On December 10, 2024 Olema Pharmaceuticals, Inc. ("Olema" or "Olema Oncology", Nasdaq: OLMA), a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of targeted therapies for breast cancer and beyond, reported updated clinical results from the ongoing Phase 1b/2 study of palazestrant in combination with CDK4/6 inhibitor, ribociclib, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer (Press release, Olema Oncology, DEC 10, 2024, View Source [SID1234649000]). Results as of September 25, 2024, will be presented in a poster session at the San Antonio Breast Cancer Symposium (SABCS 2024) being held December 10-13 at the Henry B. Gonzalez Convention Center in San Antonio, Texas. Updated results as of November 11, 2024, are detailed below.

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"We believe these data, while still maturing, are compelling and highly differentiated, with robust clinical activity shown across both ESR1 wild-type and mutant patient populations after prior treatment with a CDK4/6 inhibitor in combination with endocrine therapy. Mutations in the ESR1 gene are one of the most common resistance mechanisms arising during current front-line standard of care treatment, leading to progression. Palazestrant has demonstrated its potential to work in combination with ribociclib by completely blocking estrogen receptor signaling and suppressing tumor growth to extend progression-free survival after prior progression on the current standard of care, regardless of ESR1 status," said Sean P. Bohen, M.D., Ph.D., President and Chief Executive Officer of Olema Oncology. "These data provide the foundation to initiate OPERA-02, our planned pivotal Phase 3 trial of palazestrant in combination with ribociclib in front-line metastatic breast cancer next year. We look forward to sharing mature data from this combination in 2025 and continuing the development of palazestrant as we work to advance our goal of creating innovative therapies to improve the lives of breast cancer patients."

Interim Results from the Phase 1b/2 Study of Palazestrant in Combination with Ribociclib
Enrollment
62 patients with advanced or metastatic ER+/HER2- breast cancer were treated with palazestrant (n=56 at the recommended Phase 2 dose (RP2D) of 120 mg once daily) plus ribociclib (600 mg once daily; three weeks on treatment followed by one week off treatment).

The majority of participants (48 (77%)) were 2/3+ line patients; 48 (77%) patients received prior endocrine therapy for metastatic breast cancer, 46 (74%) patients received prior treatment of endocrine therapy with CDK4/6 inhibitors (CDK4/6i), 12 (19%) received two prior lines of treatment with CDK4/6i, and 11 (18%) patients received chemotherapy for metastatic breast cancer.
36 (58%) patients had visceral disease; 42 (68%) patients had measurable disease at baseline. Of 60 patients whose circulating tumor DNA (ctDNA) was assessed, 28% had activating mutations in ESR1 at baseline.
Efficacy
Palazestrant combined with ribociclib showed promising clinical activity including tumor responses, prolonged disease stabilization, and progression-free survival in patients with ESR1 wild-type and ESR1 activating mutations at baseline and in those previously treated with one or two lines of CDK4/6i. Efficacy data continue to mature; 30 (48%) patients remain on treatment, and the longest duration on treatment is approximately 18 months (79 weeks) and was ongoing as of the data cutoff date of November 11, 2024.

With a median follow-up of 12 months, the median PFS was not reached as of the data cutoff date. Across all patients, the 6-month PFS rate was 73%. In those who received prior treatment with a CDK4/6i plus an endocrine therapy, the 6-month PFS rate was 68%. The 6-month PFS rate in ESR1 mutant patients was 81% and in ESR1 wild-type patients it was 70%.
In those who were clinical benefit rate (CBR)1-eligible, the CBR was 76% (37/49) in all patients, 81% (13/16) in patients with ESR1 mutations, and 74% (23/31) in ESR1 wild-type patients. In patients with prior CDK4/6i treatment, the CBR was 71% (25/35), 81% (13/16) in patients with ESR1 mutations, and 65% (11/17) in ESR1 wild-type patients.
As of the data cutoff date, there were 11 responses (two confirmed complete responses, eight confirmed partial responses, and one unconfirmed partial response). Among 37 response-evaluable patients with measurable disease, the ORR was 27% (10/37). 60% of the 37 had a reduction in target lesion size.

