On September 19 2021 Novartis reported a collaboration with SOLTI Innovative Cancer Research (SOLTI) on HARMONIA, an international, randomized, Phase III, multicenter, open-label study of Kisqali (ribociclib) versus Ibrance (palbociclib), both in combination with endocrine therapy, in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer with a HER2-enriched (HER2E) intrinsic subtype (Press release, Novartis, SEP 19, 2021, View Source [SID1234587942]). HARMONIA is the first prospective Phase III trial to enroll patients selected by RNA-based molecular subtyping of their tumors and the first to directly compare two CDK4/6 inhibitors in patients with HR+/HER2- advanced breast cancer.

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"The strength and consistency of the Kisqali overall survival data across the MONALEESA program reinforce there are differences among CDK4/6 inhibitors, and that Kisqali stands apart in its ability to help patients achieve their goal of more quality time," said Susanne Schaffert, PhD, President, Novartis Oncology. "HARMONIA, a novel head-to-head trial, is a testament to our bold development approach and will provide evidence on the unique profile of Kisqali and its unmatched benefit for HR+/HER2- advanced breast cancer patients. We are grateful to be collaborating on this important study with leading academic research groups."

The primary endpoint of HARMONIA is progression free survival (PFS), and the study will evaluate if Kisqali positively alters tumor biology, enabling a better response to endocrine therapy compared to Ibrance.

"HARMONIA will significantly advance clinical and translational knowledge to optimize the diagnosis and treatment of patients with advanced breast cancer," said Aleix Prat, SOLTI President, Head of the Medical Oncology Department at Hospital Clínic of Barcelona, Head of the Translational Genomics Group and Targeted Therapies in Solid Tumors at IDIBAPS and Professor of Medicine at the University of Barcelona. "As an experienced academic research group in the field of oncology, we are proud to be pioneering this first-of-a-kind research on breast cancer at the RNA level to recognize the value of intrinsic subtypes, which impact patient outcomes in terms of incidence, survival and response to treatment."

HARMONIA enrollment is expected to begin in Q1 2022. Patients with the basal-like subtype may also enroll. This exploratory cohort of patients will be treated with a chemotherapy-based regimen as these tumors behave more like triple-negative breast cancer.

About Kisqali (ribociclib)
Kisqali is the CDK4/6 inhibitor with the largest body of clinical trial evidence demonstrating consistent and superior overall survival benefit compared to endocrine therapy alone. Overall survival results were presented previously: MONALEESA-7 (ASCO 2019) and MONALEESA-3 (ESMO 2019) and MONALEESA-2 (ESMO 2021); MONALEESA-7 and MONALEESA-3 were published in the New England Journal of Medicine, with updated exploratory analyses presented at SABCS 2020 and ASCO (Free ASCO Whitepaper) 2021, demonstrating Kisqali plus endocrine therapy significantly extends life in pre/perimenopausal or postmenopausal women with HR+/HER2- advanced breast cancer2-4, 10-11.

Kisqali is approved by the US Food and Drug Administration (FDA) and by the European Commission (EC) as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor. Kisqali in combination with an aromatase inhibitor is approved for the treatment of pre-, peri- or postmenopausal women as initial endocrine-based therapy, and also indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women by the FDA and by the EC12. Kisqali is approved in over 95 countries1.

Novartis is continuing to reimagine cancer with an additional trial of Kisqali. NATALEE is a large confirmatory clinical trial of Kisqali with endocrine therapy in the adjuvant treatment of HR+/HER2- early breast cancer being conducted in collaboration with Translational Research In Oncology (TRIO)13.

Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About Novartis in Advanced Breast Cancer
Novartis tackles breast cancer with superior science, collaboration and a passion for transforming patient care. We’ve taken a bold approach to our research by including patient populations often neglected in clinical trials, identifying new pathways or mutations that may play a role in disease progression and developing therapies that not only maintain, but also improve, quality of life for patients. Our priority over the past 30 years and today is to deliver treatments proven to improve and extend lives for those diagnosed with advanced breast cancer.

