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.

On September 19, 2021 Ipsen (Euronext: IPN; ADR: IPSEY) reported presentation of new analyses at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 across different forms of cancer for people treated with Cabometyx (cabozantinib) (Press release, Ipsen, SEP 19, 2021, View Source [SID1234587933]). Of note, the final analysis of the pivotal Phase III COSMIC-311 trial (Abstract LBA67) will be presented, with Cabometyx demonstrating a clinically meaningful, sustained efficacy benefit versus placebo in people living with previously treated radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC).

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With a median follow-up of 10.1 months, Cabometyx continued to demonstrate superior median progression-free survival (mPFS) with a reduction in the risk of disease progression or death of 78% versus placebo (hazard ratio [HR]: 0.22, 96% confidence interval [CI]: 0.15-0.32; p<0.0001).1 This final analysis is consistent with data from the interim analysis, presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2021 and published in The Lancet Oncology, (HR: 0.22; 96% CI: 0.13-0.36; p<0.0001).5,6 Further data from the final analysis also confirmed that superior efficacy with Cabometyx was maintained irrespective of previous vascular endothelial growth factor receptor (VEGFR)-targeted therapy.

Efficacy and safety data from the COSMIC-311 interim analysis formed the basis of a type II variation submission to the European Medicines Agency (EMA) for an extension of indication for Cabometyx in RAI-R DTC. On 14 August 2021, the EMA validated the type II variation, confirming the submission is complete and beginning its centralized review process.

The safety profile identified in the COSMIC-311 trial was consistent with that previously observed for cabozantinib and adverse events (AEs) were managed with dose modifications. The discontinuation rate due to treatment-emergent AEs (TEAEs) was 8.8% for Cabometyx vs. 0% for placebo. Grade 3/4 TEAEs occurred in 62% of patients who received Cabometyx vs. 28% for placebo, with no treatment-related grade 5 events.

Steven Hildemann, M.D., Executive Vice President, Chief Medical Officer, Head of Global Medical Affairs and Global Patient Safety, Ipsen said, "The therapeutic potential of Cabometyx as a key treatment option in our arsenal against a broad range of tumors is continuing to be realized. These final data from the COSMIC-311 trial are a strong example of how Cabometyx can make a tangible difference to the lives of people living with cancer and we look forward to receiving a decision from the EMA next year. We are committed to further evaluating the role Cabometyx may continue to play against difficult-to-treat cancers as we also look towards the results of the ongoing Phase III trials in non-small cell lung cancer (CONTACT-01) and metastatic castration-resistant prostate cancer (CONTACT-02)."

Additional data to be presented at ESMO (Free ESMO Whitepaper) featuring Cabometyx include new results from cohort 6 of the COSMIC-021 Phase Ib trial evaluating the combination of Cabometyx and atezolizumab in people living with previously treated metastatic castration-resistant prostate cancer (mCRPC) (Abstract LBA24).2 These additional analyses build on the interim data presented at ASCO (Free ASCO Whitepaper) 2020,7 with an expanded cohort 6 of 132 patients evaluated.2 With a median follow-up of 15.2 months, the primary endpoint of objective response rate (ORR) assessed by investigator per RECIST 1.1 (response evaluation criteria in solid tumours) was 23%, with three patients demonstrating a complete response (CR).2

Prof. Dr. Gunhild von Amsberg, University Medical Center Hamburg-Eppendorf (UKE) and investigator in the CONTACT-02 trial, said, "As a uro-oncologist, I am encouraged by the results presented at this year’s ESMO (Free ESMO Whitepaper) congress. For people living with advanced metastatic castration-resistant prostate cancer, the prognosis is often poor and the potential of new innovative therapies is critically important. Based on these clinically meaningful results of Cabometyx plus atezolizumab from cohort 6 of the COSMIC-021 trial, we now look forward to the results of the ongoing Phase III CONTACT-02."

