-3 study, which compares FOTIVDA (tivozanib) to Nexavar (sorafenib) in advanced renal cell carcinoma (RCC) patients following two or more prior systemic therapies, are being presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (ASCO GU) Cancers Symposium being held in San Francisco on February 17th – 19th (Press release, AVEO, FEB 14, 2022, View Source [SID1234608074]).

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"The long-term PFS data we are presenting at the ASCO (Free ASCO Whitepaper) GU meeting this week further strengthen the body of data supporting FOTIVDA as a potential standard of care in third- and fourth-line RCC treatment. This marks the first presentation of five year follow-up data for patients being treated in the third- or fourth-line RCC setting and helps guide clinical treatment," said Michael Bailey, President and Chief Executive Officer of AVEO. "We are excited to report that the five year follow-up data announced today show that patients receiving FOTIVDA are up to five times more likely to experience long-term progression free survival as compared to sorafenib. Long-term follow-up of the TIVO-3 study suggests early and consistent PFS benefit with FOTIVDA ultimately may be associated with the trend toward improved overall survival."

ASCO GU 2022 TIVO-3 Phase 3 Five Year Follow-up Data include:

Investigator-assessment of PFS with long-term follow-up for TIVO-3 is consistent with the primary independent review committee.
Landmark five year follow-up data show PFS rates are consistently higher with FOTIVDA vs. sorafenib, with 12% vs. 2% and 8% vs. 0% at three and four years, respectively. Long-term PFS represents a clinically meaningful outcome for patients in the third- and fourth-line treatment setting.
Long term OS was also analyzed, and a non significant trend favoring FOTIVDA continued to emerge with accumulation of events (HR, 0.89).
ASCO GU 2022 Poster/Abstract Details:
Title: Long-term PFS from TIVO-3: Tivozanib (TIVO) vs. sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC
First Author: Michael B. Atkins MD
Abstract: 362
Track: Renal Cell Cancer
Date and Time: February 19, 2022 at 10 a.m. Eastern Time

Details on the presentation are available on the 2022 ASCO (Free ASCO Whitepaper) GU website (click here). The poster scheduled to be presented at the 2022 ASCO (Free ASCO Whitepaper) GU Cancers Symposium will be available on the Publications page of the AVEO Oncology website (click here) subsequent to the presentation.

About FOTIVDA (tivozanib)

FOTIVDA (tivozanib) is an oral, next-generation vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). It is a potent, selective inhibitor of VEGFRs 1, 2, and 3 with a long half-life designed to improve efficacy and tolerability. AVEO received U.S. Food and Drug Administration (FDA) approval for FOTIVDA on March 10, 2021 for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. FOTIVDA was approved in August 2017 in the European Union and other countries in the territory of its partner EUSA Pharma (UK) Limited for the treatment of adult patients with advanced RCC. FOTIVDA has been shown to significantly reduce regulatory T-cell production in preclinical models.2 FOTIVDA was discovered by Kyowa Kirin.

INDICATIONS

FOTIVDA is indicated for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hypertension and Hypertensive Crisis: Control blood pressure prior to initiating FOTIVDA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of anti-hypertensive medications, reduce the FOTIVDA dose.

Cardiac Failure: Monitor for signs or symptoms of cardiac failure throughout treatment with FOTIVDA.

Cardiac Ischemia and Arterial Thromboembolic Events: Closely monitor patients who are at increased risk for these events. Permanently discontinue FOTIVDA for severe arterial thromboembolic events, such as myocardial infarction and stroke.

Venous Thromboembolic Events: Closely monitor patients who are at increased risk for these events. Permanently discontinue FOTIVDA for severe venous thromboembolic events.

Hemorrhagic Events: Closely monitor patients who are at risk for or who have a history of bleeding.

Proteinuria: Monitor throughout treatment with FOTIVDA. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment with FOTIVDA.

Thyroid Dysfunction: Monitor before initiation and throughout treatment with FOTIVDA.

Risk of Impaired Wound Healing: Withhold FOTIVDA for at least 24 days before elective surgery. Do not administer for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of FOTIVDA after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue FOTIVDA if signs or symptoms of RPLS occur.

Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception.

Allergic Reactions to Tartrazine: The 0.89 mg capsule of FOTIVDA contains FD&C Yellow No.5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis, and the most common Grade 3 or 4 laboratory abnormalities (≥5%) were sodium decreased, lipase increased, and phosphate decreased.

