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.

On October 21, 2023 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported initial data from the ongoing ORIC-114 Phase 1 dose escalation trial for patients with EGFR or HER2 exon 20 mutated non-small cell lung cancer (NSCLC) at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (clinical poster here) (Press release, ORIC Pharmaceuticals, OCT 21, 2023, View Source [SID1234636214]).

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"We are excited to present the first look at ORIC-114 clinical data, which we believe supports the potential to address the key attributes of a potential best-in-class program for EGFR/HER2 exon 20 mutated NSCLC: minimal EGFR toxicity, minimal off-target toxicity, CNS activity, and systemic activity including post-amivantamab," said Jacob M. Chacko, MD, chief executive officer. "Given the high rate of brain metastases in these patients and the high percentage of patients whose disease progresses in the brain, we believe that a well-tolerated CNS active agent has the potential to be transformative."

"We are pleased with the emerging profile of ORIC-114 in these heavily pretreated patients, which includes clinical activity across multiple dose levels and the first reported intracranial complete response in a patient with EGFR exon 20 lung cancer and documented untreated brain metastases," said Pratik Multani, MD, chief medical officer. "This is the first comprehensive data set for EGFR exon 20 patients with such an exceptionally high rate of CNS disease at baseline and prior exon 20 inhibitor therapy. Based on the encouraging clinical activity and favorable safety profile, we plan to advance this program into dose optimization to select RP2D and, ultimately, into one or more registrational cohorts for potential accelerated approval."

ORIC-114 Phase 1 Study Design

ORIC-114 is being evaluated in a Phase 1 dose escalation clinical trial in patients with advanced solid tumors with EGFR and HER2 exon 20 alterations or HER2 amplifications. Patients previously treated with an exon 20 targeted agent are eligible, including patients with CNS metastases that are either treated or untreated but asymptomatic. Nearly all other clinical studies with EGFR exon 20 inhibitors severely restricted the eligible patient population and excluded patients with active or untreated brain metastases and patients previously treated with an EGFR exon 20 inhibitor, making this data set one of the first and most comprehensive in this population. The primary objectives are to determine the recommended Phase 2 dose (RP2D), and additional objectives include characterization of the safety, tolerability, pharmacokinetic, and preliminary antitumor activity.

ORIC-114 Phase 1 Dose Escalation Data

As of September 26, 2023, 50 patients (21 EGFR exon 20, 24 HER2 exon 20 and 5 HER2+ patients) received ORIC-114 and were heavily pre-treated, with exceptionally high rates of prior exon 20 targeted therapies and brain metastases at baseline.

Of the 21 EGFR exon 20 insertion mutated NSCLC patients, in addition to chemotherapy
81% were treated with ≥1 prior EGFR exon 20 targeted agent, nearly all of whom received prior amivantamab;
19% were treated with multiple prior EGFR exon 20 targeted agents; and
86% presented with CNS metastases at baseline
Of the 24 HER2 exon 20 insertion mutated NSCLC patients
30% were treated with a prior HER2 targeted agent; and
38% presented with CNS metastases at baseline
Preliminary Pharmacokinetic Analysis and Safety

ORIC-114 demonstrated a favorable pharmacokinetic profile with dose proportional increase in exposure, low intra-cohort variability, and a half-life of ~10-15 hours, which supports QD dosing.

ORIC-114 was well-tolerated with mostly Grade 1 and 2 treatment-related adverse events (TRAEs) and little evidence of off-target toxicities. Rash was limited to Grade 1 and 2 events, and there was no Grade 3 or greater treatment related rash. Diarrhea was primarily Grade 1 and 2, with only 6% of patients experiencing Grade 3 diarrhea. There were only 4% discontinuations for TRAEs. The maximum tolerated dose has not been reached.

Preliminary Activity Analysis

Systemic and intracranial activity of ORIC-114 was demonstrated in this heavily pre-treated patient population across multiple dose levels. Preliminary activity data for patients treated at clinically active doses (total daily dose (TDD) ≥45 mg) as of the cut-off date were available for 15 response evaluable NSCLC patients with EGFR exon 20 insertion mutations and 13 response evaluable NSCLC patients with HER2 exon 20 insertion mutations.