Further analyses from the landmark Phase III CheckMate -9ER trial investigating the combination of Cabometyx and nivolumab were are also being presented at ESMO (Free ESMO Whitepaper), providing additional evidence to inform clinical decision-making in advanced renal cell carcinoma (RCC). New data demonstrated improved efficacy for Cabometyx and nivolumab regardless of prior nephrectomy status, when measured by PFS, ORR, CR and response durability outcomes, versus sunitinib (Abstract 663P).3 Additionally, a matching-adjusted indirect comparison analysis is being presented, demonstrating superior, statistically significant differences in health-related quality of life across all outcomes analysed in favour of Cabometyx and nivolumab versus the combination of axitinib and pembrolizumab (Abstract 668P).4

More information on these data can be found during the presentation sessions outlined below:

Title

Date and time

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC): results of expanded cohort 6 of the COSMIC-021 Study

Saturday 18 September
13:30-13:40 CEST

Cabozantinib Versus Placebo in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer (DTC) Who Have Progressed After Prior VEGFR-Targeted Therapy: Updated Results From the Phase 3 COSMIC-311 Trial

Monday 20 September
17:30-17:35 CEST

First-line nivolumab + cabozantinib (NIVO+CABO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in subgroups based on prior nephrectomy in the CheckMate 9ER trial

Poster presentation – Available on-demand beginning September 16 at 8:30 am CEST

Matching-adjusted indirect comparison (MAIC) of health-related quality of life (HRQoL) of nivolumab plus cabozantinib (N+C) vs pembrolizumab plus axitinib (P+A) in previously untreated advanced renal cell carcinoma (aRCC)

Poster presentation – Available on-demand beginning September 16 at 8:30 am CEST

About radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC)
In 2020, over 580,000 new cases of thyroid cancer were diagnosed worldwide.8 Thyroid cancer is the ninth most commonly occurring cancer globally and incidence is three times higher in women than in men, with the disease representing one in every 20 cancers diagnosed among women.7 While cancerous thyroid tumors include differentiated, medullary and anaplastic forms, differentiated thyroid tumors make up about 90 to 95% of cases.9,10 These include papillary, follicular and Hürthle cell cancer.7,8 DTC is typically treated with surgery, followed by ablation of the remaining thyroid tissue with radioactive iodine (RAI), but approximately 5 to 15% of cases are resistant to RAI treatment.11 Patients who develop RAI-R DTC have a poor prognosis with an average estimated survival of three to five years.12

About the COSMIC-311 trial
COSMIC-311 is a multicenter, randomized, double-blind, placebo-controlled Phase III trial that enrolled 258 patients at 164 sites globally.6 Patients were randomized in a 2:1 ratio to receive either Cabometyx 60 mg or placebo once-daily.6 The primary endpoints were progression-free survival and objective response rate, evaluated by a blinded independent radiology committee. Additional endpoints include safety, overall survival and quality of life.2 More information about this trial is available at ClinicalTrials.gov.

About metastatic castration-resistant prostate cancer (mCRPC)
In 2020, over 1.4 million new cases of prostate cancer were diagnosed worldwide,13 making it the fourth most commonly occurring cancer globally.13 Prostate cancer that has spread beyond the prostate and does not respond to androgen-suppression therapies which reduce the levels of testosterone, a common treatment for prostate cancer, is known as mCRPC.14 Men diagnosed with mCRPC often have a poor prognosis, with an estimated survival of 1-2 years.15

About the COSMIC-021 trial
COSMIC-021 is a multicenter, Phase Ib, open-label trial that is divided into two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase was designed to enroll patients either with advanced renal cell carcinoma (RCC) with or without prior systemic therapy or with inoperable, locally advanced, metastatic or recurrent urothelial carcinoma (UC), (including renal, pelvis, ureter, urinary bladder and urethra) after prior platinum-based therapy. Ultimately, all 12 patients who enrolled in this stage of the trial were patients with advanced RCC. The dose-escalation phase of the study determined the optimal dose of cabozantinib to be 40 mg daily when given in combination with atezolizumab (1200 mg infusion once every 3 weeks).