Safety and Tolerability
Across 62 treated patients, the combination of up to 120 mg of palazestrant with the approved dose for metastatic disease of 600 mg of ribociclib daily was well tolerated with no new safety signals or increase in toxicity. The overall safety profile was consistent with the established safety profile of ribociclib 600 mg plus an endocrine therapy.

Treatment with palazestrant up to 120 mg combined with ribociclib (600 mg) was well tolerated with no dose-limiting toxicities.
The majority of treatment-emergent adverse events (TEAEs) were Grade 1 or 2, and the severity and incidence of adverse events were consistent with the expected safety profile of ribociclib plus endocrine therapy.
Pharmacokinetics
Palazestrant did not affect ribociclib drug exposure when compared with published exposure data for single-agent ribociclib. Steady-state trough values showed no clinically significant difference between the combination and single-agent palazestrant.

Conclusions
Findings from this study support the advancement of palazestrant in combination with ribociclib into clinical development for the first-line treatment of ER+/HER2- advanced or metastatic breast cancer.

"Palazestrant is not an endocrine therapy where you need to wait six months to see a patient derive benefit. We have seen impressive responses quickly and a significant reduction of disease burden. The patients I have seen feel much better than they have on other treatments available in the armamentarium today," said Virginia Borges, M.D., Professor, Medicine-Medical Oncology at the University of Colorado, and Principal Investigator for the palazestrant plus ribociclib combination study. "The findings presented at SABCS show that the combination of palazestrant and ribociclib is well-tolerated with meaningful preliminary efficacy that I believe has the potential to outperform the current standard of care and change how metastatic breast cancer is treated. I look forward to the continued development of palazestrant."

A copy of the poster presented at SABCS reflecting a September 25, 2024 data cutoff date will be made available on the Publications page of Olema’s website in alignment with the Symposium’s embargo policy.

1CBR is the proportion of patients who remained on treatment through at least 24 weeks with a confirmed complete response or partial response, or stable disease.

Conference Call Information
Olema will hold a conference call to discuss these results today with the investment community at 8:00 a.m. ET (7:00 a.m. CT). Register to join the webcast by visiting the Events and Presentations page on the Investors section of Olema’s website.

About Palazestrant (OP-1250)
Palazestrant (OP-1250) is a novel, orally available small molecule with dual activity as both a complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD). It is currently being investigated in patients with recurrent, locally advanced or metastatic ER-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In preclinical studies, palazestrant completely blocks ER-driven transcriptional activity in both ESR1 wild-type and mutant forms of breast cancer. In Olema’s ongoing clinical trials for advanced or metastatic ER+/HER2- breast cancer, palazestrant has demonstrated anti-tumor activity along with attractive pharmacokinetics and exposure, favorable tolerability, and combinability with CDK4/6 inhibitors. Palazestrant has been granted U.S. Food and Drug Administration (FDA) Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following one or more lines of endocrine therapy with at least one line given in combination with a CDK4/6 inhibitor. It is being evaluated both as a single agent in an ongoing Phase 3 clinical trial, OPERA-01, and in Phase 1/2 combination studies with CDK4/6 inhibitors (palbociclib and ribociclib), a PI3Ka inhibitor (alpelisib), and an mTOR inhibitor (everolimus). For more information on OPERA-01, please visit www.opera01study.com.

On December 10, 2024 BostonGene, a leading provider of AI-driven molecular and immune profiling solutions, reported that three abstracts have been accepted for poster presentations at the 2024 San Antonio Breast Cancer Symposium (SABCS), to take place December 10 – 13, 2024, at the Henry B. Gonzalez Convention Center in San Antonio, Texas (Press release, BostonGene, DEC 10, 2024, View Source [SID1234649016]). BostonGene will also exhibit at booth 1317.