Important Safety Information from the Kisqali EU SmPC
Kisqali (ribociclib) is a prescription medicine approved in combination with an aromatase inhibitor as initial endocrine – based therapy in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer or fulvestrant as initial endocrine – based therapy or following disease progression on endocrine therapy in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. It is not known if Kisqali is safe and effective in children or adolescents. Kisqali can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Kisqali is not indicated for concomitant use with tamoxifen due to an increased risk of QT prolongation. Patients should tell their health care provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. Kisqali can cause serious liver problems. Patients should tell their health care provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking Kisqali and may result in infections that may be severe. Patients should tell their health care provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking Kisqali, patients should tell their health care provider if they are pregnant, or plan to become pregnant as Kisqali can harm an unborn baby. Females who are able to become pregnant and who take Kisqali should use highly effective birth control during treatment and for at least 3 weeks after the last dose of Kisqali. Do not breastfeed during treatment with Kisqali and for at least 3 weeks after the last dose of Kisqali. Patients should tell their health care provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with Kisqali. Patients should avoid grapefruit or grapefruit juice while taking Kisqali. The most common side effects (incidence >=20%) include infections, white blood cell count decreases, headache, cough, nausea, tiredness, diarrhea, vomiting, constipation, hair loss and rash. The most common Grade 3/4 side effects (incidence >5%) were infections, low neutrophils, low leukocytes, low red blood cells, abnormal liver function tests, low lymphocytes, low phosphate levels and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

On September 19, 2021 Byondis B.V., an independent, clinical stage biopharmaceutical company creating precision medicines, reported positive results from its pivotal Phase III TULIP study (Press release, Byondis, SEP 19, 2021, View Source;trastuzumab-duocarmazine-syd985-superior-to-physicians-choice-in-pre-treated-locally-advanced-or-metastatic-her2-positive-breast-cancer-301379760.html [SID1234587938]). The multi-center, open-label, randomized clinical trial compared the efficacy and safety of the company’s antibody-drug conjugate (ADC) [vic-]trastuzumab duocarmazine (SYD985) to physician’s choice (PC) treatment in patients with pretreated HER2-positive unresectable locally advanced or metastatic breast cancer (MBC).

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"SYD985 vs. Physician’s Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer" met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement over PC – 7 months for SYD985 versus 4.9 months for PC. The study also demonstrated a trend towards better overall survival (OS) for patients treated with SYD985. TULIP results were presented by Cristina Saura, M.D., head, Vall d’Hebron University Hospital Breast Cancer Unit, Medical Oncology Department, and principal investigator, Vall d’Hebron Institute of Oncology Breast Cancer Research Group in Barcelona, Spain.

"We are satisfied with the results of the TULIP study, as it bodes well for the potential of SYD985 as a new treatment option for patients with HER2-positive metastatic breast cancer, a disease typically associated with a poor prognosis," said Dr. Saura.

"The TULIP results represent a significant milestone in our R&D efforts, and we hope to make this next generation ADC available as soon as possible to the patients whose lives we are dedicated to improve," said Byondis CEO Marco Timmers, Ph.D. "We want to thank our clinical trial sites and study participants and their families for their contributions to this important research."

Byondis is working to complete the SYD985 biological license application (BLA) and intends to submit it to the U.S. Food & Drug Administration (FDA) before the end of 2021. The company is exploring partnerships with pharma and biopharma companies in order to further develop and commercialize SYD985.

The therapy was granted fast track designation by the FDA in January 2018. The designation was based on promising data from heavily pre-treated last-line HER2-positive MBC patients participating in a two-part Phase I clinical trial (SYD985.001).[i]

More TULIP (SYD985.002) Results

Starting in November 2017, TULIP enrolled 437 female patients with a median age of 56 and a median of 4 prior MBC treatments. The study was conducted at 83 sites in 11 countries across the United States, Canada, Europe and Singapore. To qualify, patients had either: (1) progression during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease; or (2) progression during or after ado-trastuzumab emtansine treatment. Patients were randomly assigned (2:1) to receive SYD985 (n=291, 1.2 mg/kg q three weeks) or PC chemotherapy (n=146) until disease progression or unacceptable toxicity. The trial was powered to detect a Hazard Ratio (HR) of 0.65 at the P < 0.05 significance level.

The study’s primary endpoint, blinded centrally reviewed median PFS, was 7.0 months (5.4-7.2, 95% CI) for SYD985 and 4.9 months (4.0-5.5) for PC (HR 0.64 [0.49-0.84], p = 0.002). Secondary endpoint results are as follows: investigator-assessed PFS significantly improved, 6.9 months (6.0-7.2) versus 4.6 months (4.0-5.6) for PC (HR 0.60 [0.47-0.77], p < 0.001); OS first analysis indicated HR was 0.83 (0.62-1.09, p = 0.153); and no significant differences were observed in objective response rate (ORR) or health-related quality of life (HRQoL).

The most frequently reported adverse events (AEs) for SYD985 were conjunctivitis (38.2%), keratitis (38.2%) and fatigue (33.3%). For PC, the most frequently reported AEs were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease/pneumonitis was reported for 7.6% of patients treated with SYD985. AEs leading to discontinuation of treatment were 35.4% and 10.2% in the SYD985 and PC groups, respectively. In the SYD985 group, these were mainly related to eye disorders (20.8%) or respiratory disorders (6.3%).