In the expansion phase, the trial is enrolling 24 cohorts in 12 tumor types: RCC, urothelial carcinoma, non-small cell lung cancer, CRPC, hepatocellular carcinoma, triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, head and neck cancer, and DTC.

Four of the cohorts are exploratory single agent cohorts. In UC, NSCLC, CRPC with cabozantinib as a single-agent, and in CRPC with single-agent atezolizumab.

Exelixis is the study sponsor of COSMIC-021. Both Ipsen Pharma SAS (Ipsen) and Takeda Pharmaceutical Company Limited (Takeda) have opted in to participate in the trial and are contributing to the funding for this study under the terms of the companies’ respective collaboration agreements with Exelixis. Roche is providing atezolizumab for the trial.

About renal cell carcinoma (RCC)
There are over 400,000 new cases of kidney cancer diagnosed worldwide each year.16 Of these, RCC is the most common type of kidney cancer, accounting for approximately 90% of cases.17,18 It is twice as common in men, and male patients account for over two thirds of deaths.16 If detected in the early stages, the five-year survival rate is high, but for patients living with advanced or late-stage metastatic RCC the survival rate is much lower, around 12%, with no identified cure for this disease.19,20

About the CheckMate -9ER trial
CheckMate -9ER was an open-label, randomized, multi-national Phase III trial evaluating people living with previously untreated advanced or metastatic RCC. A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 ≥1%) were randomized to Cabometyx plus Opdivo (n = 323) versus sunitinib (n = 328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival and objective response rate. The primary efficacy analysis compared the doublet combination versus sunitinib in all randomized patients. The trial was sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About Cabometyx (cabozantinib)
In the U.S., Cabometyx tablets are approved for the treatment of patients living with advanced RCC; for the treatment of patients living with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; and for patients living with advanced RCC as a first-line treatment in combination with nivolumab. Outside the U.S., Cabometyx is currently approved in 59 countries, including in the European Union, Great Britain, Norway, Iceland, Australia, New Zealand, Switzerland, South Korea, Canada, Brazil, Taiwan, Hong Kong, Singapore, Macau, Jordan, Lebanon, the Russian Federation, Ukraine, Turkey, United Arabic Emirates, Saudi Arabia, Serbia, Israel, Mexico, Chile, Peru, Panama, Guatemala, Dominican Republic, Ecuador, Thailand, Malaysia and Egypt for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union, Great Britain, Norway, Iceland, Canada, Australia, New Zealand, Brazil, Taiwan, Hong Kong, Singapore, Lebanon, Jordan, the Russian Federation, Ukraine, Turkey, the United Arab Emirates (U.A.E.)., Saudi Arabia, Israel, Mexico, Chile, Peru, Panama, Guatemala, the Dominican Republic, Ecuador, Thailand, Egypt and Malaysia for previously untreated intermediate- or poor-risk advanced RCC; and in the European Union, Great Britain Norway, Iceland, Canada, Australia, Switzerland, Saudi Arabia, Serbia, Israel, Taiwan, Hong Kong, South Korea, Singapore, Jordan, the Russian Federation, Ukraine, Turkey, Lebanon, the U.A.E., Peru, Panama, Guatemala, Chile, the Dominican Republic, Ecuador, Thailand, Brazil, New Zealand and Malaysia for HCC in adults who have previously been treated with sorafenib. Cabometyx is also approved in combination with nivolumab as first line treatment for people living with advanced RCC, in the European Union, Great Britain, Norway, Iceland, Switzerland, Taiwan, the Russian Federation.

The detailed recommendations for the use of Cabometyx are described in the Summary of Product Characteristics (EU SmPC) and in the U.S. Prescribing Information (USPI).

Ipsen has exclusive rights for the commercialization of Cabometyx outside the U.S. and Japan. Cabometyx is marketed by Exelixis in the U.S. and by Takeda Pharmaceutical Company Limited in Japan. Cabometyx is a registered trademark of Exelixis.