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"We’re excited to present our research at the 2024 SABCS, underscoring BostonGene’s commitment to leveraging molecular profiling as a transformative tool in breast cancer treatment," said Nathan Fowler, MD, Chief Medical Officer at BostonGene. "Our findings in transcriptomic classification aim to pave the way for more effective treatment pathways, establishing new benchmarks for precision oncology."

Details about the abstracts selected for presentation are below:

Abstract number: 1760
Title: Evaluating the Correlation Between FISH and NGS in Assessing ERBB2 Alterations in Breast Cancer
Date & time: Wednesday, December 11 | 12:00 PM – 2:00 PM
Presenter: Nikita Kotlov, BostonGene

This comparative analysis demonstrated the utility of NGS in evaluating ERBB2 (HER2) status in breast cancer compared to the gold standard, fluorescence in situ hybridization (FISH). NGS detected potentially clinically relevant ERBB2 mutations in non-amplified samples. With enhanced resolution, NGS also revealed heterogeneity among ERBB2 (HER2) amplifications in breast cancer. Identifying these nuanced genomic and transcriptomic alterations yields valuable insights for designing personalized treatment strategies for breast cancer patients.

Abstract number: 2476
Title: Comprehensive Analysis of ADC Target Expression in Invasive Lobular Carcinoma
Date & time: Wednesday, December 11 | 12:00 PM – 2:00 PM
Presenter: Jason Mouabbi, MD, The University of Texas MD Anderson Cancer Center

RNA-seq was applied to examine 82 cell surface proteins as potential antibody-drug conjugate (ADC) targets in invasive lobular carcinoma (ILC). Distinct expression landscapes of the prospective ADC targets were present across different ILC subtypes. These findings underscore the need to account for varied ADC target expression landscapes across ILC subtypes for optimal efficacy and safety of ADC-based treatments.

Research done in collaboration with MD Anderson Cancer Center

Abstract number: 1521
Title: Levels of Circulating Tumor DNA as a Predictive Marker for Early Switch in Treatment for Patients with Metastatic Breast Cancer: A Phase 2 Randomized, Open-Label Study
Date & time: Thursday, December 12 | 5:30 PM – 7:00 PM
Presenter: Frances Valdes, MD, University of Miami

This phase 2 randomized, open-label study compares patients with metastatic breast cancer receiving a CDK4/6 inhibitor combined with either an aromatase inhibitor or fulvestrant as first-line therapy. BostonGene’s liquid biopsy test was incorporated to validate the clinical utility of serial circulating tumor (ctDNA) for patient monitoring. Capable of detecting molecular progression before clinical manifestation, levels of ctDNA were predictive for early switch in treatment in metastatic breast cancer patients. While analysis and patient monitoring are ongoing, this study has yielded clinically relevant genomic findings that may shed light on strategies to extend the duration of disease control and prolong patient survival.

Research done in collaboration with the University of Miami

On December 9, 2024 GlyTherix and Nusano, a physics company transforming the production of radioisotopes, reported a supply agreement for non-carrier-added lutetium-177 (Lu-177) (Press release, Glytherix, DEC 10, 2024, View Source [SID1234648902]). The agreement also provides GlyTherix access to Nusano’s future actinium-225 (Ac-225) production, currently scheduled to begin in 2026, and planned future production of zirconium-89 (Zr-89), lead-212 (Pb-212) and terbium-161 (Tb-161).

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GlyTherix’s radiotherapy approach combines Lu-177 with an antibody targeting Glypican-1, a protein found in aggressive cancers, to deliver localized radiation while sparing healthy tissue.

Glypican-1 is an attractive tumor target that occurs in several aggressive and invasive cancers including prostate, pancreatic, bladder, lung, glioblastoma, esophageal and ovarian cancer. GlyTherix plans to use 177Lu-DOTAMiltuximab in its planned Australian Phase Ib in 2025, followed by US Phase II trials in 2026.

