On September 5, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers harboring ESR1 mutations, reported it shared an encore poster presentation at the 10th annual Metastatic Breast Cancer Research Conference (MBCRC) highlighting the results of its Phase 2 ELAINE-2 clinical study (Press release, Sermonix Pharmaceuticals, SEP 5, 2023, View Source [SID1234634994]).

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The poster, "Lasofoxifene plus abemaciclib for treating ER+/HER2-, ESR1-mutated, metastatic breast cancer after progression on prior therapies: ELAINE-2 update," was presented Wednesday, Aug. 30.

"Sermonix welcomed the opportunity to share these important ELAINE-2 findings with researchers at MBCRC, who are highly focused experts in the metastatic breast cancer arena, in addition to the patient advocates who play such a vital role," said Dr. David Portman, Sermonix founder and chief executive officer. "We also were pleased to discuss our plans for ELAINE-3, a registrational Phase 3 trial that if positive could bring lasofoxifene closer to becoming available as a potential new option to improve the lives of those confronted with this terrible disease."

ELAINE-2 (NCT04432454), an open-label Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) study of Sermonix’s lead investigational drug, lasofoxifene, in combination with Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib, evaluated 29 heavily pre-treated women with ER+/HER2- locally advanced or metastatic breast cancer and an ESR1 mutation. Results were initially shared at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and updated in June at ASCO (Free ASCO Whitepaper) 2023.

The primary endpoint was safety/tolerability, with secondary endpoints including progression-free survival (PFS) and overall response rate (ORR). With patient follow-up through Jan. 31, 2023, the combination of lasofoxifene and abemaciclib continued to be well-tolerated, with clinically meaningful efficacy in women with ER+/HER2- metastatic breast cancer and an ESR1 mutation. The PFS, a median of 13 months, and ORR of 56% were promising.

The results led Sermonix to initiate ELAINE-3, a global registrational study of 400 patients assessing the efficacy of lasofoxifene and abemaciclib compared to fulvestrant and abemaciclib, with enrollment planned to begin in the second half of 2023.

To learn more about Sermonix Pharmaceuticals and lasofoxifene, visit View Source To learn more about the ELAINE studies, visit View Source

About Lasofoxifene
Lasofoxifene is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast, particularly in the presence of ESR1 mutations. Lasofoxifene has demonstrated anti-tumor activity as monotherapy and in combination with a CDK4/6 inhibitor in Phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies, with beneficial effects seen on vagina and bone in previous clinical studies. Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ:LGND), has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a novel targeted and tissue selective oral endocrine therapy could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.

On September 5, 2023 Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, reported the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the Guardant360 CDx liquid biopsy test as a companion diagnostic to select patients with unresectable (inoperable) advanced or recurrent non-small cell lung cancer (NSCLC) with HER2 (ERBB2) mutations that has progressed after chemotherapy for treatment with ENHERTU (trastuzumab deruxtecan) (Press release, Guardant Health, SEP 5, 2023, View Source [SID1234634925]). ENHERTU is a specifically engineered HER2-directed antibody drug conjugate developed by Daiichi Sankyo.

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Mutations in the HER2 gene are responsible for approximately 2-4% of non-squamous NSCLC, which represents about 70% of NSCLC cases.1,2 Overall, NSCLC accounts for about 80-85% of all lung cancer,3 the leading cause of cancer death for men and women worldwide.4 Guardant360 CDx is a next-generation sequencing-based assay that detects genomic alterations using circulating tumor DNA from blood. The approval for use of the test as a companion diagnostic with ENHERTU in Japan is an expansion of the approval received from the U.S. Food and Drug Administration (FDA) for the same indication in August 2022.

"The ministry’s approval of Guardant360 CDx as a companion diagnostic for ENHERTU is great news for patients with metastatic non-small cell lung cancer with HER2 mutations," said Helmy Eltoukhy, Guardant Health chairman and co-CEO. "Oncologists in Japan now have the first blood-based companion diagnostic to determine if their patients are eligible to receive the first HER2 directed therapy approved to treat this specific condition. This is another step forward in achieving Guardant Health’s mission to conquer cancer globally."

In March 2022, the MHLW approved the Guardant360 CDx test for comprehensive genomic profiling in patients with advanced solid tumors, and in July 2023, the test received national reimbursement approval in Japan. The MHLW also previously approved the test as a companion diagnostic to identify patients with microsatellite instability-high (MSI-High) solid tumors who may benefit from Keytruda (pembrolizumab), patients with MSI-High advanced colorectal cancer who may benefit from Opdivo (nivolumab), and patients with metastatic NSCLC who may benefit from treatment with LUMAKRAS (sotorasib).

