At a pre-specified interim analysis in LITESPARK-005, WELIREG reduced the risk of disease progression or death compared to everolimus

First Phase 3 trial to show positive results in patients with advanced RCC following both immune checkpoint and anti-angiogenic therapies in later lines of treatment

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced 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. 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) Congress 2023 (abstract #LBA88) and are also being discussed with regulatory authorities worldwide.

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 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 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.

Merck’s focus on cancer 

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck 

At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA 

This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2022 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information, including information for the Boxed Warning about embryo-fetal toxicity, for WELIREG (belzutifan) at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf and Medication Guide for WELIREG at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_mg.pdf.

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