On December 10, 2024 IMUNON, Inc. (NASDAQ: IMNN), a clinical-stage company in late-stage development with its DNA-mediated immunotherapy, reported additional clinical data from ongoing analyses of results from the Company’s Phase 2 OVATION 2 Study of IMNN-001, its investigational interleukin-12 (IL-12) immunotherapy for the treatment of advanced ovarian cancer based on its proprietary TheraPlas technology (Press release, IMUNON, DEC 10, 2024, View Source [SID1234648985]). The updated results, based on an additional seven months of patient monitoring, show the hazard ratio (HR) decreased from 0.74 to 0.69, with an increase in median overall survival (OS) from 11.1 to 13 months following treatment with IMNN-001 plus standard-of-care (SoC) neoadjuvant and adjuvant chemotherapy (NACT) versus SoC alone. More than one-third of patients in the trial survived more than 36 months from the point of study enrollment, with 62% of those surviving patients from the IMNN-001 treatment arm and 38% from the SoC arm. Over 10% of trial participants have reached 48 months or beyond.

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"These results indicate that OS benefits are being maintained in the population of patients treated with IMNN-001, providing strong additional validation of the potential for our novel IL-12 immunotherapy to represent a historic advance in the treatment of ovarian cancer," said Stacy Lindborg, Ph.D., president and chief executive officer of IMUNON. "We understand the significant challenges that ovarian cancer presents to women and their families, especially women with advanced late-stage disease who are newly diagnosed, and that there is a desperate need for new treatments that can make a meaningful difference. We remain on track to initiate a Phase 3 pivotal clinical trial for IMNN-001 in advanced ovarian cancer in the first quarter of 2025 and look forward to updating on our progress."

The OVATION 2 Study included a total of 112 patients with newly diagnosed advanced ovarian cancer (intent-to-treat population). Study participants were randomized 1:1 to evaluate the safety and efficacy of IMNN-001 (100 mg/m2 administered intraperitoneally weekly) plus NACT of paclitaxel and carboplatin compared to SoC NACT alone. Initial results from the OVATION 2 Study were reported in July 2024 and results were recently presented in a late-breaking session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 39th Annual Meeting in November 2024.

"While most research in ovarian cancer in recent years has focused on maintenance therapies for patients who have already responded to chemotherapy, the fact that we are seeing these positive results maintained in a population of newly diagnosed patients with advanced stages of disease requiring neoadjuvant chemotherapy is unprecedented and especially encouraging," said Premal H. Thaker, M.D., Interim Chief of Gynecologic Oncology, David & Lynn Mutch Distinguished Professor of Obstetrics & Gynecology, Director of Gynecologic Oncology Clinical Research at Washington University School of Medicine, and the OVATION 2 Study Chair. "As the first immunotherapy to achieve clinically effective progression-free and overall survival in ovarian cancer in conjunction with chemotherapy, we are especially excited to advance this promising program to a pivotal Phase 3 clinical trial."

About the Phase 2 OVATION 2 Study

OVATION 2 evaluated the dosing, safety, efficacy and biological activity of intraperitoneal administration of IMNN-001 in combination with neoadjuvant and adjuvant chemotherapy (NACT) of paclitaxel and carboplatin in patients newly diagnosed with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer. Treatment in the neoadjuvant period is designed to shrink the tumors as much as possible for optimal surgical removal after three cycles of chemotherapy. Following NACT, patients undergo interval debulking surgery, followed by three additional cycles of adjuvant chemotherapy to treat any residual tumor. This open-label study enrolled 112 patients who were randomized 1:1 and evaluated for safety and efficacy to compare NACT plus IMNN-001 versus standard-of-care NACT. In accordance with the study protocol, patients randomized to the IMNN-001 treatment arm could receive up to 17 weekly doses of 100 mg/m2 in addition to NACT. As a Phase 2 study, OVATION 2 was not powered for statistical significance. Additional endpoints included objective response rate, chemotherapy response score and surgical response.