[Vic-]Trastuzumab Duocarmazine (SYD985), a Next Generation Antibody-Drug Conjugate

[Vic-]trastuzumab duocarmazine (SYD985) incorporates Byondis’ distinctive, proprietary duocarmazine linker-drug (LD) technology ByonZine. Although in general, marketed ADCs have improved therapeutic indices compared to classical non-targeted chemotherapeutic agents, there is still need for improvement.

The ADC [vic-]trastuzumab duocarmazine is comprised of the monoclonal antibody trastuzumab and a cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA). The antibody part of [vic-]trastuzumab duocarmazine binds to HER2 on the surface of the cancer cell and the ADC is internalized by the cell. After proteolytic cleavage of the linker, the inactive cytotoxin is activated and DNA damage is induced, resulting in tumor cell death. SYD985 is considered a form of targeted chemotherapy.

[Vic-]trastuzumab duocarmazine is currently being investigated in three other studies. Byondis initiated a Phase II clinical trial in HER2-expressing recurrent, advanced or metastatic endometrial cancer, and a Phase I study exploring the synergistic effects of [vic-]trastuzumab duocarmazine and niraparib in patients with HER2-expressing locally advanced or metastatic solid tumors. [Vic-]trastuzumab duocarmazine is also part of a new arm of the Quantum Leap Health Collaborative I-SPY 2 TRIAL investigating the neoadjuvant use of [vic-]trastuzumab duocarmazine in HER2-low early-stage breast cancer.

ByonZine, Byondis’ Distinctive, Proprietary Linker-Drug Technology

While earlier generation ADCs improved targeting and cell killing, they were unstable in the bloodstream, leading to premature release of the cytotoxic payload, impacting healthy tissue and narrowing the therapeutic window. Byondis’ next generation ADCs are highly stable in circulation and carry an intricate, inactivated and potent cytotoxic drug that rapidly self-destructs if prematurely released, limiting damage to healthy tissue and improving the therapeutic window.

Byondis’ differentiated linker-drug, vc-seco-DUBA, owes its potent antitumor activity to a synthetic duocarmycin-based cytotoxin. Duocarmycins, first isolated from Streptomyces bacteria in the 1970s, bind to the minor groove of DNA and disrupt the nucleic acid architecture, which eventually leads to tumor cell death.

The distinctive design of the selectively cleavable linker connecting the antibody to the duocarmycin drug leads to high stability in circulation and induces efficient release of the cytotoxin in the tumor. Uptake of the activated payload by neighboring tumor cells with lower HER2 expression may improve the efficacy potential, the so-called bystander effect.

HER2-Positive MBC: A Cancer With a Poor Prognosis

Breast cancer was the world’s most common cancer in 2020,[ii] with an estimated 2.3 million new cases.[iii] Its incidence is rising, particularly in developing countries, where the majority of cases are diagnosed in late stages.[iv] Breast cancer is the leading cause of cancer death for women in more than 100 countries.[v]

In metastatic or Stage 4 breast cancer, the cancer spreads to other parts of the body, such as the lungs, liver, bones or brain. Approximately 0.5 million people worldwide die from MBC every year.[vi]

In HER2-positive breast cancer, an overexpression of the human epidermal growth factor receptor 2 (HER2) protein causes out-of-control reproduction of breast cells. Research has shown that women with HER2-positive breast cancer have a more aggressive disease, greater likelihood of recurrence and poorer prognosis, compared to women with HER2-negative breast cancer. About 20 percent of all breast cancers are HER2-positive, with younger women being the most affected. Treatment of HER2-positive breast cancer can consist of the following: surgery, radiation, chemotherapy and targeted treatments.[vii]

On September 19, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported a new analysis from the CHRYSALIS (NCT02609776) study evaluating RYBREVANT (amivantamab-vmjw) monotherapy and a combination regimen with lazertinib in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations who progressed after osimertinib (Press release, Johnson & Johnson, SEP 19, 2021, View Source [SID1234587937]).1 The analysis showed higher activity and longer duration of response (DOR) in patients treated with the combination therapy, demonstrating the potential benefit of targeting the extracellular (outer) and catalytic (internal) domains of EGFR, even in patients with documented resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs).1 The results were presented in a mini-oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress 2021 virtual meeting on Sunday, September 19 (Abstract #1192MO).

