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.

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 primary results from the positive Phase II DESTINY-Lung01 trial of Enhertu (trastuzumab deruxtecan), the HER2-directed antibody drug conjugate (ADC), showed a robust and durable tumour response in previously treated patients with HER2-mutant (HER2m) unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, SEP 18, 2021, View Source [SID1234587917]). Results presented during a late-breaking Proffered Paper session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 and simultaneously published in The New England Journal of Medicine confirm Enhertu as the first HER2-directed therapy to show a strong tumour response in this patient population.

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Lung cancer is the leading cause of cancer death among both men and women, and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.1-3 There are currently no medicines approved specifically for the treatment of HER2m NSCLC, which affects approximately 2-4% of patients with NSCLC.4,5

Primary results from the HER2m cohort (cohort 2) of DESTINY-Lung01 in previously treated HER2m NSCLC demonstrated a confirmed objective response rate (ORR) of 54.9% in patients treated with Enhertu (6.4 mg/kg) as assessed by independent central review (ICR). One (1.1%) complete response (CR) and 49 (53.8%) partial responses (PR) were observed.

A confirmed disease control rate (DCR) of 92.3% was seen with a reduction in tumour size observed in most patients. After a median follow-up of 13.1 months, the median duration of response (DoR) for Enhertu was 9.3 months. The median progression-free survival (PFS) was 8.2 months and the median overall survival (OS) was 17.8 months.

Bob Li, MD, PhD, MPH, Memorial Sloan Kettering Cancer Center, said: "Despite more than 20 years of research into HER2-mutations in non-small cell lung cancer, there are currently no approved HER2-targeted therapies for non-small cell lung cancer. Patients with HER2-mutant non-small cell lung cancer are associated with younger age, female sex, never smoking history, and a poor prognosis with increased incidence of brain metastases, representing an unmet clinical need. The impressive results from DESTINY-Lung01 showed most patients experienced a reduction in tumour size with Enhertu treatment, suggesting this medicine has the potential to become the new standard of care for these patients."

Susan Galbraith, Executive Vice President, Oncology R&D, said: "Lung cancer is a devastating diagnosis, and for patients with HER2-mutant lung cancer, a targeted treatment for their specific disease has not been an option. These data reinforce the potential of Enhertu to become the first HER2-directed therapy for these patients and reaffirm how this treatment is truly delivering on its transformative potential."

Ken Takeshita, Global Head, Research and Development, Daiichi Sankyo, said: "Enhertu is the first HER2-directed therapy to demonstrate a robust and durable tumour response in patients with HER2-mutant non-small cell lung cancer. This is potentially great news for patients, and we are continuing to conduct research, with the goal of bringing Enhertu to those with this specific form of lung cancer."

Responses were observed across HER2m subtypes, as well as in patients with no detectable HER2 expression or HER2 gene amplification. Efficacy was observed in subgroups including prior treatment with platinum-based therapy, or platinum-based and anti–PD-(L)1 therapy, as well as asymptomatic brain metastases at baseline.

Summary of results

Efficacy Measure

HER2m Total Evaluable (n=91)i

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

54.9% (44.2-65.4)

Complete response (%)

1.1%

Partial response (%)

53.8%

Stable disease (%)

37.4%

DCR (95% CI)iv

92.3% (84.8-96.9)

Median DoR (months) (95% CI)

9.3 months (5.7-14.7)

Median PFS (months) (95% CI)

8.2 months (6.0-11.9)

Median OS (months) (95% CI)

17.8 months (13.8-22.1)

i Enhertu 6.4mg/kg; median duration of follow-up was 13.1 months
ii As assessed by independent central review
iii ORR is (CR + PR)
iv DCR is (CR + PR +SD)

The overall safety profile of Enhertu was consistent with previous Enhertu NSCLC trials, with no new safety signals identified. The most common Grade 3 or higher drug-related treatment-emergent adverse events were neutropenia (18.7%) and anaemia (9.9%). Rates of treatment-related interstitial lung disease (ILD) or pneumonitis were consistent with previous trials in lung cancer.