DRUG INTERACTIONS

Strong CYP3A4 Inducers: Avoid coadministration of FOTIVDA with strong CYP3A4 inducers.

USE IN SPECIFIC POPULATIONS

Lactation: Advise not to breastfeed.
Females and Males of Reproductive Potential: Can impair fertility.
Hepatic Impairment: Adjust dosage in patients with moderate hepatic impairment. Avoid use in patients with severe hepatic impairment.

To report SUSPECTED ADVERSE REACTIONS, contact AVEO Pharmaceuticals, Inc. at 1-833-FOTIVDA (1-833-368-4832) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see FOTIVDA Full Prescribing Information which is available at www.FOTIVDA.com.

About Advanced Renal Cell Carcinoma

According to the American Cancer Society’s 2021 statistics, renal cell carcinoma (RCC) is the most common type of kidney cancer, which is among the ten most common cancers in both men and women. Approximately 73,750 new cases of kidney cancer will be diagnosed annually and about 14,830 people will die from this disease. In patients with late-stage disease, the five-year survival rate is 13%. Agents that target the vascular endothelial growth factor (VEGF) pathway have shown significant antitumor activity in RCC.3 According to a 2019 publication, 50% of the approximately 10,000 patients who progress following two or more lines of therapy choose not to receive further treatment,4 which may be attributable to tolerability concerns and a lack of data to support evidence-based treatment decisions in this highly relapsed or refractory patient population.

On February 14, 2022 AstraZeneca reported that Positive results from the PROpel Phase III trial showed and MSD’s Lynparza (olaparib) in combination with abiraterone demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) versus current standard-of-care abiraterone as a 1st-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations (Press release, AstraZeneca, FEB 14, 2022, View Source [SID1234608073]).

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These results will be presented on 17 February at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium.

Prostate cancer is the second most common cancer in male patients, causing approximately 375,000 deaths in 2020.1 Patients with advanced prostate cancer have a particularly poor prognosis and the five-year survival rate remains low.1,2,3 Approximately half of patients with mCRPC receive only one line of active treatment, with diminishing benefit of subsequent therapies.4,5,6,7 HRR gene mutations occur in approximately 20-30% of patients with mCRPC.8

Fred Saad, Professor and Chairman of Urology and Director of Genitourinary Oncology at the University of Montreal Hospital Center and principal investigator in the trial, said: "It is clear to me that the prognosis for metastatic castration resistant prostate cancer (mCRPC) is extremely poor, and many patients are only able to receive one line of effective therapy. The results of the PROpel trial, which showed that olaparib in combination with abiraterone significantly delayed disease progression versus abiraterone by more than eight months, demonstrate the potential for this combination to become a new standard of care option in mCRPC if approved."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "This Lynparza combination has the potential to afford first-line patients more time without disease progression while also maintaining their quality of life. The PROpel results are impressive because active comparator trials set a high bar and, in this trial, Lynparza plus abiraterone showed a significant clinical improvement when compared to an active standard of care in patients with metastatic castration-resistant prostate cancer, regardless of whether they have an HRR gene mutation."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Results from the PROpel trial showed that Lynparza in combination with abiraterone plus prednisone reduced the risk of disease progression or death by a third compared to abiraterone plus prednisone in the first-line setting for patients with metastatic castration-resistant prostate cancer, regardless of their biomarker status. We look forward to discussing these important results with global health authorities as quickly as possible. We thank the patients, caregivers and health care providers for participating in this study."

In a predefined interim analysis, Lynparza in combination with abiraterone reduced the risk of disease progression or death by 34% versus abiraterone alone (based on a hazard ratio [HR] of 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.0001). Median rPFS was 24.8 months for Lynparza plus abiraterone versus 16.6 for abiraterone alone.

Results also showed a favourable trend towards improved overall survival (OS) with Lynparza plus abiraterone versus abiraterone alone, however the difference did not reach statistical significance at the time of this data cut-off (analysis at 29% data maturity). The trial will continue to assess OS as a key secondary endpoint.

Additional data from efficacy endpoints such as time to first subsequent therapy (TFST), second progression-free survival (PFS2), objective response rate (ORR), as well as prostate-specific antigen levels and circulating-tumour-cell counts further support the treatment benefit of Lynparza and abiraterone compared to abiraterone alone in the overall trial population.

