On October 22, 2023 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, reported the presentation of interim data from the Company’s Phase 1/2 clinical trial for bavdegalutamide (ARV-110), a novel PROTAC protein degrader targeting the androgen receptor (AR), in a poster session at the European Society for Medical Oncology Congress being held in Madrid from October 20 – 24, 2023 (Press release, Arvinas, OCT 22, 2023, View Source [SID1234636202]). The Company will host a conference call to discuss these data and present new data from an updated analysis of its ongoing Phase 1/2 clinical trial with its second-generation PROTAC AR degrader, ARV-766, showing clinical activity extending across patients harboring tumors with AR LBD mutations and a tolerability profile that is superior to bavdegalutamide.

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Extended follow-up of data from the Phase 1/2 clinical trial with bavdegalutamide showed radiographic progression free survival (rPFS) of 11.1 months in a subgroup of patients with metastatic castration-resistant prostate cancer (mCRPC) and tumors harboring AR T878X/H878Y mutations (AR 878/875; T878X=T878A or T878S) in the absence of co-occurring AR L702H mutations. AR L702H is a common AR ligand-binding domain (LBD) mutation that is not potently degraded by bavdegalutamide. In patients with tumors harboring any AR LBD mutation except L702H alone, bavdegalutamide showed an rPFS of 8.2 months.

"We are incredibly pleased with the results from bavdegalutamide’s Phase 1/2 trial as they demonstrate the promise of our AR PROTAC degraders to help patients with prostate cancer," said John Houston, Ph.D., chairperson, chief executive officer, and president of Arvinas. "While bavdegalutamide’s efficacy is very exciting, its breadth of activity could be limited to a small patient population in a late-line setting. Our second generation PROTAC AR degrader, ARV-766, has demonstrated a broader efficacy profile and even better tolerability compared to bavdegalutamide in clinical settings. Arvinas is committed to bringing forward the best PROTAC AR degrader for patients with prostate cancer. We believe ARV-766 has the potential to be a first- and best- in-class treatment for patients with castrate-sensitive and castrate-resistant prostate cancer, and we are prioritizing the initiation of a Phase 3 clinical trial in mCRPC with ARV-766."

Bavdegalutamide is a once-daily, oral, first-in-class PROTAC AR degrader that degrades wild type and all clinically relevant AR LBD mutations except AR L702H. ARV-766 was designed to improve upon the degradation profile of bavdegalutamide by also degrading AR L702H. The prevalence of all AR LBD mutations, especially AR L702H, has increased over time, and these mutations are present in approximately 25% of tumors after initial treatment with a novel hormonal agent (NHA) such as enzalutamide or abiraterone. This represents a potential addressable patient population for ARV-766 that is approximately three times that of bavdegalutamide in the post-NHA population due to its broader degradation profile.

New data from the ongoing Phase 1/2 clinical trial of ARV-766 continues to show robust efficacy in tumors with all LBD mutations (41% PSA50) and in patients with tumors harboring AR L702H mutations (50% PSA50). In addition to a tolerability profile that is superior to bavdegalutamide, early durability data for ARV-766 are encouraging and provide additional support for prioritizing ARV-766 over bavdegalutamide, with PFS data anticipated in 2024.

"I’ve been involved in trials with both bavdegalutamide and ARV-766. It’s gratifying to see these innovative therapies developed in advanced prostate cancer where there remains a significant need for better treatments," said Daniel Petrylak, M.D., Professor of Medicine and Urology at Yale School of Medicine and investigator in the Phase 1/2 studies with bavdegalutamide and ARV-766. "In my experience, these novel therapies have the potential to be an important treatment choice for patients whose tumors harbor androgen receptor LBD mutations, which may be present in up to 25% of metastatic castration resistant prostate cancer. The increasing prevalence of the L702H mutation means that more patients could potentially benefit from the broader efficacy profile offered with ARV-766. The improvement in tolerability that ARV-766 has shown in clinical trials compared to bavdegalutamide is also a big advantage for patients with prostate cancer."