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"Despite advances in targeted therapies, non-small cell lung cancer with EGFR mutations remains a disease with considerable unmet need, especially when prior standard treatments have failed," said Natasha B. Leighl, M.D., MMSc, FRCPC, FASCO, Lung Medical Oncology Lead, Princess Margaret Cancer Centre in Toronto, Canada, and presenting study investigator.† "This analysis shows that targeting two domains of EGFR using amivantamab and lazertinib combination therapy demonstrated higher and more durable response than targeting only one domain. These findings provide insight into a potential new treatment approach for patients whose lung cancer has progressed on standard treatment."

In this descriptive cross-cohort analysis, patients who had progressed on osimertinib received RYBREVANT as a monotherapy (n=121), with a majority (85 percent) preselected for C797S/other EGFR resistance mutations or mesenchymal-epithelial transition (MET) amplification.1 The RYBREVANT and lazertinib combination group included patients who had progressed on osimertinib but who were chemotherapy-naïve (n=45 [38 percent with EGFR/MET-based resistance]).1 Disease response using overall response rate (ORR), per Response Evaluation Criteria in Solid Tumors Version 1.1* (RECIST v1.1) was the primary endpoint.1,2

Antitumor activity was observed in the group treated with RYBREVANT in combination with lazertinib, with an ORR of 36 percent (95 percent confidence interval [CI]; 22 – 51), with one patient (2 percent) with complete response and 15 patients (33 percent) with partial responses (PR).1 The median DOR was 9.6 months (95 percent CI; 5.3 – not reached).1 In contrast, the RYBREVANT monotherapy group had an ORR of 19 percent (95 percent CI; 12 – 27) and median DOR of 5.9 months (95 percent CI; 4.2 – 12.6).1 The clinical benefit rate (CBR), which consisted of complete response, partial response or stable disease at 11 weeks or longer, was 64 percent in the combination group (95 percent CI; 49 – 78) and 48 percent in the monotherapy group (95 percent CI; 39 – 57).1 The combination group experienced central nervous system (CNS) progression in 7 percent of patients, with 4 percent being new CNS lesions, while the monotherapy group documented 17 percent of patients with CNS progression, with 13 percent being new CNS lesions.1

The safety profiles for both combination and monotherapy therapy were consistent with previously reported data, and no new safety signals were identified.1 Treatment-emergent adverse events (AEs) greater than or equal to 20 percent for RYBREVANT and lazertinib as a combination therapy include infusion-related reaction (78 percent), acneiform dermatitis (51 percent), paronychia (49 percent), nausea (44 percent), hypoalbuminemia (38 percent), peripheral edema (38 percent), pruritus (31 percent), dry skin (29 percent), rash (27 percent), constipation (27 percent), stomatitis (27 percent), fatigue (27 percent), dyspnea (24 percent), increased aspartate aminotransferase (22 percent), diarrhea (22 percent), dizziness (22 percent), hypocalcemia (20 percent), vomiting (20 percent) and headache (20 percent).1 Treatment-emergent AEs greater than or equal to 20 percent for RYBREVANT as a monotherapy include infusion-related reaction (69 percent), paronychia (37 percent), acneiform dermatitis (28 percent), hypoalbuminemia (26 percent), rash (26 percent), constipation (26 percent), nausea (24 percent), dyspnea (23 percent) and pruritus (22 percent).1

In May, the U.S. Food and Drug Administration (FDA) approved RYBREVANT, a fully human bispecific antibody, as the first targeted treatment for patients with NSCLC with EGFR exon 20 insertion mutations.3 Additional analyses of RYBREVANT are ongoing. Lazertinib was approved earlier this year in South Korea for patients with NSCLC with EFGR mutations and T90M mutations.

"The approval of RYBREVANT as a monotherapy was a pivotal moment in the treatment of patients with difficult-to-treat non-small cell lung cancer with EGFR exon 20 insertion mutations. This new analysis builds on the established safety and efficacy profile of RYBREVANT, showing its value for a broader group of patients with EGFR mutations when combined with lazertinib," said Sylvie Laquerre, Ph.D., Vice President, Disease Area Leader, Solid Tumor Targeted Therapies, Janssen Research & Development, LLC. "Janssen is committed to evaluating the potential of these treatments as we work toward transforming the treatment landscape for people with lung cancer."

*RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumors, which is a standard way to measure how well solid tumors respond to treatment and is based on whether tumors shrink, remain the same or increase in size.2

About RYBREVANT
RYBREVANT (amivantamab-vmjw) received accelerated approval by the U.S. FDA in May 2021 for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.4 Shortly after FDA approval, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer included amivantamab-vmjw (RYBREVANT) as a subsequent therapy option with a Category 2A recommendation for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.5 Janssen has filed regulatory submissions for RYBREVANT with health authorities in Europe and other markets.

