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.

On October 21, 2023 Immunocore Holdings plc (Nasdaq: IMCR), a commercial-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, infectious diseases and autoimmune conditions, reported that the three-year overall survival (OS) data from the KIMMTRAK (tebentafusp-tebn) Phase 3 trial in previously untreated HLA-A*02:01 positive patients with metastatic uveal melanoma has been published in The New England Journal of Medicine, and presented as a late breaking abstract in a mini oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (Press release, Immunocore, OCT 21, 2023, View Source [SID1234636209]).

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"These long-term overall survival results further solidify KIMMTRAK as the first-line standard of care for HLA-A*02:01 positive patients with metastatic uveal melanoma," said Mohammed Dar, Immunocore Chief Medical Officer. "The survival benefit appears early, within the first six weeks, and the survival curve remains separated from the control arm; this long-term survival benefit is a hallmark of cancer immunotherapy."

In the Phase 3 trial follow up – the longest of any randomized trial for metastatic uveal melanoma – the three-year OS rate was 27% in the KIMMTRAK arm, versus 18% in the control arm (investigator’s choice, predominantly [82%] single agent pembrolizumab). The median OS was 21.6 months on KIMMTRAK, versus 16.9 months on investigator’s choice. The OS Hazard Ratio (HR) favored KIMMTRAK, HR=0.68 (95% CI: 0.54 to 0.87), over investigator’s choice.

Overall response rate remained in favor of KIMMTRAK when compared with the control arm (11% vs 5%) and the median duration of response for KIMMTRAK patients was 11.1 months. The rate of disease control (complete response, partial response, or stable disease for ≥12 weeks) was also higher in the KIMMTRAK arm (46% vs 27%) versus the control arm. Over half (57%; n=139) of all patients treated with KIMMTRAK were treated beyond initial radiographic progression.

The trial evaluated circulating tumor DNA (ctDNA) clearance as a predictor of overall survival. ctDNA clearance on KIMMTRAK occurred in 37% of evaluable patients (compared with previously reported 13% in second-line patients1) and was associated with longer OS.

No new adverse events (AEs) related to long-term KIMMTRAK treatment were observed. The rate of discontinuation due to treatment-related AEs continued to be lower (2%) in the KIMMTRAK arm than for the control arm (5%). There were no treatment-related deaths.

In a separate poster at the Congress, an analysis of the role of subsequent therapy from the Phase 3 trial in first-line mUM patients confirmed that the survival benefit mostly comes from KIMMTRAK treatment rather than subsequent therapy.

A further poster included an analysis from the Phase 1b study in previously treated metastatic cutaneous melanoma patients, demonstrating the safety and activity of KIMMTRAK by BRAF mutation status. A third poster investigated the reprogramming effect of KIMMTRAK on immunosuppressive M2 macrophages from Phase 2 unresectable or metastatic uveal melanoma patients, as well as in vitro.

Presentation and poster details

Title: Three-year survival with tebentafusp in previously untreated metastatic uveal melanoma in a phase 3 trial
Presenting author: Sophie Piperno-Neumann
Session: Mini oral session – Melanoma and other skin tumours, Saturday 21 October, 2023

Title: Tebentafusp reprograms immunosuppressive tumor-associated M2 macrophages towards anti-tumoral M1 macrophages
Presenting author: Josep M. Piulats
Session: Poster display, Saturday 21 October, 2023

Title: BRAF mutation status does not impact outcomes with tebentafusp in advanced cutaneous melanoma
Presenting author: Alexander N. Shoushtari
Session: Poster display, Sunday 22 October, 2023

Title: Effect of subsequent therapies including checkpoint inhibitors on overall survival in a phase 3 randomized trial of tebentafusp in first line metastatic uveal melanoma: long-term follow up
Presenting author: Marcus Butler
Session: Poster display, Sunday 22 October, 2023

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About ImmTAC molecules for cancer
Immunocore’s proprietary T cell receptor (TCR) technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules that are designed to redirect the immune system to recognize and kill cancerous cells. ImmTAC molecules are soluble TCRs engineered to recognize intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the demonstrated mechanism of T cell infiltration into human tumors, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumors, regardless of mutational burden or immune infiltration, including immune "cold" low mutation rate tumors.

About KIMMTRAK
KIMMTRAK is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. This is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognize and kill tumor cells. KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom.

About Phase 3 IMCgp100-202 Trial
IMCgp100-202 (NCT03070392) is a randomized pivotal trial that evaluated overall survival (OS) of KIMMTRAK compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in HLA-A*02:01-positive adult patients with previously untreated mUM. KIMMTRAK demonstrated an unprecedented OS benefit with a Hazard Ratio (HR) in the intent-to-treat population favoring KIMMTRAK, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine).

IMPORTANT SAFETY INFORMATION

Cytokine Release Syndrome (CRS), which may be serious or life-threatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS occurred in 89% of patients who received KIMMTRAK with 0.8% being grade 3 or 4. Ensure immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK. Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS.

Skin Reactions

Skin reactions, including rash, pruritus, and cutaneous edema occurred in 91% of patients treated with KIMMTRAK. Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions.

Elevated Liver Enzymes

Elevations in liver enzymes occurred in 65% of patients treated with KIMMTRAK. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity.