Highlights from the Phase 1/2 trial with bavdegalutamide (data cut-off date Aug. 11, 2023):
In a post-NHA (median prior therapies = 4) mCRPC population, bavdegalutamide at the recommend Phase 2 dose (420 mg, oral, once daily) demonstrated:

Median rPFS of 11.1 months in patients harboring AR 878/875 mutations and without co-occurring AR L702H mutations (n=26), and median rPFS of 8.2 months in patients with tumors harboring any AR LBD mutation except L702H alone (n=45)
PSA50 rates of 54% in patients with tumors harboring AR 878/875 mutations and without co-occurring AR L702H, and 36% in patients with tumors harboring any AR LBD mutation except L702H alone
The presence of AR L702H mutations greatly diminished the efficacy of bavdegalutamide
In patients with any tumor harboring an AR L702H mutation, the PSA50 was 8%
Bavdegalutamide had a manageable tolerability profile with no grade ≥ 4 treatment-related adverse events (TRAEs). The most common TRAEs were grade 1 and 2 and included nausea (56%), fatigue (35%), vomiting (33%), decreased appetite (25%) and diarrhea (24%). The discontinuation rate due to TRAEs was 10%.
Interim data from the ongoing Phase 1/2 dose escalation and expansion trial of ARV-766 (data cut-off date Aug. 23, 2023)
Data from an updated analysis of the ongoing Phase 1/2 clinical trial demonstrate broad efficacy and excellent tolerability in mCRPC patients with tumors harboring AR LBD mutations, including AR L702H:

PSA50 of 41% in patients with tumors harboring any AR LBD mutation, and a PSA50 of 50% in patients with any tumor harboring an AR L702H mutation
ARV-766 was well-tolerated, with no grade ≥ 4 TRAEs. The most common TRAEs were grade 1 or 2 and included fatigue (29%), nausea (14%), vomiting (11%), and diarrhea (11%). The discontinuation rate due to TRAEs was 4%.
Based on ARV-766’s superior tolerability profile and encouraging efficacy data to date, Arvinas believes ARV-766 will be a superior PROTAC AR degrader versus bavdegalutamide for both metastatic castration-sensitive prostate cancer (mCSPC) and mCRPC. Arvinas will prioritize the initiation of a Phase 3 clinical trial with ARV-766 in mCRPC instead of the previously planned Phase 3 clinical trial for bavdegalutamide. The Company will initiate discussions with regulatory authorities by 2Q 2024.

Bavdegalutamide Phase 1/2 Poster Presentation
Data from the Phase 1/2 trial is available during a poster session at the 2023 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress in Madrid:

Date: Sunday, October 22, 2023
Presentation number: 1803P
Time: 12:00 – 1:00 p.m. CEST / 6:00 – 7:00 a.m. EDT
Speaker: Daniel Petrylak, M.D.
The Company will host a conference call and webcast call at 3:00 p.m. CEST / 9:00 a.m. EDT on October 22 to discuss these data as well as previously undisclosed data from the ongoing Phase 1/2 clinical trial with ARV-766. Participants are invited to listen by going to the Events and Presentation section under the Investor page on the Arvinas website at www.arvinas.com. A replay of the webcast will be archived on the Arvinas website following the presentation.

About bavdegalutamide (ARV-110) and ARV-766
Bavdegalutamide (ARV-110) and ARV-766 are investigational orally bioavailable PROTAC protein degraders designed to selectively target and degrade the androgen receptor (AR). Bavdegalutamide and ARV-766 are being developed as potential treatments for men with prostate cancer. Preclinically, both investigational agents have demonstrated activity in models of wild type androgen receptor tumors in addition to tumors with AR mutations or amplification, both common potential mechanisms of resistance to currently available AR-targeted therapies.

On October 22, 2023 Amgen (NASDAQ:AMGN) reported data from the global Phase 3 CodeBreaK 300 trial evaluating two doses of LUMAKRAS (sotorasib) (960 mg or 240 mg) in combination with Vectibix (panitumumab) (Press release, Amgen, OCT 22, 2023, View Source [SID1234636201]). Both doses demonstrated a statistically significant superiority in progression-free survival (PFS) over the investigator’s choice of therapy in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC). The results are being presented today at the Presidential Symposium 2 session as a late-breaking oral presentation (LBA10) during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 Congress in Madrid, Spain, with simultaneous publication in the New England Journal of Medicine.