The safety and tolerability of Lynparza in combination with abiraterone was in line with that observed in prior clinical trials and the known profiles of the individual medicines. There was no increase in the rate of discontinuation of abiraterone in patients treated with Lynparza in combination with abiraterone, and no detrimental effect on health-related quality of life versus those treated with abiraterone alone (FACT-P (Functional Assessment of Cancer Therapy-Prostate) questionnaire).

Summary of PROpel results

Lynparza + abiraterone

(n=399)

Placebo + abiraterone

(n=397)

rPFS by Investigator 1

Number of patients with events (%)

168 (42)

226 (57)

Median PFS (in months)

24.8

16.6

HR (95% CI)

p-value

0.66 (0.54, 0.81)

<0.0001

rPFS by BICR2

Number of patients with events (%)

157 (39)

218 (55)

Median PFS (in months)

27.6

16.4

HR (95% CI)

p-value5

0.61 (0.49, 0.74)

<0.0001

OS3

Number of patients with events (%)

107 (27)

121 (30)

Median OS (in months)

NC4

NC

HR (95% CI)

p-value

0.86 (0.66, 1.12)

0.2923

PFS2

Number of patients with events (%)

70 (18)

94 (24)

Median (in months)

NC

NC

HR (95% CI)

p-value5

0.69 (0.51, 0.94)

0.0184

TFST

Number of patients with events (%)

183 (46)

221 (56)

Median (95% CI) (in months)

25.0 (22.2, NC)

19.9 (17.1, 22.0)

HR (95% CI)

p-value5

0.74 (0.61, 0.90)

0.0040

Objective Response Rate

Number of evaluable patients6

161

160

Number of patients with responses (%)

94 (58)

77 (48)

Odds ratio (95% CI)

1.60 (1.02, 2.53)

p-value5

0.0409

rPFS by HRR gene mutation status7

HRRm

Number of patients randomized

111

115

Number of patients with events (%)

43 (39)

73 (63)

Median (in months)

NC

13.9

HR (95% CI)

0.50 (0.34, 0.73)

Non-HRRm

Number of patients randomized

279

273

Number of patients with events (%)

119 (43)

149 (55)

Median (95% CI) (in months)

24.1 (19.6, 27.6)

19.0 (14.3, 21.9)

HR (95% CI)

0.76 (0.60, 0.97)

1. Investigator-assessed PFS data; Interim analysis with 50% maturity (394 events in 796 patients)

2. Assessed by blinded independent central review (BICR)

3. OS analysis was done at 29% maturity (228 events in 796 patients) and boundary for significance 0.001 (2-sided); statistical significance not reached. Survival follow up continues and further analyses were planned.

4. Not calculable

5. Nominal

6. Patients with measurable disease at baseline as per RECIST 1.1 criteria, investigator assessment.

7. Exploratory subgroup analysis by HRR status. The HRRm status of patients in PROpel was determined retrospectively using results from tumour tissue and plasma ctDNA HRRm tests. Patients were classified as HRRm if (one or more) HRR gene mutation was detected by either test; patients were classified as non-HRRm if no HRR gene mutation was detected by either test; 18 patients did not have a valid HRR testing result from either a tumour tissue or ctDNA test and were excluded from this subgroup analysis. The analysis was performed using a Cox proportional hazards model including terms for treatment group, the subgroup factor, and a treatment by subgroup interaction.

The most common adverse events (AEs) (greater than or equal to 20% of patients) were anaemia (45%), nausea (28%) and fatigue (28%). Grade 3 or higher AEs were anaemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (1%), decreased appetite (1%), vomiting (1%), asthenia (1%), back pain (1%), diarrhoea (1%). Approximately 86% of patients treated with Lynparza in combination with abiraterone who experienced AEs remained on treatment at the time of data cut-off.

In September 2021 at a planned interim analysis, the Independent Data Monitoring Committee concluded that the PROpel trial met the primary endpoint of rPFS.

Lynparza is approved in the US for patients with HRR gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations); and in the EU, Japan and China for patients with BRCA-mutated mCRPC.

Notes

Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant mortality rate.3 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.9

In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.10 Approximately 10-20% of patients with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these patients will have metastases at the time of CRPC diagnosis.10

Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.11 Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, once patients failed first line therapy, the treatment effect of second line anti-cancer therapy diminished significantly hence there is high unmet medical need in this population.10,12,13,14

PROpel
PROpel is a randomised, double-blind, multi-centre Phase III trial testing the efficacy, safety, and tolerability of Lynparza versus placebo when given in addition to abiraterone in men with mCRPC who had not received prior chemotherapy or NHAs in the 1st-line setting.