RYBREVANT is being studied in multiple clinical trials, including the Phase 1/1b CHRYSALIS-2 (NCT04077463) study assessing the combination of RYBREVANT and lazertinib in patients who have progressed after treatment with osimertinib and chemotherapy; as first-line therapy in untreated advanced EGFR-mutated NSCLC in the Phase 3 MARIPOSA (NCT04487080) study assessing amivantamab in combination with lazertinib; the planned Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of lazertinib, RYBREVANT and carboplatin-pemetrexed vs. withversus carboplatin-pemetrexed in patients with locally advanced or metastatic EGFR exon 19 deletion or exon 21 L858R substitution NSCLC after osimertinib failure; the Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT in combination with carboplatin-pemetrexed versus chemotherapy alone in patients with advanced or metastatic EGFR-mutated NSCLC and exon 20 insertion mutations; and the Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous (SC) administration of RYBREVANT based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for RYBREVANT SC delivery. 6,7,8,9,10,11

*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer V.5.2021. ©National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed June 15, 2021. To view the most recent and complete version of the guidelines, visit NCCN.org.

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.

About Lazertinib
Lazertinib is an oral, third-generation, brain-penetrant, EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR.12 Interim safety and efficacy results from the lazertinib Phase 1/2 study were published in The Lancet Oncology in 2019. In 2018, Janssen Biotech, Inc. entered into a license and collaboration agreement with Yuhan Corporation for the development of lazertinib.

About the CHRYSALIS Study
CHRYSALIS (NCT02609776) is an open-label, multicenter, first-in-human Phase 1 study to evaluate the safety, pharmacokinetics and preliminary efficacy of RYBREVANT as a monotherapy and in combinations, including with lazertinib, in patients with advanced NSCLC with various EGFR mutations.6 The study is enrolling 460 patients with advanced NSCLC.6 The study consists of two parts: The first consists of amivantamab monotherapy and combination dose escalations, and the second consists of amivantamab monotherapy and combination dose expansions.6

About Non-Small Cell Lung Cancer (NSCLC)
Worldwide, lung cancer is one of the most common cancers, and NSCLC makes up 80 to 85 percent of all lung cancers.13,14 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.14 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase supporting cell growth and division.15 Epidermal growth factor receptor mutations are present in 10 to 15 percent15,16,17,18,19 of people with NSCLC adenocarcinoma and occur in 40 to 50 percent of Asians.20,21 The five-year survival rate for all people with metastatic NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent.22,23

RYBREVANT IMPORTANT SAFETY INFORMATION4
WARNINGS AND PRECAUTIONS
Infusion Related Reactions4
RYBREVANT can cause infusion related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.

Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT due to IRR.

Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended. Administer RYBREVANT via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity.

Interstitial Lung Disease/Pneumonitis4
RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Dermatologic Adverse Reactions4
RYBREVANT can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients.

Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT.

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad spectrum UVA/UVB sunscreen. Alcohol free emollient cream is recommended for dry skin.

If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity.

Ocular Toxicity4
RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity.

Embryo Fetal Toxicity4
Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT.

Adverse Reactions4
The most common adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium.

On September 19, 2021 CARsgen Therapeutics (stock code: 2171.HK) reported the latest progress of the investigator-initiated trial (IIT) of Claudin18.2 (CLDN18.2) CAR-T (CT041) for the treatment of digestive system tumors (Press release, Carsgen Therapeutics, SEP 19, 2021, View Source [SID1234587936]). Results of this trial have been orally presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 (ESMO 2021). The presenter was Dr. Changsong Qi from Beijing Cancer Hospital.

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Appealing Data of CARsgen Therapeutics’ CAR-T (CT041) in Advanced Gastric Cancer Presented at ESMO (Free ESMO Whitepaper)
CT041, developed by CARsgen Therapeutics, is currently the only CLDN18.2-targeted CAR-T cell therapy that has obtained IND clearance and is under clinical trials in both China and the United States. CT041 was granted an "Orphan Drug" designation by the FDA in 2020 for the treatment of gastric cancer/gastroesophageal junction (GC/GEJ) cancer and was granted the "Orphan Medicinal Product" designation by the EMA for the treatment of gastric cancer in 2021.

Appealing Data of CLDN18.2 CAR-T in Advanced Gastric Cancer Revealed at ESMO (Free ESMO Whitepaper)

This trial is a multicenter open-label investigator-initiated clinical trial in China for patients with CLDN18.2+ (≥+, ≥10%) digestive system tumors. This clinical trial consists of a dose escalation stage and a dose expansion stage. The primary objective of this trial is to assess the safety and tolerability of CT041 and the secondary objective is to assess the efficacy and pharmacokinetics.

