On September 9, 2024 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported five-year results from the final pre-specified overall survival (OS) analysis of the Phase 3 EMPOWER-Lung 1 trial, which evaluated Libtayo (cemiplimab) monotherapy versus chemotherapy as a first-line treatment for adults with advanced non-small cell lung cancer (NSCLC) with ≥50% PD-L1 expression and no EGFR, ALK or ROS1 aberrations (Press release, Regeneron, SEP 9, 2024, View Source [SID1234646440]). The late-breaking results will be presented in an oral session at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer.

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"The five-year results from EMPOWER-Lung 1 showcase the durable survival benefit and impressive efficacy of first-line Libtayo monotherapy compared to chemotherapy in patients with PD-L1 high, advanced NSCLC, including a direct correlation between survival benefits and PD-L1 expression level," says Ana Baramidze, MD, PhD, Head of Clinical Research Department at Todua Clinic, Tbilisi, Georgia. "Furthermore, EMPOWER-Lung 1 continues to offer important new data to help doctors increase their understanding of investigational treatment strategies for patients who progress on PD-1 inhibitor monotherapy. For instance, EMPOWER-Lung 1 was one of the few trials to evaluate survival when adding chemotherapy to a PD-1 inhibitor following progression."

At the five-year follow-up, Libtayo remained superior to chemotherapy in the population of patients confirmed to have ≥50% PD-L1 expression (using an FDA approved assay), demonstrating continued and clinically meaningful benefits consistent with the prior 1-year analysis in this study population (as previously published in The Lancet and also as previously provided in the approved label for the FDA-approved assay):

1-year Analysis 5-year Analysis
Libtayo
(n=283) Chemotherapy
(n=280) Libtayo
(n=284) Chemotherapy
(n=281)
Overall survival (OS)
Mediana not reached 14 months 26 months 13 months
Hazard ratio (HR)
(95% confidence
interval [CI]; p-value)b 0.57
(0.42 to 0.77; p=0.0002) 0.59
(0.48 to 0.72; p<0.0001)
Progression-free survival (PFS)
Mediana 8 months 6 months 8 months 5 months
HR (95% CI; p-value)b 0.54
(0.43 to 0.68; p<0.0001) 0.50
(0.41 to 0.61; p<0.0001)
Objective response
rate (ORR) 39% 20% 46.5% 21%
Median duration of
response (DoR) 17 months 6 months 24 months 6 months
NOTE: The analysis was conducted in a subset of the randomized population that excluded 147 patients whose tumors could not be retested or were later found to have <50% PD-L1 expression.
a Based on Kaplan-Meier method
b Based on stratified proportional hazards model

Continued and clinically meaningful benefits were also observed at this five-year follow-up of the overall trial population (in which not all patients were confirmed to have ≥50% PD-L1 expression), as compared to the prior 1-year analysis in this population.

1-year Analysis 5-year Analysis
Libtayo
(n=356) Chemotherapy
(n=354) Libtayo
(n=357) Chemotherapy
(n=355)
OS
Mediana 22 months 14 months 23 months 14 months
HR (95% CI; p-value)b 0.68
(0.53 to 0.87; p=0.0022) 0.64
(0.54 to 0.77; p<0.0001)
PFS
Mediana 6 months 6 months 6 months 5 months
HR (95% CI; p-value)b 0.59
(0.49 to 0.72; p<0.0001) 0.55
(0.46 to 0.66; p<0.0001)
ORR 37% 21% 42% 21%
Median DoR 21 months 6 months 24 months 6 months
a Based on Kaplan-Meier method
b Based on stratified proportional hazards model

Importantly, EMPOWER-Lung 1 allowed patients who experienced disease progression to change their therapy, with those assigned to Libtayo having the option to add four cycles of chemotherapy. Among these patients (n=75), the addition of chemotherapy was associated with a 15-month median OS (95% CI: 11 to 18 months), 7-month median PFS (95% CI: 6 to 8 months) and 28% ORR (95% CI: 18% to 40%).