About Guardant360 CDx

For oncologists, the FDA-approved Guardant360 CDx test provides comprehensive genomic results from a simple blood draw in seven days, helping them move beyond the limitations of tissue biopsies to rapidly obtain clinically relevant information in time to match patients to the optimal personalized treatment. Guardant360 CDx covers all genes recommended by the National Comprehensive Cancer Network, including those most relevant to clinical care and NSCLC treatment guidelines.

Since being introduced, Guardant360 has become widely accepted for blood-based comprehensive genomic profiling with more than 400 peer-reviewed publications. It has been used by more than 12,000 oncologists, with more than 400,000 tests performed to date, and is broadly covered by Medicare and private payers, insuring over 300 million people.

On September 5, 2023 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the initiation of the Phase 2 portion of ARROS-1, its Phase 1/2 clinical trial of NVL-520 for patients with ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors, following alignment with the US Food and Drug Administration (FDA) on a recommended Phase 2 dose (RP2D) of 100 mg daily (Press release, Nuvalent, SEP 5, 2023, View Source [SID1234634924]).

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NVL-520 is a novel brain-penetrant ROS1-selective tyrosine kinase inhibitor (TKI) created with the aim to simultaneously overcome the clinical challenges of emergent treatment resistance, off-target central nervous system (CNS) adverse events associated with TRK inhibition, and brain metastases that may limit the use of currently available ROS1 TKIs.

"The ARROS-1 trial was designed to support a seamless transition from first-in-human dose-exploration in a heavily pre-treated population to a Phase 2 portion designed with the potential to support registration. We are thrilled to achieve this milestone towards our goal of bringing a potential best-in-class therapy to patients with ROS1-positive NSCLC as efficiently as possible," said Darlene Noci, A.L.M., Chief Development Officer at Nuvalent.

"The Phase 2 portion of the ARROS-1 trial includes multiple cohorts which enable the parallel investigation of NVL-520 for patients with ROS1-positive NSCLC who are either TKI naïve or pre-treated with a ROS1 TKI," Ms. Noci continued. "Support for the Phase 2 cohort design includes the demonstrated nonclinical activity of NVL-520 in the periphery and in the CNS, and its selective inhibition of ROS1 and ROS1 drug-resistance mutant G2032R over the structurally-related TRK kinases. Combined with the broad clinical activity and favorable tolerability observed to date in heavily pre-treated patients in the Phase 1 portion of ARROS-1, we believe there is the potential for NVL-520 to provide durable responses while minimizing adverse events and dose limiting toxicities for patients with ROS1-positive cancers throughout the treatment paradigm."

In the Phase 1 portion of ARROS-1, six dose levels (25 mg to 150 mg daily) of NVL-520 were evaluated in heavily pre-treated patients with ROS1-positive solid tumors. A maximum tolerated dose (MTD) was not reached, and no clinically significant exposure-response relationships for safety and efficacy were observed across the dose levels evaluated. The RP2D of 100 mg daily maintained steady state plasma levels above all target efficacy thresholds (ROS1 wild type and ROS1 G2032R in both the periphery and in the CNS).

"With the advancement of the first of our parallel lead programs into a Phase 2 trial with registrational intent, the Nuvalent team demonstrates its continued ability to scale while maintaining ambitious timelines towards our goal of delivering precisely targeted therapies to patients with cancer," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "We look forward to providing an update from the ARROS-1 trial at a medical meeting in 2024."

ARROS-1 Phase 2 Design

The Phase 2 portion of the ARROS-1 trial will be conducted globally across North America, Europe, Asia and Australia with planned enrollment of approximately 225 TKI naïve and TKI pre-treated patients with ROS1-positive NSCLC and other solid tumors. The single arm, open label Phase 2 cohorts are designed to evaluate NVL-520 across the treatment paradigm for patients with ROS1-positive NSCLC, and include both potentially registration-directed pivotal cohorts and an additional exploratory cohort:

Potential Pivotal Cohorts
Cohort 2a: Patients with advanced/metastatic ROS1-positive NSCLC naïve to TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.
Cohort 2b: Patients with advanced/metastatic ROS1-positive NSCLC treated with 1 prior ROS1 TKI (either crizotinib or entrectinib) and no prior chemotherapy or immunotherapy allowed.
Cohort 2c: Patients with advanced/metastatic ROS1-positive NSCLC treated with 1 prior ROS1 TKI (either crizotinib or entrectinib) and 1 prior line of platinum-based chemotherapy with or without immunotherapy.
Cohort 2d: Patients with advanced/metastatic ROS1-positive NSCLC treated with at least 2 prior ROS1 TKIs (with crizotinib or entrectinib as the initial ROS1 TKI) and up to 1 line of chemotherapy and/or immunotherapy.
Exploratory Cohort
Cohort 2e: Patients with any advanced/metastatic ROS1-positive solid tumor (including patients with ROS1-positive NSCLC not otherwise eligible for any other cohorts) and progressed on any prior therapy (includes, but is not limited to, patients who have progressed on prior ROS1 TKIs).
Additional details can be found on www.clinicaltrials.gov (NCT05118789).