As of April 8, 2021, 37 patients received CT041 infusion and completed at least 12 weeks of evaluation, including 28 cases of gastric/ gastroesophageal junction cancer (GC/GEJ), 5 cases of pancreatic cancer (PC) and 4 cases of other types of digestive system tumors. The cell dose levels were 2.5×108, 3.75×108 and 5.0×108 CAR-T cells respectively. Approximately 84% of patients had received at least 2 prior lines of therapies and the median number of metastatic organs was 3. For the 28 patients with GC/GEJ, 67.9% of the subjects had peritoneal metastases. 42.9% and 35.7% of the subjects had been exposed to anti-PD-(L)1 antibody and polykinase inhibitors respectively.

In terms of safety profile, CT041 was generally well-tolerated. No treatment-related death or immune cell therapy-associated neurotoxicity syndrome (ICANS) were reported. Approximately 95% of patients experienced CRS, all being grade 1 or 2.

For the 36 patients with target tumor lesions (GC/GEJ, PC and other types of digestive system tumors), 31 subjects had different degrees of shrinkage of target lesions with an ORR of 48.6% and a disease control rate (DCR) of 73.0%.

18 GC/GEJ patients who failed at least 2 prior lines of therapy (including 8 (44% of) patients ever exposed to an anti-PD-(L)1 antibody) at the dose of 2.5×108 (recommended phase 2 dose (RP2D)) CAR-T cells achieved an ORR of 61.1%, DCR of 83.3%, median PFS of 5.6m, median DOR of 6.4m, median OS of 9.5m with a median follow up of 7.6m.

For the 28 GC/GEJ patients, subgroup analysis revealed that ORR could be maintained at 50% and above in patients with different baseline characteristics.

Historical data shows that for the GC/GEJ patients who failed at least 2 prior lines of therapy, the efficacy rate of chemotherapy is about 4% to 8%, and the efficacy rate of anti-PD-1 antibody is about 11%. Therefore, compared with other treatments for GC/GEJ patients who failed at least two prior lines of therapies, CT041 has a significant improvement of ORR. Since many patients in this phase of the trial had received anti-PD-(L)1 antibody treatment, the efficacy data disclosed indicate that CT041 may become a new treatment for advanced GC/GEJ patients.

Further data of this clinical trial is planned to be disclosed in academic journals or conferences.

In 2020, there were 480,000 new cases of gastric cancer in China, accounting for 43.9% of the total incidence globally. Moreover, there is a rising trend in the incidence of gastric cancer among young people. Major treatments for advanced gastric cancer are chemotherapy and HER2-targeted therapy, but the percentage of HER2 positive patients in gastric cancer is only 7-20%. Despite several products such as PD-1 monoclonal antibodies that have been approved for advanced gastric cancer in recent years, there are still significant needs for innovative therapies.

Professor Lin Shen of Beijing Cancer Hospital commented that, "Gastric cancer is of high incidence globally and particularly in Asia. Gastric cancer incidence in China is approximately 50% of the overall global incidence. Research and treatment options for gastric cancer are still quite limited and there are strong needs for more innovative therapies to change the treatment paradigm. Data presented at ESMO (Free ESMO Whitepaper) showed significant efficacy and excellent tolerability of CT041 and we hope that it could benefit more cancer patients."

Dr. Zonghai Li, Co-founder, CEO, CSO, Chairman of the Board of CARsgen Therapeutics, commented that, "I would like to express the sincere gratitude to Dr. Changsong Qi for presenting the latest clinical trial data of CT041 in ESMO (Free ESMO Whitepaper) 2021 and to all the other investigators and researchers involved in the development of this CLDN18.2 CAR-T, which offers new hope for the gastric cancer patients. With the mission of ‘making cancer curable’, we will continue our endeavours in developing more innovative technology and products for cancer patients worldwide."

CARsgen Therapeutics has applied to China NMPA for the initiation of the pivotal phase II trial of CT041 in China. In US and Europe, CT041 has obtained the Orphan Drug Designation from the FDA and the EMA. The pivotal phase II clinical trial in the United States is anticipated to initiate in 2022.

CARsgen Therapeutics currently has 11 product candidates, all of which were fully developed in house with global rights, covering conventional 2nd-generation, next-generation, and allogeneic CAR-T cell therapies, indicating a comprehensive and visionary portfolio development. CARsgen Therapeutics has obtained 7 IND approvals for CAR-T therapies in China, the United States and Canada, ranking the first among all CAR-T companies in China.

(Source: View Source)

According to the data from Nature Biotechnology, by the end of 2019, ranked by the total number of CAR-T patents, CARsgen Therapeutics was the only Asian company among the top 20 institutes or companies globally.