The exploratory subgroup analysis of EMPOWER-Lung 1 also showed direct correlations between survival and disease progression benefits and PD-L1 expression level among Libtayo patients, supporting the direct correlation between tumor response and PD-L1 expression level previously observed. At five years, those with tumor PD-L1 expression of ≥90% (n=99) derived the greatest benefit with a median OS of 39 months (95% CI: 23 months to not evaluable) and a 15-month median PFS (95% CI: 10 to 21 months). These correlations with PD-L1 expression level were not observed with chemotherapy.

No new safety signals were observed at five years among evaluable patients (Libtayo=356; chemotherapy=343), following a median duration of exposure of 36 weeks to Libtayo and 18 weeks to chemotherapy. Adverse events (AEs) of any grade occurred in 93% of Libtayo patients (46% ≥Grade 3) and 96% of chemotherapy patients (52% ≥Grade 3). The most common AEs occurring in at least 10% of Libtayo patients included anemia (20%), decreased appetite (14%), fatigue (14%), pneumonia (12%), arthralgia (12%), back pain (12%), dyspnea (11%), cough (10%) and pruritus (10%). Among Libtayo patients, AEs were serious in 36% and led to permanent discontinuation in 9% and death in 10%, compared to 29%, 5% and 10% in the chemotherapy arm, respectively.

Among the 75 Libtayo patients who received additive chemotherapy after disease progression, AEs of any grade occurred in 89% (36% ≥Grade 3), following a median duration of exposure of 27 weeks to Libtayo. The most common AEs included anemia (35%), alopecia (24%), diarrhea (21%), nausea (20%), neutropenia (15%) and asthenia (11%). AEs were serious in 27% of patients and led to discontinuation of treatment in 5% of patients and death in 4% of patients.

Additional presentations on data from Regeneron’s oncology portfolio and pipeline are being shared at WCLC.

The potential use of adding chemotherapy to Libtayo following disease progression as described above is investigational, and the safety and efficacy of this regimen have not been fully evaluated by any regulatory authority.

On September 9, 2024 Compugen Ltd. (Nasdaq: CGEN) (TASE: CGEN) a clinical-stage cancer immunotherapy company and a pioneer in computational target discovery, reported that Dr. Roy Granit, Head of Computational Discovery at Compugen will present a poster on applying AI to gain insights into the novel immune checkpoint PVRIG through single-cell and spatial transcriptomics at the Single Cell Genomics 2024 conference taking place between September 16-18, 2024, Corinthia, Greece (Press release, Compugen, SEP 9, 2024, View Source [SID1234646456]).

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Additional biological insights characterizing the uniqueness of the novel immune checkpoint PVRIG discovered by Compugen, were generated using Compugen’s AI/ML-powered computational discovery platform, recently branded as UnigenTM. The data further support previous findings that PVRIG inhibition may be differentiated from other immune checkpoints and may have the potential to induce anti-tumor activity in indications previously refractory to immunotherapy.

Poster presentation details:
Poster title: Applying AI to Gain Insights into the Novel Immune Checkpoint PVRIG Through Single-Cell and Spatial Transcriptomics
Poster number: 40
Presenter: Roy Granit, Ph.D., Head of Computational Discovery, Compugen Ltd.
Date: Monday, September 16, 2024

The poster will be available on the publications section of Compugen’s website, www.cgen.com, following presentation.

About Unigen
Compugen has been at the forefront of decoding cancer biology, with its AI/ML powered predictive computational discovery platform, recently branded as Unigen. Unigen is Compugen’s code-to-cure, flexible-loop platform for the computational prediction of novel drug target discovery and development of cancer immunotherapy. Unigen combines Compugen’s deep scientific knowledge, AI/ML predictive algorithms and a cloud-based, technology-agnostic platform integrating a variety of biological data such as multi-omics, single-cell RNA sequencing and spatial omics data. The outcomes from Compugen’s preclinical and clinical trials enrich the proprietary knowledgebase to discover additional novel drug targets and further understand complex biology. To date, Unigen has yielded multiple novel immuno-oncology drug targets, potential first- or best-in-class clinical stage immuno-oncology programs, validating partnerships with multiple pharmaceutical companies and undisclosed programs in its early-stage pipeline.