About IMNN-001 Immunotherapy

Designed using IMUNON’s proprietary TheraPlas platform technology, IMNN-001 is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system that enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anticancer immunity acting through the induction of T-lymphocyte and natural killer cell proliferation. IMUNON previously reported positive safety and encouraging Phase 1 results with IMNN-001 administered as monotherapy or as combination therapy in patients with advanced peritoneally metastasized primary or recurrent ovarian cancer and completed a Phase 1b dose-escalation trial (the OVATION 1 Study) of IMNN-001 in combination with carboplatin and paclitaxel in patients with newly diagnosed ovarian cancer.

About Epithelial Ovarian Cancer

Epithelial ovarian cancer is the sixth deadliest malignancy among women in the U.S. There are approximately 20,000 new cases of ovarian cancer every year and approximately 70% are diagnosed in advanced Stage III/IV. Epithelial ovarian cancer is characterized by dissemination of tumors in the peritoneal cavity with a high risk of recurrence (75%, Stage III/IV) after surgery and chemotherapy. Since the five-year survival rates of patients with Stage III/IV disease at diagnosis are poor (41% and 20%, respectively), there remains a need for a therapy that not only reduces the recurrence rate, but also improves overall survival. The peritoneal cavity of advanced ovarian cancer patients contains the primary tumor environment and is an attractive target for a regional approach to immune modulation.

On December 10, 2024 Novartis reported results from an updated analysis of the pivotal Phase III NATALEE trial of Kisqali (ribociclib) that underscore the extended efficacy beyond the duration of treatment in combination with endocrine therapy (ET) (Press release, Novartis, DEC 10, 2024, View Source [SID1234649002]). Results showed a sustained reduction in distant recurrence of 28.5% (HR=0.715; 95% CI 0.604-0.847; nominal P<0.0001), compared to ET alone, in patients with stage II and III hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC)1.

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Reduction in distant recurrence, known as distant disease-free survival (DDFS), is a decrease in the rate of cancer returning and spreading to other organs. The DDFS with Kisqali was consistent across all pre-specified patient subgroups, including those with node-negative (N0) disease1. These late-breaking data are being presented at the 2024 San Antonio Breast Cancer Symposium (SABCS).

"In day-to-day practice, we see a real and persistent risk of breast cancer coming back after early diagnosis, often as metastatic disease," said Paolo Tarantino, M.D., Advanced Fellow at Dana-Farber Cancer Institute and Harvard Medical School. "The latest NATALEE and real-world data presented at SABCS reaffirm we can better address risk of recurrence for all patients at high-risk, including selected patients with node-negative disease, by offering them adjuvant CDK4/6 inhibitor treatment in addition to endocrine therapy."

DDFS results across pre-specified subgroups1,4**:

Subgroup Hazard Ratio 95% CI
Intention-To-Treat Population 0.715 0.604-0.847
AJCC Tumor Stage IIA 0.396 0.218-0.720
AJCC Tumor Stage IIB 0.806 0.524-1.238
AJCC Tumor Stage IIIA 0.697 0.524-0.926
AJCC Tumor Stage IIIB 0.569 0.326-0.994
AJCC Tumor Stage IIIC 0.878 0.649-1.188
Node-negative disease 0.696 0.403-1.204
Node-positive disease 0.726 0.608-0.867
Safety remains consistent with previous reports, and no new safety signals were identified5. Adverse events (AEs) of special interest (grade 3 or higher) were neutropenia (44.4%), liver-related AEs (e.g., elevated transaminases) (8.6%), and QT interval prolongation (1.0%)5.