In addition to existing product pipeline, CARsgen Therapeutics strives to continue advancing technologies centered on 4 strategic pilliars against the major challenges of the industry: 1) increasing efficacy against solid tumors 2) enhancing safety profile 3) expanding patient accessibility and 4) improving target availability. Powered by these proprietary technologies, such as CycloCAR and THANK-uCAR, CARsgen Therapeutics plans to develop more innovative product candidates for the cancer patients worldwide.

About CT041

CT041, developed by CARsgen Therapeutics, showed acceptable safety profile and promising antitumor activities in patients with refractory CLDN18.2 + cancer of digestive system. CARsgen Therapeutics is the first in the world to successfully identify, validate, and report CLDN18.2 and GPC3 as rational targets for CAR-T cell therapies. In addition to the investigator-initiated trials in China, we have initiated a Phase Ib/II clinical trial for advanced (unresectable or metastatic) GC/GEJ and PC in China and a Phase Ib clinical trial for advanced (unresectable or metastatic) gastric or pancreatic adenocarcinoma in the United States.

CT041 is the only CLDN18.2 targeted CAR-T cell product that has obtained IND approval globally. CT041 was granted an "Orphan Drug" designation by the FDA in 2020 for the treatment of gastric cancer or gastroesophageal junction (GC/GEJ) cancer and was granted the "Orphan Medicinal Product" designation by the EMA for the treatment of gastric cancer in 2021.

(Press release, Carsgen Therapeutics, SEP 19, 2021, View Source [SID1234587936])

On September 19, 2021 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca reported that New data for datopotamab deruxtecan (Dato-DXd), a TROP2 directed DXd antibody drug conjugate (ADC) being developed by show an encouraging tumor response rate in patients with advanced non-small cell lung cancer (NSCLC) with actionable genomic alterations (Press release, Daiichi Sankyo, SEP 19, 2021, View Source [SID1234587934]). A sub-analysis of the NSCLC cohort of the TROPION-PanTumor01 phase 1 trial was presented as a late-breaking Mini Oral presentation (#LBA49) at the European Society for Medical Oncology (#ESMO21) 2021 Virtual Congress.

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Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide, with 80 to 85% classified as NSCLC.1,2,3 For patients with advanced NSCLC with certain genomic alterations, treatment with targeted therapy offers improved response rates or survival compared to traditional chemotherapy.4 However, once these targeted therapies are exhausted, treatment options are more limited.5 While TROP2 has been found to be highly expressed in NSCLC and associated with poor survival, there currently are no TROP2 directed therapies approved for the treatment of patients with NSCLC.6,7

A confirmed objective response rate (ORR) of 35% was observed in 34 evaluable patients with NSCLC with actionable genomic alterations treated with datopotamab deruxtecan as assessed by blinded independent central review. Twelve partial responses (35%) and 14 cases of stable disease (41%) were observed. With a median follow-up of 13.4 months (range, 7-28 months), the median duration of response (DOR) was 9.5 months (95% CI: 3.3-NE). Clinical activity was observed in patients with EGFR mutations (Ex19del, L858R), including after osimertinib therapy, and across other actionable genomic alterations.

The safety profile of datopotamab deruxtecan was consistent with that observed in the overall NSCLC population of the TROPION-PanTumor01 trial. The most common treatment-emergent adverse events (TEAEs) were nausea and stomatitis. One case of interstitial lung disease (grade 5 at the 8 mg/kg dose) was observed and adjudicated as treatment-related.

"Identification of genomic alterations serves as an important roadmap for the treatment of patients with non-small cell lung cancer. However, prognosis is poor after progression on currently available therapies targeted to the underlying oncogenic alteration," said Edward B. Garon, MD, Director of Thoracic Oncology, Jonsson Comprehensive Cancer Center at University of California, Los Angeles. "We are highly encouraged by the tumor responses seen in this analysis as these results support the potential of datopotamab deruxtecan in patients with advanced non-small cell lung cancer with actionable genomic alterations and disease progression following standard treatment."

"These data provide preliminary evidence that datopotamab deruxtecan elicits tumor responses in patients with previously treated advanced non-small cell lung cancer with actionable genomic alterations," said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. "Further validation of these initial results is underway in the TROPION-Lung05 phase 2 trial where datopotamab deruxtecan is being evaluated in this specific type of NSCLC with disease progression following targeted therapy and platinum-based chemotherapy."

"TROP2 may be associated with poor prognosis and short median overall survival in some patients with advanced non-small cell lung cancer, one of the most common forms of cancer," said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. "This setting represents high unmet need as the patients in this trial have exhausted many of the available options. These updated results from our TROPION clinical development program, add to the evidence for the potential role of datopotamab deruxtecan across non-small cell lung cancer disease."

