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 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 18, 2021 Personalis, Inc. (Nasdaq: PSNL), a leader in advanced genomics for population sequencing and cancer, reported that the U.S. Department of Veterans Affairs Million Veteran Program (VA MVP) has issued a new task order under its current contract with the company, with a value of up to approximately $10 million (Press release, Personalis, SEP 18, 2021, View Source [SID1234587935]). The company also announced that it has received, so far in Q3, more than $25M in orders from its oncology customers, a new record. Together these orders allow the company to reconfirm its total revenue outlook for 2021, with oncology revenue growth now projected to be at least 50% above 2020.

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"We are extremely pleased with our on-going relationship with the VA MVP, which represents the largest whole genome sequencing project in the United States," said John West, Chief Executive Officer. "Although this new task order is less than in pre-Covid years, we do expect this program to continue for many years to come, and to reaccelerate after the pandemic. In addition, our record oncology orders have largely offset the VA MVP order decline. Oncology orders received so far in Q3 have already exceeded the orders received in the first half of 2021, and are more than double our level in Q3 2020."

Personalis has delivered over 140,000 whole human genomes to date, and with this new task order remains on track to reach its goal of 150,000 by the end of 2021. ​​ Personalis also takes advantage of this experience and infrastructure to offer whole genome sequencing in cancer, and expects this to be an increasingly important contributor to its business in the future.

The performance period for the new VA MVP task order will be September 17, 2021 through March 31, 2022. Realizing revenue from this contract is subject to the receipt of samples from the VA MVP and performance of services by Personalis. The cumulative value of task orders received to date from the VA MVP has increased to approximately $185M. Following a pause during the pandemic, the VA MVP has resumed enrollment, now with approximately 840,000 veterans and the ultimate goal of enrolling two million.

Some of the new oncology orders received are for prospective projects, which are expected to provide revenue over several years, compared with retrospective projects that may be completed in less than two years. The company now expects that its oncology business will become the larger portion of its total revenue in 2022 and, long-term, the company expects that it represents Personalis’ largest market opportunity.

Updated Business Outlook

Personalis now expects the following for the third quarter of 2021:

Total revenue to be approximately $22.2 million (no change from previous outlook)
Revenue from biopharma and all other customers, excluding VA MVP, to be in the range of $8.3 million to $8.8 million (up from previous guidance of $7.5 million to $8.5 million)
Net Loss to be in the range of $17 million to $18 million; estimated outstanding shares of 44 million (no change from previous outlook)
Personalis expects the following for the full year of 2021:

Total revenue to be approximately $85 million (no change from previous outlook)
Revenue from biopharma and all other customers, excluding VA MVP, to be in the range of $34 million to $35 million (up from previous guidance of $33 million to $34 million)
Net Loss to be in the range of $65 million to $70 million; estimated outstanding shares of 44 million (no change from previous outlook)
The company is not providing a business outlook for fiscal year 2022 at this time. However, the company is targeting approximately 50% growth in biopharma and other customer (excluding VA MVP) revenue for the full year 2022.

Webcast and Conference Call Information

Personalis will host a conference call to discuss the announcement and updated business outlook before market open on Monday, September 20, 2021 at 6:00 a.m. Pacific Time / 9:00 a.m. Eastern Time. The conference call can be accessed live over the phone by dialing (866) 220-8061 for U.S. callers or (470) 495-9168 for international callers, using the conference ID: 8835748. The live webinar can be accessed at View Source