EGFR exon 20 patients:

Observed systemic and CNS activity at multiple dose levels, consisting of multiple partial responses and one ongoing confirmed complete response, including a confirmed complete response in the brain.
Within the 45 mg dose level, a patient had an ongoing confirmed partial response and two of three brain lesions resolved on therapy.
Within the 75 mg dose level, identified as a potential RP2D, of the three patients previously treated with amivantamab
All three patients experienced tumor shrinkage, and
There was an unconfirmed ORR of 67% and a confirmed ORR of 33%, including an ongoing systemic confirmed complete response and the first confirmed CNS complete response reported by an EGFR exon 20 inhibitor in a patient with documented untreated brain metastases at baseline.
HER2 exon 20 patients:

Observed systemic and CNS activity at multiple dose levels, consisting of multiple partial responses, including an ongoing confirmed partial response with 100% regression of all target lesions, with only persistent non-target lesions preventing a complete response.
Within the 30 mg BID dose level, a patient had an ongoing confirmed partial response and shrinkage of multiple brain lesions on therapy.
Next Steps

The Phase 1 trial of ORIC-114 is ongoing to determine the candidate recommended RP2Ds for dose optimization, and subsequently the selection of the final RP2D. Since the September 26, 2023 data cutoff, the 40 mg BID dose level has cleared the DLT evaluation period, and the study is now evaluating 50 mg BID and 120 mg QD dose levels. The Phase 1 trial will enroll patients with EGFR exon 20 insertion mutations that are EGFR exon 20 inhibitor-naïve, and additional patients who are post-amivantamab. Additionally, enrollment will be expanded to include patients with atypical EGFR mutations based on the promising preclinical activity presented at ESMO (Free ESMO Whitepaper) 2023 (preclinical poster here).

Conference Call and Webcast Details

To join the conference call via phone and participate in the live Q&A session, please pre-register online here to receive a telephone number and unique passcode required to enter the call. A live webcast and audio archive of the conference call will be available through the investor section of the company’s website at www.oricpharma.com. The webcast will be available for replay for 90 days following the presentation.

About ORIC-114

ORIC-114 is a highly selective, brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations, making it a promising therapeutic candidate to address the unmet medical need of having both meaningful systemic as well as CNS antitumor activity.

On October 21, 2023 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported results from the Phase 3 LITESPARK-005 trial investigating WELIREG, Merck’s first-in-class, oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adult patients with advanced renal cell carcinoma (RCC) that progressed following PD-1/L1 and vascular endothelial growth factor receptor (VEGFR) targeted therapies (Press release, Merck & Co, OCT 21, 2023, View Source [SID1234636210]). In the study, WELIREG demonstrated a statistically significant improvement in one of the trial’s dual primary endpoints of progression-free survival (PFS) and in a key secondary endpoint of objective response rate (ORR) compared to everolimus. These late-breaking data are being presented for the first time today during a proffered paper session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (abstract #LBA88) and are also being discussed with regulatory authorities worldwide.

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At the first pre-specified interim analysis (IA1) at a median follow-up of 18.4 months (range, 9.4-31.7), WELIREG significantly reduced the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p<0.001) versus everolimus in these patients. Results at the second pre-specified interim analysis (IA2) were consistent with IA1. At a median follow-up of 25.7 months (range, 16.8-39.1), WELIREG reduced the risk of disease progression or death by 26% (HR=0.74 [95% CI, 0.63-0.88]) versus everolimus.

Treatment with WELIREG was also associated with a statistically significant improvement in ORR at IA1; the ORR was 21.9% (95% CI, 17.8-26.5), with a complete response (CR) rate of 2.7%, for patients who received WELIREG versus an ORR of 3.5% (95% CI, 1.9-5.9), with no patients achieving a CR rate, for patients who received everolimus (p<0.00001). At IA2, the ORR was 22.7% (95% CI, 18.6-27.3), with a CR rate of 3.5% for patients who received WELIREG versus a 3.5% ORR (95% CI, 1.9-5.9), with no patients achieving a CR rate, for patients who received everolimus.