On September 19, 2021 Verastem Oncology (Nasdaq:VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported a mini oral presentation highlighting updated data from the ongoing investigator-sponsored Phase 1/2 FRAME study (Press release, Verastem, SEP 19, 2021, View Source [SID1234587932]). The FRAME study, led by The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, is investigating VS-6766, Verastem’s RAF/MEK inhibitor, in combination with defactinib, its FAK inhibitor, in patients with low grade serous ovarian cancer (LGSOC). The findings will be presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021, taking place September 16-21, 2021.

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"Low-grade serous ovarian cancer is a rare, slow-growing cancer that does not respond well to chemotherapy or hormone therapy, and disproportionately affects younger women. The results presented at ESMO (Free ESMO Whitepaper) this year show that VS-6766 combined with defactinib continues to demonstrate encouraging response rates in patients with LGSOC, including a 46% partial response rate across the overall patient population and a 64% partial response rate in patients with KRAS-mutated LGSOC, with manageable rates of side-effects," said Dr Susana Banerjee, MBBS, MA, PhD, FRCP, lead author of the presentation, Team Leader in Women’s Cancers at The Institute of Cancer Research, London, and Consultant Medical Oncologist and Research Lead for The Royal Marsden NHS Foundation Trust Gynaecology Unit.

"It’s particularly promising that the combination was also effective in patients who had previously received a MEK inhibitor. I am delighted that this drug combination has shown such encouraging results in a group of patients who urgently need new treatments."

"The investigator-sponsored FRAME study, the initial results of which led the U.S. Food and Drug Administration (FDA) to grant Breakthrough Therapy designation for the VS-6766 and defactinib combination in LGSOC, continues to be instrumental in providing the foundational data for safety, efficacy and durability in this novel combination for RAS pathway tumors," said Brian Stuglik, Chief Executive Officer of Verastem Oncology. "These data indicate that combining VS-6766 with defactinib results in promising response rates and median progression-free survival in patients who have already received MEK inhibitors. Verastem’s company-sponsored, registration-directed Phase 2 RAMP 201 study evaluating VS-6766 both alone and in combination with defactinib in patients with recurrent LGSOC is ongoing and we look forward to reporting top-line results from the selection portion of the study during the first half of 2022."

Updated Phase 1/2 FRAME Study Results in Patients with LGSOC

Among the evaluable patients with LGSOC (n=24), the overall response rate (ORR) was 46% (11 of 24). Among the patients with KRAS mutant LGSOC (n=11), the ORR was 64% (7 of 11). Among the patients with KRAS wild type LGSOC (n=9), the ORR was 44% (4 of 9). Of the evaluable patients, 10 (42%) received previous MEK inhibitor therapy.

The mPFS across all patients was 23.0 months (95% CI: 10.6- not reached). As of the April 2021 data cutoff date, 13 of 24 patients (54%) remained on study.

For context, for other therapies studied in recurrent LGSOC, response rates have been between 6% and 26% and mPFS was between 7.2 and 13.0 months.1,2

In the FRAME study, the most common Grade 3/4 treatment-related adverse events (AEs) were creatine kinase elevation (12%), rash (8%), diarrhea (4%), mouth ulcer/mucositis/glossitis (4%) and hyperbilirubinemia (4%), with only one discontinuation due to AEs as of the data cutoff.

These updated data suggest that the novel, intermittent dosing schedule used in the FRAME study continues to show encouraging clinical activity in patients with recurrent LGSOC, including in patients previously treated with a MEK inhibitor. Expansion cohorts are also ongoing in pancreatic cancer, KRAS/BRAF mutant endometrioid cancer and KRAS-G12V NSCLC.