Selection of NVL-520 RP2D

The selection of 100 mg daily as the RP2D for NVL-520 was discussed and supported by FDA based on clinical data from the Phase 1 dose escalation portion of the ARROS-1 trial with a data cut-off of May 17, 2023. These data included a safety database of 87 ROS1-positive patients enrolled across six dose levels from 25 mg to 150 mg daily, including 37 patients at dose levels of ≥100 mg daily. The selection was based on the following considerations:

The dose level of 100 mg daily maintained steady state plasma levels above all target efficacy thresholds (ROS1 wild type and ROS1 G2032R in both the periphery and in the CNS).
Favorable tolerability of NVL-520 was observed across all dose levels to date.
No clinically significant exposure-response relationships for safety and efficacy were observed across the dose levels evaluated (25 mg – 150 mg daily).
Based on these data, early anti-tumor activity continued to be observed in ROS1-positive NSCLC patients, including objective responses (RECIST 1.1) in heavily pre-treated patients, patients previously treated with lorlatinib or repotrectinib, patients with ROS1 G2032R resistance mutations, and patients with CNS metastases. A favorable preliminary safety profile continued to suggest the potential for a highly ROS1-selective, TRK sparing design. Overall, the company believes these findings to be consistent with the conclusions from a preliminary data disclosure in October 2022 with data cut-off date of September 13, 2022, and believes that these data continue to support the opportunity for NVL-520 as a potential best-in-class therapy that may be able to move up the treatment paradigm for patients with ROS1-positive NSCLC.

The company expects to share an update from the ARROS-1 trial at a medical meeting in 2024.

About NVL-520
NVL-520 is a brain-penetrant ROS1-selective inhibitor designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with the prevalent G2032R resistance mutation and those with the S1986Y/F, L2026M, or D2033N resistance mutations. NVL-520 has been designed for brain penetrance to potentially improve treatment options for patients with brain metastases. NVL-520 has been observed in preclinical studies to selectively inhibit wild-type ROS1 and its resistance variants over the structurally related tropomyosin receptor kinase (TRK) family to potentially avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and drive more durable responses for patients. NVL-520 is currently being investigated in the ARROS-1 trial (NCT05118789), a first-in-human Phase 1/2 clinical trial for patients with advanced non-small cell lung cancer (NSCLC) and other solid tumors.

On September 5, 2023 Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported that Douglas E. Onsi, President and Chief Executive Officer, will participate in two upcoming investor conferences (Press release, Leap Therapeutics, SEP 5, 2023, View Source [SID1234634923]):

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Leap Presentation Details:

H.C. Wainwright 25th Annual Global Investment Conference
Date: Monday, September 11th, 2023
Time: 7:00 a.m. Eastern Time

Baird Global Healthcare Conference
Date: Wednesday, September 13th, 2023
Time: 3:10 p.m. Eastern Time

A replay of the pre-recorded H.C. Wainwright presentation and a live webcast of the Baird fireside chat may be accessed on the Investors page of the company’s website at View Source, where a replay of the events will also be available for a limited time.

On September 5, 2023 XtalPi, a global leader in AI-powered drug discovery, and Parthenon Therapeutics, a clinical-stage biotechnology company dedicated to reprogramming the tumor microenvironment, reported their collaboration today to discover novel therapeutic antibodies for the treatment of solid tumors (Press release, Parthenon Therapeutics, SEP 5, 2023, View Source [SID1234634921]).

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Under this agreement, XtalPi will grant Parthenon Therapeutics access to its proprietary XupremAb antibody discovery platform, which is a collection of solutions that leverage AI and wet lab techniques to deliver therapeutic antibody candidates with superior efficacy and developability profiles. Parthenon Therapeutics and XtalPi will utilize multiple approaches in the XupremAb platform for deeper interrogation of the immune repertoire and generating a large, consolidated dataset, which will be further mined by XtalPi’s proprietary algorithms for exceptional candidates.

"We are excited to work with Parthenon Therapeutics on this pioneering project. Their strong innovation in tumor barrier disruption and deep understanding of the target, coupled with our broadly validated AI-powered antibody discovery platform, forms a solid foundation for the development of next-generation cancer therapeutics," said Yi Li, VP of Antibody Discovery, XtalPi.

"We are very pleased to collaborate with XtalPi to leverage their cutting-edge proprietary platform to deeply mine the immune repertoire to discover novel state-of-the-art antibody therapeutics. Combined with Parthenon’s vast expertise in biotherapeutic drug discovery and unique insights into the tumor microenvironment and the mechanisms underlying immune exclusion, we look forward to developing transformative therapies for cancer patients," said Tom McCaughtry, VP – Head of Research, Parthenon Therapeutics.