Additionally, overall survival (OS), the trial’s dual primary endpoint, favored WELIREG versus everolimus (HR=0.87 [95% CI, 0.71-1.07]; p=0.096) and (HR=0.88 [95% CI, 0.73-1.07]; p=0.099) at IA1 and IA2, respectively; however, this result did not reach statistical significance.

"There are limited treatment options for patients with advanced RCC whose cancer progresses after both immune checkpoint and anti-angiogenic therapies," said Professor Laurence Albiges, chair, Gustave Roussy Cancer Medicine Department and study investigator for LITESPARK-005. "Therefore, it is an important step forward to see that in this study, belzutifan demonstrated a statistically significant reduction in the risk of disease progression or death, and an improvement in overall response rate compared to everolimus for these patients who urgently need additional treatment options after their disease progresses."

"These are the first positive Phase 3 data in patients with advanced RCC following both immune checkpoint and anti-angiogenic therapies, and the first Phase 3 data to readout from the WELIREG clinical program," said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. "This latest research demonstrates that WELIREG has the potential to improve outcomes for these patients and reinforces Merck’s commitment to advance research for patients with difficult-to-treat cancers through our robust clinical development program evaluating multiple novel mechanisms, including WELIREG."

Additional data from the LITESPARK clinical development program being presented at the ESMO (Free ESMO Whitepaper) Congress 2023 include Phase 2 results from the LITESPARK-003 (#LBA87) and LITESPARK-013 (#1881O) trials evaluating WELIREG in advanced RCC. As announced, data spanning more than 15 types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at the ESMO (Free ESMO Whitepaper) Congress 2023, in addition to a Merck-sponsored study evaluating the impact of Von-Hippel Lindau (VHL) disease-associated tumor treatment on mental health (#83P).

"Belzutifan is a HIF-2α inhibitor, a first-in-class anti-cancer therapy that has shown strong early clinical results in renal cell carcinoma," said Dr. Toni K. Choueiri, LITESPARK-005 study chair, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Jerome and Nancy Kohlberg professor of medicine, Harvard Medical School. "For patients with advanced RCC, these results from LITESPARK-005 marks a first step in helping to address the unmet medical need for additional treatment options for adult patients with advanced RCC following both prior VEGFR and PD-1/L1 targeted therapies, and we look forward to further findings across the first-line, second-line and adjuvant settings of RCC, as part of the broader LITESPARK clinical development program."

WELIREG is a first-in-class, HIF-2α inhibitor therapy approved in the U.S. for the treatment of adult patients with VHL disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, not requiring immediate surgery based on data from the Phase 2 LITESPARK-004 trial. Additional applications are currently under regulatory agency review worldwide based on LITESPARK-004.

LITESPARK-005 is part of a comprehensive development program for WELIREG, comprised of four Phase 3 trials in RCC, including LITESPARK-011 and LITESPARK-012, evaluating WELIREG in the second-line and treatment-naïve advanced disease settings, and LITESPARK-022, evaluating WELIREG in the adjuvant setting.

Merck previously announced that based on these positive results from LITESPARK-005, the U.S. Food and Drug Administration (FDA) has granted priority review for a supplemental new drug application (sNDA) for WELIREG for the treatment of adult patients with advanced RCC following immune checkpoint and anti-angiogenic therapies. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of January 17, 2024.

Study design and additional data from LITESPARK-005
LITESPARK-005 is a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT04195750) evaluating WELIREG compared to everolimus for the treatment of patients with advanced clear cell RCC that has progressed after prior treatment with PD-1/L1 and VEGF-TKI therapies, in sequence or in combination. The dual primary endpoints are PFS and OS. Secondary endpoints include ORR, duration of response and safety. The trial enrolled 746 patients who were randomized to receive WELIREG (120 mg orally once daily) or everolimus (10 mg orally once daily).