About the VA Million Veteran Program

Launched in 2011, the VA MVP is a landmark research effort aimed at better understanding how genetic variations affect health. Up to two-million veterans are expected to enroll in the VA MVP. Data and genetic samples collected through the program are stored securely and made available for studies by authorized researchers, with stringent safeguards in place to protect Veterans’ private health information. The VA MVP was enrolling veterans at 63 VA medical centers nationwide prior to the pandemic. The VA’s central biorepository is equipped with a state-of-the-art robotic system for DNA extraction and storage and is currently being expanded to support up to 4 million samples. With approximately 840,000 enrollees since 2011, the VA MVP already far exceeds the enrollment numbers of any single VA study or research program in the past, and is in fact one of the largest research cohorts of its kind in the world. The VA MVP provides researchers with a rich resource of genetic, health, lifestyle, and military-exposure data collected from questionnaires, medical records, and genetic analyses. By combining this information into a single database, the VA MVP promises to advance knowledge about the complex links between genes and health. Veterans’ privacy and confidentiality are top priorities in the VA MVP, as in all VA research. For more information about the VA MVP, visit www.research.va.gov/MVP. This press release does not imply a Department of Veterans Affairs endorsement, and is neither paid for nor sponsored, in whole or in part, by any element of the United States government.

On September 18, 2021 Exelixis, Inc. (Nasdaq: EXEL) reported detailed results from the expanded cohort 6 of the phase 1b COSMIC-021 trial of cabozantinib (CABOMETYX) in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer (CRPC) (Press release, Exelixis, SEP 18, 2021, View Source [SID1234587920]). Cohort 6 included patients with metastatic CRPC who had been previously treated with the novel hormone therapies (NHT) enzalutamide and/or abiraterone acetate used along with prednisone. The data are being presented during the Proffered Paper Session: GU Tumours, Prostate today at 1:30 p.m. CEST at the 2021 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (LBA24).

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Eligible patients in the trial had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) per investigator assessment, had progressed on prior NHT, and could have received prior docetaxel for metastatic hormone-sensitive disease. The analysis included 132 patients with metastatic CRPC, 101 of whom were high-risk, which was defined as having measurable visceral metastases and/or extrapelvic lymphadenopathy. The median follow-up for all patients was 15.2 months, and the primary endpoint was objective response rate (ORR) by investigator per RECIST 1.1.

As previously announced, in the high-risk patient population, investigator-assessed ORR was 27%, including 2% complete responses (CRs). The Blinded Independent Radiology Committee (BIRC)-assessed ORR was 18%, all partial responses (PRs). The disease control rate (CR + PR + stable disease) was 88% by investigator assessment and 84% by BIRC assessment.

New detailed results being presented at the 2021 ESMO (Free ESMO Whitepaper) Congress demonstrate that median progression-free survival per RECIST 1.1 for the high-risk population was 5.6 months (95% confidence interval [CI]: 5.4-8.2) as assessed by investigators and 6.8 months (95% CI: 5.5-9.7) as assessed by BIRC. The exploratory endpoint of overall survival for the high-risk patient population was 18.4 months (95% CI: 13.6-24.7). Tumor PD-L1 status, which was known for 75 patients, was not associated with response.

"These detailed results confirm previous findings from cohort 6 of COSMIC-021, further suggesting the promise cabozantinib in combination with atezolizumab may hold for patients with high-risk metastatic castration-resistant prostate cancer whose disease progressed following treatment with novel hormone therapy," said Neeraj Agarwal, M.D., Professor of Medicine, Huntsman Cancer Institute, University of Utah and a trial investigator. "A significant number of these patients are looking for treatment options beyond chemotherapy, so these clinically meaningful response rates and progression-free survival results of cabozantinib in combination with atezolizumab are encouraging for this patient community and their physicians."

The safety profile was consistent with that previously observed for each single agent. No new safety signals were observed. Discontinuation of both agents due to treatment-related adverse events (AEs) occurred in 10% of patients. Frequent treatment-related AEs were diarrhea (55%), fatigue (43%), nausea (42%) and decreased appetite (34%). Grade 3 or 4 treatment-related AEs occurred in 55% of patients (of which 3% experienced grade 4 AEs), and one grade 5 treatment-related AE was reported.

Following discussions with the U.S. Food and Drug Administration (FDA), Exelixis will not pursue a regulatory submission for the combination regimen based on cohort 6 of the COSMIC-021 trial. The CONTACT-02 study, a global phase 3 pivotal trial, initiated enrollment in June 2020 and is evaluating cabozantinib in combination with atezolizumab versus a second NHT in patients with metastatic CRPC who have been previously treated with one NHT. Pending results, CONTACT-02 may serve as a basis for future regulatory applications in this setting.