Details for the ESMO (Free ESMO Whitepaper) 2021 mini oral presentation are as follows:

Title: Phase I study of the combination of the dual RAF/MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Results of efficacy in low grade serous ovarian cancer

Speaker: Dr Susana Banerjee, Team Leader in Women’s Cancers at The Institute of Cancer Research, London, and Consultant Medical Oncologist and Research Lead for The Royal Marsden NHS Foundation Trust Gynaecology Unit

Presentation #: 725MO
Session: Mini oral – Gynaecological cancers
Date and Time: Sunday, September 19, 2021; 17:50-17:55 CEST

About the Phase 1/2 FRAME Study

The FRAME study is an open-label, investigator-initiated study that is designed to assess safety, dose response and preliminary efficacy of the VS-6766/defactinib combination in patients with KRAS mutant solid tumors, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). The FRAME study is being led by Professor Udai Banerji, MBBS, MD, DNB, PhD, FRCP, Deputy Director of the Drug Development Unit at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and is being conducted in the United Kingdom. In this study, VS-6766 was administered using a twice-weekly dose escalation schedule and is administered 3 out of every 4 weeks. Defactinib is administered using a twice-daily dose escalation schedule, also 3 out of every 4 weeks. Dose levels are assessed in 3 cohorts: cohort 1 (VS-6766 3.2mg, defactinib 200mg); cohort 2a (VS-6766 4mg, defactinib 200mg); and cohort 2b (VS-6766 3.2mg, defactinib 400mg). The recommended Phase 2 dose was determined to be cohort 1 (VS-6766 3.2mg, defactinib 200mg).

About RAMP 201

Verastem Oncology has initiated a Phase 2 registration-directed trial evaluating VS-6766 alone and in combination with defactinib in patients with recurrent LGSOC as part of RAMP (Raf And Mek Program). RAMP 201 (ENGOTov60/GOG3052) is an adaptive, two-part multicenter, parallel cohort, randomized, open-label trial to evaluate the efficacy and safety of VS-6766 alone and in combination with defactinib in patients with recurrent LGSOC.3 The first part of the study will determine the optimal regimen of either VS-6766 monotherapy or in combination with defactinib in patients with recurrent LGSOC randomized 1:1 in each treatment arm. The determination of which regimen to take forward into the expansion phase of the trial will be made based on objective response rate data. The expansion phase of the study will examine efficacy and safety parameters of the regimen selected.

For more information, please visit www.RAMP201Study.com.

About the VS-6766/Defactinib Combination

The combination of VS-6766 and defactinib has been found to be clinically active in patients with KRAS mutant tumors. In an ongoing investigator-initiated Phase 1/2 FRAME study, the combination of VS-6766 and defactinib is being evaluated in patients with LGSOC, KRAS mutant NSCLC and colorectal cancer (CRC). The FRAME study was expanded to include new cohorts in pancreatic cancer, KRAS mutant endometrioid cancer and KRAS-G12V NSCLC. Verastem Oncology is also supporting an investigator-initiated Phase 2 trial evaluating VS-6766 with defactinib in patients with metastatic uveal melanoma. Verastem Oncology has initiated Phase 2 registration-directed trials of VS-6766 with defactinib in patients with recurrent LGSOC and in patients with recurrent KRAS-G12V mutant NSCLC as part of its RAMP (Raf And Mek Program).

The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK inhibitor VS-6766, with defactinib, its FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.

On September 19, 2021 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported results from a cohort of the Phase 1/2 KRYSTAL–1 study evaluating adagrasib at the 600mg BID dose as both monotherapy and in combination with cetuximab in patients with heavily pretreated colorectal cancer harboring a KRASG12C mutation (Press release, Mirati, SEP 19, 2021, View Source [SID1234587931]). Results showed that adagrasib alone and with cetuximab demonstrated significant clinical activity and broad disease control in these patients. The findings (Abstract # LBA6) will be presented today at 9:47 a.m. ET as a late-breaking oral presentation during the Presidential Symposium II session at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) 2021.