The majority of patients (82%) in this sub-analysis had received three or more prior lines of therapy including platinum-based chemotherapy (91%), TKIs (85%), and immunotherapy (41%). Patients included in this analysis had tumors with EGFR mutations (85%), ALK fusion (9%), ROS1 fusion (3%), and RET fusion (3%). Of those with EGFR mutations, 69% had received prior treatment with osimertinib. As of data cut-off on April 6, 2021, 12% of patients remained on treatment with datopotamab deruxtecan.

Summary of TROPION-PanTumor01 Results in NSCLC with Actionable Genomic Alterations

Efficacy Measure

Total Evaluable (n=34)i,ii,iii

Confirmed ORR (%, n)iv

35% (n=12)

CR (%, n)

0% (n=0)

PR (%, n)

35% (n=12)

SD (%, n)

41% (n=14)

DoR, median (95% CI), months

9.5 months (3.3-NE)

CI, confidence interval; CR, complete response; DoR, duration of response; ORR, objective response rate; PR, partial response; SD, stable disease;
i Assessed across doses [4 mg/kg (n=8), 6 mg/kg (n=10), and 8 mg/kg (n=16)]
ii As assessed by blinded independent central review
iii Includes response-evaluable patients who had ≥1 postbaseline tumor assessment or discontinued treatment.
iv ORR is (CR + PR)

About TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicenter phase 1 trial evaluating the safety, tolerability and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumors refractory to or relapsed from standard treatment or for whom no standard treatment is available, including NSCLC, triple negative breast cancer (TNBC), hormone receptor (HR) positive breast, urothelial, gastric and esophageal cancers.

The dose escalation part of the study assessed the safety and tolerability of increasing doses of datopotamab deruxtecan to determine the maximum tolerated dose and/or recommended dose for expansion in patients with unresectable advanced NSCLC. The dose expansion part of the study further assessed the safety and tolerability of datopotamab deruxtecan at selected dose levels (4 mg/kg, 6 mg/kg and 8 mg/kg) in patients with NSCLC. Based on the preliminary efficacy and safety profile, the 6 mg/kg dose has been chosen for further development.8,9

Safety endpoints include dose limiting toxicities and serious adverse events. Efficacy endpoints include ORR, disease control rate, DOR, time to response, progression-free survival and overall survival. Pharmacokinetic, biomarker and immunogenicity endpoints also are being evaluated.

About Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide, with 80 to 85% classified as NSCLC.1,3 NSCLC is diagnosed at an advanced stage in more than 50% of patients and often has a poor prognosis with worsening outcomes after each line of subsequent therapy.10,11,12

The majority of patients with advanced NSCLC traditionally received platinum-based chemotherapy as first-line treatment.13 The introduction of targeted therapies and immune checkpoint inhibitors in the past two decades has created new options and shifted treatment to a more personalized approach.13

A number of targeted therapies offer improved efficacy over traditional chemotherapy regimens and are approved for treatment of NSCLC with specific genomic alterations.4 The most common alterations for which targeted therapies are approved are EGFR (approximately 10 to 35% frequency) and ALK rearrangement (approximately 3 to 7%). Patients eventually develop resistance to available therapies.5

About TROP2
TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is widely expressed in several types of solid tumors, including NSCLC.6,14 Research indicates that TROP2 expression is associated with increased tumor progression and poor overall and disease free survival in several types of solid tumors.6,14 While TROP2 is expressed across all lung cancer subtypes, results from one NSCLC study demonstrated TROP2 expression in all adenocarcinoma cases and 92% of squamous cell carcinoma cases (the most common forms of NSCLC), while a separate study found high TROP2 expression in 64% of adenocarcinoma and 75% of squamous cell carcinoma cases.6,15 However, no TROP2 directed therapies are currently approved for the treatment of patients with NSCLC.7

About Datopotamab Deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed antibody drug conjugate (ADC). Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of three lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG13 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker.16

A comprehensive development program called TROPION is underway globally with trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple solid tumors, including NSCLC, TNBC, HR positive breast, urothelial, gastric and esophageal cancer. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of datopotamab deruxtecan.

About Daiichi Sankyo in Oncology
The oncology portfolio of Daiichi Sankyo is powered by our team of world-class scientists that push beyond traditional thinking to create transformative medicines for people with cancer. Anchored by our DXd antibody drug conjugate (ADC) technology, our research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in the U.S. We also work alongside leading academic and business collaborators to further advance the understanding of cancer as Daiichi Sankyo builds towards our ambitious goal of becoming a global leader in oncology by 2025.