"We are pleased to provide a more detailed picture at ESMO (Free ESMO Whitepaper) of cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer who are in need of additional treatment options," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer, Exelixis. "The benefits of this combination regimen are encouraging, and we remain steadfast in our commitment to addressing unmet needs for patients with this form of prostate cancer. The CONTACT-02 continues to enroll patients, and we eagerly await a future readout from this global, phase 3 pivotal trial as we advance our goal of bringing treatments to patients with advanced, difficult-to-treat cancers."

About COSMIC-021

COSMIC-021 is a multicenter, phase 1b, open-label study 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 recommended dose of cabozantinib to be 40 mg daily when given in combination with atezolizumab (1200 mg infusion once every three weeks).

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

Four of the cohorts are exploratory single agent cohorts: two enrolled approximately 30 patients each with advanced UC or NSCLC, and one is enrolling approximately 80 patients with advanced CRPC to be treated with cabozantinib as a single-agent, and one enrolled approximately 10 patients with advanced CRPC to be treated with single-agent atezolizumab. Exploratory single agent cohorts have the option to be expanded up to 80 patients (cabozantinib) and 30 patients (atezolizumab) total.

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 CRPC

According to the American Cancer Society, in 2021, approximately 250,000 new cases of prostate cancer will be diagnosed, and 34,000 people will die from the disease.1 Prostate cancer that has spread beyond the prostate and does not respond to androgen-suppression therapies — a common treatment for prostate cancer — is known as metastatic CRPC.2 Researchers estimate that in 2020, 43,000 people were diagnosed with metastatic CRPC, which has a median survival of less than two years.3,4,5

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (RCC); for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

CABOMETYX is not indicated as a treatment for metastatic CRPC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information View Source

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

On September 18, 2021 AstraZeneca and Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that Detailed positive results from the head-to-head DESTINY-Breast03 Phase III trial showed that Enhertu (trastuzumab deruxtecan), the HER2-directed antibody drug conjugate (ADC), demonstrated superior progression-free survival (PFS) versus trastuzumab emtansine (T-DM1), a HER2-directed ADC currently approved to treat patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane (Press release, AstraZeneca, SEP 18, 2021, View Source [SID1234587922]). Results were presented today in a Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021.

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At a prespecified interim analysis of DESTINY-Breast03, Enhertu demonstrated a 72% reduction in the risk of disease progression or death compared to T-DM1 (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.22-0.37; p=7.8×10-22). After 15.5 and 13.9 months of follow-up in the Enhertu and T-DM1 arms respectively, the median PFS for patients treated with Enhertu was not reached (95% CI 18.5-NE) compared to 6.8 months for T-DM1 (95% CI 5.6-8.2) as assessed by blinded independent central review (BICR).

In the key secondary endpoint of PFS assessed by investigators, patients treated with Enhertu experienced a three-fold improvement in PFS of 25.1 months versus 7.2 months for T-DM1 (HR 0.26; 95% CI 0.20-0.35; p=6.5×10-24). A consistent PFS benefit was observed in key subgroups of patients treated with Enhertu, including those with a history of stable brain metastases.

There was a strong trend towards improved overall survival (OS) with Enhertu (HR 0.56; 95% CI 0.36-0.86; nominal p=0.007172), however this analysis is not yet mature and is not statistically significant. Nearly all patients treated with Enhertu were alive at one year (94.1%) compared to 85.9% of patients treated with T-DM1.

Confirmed objective response rate (ORR) more than doubled in the Enhertu arm versus the T-DM1 arm (79.7% vs. 34.2%). Forty-two (16.1%) complete responses (CR), and 166 (63.6%) partial responses (PR) were observed in patients treated with Enhertu compared to 23 (8.7%) CRs and 67 (25.5%) PRs in patients treated with T-DM1.

Javier Cortés, MD, PhD, Head, International Breast Cancer Center (IBCC), Barcelona, said: "Patients with previously treated HER2-positive metastatic breast cancer will typically experience disease progression in less than a year with available HER2-directed treatments. The high and consistent benefit seen across efficacy endpoints and key subgroups of patients receiving Enhertu in DESTINY-Breast03 is remarkable and supports the potential of Enhertu to become the new standard of care for those who have previously been treated for HER2-positive metastatic breast cancer."