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"The CodeBreaK 300 trial demonstrated the benefit of LUMAKRAS plus Vectibix to deliver statistically significant PFS outcomes for patients compared to the investigator’s choice of therapy, offering new hope to this population with historically poor outcomes," said David M. Reese, M.D., executive vice president, Research and Development at Amgen.

After a median follow-up of 7.8 months, the median PFS was 5.6 months and 3.9 months with LUMAKRAS 960 mg plus Vectibix and LUMAKRAS 240 mg plus Vectibix respectively, versus 2.2 months with investigator’s choice of therapy (trifluridine and tipiracil, or regorafenib). The improvement in PFS for patients treated with LUMAKRAS plus Vectibix was seen across key subgroups, including tumor sidedness, primary tumor location, prior lines of therapy and presence or absence of liver metastases. Among secondary endpoints, higher objective response rate (ORR) and disease control rate (DCR) were observed in patients treated with LUMAKRAS plus Vectibix at both doses versus investigator’s choice of care. Patients at both dose regimens of LUMAKRAS plus Vectibix experienced a longer duration of treatment than those treated with investigator’s choice therapy.

"With these new data, sotorasib plus panitumumab showed consistent efficacy across key subgroups at both doses and supports the biologic rationale of combining these two biomarker-directed therapies," said Filippo Pietrantonio, M.D., Fondazione IRCCS Istituto Nazionale dei Tumori. "Fewer than 20% of people diagnosed with mCRC survive beyond five years, and additional treatment options are clearly needed, particularly for the patients with KRAS mutations for whom evidence-based targeted options were not yet available."

The most common Grade ≥3 treatment-related adverse events (TRAEs) with LUMAKRAS plus Vectibix were dermatitis acneiform (960 mg: 11%; 240 mg: 4%), hypomagnesemia (960 mg: 6%; 240 mg: 8%), rash (960 mg: 6%; 240 mg: 2%), and diarrhea (960 mg: 4%; 240 mg: 6%).

Based on the CodeBreaK 300 primary analysis results, Amgen is planning to submit these data to regulatory authorities.

About CodeBreaK 300
The CodeBreaK 300 trial enrolled 160 participants and compared LUMAKRAS at doses of 960 mg and 240 mg in combination with Vectibix to investigator’s choice of standard of care (trifluridine and tipiracil, or regorafenib) in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC).

The primary endpoint was PFS, and key secondary endpoints were overall survival (OS) and objective response rate (ORR).

The median PFS for patients treated with the 960 mg dose of LUMAKRAS plus Vectibix (n=53) was 5.6 months (Hazard Ratio (HR) 0.49 (95% Confidence Interval (CI): 0.30, 0.80)).
The median PFS for patients treated with the 240 mg dose of LUMAKRAS plus Vectibix (n=53) was 3.9 months (HR 0.58 (95% CI: 0.36, 0.93)).
The median PFS for patients treated with investigator’s choice (n=54) was 2.2 months.
LUMAKRAS plus Vectibix combination regimens demonstrated higher ORR compared with investigator’s choice (95% CI; 960 mg: 26% [15.3–40.3]; 240 mg: 6% [1.2–15.7]; investigator’s choice of care: 0% [0–6.6]). Similarly, consistent improvement in DCR was observed in patients treated with LUMAKRAS plus Vectibix (95% CI; 960 mg: 72% [57.7–83.2]; 240 mg: 68% [53.7–80.1]; investigator’s choice: 46% [32.6–60.4]). Tumor shrinkage of any level from baseline was observed in 81%, 57% and 20% of patients in the 960 mg dose, 240 mg dose and investigator’s choice cohorts, respectively. The OS was immature at the time of the data cutoff.