There were 24 cases of ILD or pneumonitis, as determined by an independent adjudication committee, with the majority (75%) low Grade (Grade 1 or 2), four Grade 3 and two Grade 5 (ILD or pneumonitis-related death).

In May 2020, Enhertu was granted Breakthrough Therapy Designation in the US for the treatment of HER2m metastatic NSCLC.

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-mutant NSCLC
Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.1-3 For patients with metastatic disease, prognosis is particularly poor, as only approximately 6% will live beyond five years after diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including lung, breast, gastric and colorectal cancers. HER2 gene alterations (called HER2 mutations) have been identified in NSCLC, specifically adenocarcinomas, as distinct molecular targets and have been reported in approximately 2-4% of patients with NSCLC.4,5

These HER2 gene mutations are predominantly seen in younger women, with no smoking history and have been independently associated with cancer cell growth and poor prognosis with an increased incidence of brain metastases.4,6-10 Although the role of anti-HER2 treatment is well established in breast and gastric cancer, HER2 is still an emerging biomarker in NSCLC with no approved HER2-directed therapies.4,11

DESTINY-Lung01
DESTINY-Lung01 is a global, Phase II, open-label, multi-centre, two-cohort trial testing the safety and efficacy of Enhertu in patients with HER2-mutant (6.4 mg/kg) or HER2 overexpressing (defined as IHC3+ or IHC2+) unresectable and/or metastatic non-squamous NSCLC. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy.

The primary endpoint is confirmed ORR by independent central review. ORR, or tumour response rate, represents the percentage of patients whose disease decreased and/or disappears. Key secondary endpoints include DoR, DCR, PFS and OS.

DESTINY-Lung01 enrolled approximately 180 patients at multiple sites including the US, Europe and Japan. 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-mutant 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 lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and tremelimumab; Enhertu and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

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.

On September 18, 2021 AstraZeneca reported that Updated results from the CASPIAN Phase III trial showed it’s Imfinzi (durvalumab) in combination with a choice of chemotherapies, etoposide plus either carboplatin or cisplatin, demonstrated a sustained, clinically meaningful overall survival (OS) benefit at three years for adults with extensive-stage small cell lung cancer (ES-SCLC) treated in the 1st-line setting (Press release, AstraZeneca, SEP 18, 2021, View Source [SID1234587916]).

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These data, which show the longest survival update ever reported for an immunotherapy treatment in this setting, were presented during a mini-oral session on 18 September 2021 at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021.

The CASPIAN trial met the primary endpoint of OS in June 2019, reducing the risk of death by 27% (based on a hazard ratio [HR] of 0.73; 95% confidence interval [CI] 0.59-0.91; p=0.0047), which has formed the basis of regulatory approvals in many countries around the world. Updated results were previously presented during the ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program in May 2020 with a median follow up of more than two years.

The latest results for Imfinzi plus chemotherapy showed sustained efficacy after a median follow up of more than three years for censored patients, with a 29% reduction in the risk of death versus chemotherapy alone (based on an HR of 0.71; 95% CI 0.60-0.86; nominal p=0.0003). Updated median OS was 12.9 months versus 10.5 for chemotherapy.

The results included a planned exploratory analysis, where an estimated 17.6% of patients treated with Imfinzi plus chemotherapy were alive at three years, versus 5.8% of patients treated with chemotherapy alone. The survival benefits were consistent across all subgroups, in line with previous analyses.

Luis Paz-Ares, MD, PhD, Chair, Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain and principal investigator in the CASPIAN Phase III trial said: "Patients with extensive-stage small cell lung cancer historically have had limited treatment options and still face a dire prognosis, which makes these data showing that three times as many patients survive three years following Imfinzi treatment especially meaningful. These results reinforce Imfinzi plus platinum chemotherapy as an important standard of care in this setting."