On September 9, 2024 Circle Pharma, a clinical-stage biopharmaceutical company dedicated to discovering and developing cell-permeable macrocycle therapies, reported that it presented a digital poster at the 2024 World Conference on Lung Cancer (Press release, Circle Pharma, SEP 9, 2024, View Source;utm_medium=rss&utm_campaign=circle-pharma-announces-preclinical-data-poster-presentation-of-cid-078-a-first-and-only-in-class-cyclin-a-b-rxl-inhibitor-at-the-2024-world-conference-on-lung-cancer [SID1234646426]).

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CID-078, Circle Pharma’s first-and-only-in-class cyclin A/B RxL inhibitor, demonstrated single-agent tumor regressions in both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) preclinical models. Tumor models with high E2F targets and G2M checkpoint hallmark pathways scores and elevated levels of E2F1, cyclin B1 and ESPL1 demonstrate tumor growth inhibition and/or regression when treated with CID-078 dosed at clinically achievable doses. CID-078 activity correlated with E2F1 and ESPL1 expression and was consistent with the proposed mechanism of action of cyclin A/B RxL inhibition leading to DNA damage. The data suggest that CID-078 holds promise as a monotherapy for patients with these cancers, which will be evaluated in a phase 1 clinical trial.

The digital poster can be viewed here.

About CID-078, Circle Pharma’s Cyclin A/B RxL Inhibitor Program

CID-078 is an orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle Pharma’s cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple xenograft models.

On September 9, 2024 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported the presentation of data from its oncology portfolio at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer (September 7-10) and the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting (September 13-17) (Press release, Regeneron, SEP 9, 2024, View Source [SID1234646441]). A combined 11 presentations across both congresses highlight Regeneron’s commitment to transforming care for people living with difficult-to-treat cancers, including advanced melanoma, advanced non-melanoma skin cancer, and different types of lung cancer.

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"The breadth of our presentations at ESMO (Free ESMO Whitepaper) and WCLC underscore our progress in advancing treatment approaches for cancer that have the potential to be among the best in their class," said Israel Lowy, MD, PhD, Clinical Development Unit Head, Oncology, at Regeneron. "At WCLC, five-year outcomes for Libtayo monotherapy in advanced NSCLC reinforce its position as the anti-PD-1 backbone of our oncology portfolio. At ESMO (Free ESMO Whitepaper), the latest two-year data for our LAG-3 inhibitor fianlimab combined with Libtayo show persistent and high clinical activity in advanced melanoma patients. As our portfolio and pipeline mature, the insights from these data are helping us advance our differentiated and novel combination approaches – all with the goal of transforming care for those living with cancer."

Notably, at ESMO (Free ESMO Whitepaper), Regeneron will present new, two-year results evaluating the investigational combination of LAG-3 inhibitor fianlimab and Libtayo (cemiplimab) in adults with advanced melanoma across three independent expansion cohorts of a first-in-human, multi-cohort trial. The combination is being further studied in an ongoing, randomized, placebo-controlled, blinded Phase 3 trial of fianlimab and Libtayo versus pembrolizumab in previously untreated unresectable locally advanced or metastatic melanoma. Additional trials are underway in the adjuvant and perioperative settings, as well as against other first-line, standard-of-care LAG3 and PD-1 combinations.

The longer-term analysis of 98 patients from the initial trial builds on results presented at ASCO (Free ASCO Whitepaper) 2023, with data assessed per blinded independent central review presented for the first time. With a median follow-up of 23 months and median treatment duration of 35 weeks, the results show persistent and deepening tumor responses across all three independent cohorts. Results were as follows:

In MM1, the initial cohort (n=40), there was a 23% complete response (CR) rate and a 60% objective response rate (ORR).
In MM2, the confirmatory cohort (n=40), there was a 25% CR rate and a 63% ORR.
In MM3, the cohort of patients with prior neoadjuvant or adjuvant systemic therapy (n=18; including 13 patients who had progressed despite prior anti-PD-1 treatments, and thus might be expected to have lower response rates to the combination), there was a 28% CR rate and a 39% ORR.
In a post-hoc analysis of the three cohorts combined, there was a 25% CR rate (24 of 98 patients) and a 57% ORR (56 of 98 patients).
Initial progression-free survival (PFS) and overall survival (OS) assessments from this single arm trial, which support the ongoing Phase 3 trial designed to evaluate these survival endpoints for the Libtayo and fianlimab combination, were as follows:

PFS for the MM1, MM2, and MM3 cohorts, respectively: Not reached (95% CI: 8 months to not evaluable [NE]), 19 months (95% CI: 8 months to NE), and 12 months (95% CI: 1 month to NE).
In a post-hoc analysis of the three cohorts combined, median PFS was 24 months (85% CI: 12 months to NE) and median OS was not reached (95% CI: 42 months to NE). Median OS was also not reached for any individual cohort.
Additional analyses on difficult-to-treat subgroups, including patients who had received prior adjuvant anti-PD-1 therapy, will be presented.

The safety profile of the fianlimab and Libtayo combination was generally consistent with the safety profile of Libtayo monotherapy and other anti-PD-(L)1 agents, except for higher rates of treatment-related adrenal insufficiency (12% of patients; 5% were ≥Grade 3). Adverse events (AEs) of any grade occurred in 95% of patients. Grade 3 or greater AEs, serious AEs, and immune-mediated AEs (IMAEs) occurred in 47%, 36%, and 13% of patients, respectively. AEs leading to death occurred in seven patients; two were considered treatment related.

An overview of all data presentations at both congresses is summarized below:

Regeneron presentations at WCLC:

Medicine Abstract title Abstract Presenter Presentation date/time
(all PDT)
Libtayo

Cemiplimab monotherapy for first line advanced NSCLC patients with PD-L1 expression ≥50%: 5-year outcomes of EMPOWER-Lung 1 #OA11.06
Oral Session: Shifting the Bar in the Front Line Immunotherapy Setting
Ana Baramidze Monday, September 9
2:32 p.m. – 2:42 p.m.
Prognostic utility of peripheral myeloid cells for clinical outcomes in patients with NSCLC treated with cemiplimab # P2.11A.26
Poster Presentation
Session: Metastatic Non-small Cell Lung Cancer—Immunotherapy—Immunobiology
Rolando J. Acosta Sunday, September 8
6:15 p.m. – 7:45 p.m
Real-world comparative effectiveness in advanced NSCLC and high PD-L1 with 1L immune checkpoint inhibitors ± chemotherapy
#EP.11A.08
e-Poster Presentation Melinda L. Hsu N/A
Fianlimab

Fianlimab-based combination therapies in patients with advanced non-small cell lung cancer: Trials in progress updates # P4.11D.09
Poster Presentation
Session: Metastatic Non-small Cell Lung Cancer—Immunotherapy—Clinical Trials in Progress
Ana Baramidze Monday, September 9
6:30 p.m. – 8:00 p.m.
Phase 2 peri-operative study of fianlimab + cemiplimab + chemotherapy vs cemiplimab + chemotherapy in resectable early-stage NSCLC #P4.07D.03
Poster Presentation
Session: Early-Stage Non-small Cell Lung Cancer —Clinical Trials in Progress
Luis Paz-Ares Monday, September 9
6:30 p.m. – 8:00 p.m.
REGN7075, Libtayo A Phase 1/2 Study of REGN7075 (EGFR×CD28) Combined with Cemiplimab (anti–PD-1) in NSCLC: Trial in Progress Update #P4.11D.04
Poster Presentation
Session: Metastatic Non-Small Cell Lung Cancer—Immunotherapy—Clinical Trials in Progress
Melissa Johnson Monday, September 9
6:30 p.m. – 8:00 p.m.

Regeneron presentations at ESMO (Free ESMO Whitepaper):

Medicine Abstract title Abstract Presenter Presentation date/time
(all CDT)
Skin Cancer
Libtayo

Neoadjuvant Cemiplimab for Stage II–IV Cutaneous Squamous Cell Carcinoma (CSCC): 2-year Follow-up and Biomarker Analyses
#1091
Poster
Session
Danny Rischin Saturday, September 14
9:00 a.m. – 5:00 p.m.