About LUMAKRAS/LUMYKRAS (sotorasib)
LUMAKRAS received accelerated approval from the U.S. Food and Drug Administration on May 28, 2021. The supplemental New Drug Application (sNDA) for full approval of LUMAKRAS was accepted by the FDA for standard review and a Prescription Drug User Fee Act (PDUFA) target action date of December 24, 2023, has been set.

About Advanced Colorectal Cancer and the KRAS G12C Mutation
Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, comprising 10% of all cancer diagnoses.1 It is also the third most commonly diagnosed cancer globally.2 Patients with previously treated metastatic CRC need more effective treatment options.

KRAS mutations are among the most common genetic alterations in colorectal cancers, with the KRAS G12C mutation present in approximately 3-5% of colorectal cancers.3,4,5

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 occurring in ≥ 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.
Please see LUMAKRAS full Prescribing Information.

About Vectibix (panitumumab)
Vectibix is the first fully human monoclonal anti-EGFR antibody approved by the FDA for the treatment of mCRC. Vectibix was approved in the U.S. in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

In May 2014, the FDA approved Vectibix for use in combination with FOLFOX, as first-line treatment in patients with wild-type KRAS (exon 2) mCRC. With this approval, Vectibix became the first-and-only biologic therapy indicated for use with FOLFOX, one of the most commonly used chemotherapy regimens, in the first-line treatment of mCRC for patients with wild-type KRAS mCRC.

In June 2017, the FDA approved a refined indication for Vectibix for use in patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) mCRC.

INDICATION AND LIMITATION OF USE
Vectibix is indicated for the treatment of patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) metastatic colorectal cancer (mCRC): as first-line therapy in combination with FOLFOX, and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS mutant mCRC or for whom RAS mutation status is unknown.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: DERMATOLOGIC TOXICITY
Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

In Study 20020408, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.
Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications, including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix concerning dermatologic toxicity are provided in the product labeling.
Vectibix is not indicated for the treatment of patients with colorectal cancer that harbor somatic RAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as "RAS."
Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents. Additionally, in Study 20050203, 272 patients with RAS-mutant mCRC tumors received Vectibix in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix and FOLFOX versus FOLFOX alone.
Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 20080763) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix treatment, periodically during Vectibix treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.
In Study 20020408, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.
Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy.
Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. In the event of acute onset or worsening of pulmonary symptoms interrupt Vectibix therapy. Discontinue Vectibix therapy if ILD is confirmed.
In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix versus the risk of pulmonary complications must be carefully considered.
Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.
Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix for acute or worsening keratitis.
In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).
NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.
Vectibix can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 months after the last dose of Vectibix.
In monotherapy, the most commonly reported adverse reactions (≥ 20%) in patients with Vectibix were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.
The most commonly reported adverse reactions (≥ 20%) with Vectibix + FOLFOX were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. The most common serious adverse reactions (≥ 2% difference between treatment arms) were diarrhea and dehydration.
To see the Vectibix Prescribing Information, including Boxed Warning visit www.vectibix.com.

On October 21, 2023 ESSA Pharma Inc. ("ESSA", or the "Company") (NASDAQ: EPIX), a clinical-stage pharmaceutical company focused on developing novel therapies for the treatment of prostate cancer, reported the presentation of updated dose escalation data from its Phase 1/2 study evaluating masofaniten (formerly EPI-7386) in combination with enzalutamide at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 Congress, taking place October 20-24, 2023, in Madrid, Spain (Press release, ESSA, OCT 21, 2023, View Source [SID1234636227]). Masofaniten is a first-in-class N-terminal domain androgen receptor ("AR") inhibitor that suppresses androgen activity through a novel mechanism of action and is being developed for the treatment of prostate cancer. The poster presentation is available on the ESMO (Free ESMO Whitepaper) Digital Program and in the "Publications" section of the Company’s website at www.essapharma.com.

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"The dose escalation data presented at ESMO (Free ESMO Whitepaper) this year continue to demonstrate that the combination of masofaniten and enzalutamide is well tolerated and results in deep and durable reductions in prostrate-specific antigen ("PSA") in patients with metastatic castration-resistant prostate cancer ("mCRPC")," said David Parkinson, MD, President and CEO of ESSA. "While the data for patients in cohort four are not yet mature, we are highly encouraged by the PSA responses seen thus far in the cohort and in the study as a whole. We look forward to further elucidating the potential clinical benefit of this combination in the randomized Phase 2 portion of the study which is currently underway."