Men in both treatment groups will also receive either prednisone or prednisolone twice daily. The primary endpoint is rPFS and secondary endpoints include OS, PFS2, and TFST.

For more information about the trial please visit ClinicalTrials.gov.

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in HRR, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as NHAs).

Inhibition of PARP proteins with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. In the PROpel Phase III trial, Lynparza is combined with abiraterone, an NHA which targets the androgen receptor (AR) pathway.

Androgen receptor signalling engages a transcriptional programme that is critical for tumour cell growth & survival in prostate cancer.15,16 Preclinical models have identified interactions between PARP signalling and the AR pathway which support the observation of a combined anti-tumour effect of Lynparza and NHAs, like abiraterone, in both HRR deficient and HRR proficient prostate cancer.17,18,19

The PARP1 protein has been reported to be required for the transcriptional activity of androgen receptors; therefore inhibiting PARP with Lynparza may impair the expression of androgen receptor target genes and enhance the activity of NHAs.15,18,20 Additionally, it is thought that abiraterone may alter/inhibit the transcription of some HRR genes which may induce HRR deficiency and increase sensitivity to PARP inhibition.17,19,21,22

Lynparza is currently approved in a number of countries across PARP-dependent tumour types with defects and dependencies in the DDR pathway. It is approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer as a monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination deficiency (HRD) positive advanced ovarian cancer, respectively.

Lynparza is also approved for BRCAm, HER2-negative metastatic breast cancer (in the EU this includes locally advanced breast cancer); for germline BRCAm metastatic pancreatic cancer, and for HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm only in the EU and Japan).

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza (olaparib), the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types.

Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On February 14, 2022 Amgen (NASDAQ: AMGN) reported the presentation of efficacy and safety data from the CodeBreaK 100 Phase 1/2 trial in patients with KRAS G12C-mutated advanced pancreatic cancer who received LUMAKRAS (sotorasib)* (Press release, Amgen, FEB 14, 2022, View Source [SID1234608072]). The data will be presented at the monthly American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series on Feb. 15, 2022. Data show encouraging and clinically meaningful anticancer activity and a positive benefit:risk profile.

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"Based on these exciting data, we are expanding CodeBreaK 100 to enroll more patients with pancreatic and other tumor types to better understand the efficacy and safety of LUMAKRAS in tumors outside of non-small cell lung and colorectal cancers," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "CodeBreaK is the largest and broadest global clinical trial program to date with one of the most robust, centrally reviewed datasets. As we learn more from the extensive data that we collect, we’ll continue to invest in the program by expanding cohorts and exploring new combinations so that we can help as many patients as possible."

LUMAKRAS demonstrated a centrally confirmed objective response rate (ORR) of 21% and disease control rate (DCR) of 84% across 38 heavily pre-treated advanced pancreatic cancer patients. Nearly 80% of patients received LUMAKRAS as a third-line or later therapy. Eight of the 38 patients achieved a confirmed partial response (PR) performed by a blinded independent central review (BICR). Two of the eight patients with PR have ongoing responses. Median duration of response was 5.7 months with a median follow-up of 16.8 months as of the data cutoff date of Nov. 1, 2021. The results also show a median progression free survival (PFS) of 4 months and a median overall survival (OS) of almost 7 months. No new safety signals were identified with this study of patients with advanced pancreatic cancers. Treatment-related adverse events (TRAEs) of any grade occurred in 16 (42%) patients with diarrhea (5%) and fatigue (5%) as the most common grade 3 TRAEs. No TRAEs were fatal or resulted in treatment discontinuation.

"After decades of research, current treatments for patients with pancreatic cancer provide limited survival benefit, illustrating the critical need for novel, safe and effective treatment options," said John Strickler, M.D. associate professor of medicine, Duke University School of Medicine and gastrointestinal oncologist. "In the largest dataset evaluating the efficacy and safety of a KRASG12C inhibitor in heavily pretreated advanced pancreatic cancer, sotorasib achieved a centrally confirmed response rate of 21% and a disease control rate of 84%. This is clinically meaningful for patients because there is not an established standard therapy for these patients once they get to a third-line of treatment."