Susan Galbraith, Executive Vice President, Oncology R&D, said: "This remarkable improvement in survival is an unprecedented achievement at three years for patients with extensive-stage small cell lung cancer. We are deeply committed to helping improve survival rates in this disease with research into new treatment options to transform outcomes at various stages, not only with the CASPIAN trial, but also with the ADRIATIC trial in limited-stage disease."

Imfinzi plus chemotherapy continued to demonstrate a well-tolerated safety profile consistent with the known profiles of these medicines. Results showed 32.5% of patients experienced a serious adverse event (all causality) with Imfinzi plus chemotherapy versus 36.5% with chemotherapy alone.

Imfinzi in combination with etoposide and either carboplatin or cisplatin is approved in the 1st-line setting of ES-SCLC in more than 55 countries, including the US, Japan, China and across the EU.

Imfinzi is also being tested following concurrent chemoradiation therapy (CRT) in patients with limited-stage SCLC in the ADRIATIC Phase III trial as part of a broad development programme. In addition, Imfinzi is also approved to treat non-small cell lung cancer (NSCLC) in the curative-intent setting of unresectable, Stage III disease after CRT in the US, Japan, China, across the EU and in many other countries, based on results from the PACIFIC Phase III trial.

Small cell lung cancer
Lung cancer is the leading cause of cancer death among men and women and accounts for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and SCLC, with about 15% classified as SCLC.2

SCLC is a highly aggressive, fast-growing form of lung cancer that typically recurs and progresses rapidly despite initial response to chemotherapy.3,4 About two-thirds of SCLC patients are diagnosed with extensive-stage disease, in which the cancer has spread widely through the lung or to other parts of the body.5

Prognosis is particularly poor, as prior to the approval of immunotherapy regimens for ES-SCLC, only 7% of all patients with SCLC and only 3% of patients with extensive-stage disease will be alive five years after diagnosis.5

CASPIAN
CASPIAN was a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of 805 patients with ES-SCLC. The trial compared Imfinzi in combination with chemotherapy (etoposide and either carboplatin or cisplatin), or Imfinzi and chemotherapy with the addition of a second immunotherapy, tremelimumab, versus chemotherapy alone.

In the two experimental arms, patients were treated with four cycles of chemotherapy. In comparison, the control arm allowed up to six cycles of chemotherapy and optional prophylactic cranial irradiation.

The trial was conducted in more than 200 centres across 23 countries, including the US, Europe, South America, Asia and the Middle East. The primary endpoint was OS in each of the two experimental arms.

In June 2019, AstraZeneca announced the CASPIAN Phase III trial had met one primary endpoint of demonstrating OS for Imfinzi plus chemotherapy at a planned interim analysis. In March 2020, however, it was announced that the second experimental arm with tremelimumab did not meet its primary endpoint of OS.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

In addition to approvals in ES-SCLC and unresectable, Stage III NSCLC, Imfinzi is approved for previously treated patients with advanced bladder cancer in several countries. Since the first approval in May 2017, more than 100,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with NSCLC, SCLC, bladder cancer, hepatocellular carcinoma, biliary tract cancer (a form of liver cancer), oesophageal cancer, gastric and gastroesophageal cancer, cervical cancer, ovarian cancer, endometrial cancer, and other solid tumours.

AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and tremelimumab; Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in immunotherapy
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored in immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a single treatment and in combination with tremelimumab and other novel antibodies in multiple tumour types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine the IO portfolio with radiation, chemotherapy, small, targeted molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

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.

On September 17, 2021 Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company developing next generation cancer and infectious disease immunotherapies, reported results with its SLATE v1 product ("off-the-shelf" shared neoantigen immunotherapy in combination with intravenous nivolumab and subcutaneous ipilimumab) and dosing of the first patient in a Phase 2 clinical trial of the optimized SLATE v2 product (Press release, Gritstone Oncology, SEP 17, 2021, View Source [SID1234592015]). SLATE v2 has been engineered, based on human translational immunology data from v1 patients, to drive a more potent immune response to mutant KRAS neoantigens than were observed with SLATE v1. The data from SLATE v1 will be reviewed during the company’s previously announced investor event taking place today at 1:30pm ET.