Susan Galbraith, Executive Vice President, Oncology R&D, said: "Today’s results are ground-breaking. Enhertu tripled progression-free survival as assessed by investigators, and provided a disease control rate exceeding 95% compared to 77% for T-DM1 in DESTINY-Breast03. In addition, the safety profile was encouraging with no Grade 4 or 5 interstitial lung disease events in this trial. These unprecedented data represent a potential paradigm shift in the treatment of HER2-positive metastatic breast cancer, and illustrate the potential for Enhertu to transform more patient lives in earlier treatment settings."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "The early survival data, which evaluated Enhertu against another HER2-directed ADC, showed that nearly all patients treated with Enhertu were alive after a year and is a positive indication of the potential of this medicine to transform the treatment of HER2-positive metastatic breast cancer. These landmark data will form the basis of our discussions with global health authorities to potentially bring Enhertu to patients with previously treated HER2-positive metastatic breast cancer as a more effective treatment option as soon as possible."

Summary of results: DESTINY-Breast03

Efficacy Measure

Enhertu (5.4 mg/kg)

Total Evaluable (n=261)i

T-DM1 (3.6 mg/kg)

Total Evaluable (n=263)

PFSii (95% CI)

Hazard ratio (95% CI)

0.28 (0.22-0.37)

p-value

p=7.8×10-22

Median PFS (months) (95% CI)ii

NR (18.5-NE)

6.8 months (5.6-8.2)

Landmark 12-month PFS (%) (95% CI)ii

75.8% (69.8-80.7)

34.1% (27.7-40.5)

PFS as assessed by investigators (95% CI)

Hazard ratio (95% CI)

0.26 (0.20-0.35)

p-value

p=6.5×10-24

Median PFS (months) (95% CI)

25.1 months (22.1-NE)

7.2 months (6.8-8.3)

OS

Hazard ratio (95% CI)

0.56 (0.36-0.86)

p-value

p=0.007172iii

Landmark 12-month OS (%) (95% CI)

94.1% (90.3-96.4)

85.9% (80.9-89.7)

Median OS (months) (95% CI)

NE

NE

Confirmed ORR (%) (95% CI)ii,iv

79.7% (74.3-84.4)

34.2% (28.5-40.3)

Complete response (%)

16.1% (42)

8.7% (23)

Partial response (%)

63.6% (166)

25.5% (67)

Stable disease (%)

16.9% (44)

42.6% (112)

Progressive disease (%) (95% CI)

1.1% (3)

17.5% (46)

DCRv

96.6% (252)

76.8% (202)

i Dose used in the study being presented
ii As assessed by blind independent central review
iii Not statistically significant
iv ORR is (CR + PR)
v DCR is (CR+PR+SD)

The safety profile of the most common adverse events with Enhertu in DESTINY-Breast03 was consistent with previous clinical trials with no new safety concerns identified. The most common Grade 3 or higher treatment-emergent adverse events in the Enhertu arm were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%) and nausea (6.6%).

There were 27 cases (10.5%) of treatment-related interstitial lung disease (ILD) or pneumonitis reported, as determined by an independent adjudication committee. The majority (9.7%) were low Grade (Grade 1 or Grade 2), with two Grade 3 (0.8%) events reported. No Grade 4 or Grade 5 ILD or pneumonitis events occurred.

DESTINY-Breast01 Updated Results
Updated results from the pivotal DESTINY-Breast01 Phase II trial were also presented at ESMO (Free ESMO Whitepaper) and showed that Enhertu (5.4 mg/kg) continued to demonstrate impressive efficacy and durable responses in patients with HER2-positive metastatic breast cancer following two or more prior HER2-based regimens.

With a median duration of follow-up of 26.5 months, a continued increase in response was seen in patients treated with Enhertu with an updated ORR of 62.0%, including one additional CR (7.1%). A median duration of response (DoR) of 18.2 months was also observed.