Real-World Risk of Distant Recurrence
Further, real-world evidence presented at the meeting highlights the relatively high incidence of distant recurrences within 5 years despite ET monotherapy for patients at high-risk, regardless of nodal involvement2.

"On the heels of its U.S. FDA and EMA approvals in early breast cancer, it is encouraging to see the continued benefit of adding Kisqali to standard endocrine therapy to help reduce the risk of recurrence," said Jeff Legos, Executive Vice President, Global Head of Oncology Development, Novartis. "These data, together with the recent NCCN Guidelines Category 1 preferred treatment recommendation for all eligible patients with early breast cancer, reinforce the opportunity to evolve adjuvant treatment to help a broader group of people."

Additional research presented at the meeting further demonstrates the ongoing focus of Novartis to advance the care of people with breast cancer, including studies investigating the potential of radioligand therapies in the treatment of metastatic breast cancer (MBC)6.

*NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

**The 4-year DDFS analysis was not prespecified and the trial was not powered to demonstrate statistical significance of these results.

About NATALEE
NATALEE is a global Phase III multi-center, randomized, open-label trial to evaluate the efficacy and safety of Kisqali with ET as an investigational adjuvant treatment versus ET alone in patients with stage II and III HR+/HER2- EBC, being conducted in collaboration with TRIO7,8. The adjuvant ET in both treatment arms was a non-steroidal aromatase inhibitor (NSAI; anastrozole or letrozole) and goserelin if applicable7,8. The primary endpoint of NATALEE is invasive disease-free survival (iDFS) as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria7,8. A total of 5,101 adult patients with HR+/HER2- EBC across 20 countries were randomized in the trial7,8.

About Kisqali (ribociclib)
Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali has been approved as a treatment for breast cancer by regulatory authorities in 99 countries worldwide, including the U.S. FDA and the European Commission9,10. In the US, Kisqali is indicated in combination with an AI as an adjuvant treatment for adults with HR+/HER2- stage II and III early breast cancer at high risk of recurrence, as well as for the treatment of adults with HR+/HER2- advanced or MBC as initial ET; Kisqali is also approved in the metastatic indication in combination with fulvestrant as initial ET or following disease progression on ET in post-menopausal women or in men9. In the EU, Kisqali is approved for the treatment of women with HR+/HER2- advanced or MBC in combination with either an AI or fulvestrant as initial ET or following disease progression10. In pre- or peri-menopausal women, the ET should be combined with a luteinizing hormone-releasing hormone agonist9,10.

In EBC, ribociclib (Kisqali) is the only CDK4/6 inhibitor recommended by the NCCN Guidelines for breast cancer for both all node-positive disease as well as for patients with no nodal involvement with high-risk disease characteristics, such as tumor size >5 cm, or for tumors sized 2-5 cm, either Grade 2 with high genomic risk/Ki-67 ≥20% or Grade 33. In MBC, Kisqali has consistently demonstrated statistically significant overall survival benefit across three Phase III trials11-21. The NCCN Guidelines also recommend ribociclib (Kisqali) as the only Category 1 preferred CDK4/6 inhibitor for first-line treatment of people living with HR+/HER2- when combined with an AI3, making Kisqali the preferred first-line treatment of choice for US prescribers in HR+/HER2- MBC.

In addition, Kisqali has achieved the highest score (A) on the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) for EBC22; and has the highest rating of any CDK4/6 inhibitor on the ESMO (Free ESMO Whitepaper) Magnitude of Clinical Benefit Scale, achieving a score of five out of five for first-line pre-menopausal patients with HR+/HER2- advanced breast cancer23. Further, Kisqali in combination with either letrozole or fulvestrant has uniquely, among other CDK4/6 inhibitors, received a score of four out of five for post-menopausal patients with HR+/HER2- advanced breast cancer treated in the first line24.

Kisqali was developed by Novartis under a research collaboration with Astex Pharmaceuticals.

Please see full Prescribing Information for Kisqali, available at www.Kisqali.com