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"Patients living with KRAS-mutated colorectal cancer face a significant medical need for new treatment options," said Dr. Jared Weiss M.D., lead study investigator and associate professor of medicine, division of oncology at University of North Carolina-Chapel Hill. "The positive results presented today show that adagrasib alone or in combination with cetuximab may improve clinical outcomes in patients with colorectal cancer harboring a KRASG12C mutation."

Summary of Clinical Results

As of May 25, 2021, 80% of patients enrolled in the adagrasib monotherapy arm (n=46) received at least two prior lines of systemic anticancer therapies, and had a median follow up of 8.9 months. Of the evaluable patients (n=45), results showed an investigator assessed response rate (RR) of 22%, including one unconfirmed partial response (PR), and a disease control rate (DCR) of 87%; the median duration of response (DOR) was 4.2 months. In all enrolled patients, the median progression free survival (PFS) was 5.6 months (95% Confidence Interval, CI: 4.1,8.3).
As of July 9, 2021, 90% patients enrolled in the adagrasib plus cetuximab arm (n=32) received at least two prior lines of systemic anticancer therapies, and had a median follow up of 7 months. Of the evaluable patients (n=28), results showed an investigator assessed RR of 43%, including two unconfirmed PRs and a DCR rate of 100%. After the data cutoff date, of the two unconfirmed PRs, follow up scans showed one patient had a confirmed PR, and the second patient progressed. At the time of the analysis, 63% (20/32) of enrolled patients remained on treatment.
Adagrasib monotherapy and in combination with cetuximab was well-tolerated in this study, with a manageable safety profile. Grade 3/4 treatment related adverse events (TRAEs) were observed in 30% of patients treated with adagrasib alone, and in 16% of patients treated with the combination. Treatment related adverse events led to treatment discontinuation in 6% of patients who received combination therapy and in none (0%) of those who received adagrasib monotherapy. No Grade 5 TRAEs were observed in either treatment arm.
"Adagrasib represents Mirati’s scientific commitment to the discovery and development of novel targets that may lead to new treatment options for people with cancer," said Charles M. Baum, M.D., Ph.D., president and chief executive officer, Mirati Therapeutics, Inc. "The results presented at ESMO (Free ESMO Whitepaper) support further study of adagrasib in KRAS-mutated colon cancer, including with our ongoing, global registrational Phase 3 trial, KRYSTAL–10, comparing adagrasib plus cetuximab to standard of care chemotherapy in second-line KRASG12C-mutated colorectal cancer."

Virtual Investor Event

Mirati Therapeutics will host a virtual Investor Event on Monday, September 20, 2021 at 8:30 a.m. ET / 5:30 a.m. PT.

Company executives will discuss:

A top-line update from the Phase 2 registrational cohort of the KRYSTAL-1 study evaluating adagrasib in previously-treated patients with KRASG12C-mutated non-small cell lung cancer (NSCLC)
Findings from the CRC cohort of the Phase 1/2 KRYSTAL-1 study evaluating adagrasib as monotherapy and in combination with cetuximab in patients with heavily pretreated CRC harboring the KRASG12C mutation, as presented at the 2021 ESMO (Free ESMO Whitepaper) Congress
Results from the Phase 2 MRTX-500 study evaluating sitravatinib combined with nivolumab in patients with non-squamous NSCLC who progressed on or after prior checkpoint inhibitor therapy, to be presented at the 2021 ESMO (Free ESMO Whitepaper) Congress
Investors and the general public are invited to register and listen to a live webcast of the event through the "Investors and Media" section on Mirati.com. A replay of the event will be available shortly after the conclusion of the event.

About the KRYSTAL-1 Study

KRYSTAL–1 is an open-label Phase 1/2 multiple expansion cohort trial evaluating adagrasib as monotherapy and in combination with other anticancer therapies in patients with advanced solid tumors harboring a KRASG12C mutation.

About Adagrasib (MRTX849)

Adagrasib is an investigational, highly selective, and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24−48 hours. Adagrasib is a being evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including non-small cell lung cancer (NSCLC), colorectal cancer and pancreatic cancer. For more information visit Mirati.com/science.