Poster presentation details:

Title: Phase 1/2 Trial of Oral EPI-7386 (masofaniten) in Combination with Enzalutamide (Enz) Compared with Enz Alone in Subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC): Current Phase 1 (P1) results
Presenting Author: Andrew Laccetti, MD, MS, Memorial Sloan Kettering Cancer Center
Abstract # 1813P
Date: Sunday, October 22, 2023

Data summary: This Phase 1/2 multicenter, open-label clinical trial is enrolling patients with mCRPC who have received androgen deprivation therapy and who are naïve to second-generation antiandrogens but may have been treated previously with one line of prior chemotherapy in the metastatic hormone-sensitive prostate cancer setting. The data presented today are from the first four cohorts of patients in the Phase 1 dose escalation portion of the study. Masofaniten has no effect on enzalutamide exposure, thus allowing the use of full dose per label (160mg) of enzalutamide in combination. Enzalutamide reduces masofaniten exposure but twice daily dosing of masofaniten appears to mitigate the reduction and maintains clinically relevant drug exposures.

In patients evaluable for safety (n=18), masofaniten combined with enzalutamide, continues to be well-tolerated at the doses tested through 21 cycles of dosing in some patients. Most frequent adverse events were Grade 1 and 2, related to either AR inhibition or gastrointestinal tract irritation. In Cohort 4, one patient experienced a Grade 3 rash, which was observed immediately following administration of masofaniten combined with enzalutamide and deemed probably related.

In the patients evaluable for efficacy (n=16), rapid, deep and durable reductions in PSA were observed, regardless of previous chemotherapy status, including in patients who received lower than the full dose of enzalutamide (120 mg). In the first three cohorts, 90% of patients (9 of 10) achieved PSA50 and PSA90, 80% of patients (8 of 10) achieved PSA90 in less than 90 days, and 70% of patients (7 of 10) achieved PSA <0.2mg/mL. Across all dose cohorts including patients in the recently enrolled cohort four, 88% of patients (14 of 16) achieved PSA50, 69% of patients (11 of 16) achieved PSA90, 63% of patients (10 of 16) achieved PSA90 in less than 90 days, and 56% of patients (9 of 16) achieved PSA <0.2mg/mL. The randomized Phase 2 dose expansion portion of the study is currently enrolling.

About Masofaniten
Masofaniten (formerly known as EPI-7386) is a first-in-class investigational, highly selective, oral, small molecule inhibitor of the N-terminal domain ("NTD") of the androgen receptor ("AR"). Masofaniten’s unique mechanism of action disrupts the AR signaling pathway, the primary pathway that drives prostate cancer growth, by selectively binding to the NTD, a region of the AR that is not currently targeted by other therapies. Masofaniten is currently being studied in an open-label, randomized Phase 2 clinical trial (NCT05075577) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) naïve to second-generation antiandrogens. ESSA is also conducting a Phase 1 monotherapy study (NCT04421222) in patients with mCRPC whose tumors have progressed on standard-of-care therapies. The U.S. Food and Drug Administration has granted Fast Track designation to masofaniten for the treatment of adult male patients with mCRPC resistant to standard-of-care treatment. ESSA retains all rights to masofaniten worldwide.

On October 21, 2023 MEDSIR, a company specializing in the strategic design of independent clinical research, reported that the results of three new studies at the European Society for Medical Oncology (ESMO 2023), one of the most prestigious oncology platforms for clinicians, researchers and healthcare industry representatives in Europe and with global influence: LUPER, focused on patients with small-cell lung cancer; and two translational studies extending the results of the PHERGain study, focused on HER2-positive breast cancer (Press release, MedSIR, OCT 21, 2023, View Source [SID1234636226]).