Embryo-Fetal Toxicity
KIMMTRAK may cause fetal harm. Advise pregnant patients of potential risk to the fetus and patients of reproductive potential to use effective contraception during treatment with KIMMTRAK and 1 week after the last dose.

The most common adverse reactions (≥30%) in patients who received KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate.

For more information, please see full Summary of Product Characteristics (SmPC) or full U.S. Prescribing Information (including BOXED WARNING for CRS).

On October 21, 2023 Agenus Inc. (Nasdaq:AGEN), a leader in developing novel immunological agents to treat various cancers, reported expanded data from the company’s phase 1b study of botensilimab (BOT, multifunctional immune activator) in combination with balstilimab (BAL, anti-PD-1) in patients with advanced sarcomas (Press release, Agenus, OCT 21, 2023, View Source [SID1234636195]). The results were presented in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023.

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Relapsed/refractory sarcoma represents a significant unmet medical need where existing standard of care options and previous immunotherapies have shown limited activity. At present, available treatments for advanced soft tissue sarcoma patients only have modest activity. The sarcoma cohort presented is part of a larger phase 1b study evaluating the safety, efficacy, and dose optimization of BOT alone and in combination with BAL in multiple advanced solid tumors.

"These results reinforce the promising potential of BOT+BAL in multiple cold, treatment-resistant solid tumors," said Dr. Steven O’Day, Chief Medical Officer. "Notably, we observed several durable responses extending past one year, including patients with visceral angiosarcoma, which is traditionally unresponsive to immunotherapy, as well as other cold subtypes like leiomyosarcoma. As we expand the study, we aim to focus on key subsets and dosing strategies to maximize benefit for patients."

"As the study has advanced, BOT+BAL continues to demonstrate encouraging results in a larger population of patients with difficult to treat sarcomas, with a median response duration of 19.4 months and a 40% 6-month progression-free survival rate. We’re also seeing a dose-dependent effect, with a 29% objective response rate at 2 mg/kg," said Dr. Breelyn Wilky, MD, Director of Sarcoma Medical Oncology at the University of Colorado, and study investigator.

Study Design and Highlights

A total of 41 evaluable patients received either 1 or 2 mg/kg BOT every 6 weeks and 3 mg/kg BAL every 2 weeks.

Patient Demographics

Majority of patients had either angiosarcoma (29%) or leiomyosarcoma (39%) subtypes
Patients were heavily pre-treated, with a median of three prior lines of therapy, including 16% who received prior PD-(L)1 therapy
Majority of patients had biomarkers associated with poor response to immunotherapy:
87% had a low tumor mutation burden (<10 mutations per megabase)
74% of patients were PD-L1 negative by immunohistochemistry
Clinical Findings

Efficacy in all comers (as measured by iRECIST; n=41)

40% 6-month PFS
20% ORR
29% ORR at the BOT 2 mg/kg dose level
15% ORR at the 1 mg/kg dose level
63% disease control rate (best response of a complete response + partial response + stable disease)
Median duration of response was 19.4 months
Safety in all comers (N=50)

No new safety signals reported, with tolerability consistent across tumor types
Adverse events were generally manageable and reversible
Diarrhea/colitis was the most clinically significant immune-mediated adverse event
No grade 4 or 5 treatment-related adverse events and no related cases of irreversible events such as hypophysitis, pneumonitis, hepatitis, or myocarditis were reported
Presentation Details

Abstract Title: Efficacy and safety of botensilimab (BOT) plus balstilimab (BAL) in patients (pts) with refractory metastatic sarcoma (NCT03860272)
Abstract Number: 1919MO
Presenting Author: Breelyn A. Wilky, MD, Director of Sarcoma Medical Oncology, Deputy Associate Director for Clinical Research, University of Colorado Cancer Center
Session Date and Time: 10/21/2023, 10:15 a.m. – 11:45 a.m. CEST
Presentation Date and Time: 10/21/2023, 11:00 a.m. – 11:05 a.m. CEST

The presentation is available on the Agenus website at View Source

References

1 . D’Angelo SP, et al. Lancet Oncol. 2018;19
2. Chen JL, et al. J Clin Oncol. 2020;38(15)_suppl:11511-11511
3. Wagner MJ, et al. J Immunother Cancer. 2021;9:e002990.

About Botensilimab

Botensilimab is an investigational multifunctional anti-CTLA-4 immune activator designed to boost both innate and adaptive anti-tumor immune responses. Its novel design leverages mechanisms of action to extend immunotherapy benefits to "cold" tumors which generally respond poorly to standard of care or are refractory to conventional PD-1/CTLA-4 therapies and other investigational therapies. Botensilimab augments immune responses across a wide range of tumor types by priming and activating T cells, downregulating intratumoral regulatory T cells, activating myeloid cells and inducing long-term memory responses.

Approximately 600 patients have been treated with botensilimab in phase 1 and phase 2 clinical trials. Botensilimab alone, or in combination with Agenus’ investigational anti-PD-1, balstilimab, has shown clinical responses across nine metastatic, late-line cancers. For more information about botensilimab trials, visit www.clinicaltrials.gov with the identifiers NCT03860272, NCT05608044, NCT05630183, and NCT05529316.