Fianlimab Long-term follow-up of advanced melanoma (unresectable/metastatic – aMel) patients (pts) treated with fianlimab (FIAN) + cemiplimab (CEMI): Results from blinded independent central review (BICR) efficacy assessment
#1097
Poster
Session
Meredith McKean Saturday, September 14
9:00 a.m. – 5:00 p.m.

Lung Cancer

Libtayo

Efficacy of Cemiplimab as Monotherapy or in Combination with Chemotherapy in Japanese Patients with Advanced Non-Small Cell Lung Cancer (aNSCLC)
#1384PPoster
Session
Yuki Sato Saturday, September 14
9:00 a.m. – 5:00 p.m.

Risk model for overall survival (OS) based on composite patient-reported outcomes (PROs) in aNSCLC patients treated with first-line (1L) cemiplimab-based therapy
#1853P
Poster
Session
David Gandara Sunday, September 15
9:00 a.m. – 5:00 p.m.
METxMET

MET×MET bispecific antibody davutamig (REGN5093) for MET-altered advanced non-small cell lung cancer (aNSCLC): Update from a first-in-human (FIH) study
#1302P
Poster
Session
Byoung Chul Cho Saturday, September 14
9:00 a.m. – 5:00 p.m.

The potential uses of Libtayo in neoadjuvant CSCC, fianlimab and Libtayo, davutamig, and REGN7075 described above are investigational, and their safety and efficacy have not been fully evaluated by any regulatory authority. Fianlimab, davutamig, and REGN7075 are not currently approved for use in any indication.

On September 9, 2024 Vir Biotechnology, Inc. (Nasdaq: VIR) reported that the exclusive worldwide license agreement with Sanofi announced on August 1, 2024, has closed following expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 (Press release, Sanofi, SEP 9, 2024, View Source [SID1234646457]). The agreement provides Vir with an exclusive worldwide license to three clinical-stage masked T-cell engagers (TCEs) with potential applications in a range of cancers and exclusive use of the proprietary PRO-XTENTM masking platform for oncology and infectious disease. Key employees from Sanofi with extensive scientific and development expertise in TCEs, and in-depth experience using the PRO-XTEN platform, will join Vir. Further information about the TCEs and their respective development plans will be provided at Vir’s upcoming R&D Day in November.

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"The closing of this strategic agreement with Sanofi is a pivotal moment for Vir and a significant opportunity to help address patient unmet needs. We are excited to further advance the masked T-cell engagers in clinical development, bolstering our clinical pipeline and adding near-term value creation opportunities," said Marianne De Backer, M.Sc., Ph.D., MBA, Vir’s Chief Executive Officer. "Our proven expertise in antibody engineering and clinical development combined with the innovative PRO-XTEN masking platform offers a unique opportunity to discover and develop therapies in oncology and infectious disease."

The clinical-stage assets Vir is licensing under the agreement are:

SAR446309 is a dual-masked HER2-targeted TCE in phase 1 clinical study including participants with metastatic treatment resistant HER2+ tumors such as breast and colorectal cancers.
SAR446329 is a dual-masked PSMA-targeted TCE in phase 1 clinical study including participants with metastatic castration-resistant prostate cancer.
SAR446368 is a dual-masked EGFR targeted TCE with an active IND. A phase 1 clinical study, which is expected to begin enrollment in the first quarter of 2025, will include participants with EGFR-expressing tumors of various types.
About the PRO-XTENTM Masking Platform

The PRO-XTEN proprietary masking platform can be applied to TCEs, cytokines, and other molecules potentially broadening the therapeutic index (TI) for patients. This technology exploits the high protease activity of the tumor microenvironment (TME) to specifically activate (unmask) drug candidates in tumor tissues. The selective cleavage results in the active molecule being released preferentially in the TME, potentially increasing the TI by minimizing off-target activity and toxicity associated with the systemic immune activation seen with traditional TCEs. Vir has exclusively licensed the PRO-XTEN proprietary masking platform from Sanofi in the fields of oncology and infectious diseases.