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The pan-tumor research company reached a major milestone with the presentation of the landmark results of the PHERGain study at ASCO (Free ASCO Whitepaper) 2023, the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), in June. These results showed that approximately one third of patients with early-stage HER2-positive breast cancer could be treated without chemotherapy and remain free of breast cancer for up to three years after surgery. PHERGain is a groundbreaking trial that uses a personalized treatment strategy for each patient.

LUPER: Efficacy and safety through a combination of lurbinectedin and pembrolizumab in patients with small cell lung cancer

The LUPER trial, which was presented during an oral session at the congress, is being led by Dr. Antonio Calles, a medical oncologist at the Gregorio Marañón Hospital in Madrid.

The LUPER trial is evaluating the efficacy of the combination of lurbinectedin (a drug that promotes tumor cell death and regulates the ecosystem surrounding a tumor in the body) and pembrolizumab (an immunotherapy drug) in patients with small-cell lung cancer (SCLC) who have relapsed after initial platinum-based chemotherapy. A total of 28 patients with SCLC who had not previously received immunotherapy were enrolled in the LUPER trial.

The analysis of results from the ongoing LUPER study shows that the combination of lurbinectedin and pembrolizumab is effective in treating patients with SCLC who have relapsed after platinum-based chemotherapy without prior immunotherapy. The main results of the study were presented at ESMO (Free ESMO Whitepaper) and show that more than 46% of patients experienced a reduction in tumor size (objective response rate), in some cases with strong and durable responses lasting more than 12 months.

Lurbinectedin is approved by the US Food and Drug Administration (FDA) for the treatment of metastatic small-cell lung cancer patients with progressive disease on or after platinum-based chemotherapy. The results of the LUPER study presented at this edition of ESMO (Free ESMO Whitepaper) encourage further research into this drug in combination with immunotherapy.

It is therefore a cancer with a clear unmet need for innovative treatment options that may be viable for patients with small-cell lung cancer whose cancer has progressed on first-line chemotherapy.

PHERGain TRANSLATIONAL STUDIES in breast cancer

Trop-2, a biomarker for treatment resistance in HER2-positive breast cancer patients?

In the first of the translational studies presented by MEDSIR at ESMO (Free ESMO Whitepaper), we analyzed the expression levels of the Trop-2 protein in tumor samples from patients with HER2-positive early breast cancer. The aim is to determine whether there is a link between the levels of this protein prior to treatment and pathological complete response (the absence of residual cancer cells) to the standard treatment for this type of cancer. The study is being led by Dr María Gion.

The Trop-2 protein is present at low levels in healthy cells, but elevated levels of this protein have been found in many cancers and is associated with increased tumor aggressiveness, metastasis and poor outcome. However, the role of Trop-2 in HER2-positive breast cancer patients and whether Trop-2 is able to predict disease progression or response to treatment (two important parameters for clinicians) remains largely unexplored.

Researchers found that patients who had high levels of the Trop-2 protein prior to treatment had lower pathological complete response rates, meaning they were less likely to respond to treatment, while patients who did not have high levels of Trop-2 protein were significantly more likely to achieve a response. Therefore, Trop-2 could potentially be used in future research to identify patients who are most likely to benefit from treatment. This also opens up the possibility of it becoming a target for future therapeutic combinations.

HER2DX: a genomic test for predicting patient survival

Another study presented, with the aim of identifying strategies to select the most appropriate treatment for patients with early HER2-positive breast cancer, compared the association between the HER2DX test prediction of pathological complete response with actual pathological complete response observed in the PHERGain clinical trial; and the HER2DX risk (prognostic) score with actual clinical data on invasive disease-free survival 3 years after surgery. This study was performed on samples and clinical data from 292 patients who participated in the PHERGain clinical trial (82% of the total number of participants).

This project was led by Dr Antonio Llombart-Cussac, in collaboration with Dr Javier Cortés (both co-founders of MEDSIR), with REVEAL GENOMICS, S.L. as the main scientific partner, led by Dr Aleix Prat.