Results at IA1 showed that among patients who received WELIREG, median PFS was 5.6 months (95% CI, 3.9-7.0) versus 5.6 months (95% CI, 4.8-5.8) among patients who received everolimus. At IA2, for patients who received WELIREG, median PFS was 5.6 months (95% CI, 3.8-6.5) versus 5.6 months (95% CI, 4.8-5.8) for patients who received everolimus. The estimated 12-month PFS rate was 33.7% for patients who received WELIREG versus 17.6% for patients who received everolimus, and the estimated 18-month PFS rate was 22.5% for patients who received WELIREG versus 9.0% for patients who received everolimus. At IA1, median OS was 21.0 months (95% CI, 17.2-24.3) for patients who received WELIREG versus 17.2 months (95% CI, 15.3-19.0) for patients who received everolimus. At IA2 median OS was 21.4 months (95% CI, 18.2-24.3) for patients who received WELIREG versus 18.1 months (95% CI, 15.8-21.8) for patients who received everolimus. Overall survival will be tested at a subsequent analysis.

The safety profile of WELIREG in this study was consistent with previously reported studies; no new safety concerns were identified. Treatment-related adverse events (TRAEs) occurred in 89% of patients who received WELIREG (n=331) versus 89.4% of patients who received everolimus (n=322). Grade ≥3 TRAEs occurred in 38.7% of patients who received WELIREG versus 39.4% of patients who received everolimus. Adverse events led to discontinuation of study treatment in 5.9% of patients who received WELIREG and 14.7% who received everolimus. Treatment-related adverse events led to death in 0.3% of patients who received WELIREG (n=1) and 0.6% of patients who received everolimus (n=2).

The most common all-cause adverse events (occurring in ≥10% of patients) in the WELIREG arm were anemia (82.8%), fatigue (31.5%), nausea (18.0%), constipation (16.7%), peripheral edema (16.1%), dyspnea (15.1%), back pain (14.8%), asthenia, decreased appetite, arthralgia and hypoxia (14.5% each), vomiting (12.9%), dizziness (12.4%), headache and increased alanine aminotransferase (12.1% each), diarrhea (11.8%) and increased aspartate aminotransferase (11.6%).

About renal cell carcinoma
Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCCs. Renal cell carcinoma is about twice as common in men than in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Clear cell RCC is the most common histological subtype of RCC and accounts for approximately 80% of all RCC cases. Approximately 15% of patients with kidney cancer are diagnosed at an advanced stage.

About WELIREG (belzutifan) 40 mg tablets, for oral use
Indication in the U.S.
WELIREG (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

Selected Safety Information for WELIREG
Warning: Embryo-Fetal Toxicity
Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.

Anemia
WELIREG can cause severe anemia that can require blood transfusion. In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). In Study 001, a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose, anemia occurred in 76% of patients and 28% had Grade 3 anemia.

Monitor for anemia before initiation of and periodically throughout treatment. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia.

Transfuse patients as clinically indicated. For patients with hemoglobin (Hb) <9g/dL, withhold WELIREG until Hb≥9g/dL, then resume at reduced dose or permanently discontinue depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until Hb ≥9g/dL, then resume at a reduced dose or permanently discontinue.

The use of erythropoiesis stimulating agents (ESAs) for treatment of anemia is not recommended in patients treated with WELIREG.

Hypoxia
WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. In Study 004, hypoxia occurred in 1.6% of patients. In Study 001, a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose, hypoxia occurred in 29% of patients; 16% were Grade 3 hypoxia.

Monitor oxygen saturation before initiation of and periodically throughout treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider.

Embryo-Fetal Toxicity
Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.

Adverse Reactions
In Study 004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).

WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each).

Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness.

Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%).

The most common adverse reactions (≥25%) were decreased hemoglobin (93%), anemia (90%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).

In Study 001, a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose, the following additional adverse reactions have been reported: edema, cough, musculoskeletal pain, vomiting, diarrhea, and dehydration.

Drug Interactions
Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended.

Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.

Lactation
Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose.

Females and Males of Reproductive Potential
WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG.

Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.

Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown.

Pediatric Use
Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established.