The median PFS was 19.4 months. In an exploratory analysis of OS with a median follow-up of 31.1 months, evaluated at a greater maturity (52%), the updated median OS was 29.1 months.

The overall safety and tolerability profile seen with Enhertu in DESTINY-Breast01 continues to be consistent with what has been previously observed. There has been one new case of treatment-related Grade 1 ILD or pneumonitis determined by an independent adjudication committee as of data cut-off of March 26, 2021.

Enhertu is approved for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting in the US, Japan, the EU and several other countries based on the results from the DESTINY-Breast01 trial.

Enhertu is being further assessed in a comprehensive clinical development programme evaluating efficacy and safety across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers.

Several presentations featured during the ESMO (Free ESMO Whitepaper) Congress 2021 will showcase the strength and depth of Enhertu data across multiple tumour types, including gastric, lung and breast cancers, reinforcing the transformational potential of this medicine in the treatment of HER2-targetable cancers.

HER2-positive breast cancer
Breast cancer remains the most common cancer and is one of the leading causes of cancer-related deaths in women worldwide.1 More than two million patients with breast cancer were diagnosed in 2020, resulting in nearly 685,000 deaths globally.1 Approximately one in five cases of breast cancer are considered HER2-positive.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast, gastric, lung and colorectal cancers.3 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and a poor prognosis in breast cancer.4

Despite initial treatment with trastuzumab and a taxane, people with HER2-positive metastatic breast cancer will often experience disease progression.5 More effective options are needed to further delay progression and extend survival.5-7

DESTINY-Breast03
DESTINY-Breast03 is a global head-to-head, randomised, open-label, registrational Phase III trial evaluating the safety and efficacy of Enhertu (5.4mg/kg) versus T-DM1 in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane.

The primary efficacy endpoint of DESTINY-Breast03 is PFS based on blinded independent central review. Secondary efficacy endpoints include OS, objective response rate, duration of response, clinical benefit rate, PFS based on investigator assessment and safety.

DESTINY-Breast03 enrolled approximately 500 patients at multiple sites in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-Breast01
DESTINY-Breast01 is a registrational Phase II, single-arm, open-label, global, multi-centre, two-part trial evaluating the safety and efficacy of Enhertu in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with T-DM1.

The primary endpoint of the trial is ORR, as determined by ICR. Secondary objectives include DoR, disease control rate, clinical benefit rate, PFS and OS.

DESTINY-Breast01 enrolled 253 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Enhertu (5.4mg/kg) is approved in Canada, the EU, Israel, Japan, the UK and the US for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting based on the results from the DESTINY-Breast01 trial.

Enhertu (6.4mg/kg) is also approved in Israel, Japan and the US for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

Enhertu development programme
A comprehensive development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Enhertu was highlighted in the Clinical Cancer Advances 2021 report as one of two significant advancements in the "ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers," based on data from both the DESTINY-CRC01 and DESTINY-Gastric01 trials, as well as one of the targeted therapy advances of the year in non-small cell lung cancer (NSCLC), based on the interim results of the HER2-mutated cohort of the DESTINY-Lung01 trial.

In May 2020, Enhertu also received Breakthrough Therapy Designation for the treatment of patients with metastatic NSCLC whose tumours have a HER2-mutation and with disease progression on or after platinum-based therapy.

Daiichi Sankyo collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment. AstraZeneca aims to continue to transform outcomes for HR-positive breast cancer with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and the next-generation oral SERD and potential new medicine AZD9833.

PARP inhibitor, Lynparza (olaparib) is a targeted treatment option for metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research Lynparza in metastatic breast cancer patients with an inherited BRCA mutation and are exploring new opportunities to treat these patients earlier in their disease.

Building on the first approval of Enhertu, a HER2-directed ADC, in previously treated HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are exploring its potential in earlier lines of treatment and in new breast cancer settings.

To bring much needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in combination with other oncology medicines, including Lynparza and Enhertu, investigating the potential of AKT kinase inhibitor, capivasertib, in combination with chemotherapy, and collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.