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The v1 format of the SLATE immunotherapy was studied in a Phase 1/2 study, in collaboration with Bristol-Myers Squibb, in 26 patients with metastatic solid tumors, largely focused on non-small cell lung cancer (NSCLC), microsatellite-stable colorectal cancer (MSS-CRC) and pancreatic ductal adenocarcinoma (PDAC). There were no safety signals of note with the most common adverse events being low grade, self-limiting fever and injection site reactions. SLATE v1 exhibited evidence of efficacy in patients with NSCLC who had all progressed on prior anti-PD-(L)1 therapy (often in combination with chemotherapy) – with molecular responses (>50% decrease in ctDNA levels in the blood from baseline) observed in 3/5 NSCLC patients who were eligible for analysis.

SLATE v1 demonstrated the greatest activity in 6 NSCLC patients with the KRASmut G12C presented by the HLA protein A*02:01. Among these patients, ctDNA responses were observed in 66% of these patients (2/3 eligible for analysis), correlating with clinical benefit, and a RECIST radiologic response (unconfirmed) was observed in one 2nd line patient who had progressed after 3 months of 1st line chemo-immunotherapy. One patient who had progressed on prior chemo-immunotherapy after 8 months of treatment is nearing completion of 2 years of therapy with persistent ~20% tumor lesion shrinkage. The patient’s ctDNA was undetectable throughout the study.

A next generation, optimized SLATE cassette (v2), which exclusively includes epitopes from mutated KRAS and exhibited immunogenic superiority over v1 in human HLA-transgenic mice, is now in Phase 2 testing in patients with advanced NSCLC and CRC.

"We are excited to dose the first patient with the KRAS-specific version (v2) of our SLATE immunotherapy," said Andrew Allen, M.D., Ph.D., co-founder, president and chief executive officer of Gritstone. "We are very encouraged by the clinical data generated with v1, and product redesign using translational immunology data has enabled this optimized v2, which we are initially evaluating in more non-small cell lung cancer patients following progression on immunotherapy, as well as patients with microsatellite-stable colorectal cancer. We expect that these treatment settings will enable us to demonstrate the differentiated therapeutic potential of SLATE v2, and we anticipate having initial data by mid-2022. We look forward to presenting the data from SLATE v1 and from our individualized GRANITE program during our investor event in conjunction with ESMO (Free ESMO Whitepaper) 2021 later this week."

The SLATE v2 Phase 2 portion of the study is expected to enroll up to 60 patients with KRAS mutant-driven tumors in total across three cohorts: NSCLC post chemo-immunotherapy, first line MSS-CRC and third-line MSS-CRC. All patients will receive SLATE v2, consisting of a dose of intramuscular adenovirus-based prime with intramuscular self-amplifying mRNA-based boost vaccinations, in combination with PD-1 checkpoint inhibitor Opdivo (nivolumab) and subcutaneous anti-CTLA-4 antibody Yervoy (ipilimumab).
Opdivo and Yervoy are trademarks of Bristol-Myers Squibb Company.

About SLATE

Gritstone’s neoantigen-based immunotherapies are engineered to elicit a significant T-cell response (particularly CD8+ cytotoxic T cells) against mutation-derived tumor-specific neoantigens, or TSNA, that are identified by the company using its proprietary Gritstone EDGETM artificial intelligence platform and tumor HLA peptide sequencing. Gritstone’s SLATE "off-the-shelf" immunotherapy uses a priming adenoviral vector (GRT-C903) and self-amplifying mRNA vector (GRT-R904) to deliver a cassette of shared TSNA, representing mutated gene sequences that are found in multiple patients (such as KRAS mutations). SLATE is being evaluated in combination with immune checkpoint blockade in the Phase 2 portion of its clinical study (NCT03953235).