HER2DX is an in vitro diagnostic test developed by REVEAL GENOMICS, S.L. HER2DX is the first genomic tool for patients with early-stage HER2-positive breast cancer. The test measures the expression of 27 cancer-related genes and combines this information with clinical characteristics such as tumor size and lymph node involvement. This personalized data is then processed by an algorithm that calculates two independent scores: one indicating a patient’s likelihood of relapse (prognosis) after treatment with trastuzumab-based chemotherapy (risk score) and another indicating the likelihood of response to anti-HER2 treatment (pathological complete response probability score).

The HER2DX genomic test may prove to be a valuable tool to guide healthcare professionals and patients in personalizing treatment for HER2-positive early breast cancer.

On October 21, 2023 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported the first presentation of key secondary endpoints for an investigational regimen of PD-1 inhibitor Libtayo (cemiplimab) as a neoadjuvant monotherapy in stage II to IV resectable cutaneous squamous cell carcinoma (CSCC) (Press release, Regeneron, OCT 21, 2023, View Source [SID1234636215]). The results from an international Phase 2 trial were presented in an oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 and concurrently published in The Lancet Oncology.

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"Advanced, resectable cutaneous squamous cell carcinoma can lead to reduced patient function and quality of life following the cumulative effects of treatment, typically surgery and radiation. Additionally, risk of recurrence and death is a consideration for these patients," said Neil D. Gross, M.D., F.A.C.S., Director of Clinical Research, Department of Head and Neck Surgery at the University of Texas MD Anderson Cancer Center and principal investigator of the trial. "Results from both the single-institution pilot trial and the multi-center Phase 2 trial found neoadjuvant cemiplimab was highly active in patients with resectable cutaneous squamous cell carcinoma. These robust responses were durable, translating into event-free survival for the vast majority of patients at one and two years."

The multicenter, single-arm Phase 2 trial included two parts. In Part 1, patients (n=79) received Libtayo 350 mg every three weeks for up to four doses, followed by curative-intent surgery. Per the primary analysis presented at ESMO (Free ESMO Whitepaper) 2022 and published in the New England Journal of Medicine, there was a 63.3% (n=50) combined pathologic response rate. This included a 50.6% (n=40) pathologic complete response rate (pCR; 0% residual viable tumor) and a 12.7% (n=10) major pathologic response rate (MPR; >0% and ≤10% residual tumor cells). In Part 2, the post-surgical part of the trial, patients who completed curative intent surgery (n=70), received an investigator’s choice of Libtayo, radiation or observation.

The presentation at this year’s ESMO (Free ESMO Whitepaper) shared secondary survival endpoints among all 79 patients in the trial, continuing to demonstrate encouraging outcomes at one-year (median duration of follow-up: 19 months; range: 1-30 months), including:

89% event-free survival rate (95% confidence interval [CI]: 79%-94%) at one year, per Kaplan-Meier estimates, with the median not reached
No disease recurrence among patients who achieved a pCR (n=40). Among those achieving an MPR, 9 of 10 remained disease-free at one year
92% overall survival rate (95% CI: 83%-96%) at one year, per Kaplan-Meier estimates, with the median not reached
Among all patients, adverse events (AE) of any grade occurred in 89% of patients, with 19% being ≥grade 3, and one death due to worsening congestive heart failure considered possibly related to treatment. Among those who received adjuvant Libtayo in Part 2 of the trial (n=16), there were two grade 3 serious AEs including worsening cardiomyopathy and hypophysitis (n=1 each) and no deaths considered related to treatment.

"The primary analysis of this Phase 2 trial demonstrated greater than 60% response rates, and it is encouraging that Libtayo may have utility in this earlier stage of cutaneous squamous cell carcinoma," said Israel Lowy, M.D., Ph.D., Senior Vice President, Translational and Clinical Sciences, Oncology at Regeneron. "These new data add to the growing body of evidence for Libtayo in this investigational setting where high unmet patient need remains."

A separate ongoing global Phase 3 trial is investigating Libtayo in the adjuvant CSCC setting for patients at heightened risk (i.e., due to involvement of multiple lymph nodes, extension of cancer through the lymph node capsule, perineural invasion) for recurrence after surgery and radiotherapy.

The potential use of Libtayo described above is investigational, and its safety and efficacy has not been evaluated by any regulatory authority for this indication.