Cancer of the pancreas is a highly lethal malignancy. It is the fourth leading cause of cancer-related deaths in both men and women in the U.S. with a 5-year survival rate of approximately 10%.1 There is a high unmet need for patients with advanced pancreatic cancer that has progressed after first-line treatment, where FDA-approved second-line therapy has provided survival of about six months and a response rate of 16%.2 After progression on first- and second-line chemotherapy, there are no therapies with a demonstrated survival benefit.2,3 Despite advances in treatment, few improvements have been made to improve diagnosis and treatment of pancreatic cancer.

It is estimated that approximately 90% of patients with pancreatic cancer harbor a KRAS mutation with KRAS G12C accounting for approximately 1-2% of these mutations.4-5

ASCO Plenary Series Session
ASCO will host a livestream event on Tuesday, Feb. 15 at 3 p.m. ET featuring presentation of the abstract "First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: A phase I/II study evaluating efficacy and safety" by Dr. John Strickler from Duke University. To participate in the free and open session, participants may register and login at View Source

*LUMAKRAS is marketed as LUMYKRAS (sotorasib) in the European Union and the United Kingdom.

About LUMAKRAS/LUMYKRAS (sotorasib)
Amgen took on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS/LUMYKRAS, a KRASG12C inhibitor.6 LUMAKRAS/LUMYKRAS has demonstrated a positive benefit-risk profile with rapid, deep and durable anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation with a once daily oral formulation.7

Amgen is progressing the largest and broadest global KRASG12C inhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, including triplets, with clinical trial sites spanning five continents. To date, over 4,000 patients around the world have received LUMAKRAS/LUMYKRAS through the clinical development program and commercial use.

In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval anywhere in the world with its approval in the U.S., under accelerated approval. LUMAKRAS/LUMYKRAS is also approved in the United Arab Emirates, the European Union, Japan and Switzerland, and in Canada and Great Britain under the FDA’s Project Orbis. Through Project Orbis, Amgen also has Marketing Authorization Applications (MAAs) for sotorasib in review in Australia, Brazil, Singapore and Israel. Additionally, Amgen has submitted MAAs in South Korea, Turkey, Taiwan, Colombia, Thailand, Mexico, Hong Kong, Saudi Arabia, Argentina, Kuwait and Qatar.

LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.8

About CodeBreaK
The CodeBreaK clinical development program for Amgen’s drug sotorasib is designed to treat patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers.

CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors.7.8 Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline.7 The Phase 2 trial in colorectal cancer (CRC) is fully enrolled and results have been published.9

CodeBreaK 200, the global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC completed enrollment of 345 patients. Eligible patients had previously treated (previous treatment with both platinum doublet chemotherapy and a checkpoint inhibitor), locally-advanced and unresectable or metastatic KRAS G12C-mutated NSCLC. The primary endpoint is progression-free survival and key secondary endpoints include overall survival, objective response rate, and patient-reported outcomes.

Amgen also has several Phase 1b studies investigating sotorasib monotherapy and sotorasib combination therapy across various advanced solid tumors (CodeBreaK 101) open for enrollment. A Phase 2 randomized study will evaluate sotorasib in patients with stage IV KRAS G12C-mutated NSCLC in need of first-line treatment (CodeBreaK 201). For information, please visit www.hcp.codebreaktrials.com.

LUMAKRAS (sotorasib) U.S. Indication
LUMAKRAS is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

LUMAKRAS (sotorasib) Important U.S. Safety Information

Hepatotoxicity

LUMAKRAS can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
Among 357 patients who received LUMAKRAS in CodeBreaK 100, hepatotoxicity occurred in 1.7% (all grades) and 1.4% (Grade 3). A total of 18% of patients who received LUMAKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.
Monitor liver function tests (ALT, AST and total bilirubin) prior to the start of LUMAKRAS every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations.
Withhold, dose reduce or permanently discontinue LUMAKRAS based on severity of adverse reaction.
Interstitial Lung Disease (ILD)/Pneumonitis

LUMAKRAS can cause ILD/pneumonitis that can be fatal. Among 357 patients who received LUMAKRAS in CodeBreaK 100, ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset, and 1 case was fatal. LUMAKRAS was discontinued due to ILD/pneumonitis in 0.6% of patients.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified.
Most Common Adverse Reactions

The most common adverse reactions ≥ 20% were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity and cough.
Drug Interactions

Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, dietary and herbal products.
Inform patients to avoid proton pump inhibitors and H2 receptor antagonists while taking LUMAKRAS.
If coadministration with an acid-reducing agent cannot be avoided, inform patients to take LUMAKRAS 4 hours before or 10 hours after a locally acting antacid.