On June 5, 2022 AstraZeneca reported that Detailed positive results from the pivotal DESTINY-Breast04 Phase III trial showed that Enhertu (trastuzumab deruxtecan) demonstrated superior and clinically meaningful progression-free survival (PFS) and overall survival (OS) in previously treated patients with HER2-low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridisation (ISH)-negative) unresectable and/or metastatic breast cancer with hormone receptor (HR) positive or HR-negative disease versus standard of care physician’s choice of chemotherapy (Press release, AstraZeneca, JUN 5, 2022, View Source [SID1234615560]). Results will be presented during the Plenary Session today at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, and have been simultaneously published in The New England Journal of Medicine.

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Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

In the primary endpoint analysis for DESTINY-Breast04, Enhertu demonstrated a 49% reduction in the risk of disease progression or death versus physician’s choice of chemotherapy in patients with HER2-low metastatic breast cancer with HR-positive disease (PFS hazard ratio [HR] 0.51; 95% confidence interval [CI]: 0.40-0.64; p<0.001). A median PFS of 10.1 months was seen in patients treated with Enhertu compared to 5.4 months with chemotherapy, as assessed by blinded independent central review (BICR).

Results also showed a 36% reduction in the risk of death with Enhertu compared to chemotherapy in patients with HR-positive disease (OS HR 0.64; 95% CI: 0.48-0.86; p=0.003) with a median OS of 23.9 months with Enhertu versus 17.5 months with chemotherapy, meeting a key secondary endpoint of the trial.

Additionally, data showed consistent efficacy for Enhertu in the overall trial population of patients with HER2-low metastatic breast cancer with HR-positive or HR-negative disease and across levels of HER2 expression (IHC 1+ and IHC 2+/ISH-). In the key secondary endpoint analysis of PFS by BICR in all patients, a similar 50% reduction in the risk of disease progression or death was observed between Enhertu and chemotherapy (PFS HR 0.50; 95% CI: 0.40-0.63; p<0.001). Results also showed a 36% reduction in the risk of death with Enhertu compared to chemotherapy (OS HR 0.64; 95% CI: 0.49-0.84; p=0.001) with a median OS of 23.4 months for Enhertu versus 16.8 months with chemotherapy.

Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, US and Principal Investigator for the trial, said: "The results of DESTINY-Breast04 show for the first time that a HER2-directed therapy can provide a survival benefit to patients with low HER2 expression, indicating we must reconsider the way we categorise patients with metastatic breast cancer. The efficacy seen with Enhertu also reinforces the potential to establish a new standard of care for more than half of all patients with breast cancer currently categorised as having HER2-negative disease, but who actually have tumours with low HER2 expression."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: "Today’s results represent a pivotal moment demonstrating the potential for Enhertu to redefine the treatment of HER2-targetable cancers. DESTINY-Breast04 validates targeting the lower end of the spectrum of HER2 expression, since Enhertu reduced the risk of disease progression or death across all types of patients in the trial by half, and reduced the risk of death by over a third. We must now evolve the way we classify and treat metastatic breast cancer to ensure these patients are effectively diagnosed and treated."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: "As innovative research organisations, extending the survival for patients is one of our primary goals as we seek to identify potentially new treatment options for patients with metastatic breast cancer. These potentially practice-changing data show that DESTINY-Breast04 takes us one step closer to achieving this goal, as Enhertu is the first HER2-directed medicine to demonstrate a survival benefit in patients with HER2-low metastatic breast cancer. We are honoured by the recognition these important findings are receiving at one of the world’s most prominent oncology meetings as well as in one of the leading medical journals."

Summary of results: DESTINY-Breast04

table data
CI, confidence interval; CBR, clinical benefit rate; DCR, disease control rate; DoR, Duration of Response; HR, hazard ratio; NE, not evaluable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival
i For the primary end point (PFS in the HR-positive cohort) and key secondary end points (PFS among all patients and OS in the HR-positive cohort and among all patients), the HR status is based on data collected with the use of the interactive web-response and voice-response system at the time of randomisation, which includes patients who were mis-stratified. For the other end points, HR status is based on data from the electronic data capture that was corrected for mis-stratification
ii As assessed by BICR
iii ORR is (Complete Response + Partial Response)
iv CBR is Complete Response + Partial Response + Stable Disease (≥ 6 months)
v DCR is (Complete Response + Partial Response + Stable Disease)

In an exploratory analysis of patients with HR-negative disease (n=58), median PFS was 8.5 months with Enhertu versus 2.9 months with chemotherapy (PFS HR 0.46; 95% CI: 0.24-0.89) and median OS was 18.2 months with Enhertu versus 8.3 months with chemotherapy (OS HR 0.48; 95% CI: 0.24-0.95).

The safety profile of Enhertu was consistent with previous clinical trials with no new safety concerns identified. The most common Grade 3 or higher treatment-emergent adverse events were neutropenia (13.7%), anaemia (8.1%), fatigue (7.5%), leukopenia (6.5%), thrombocytopenia (5.1%), and nausea (4.6%).

Interstitial lung disease (ILD) or pneumonitis rates were consistent with that observed in late-line HER2-positive breast cancer trials of Enhertu with a lower rate of Grade 5 ILD observed, as determined by an independent adjudication committee. The majority (10%) were primarily low Grade (Grade 1 or 2) with five Grade 3 (1.3%), no Grade 4 and three Grade 5 (0.8%) events reported.

Notes

Breast cancer and HER2 expression
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.1 More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.1

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, and is one of many biomarkers expressed in breast cancer tumours.2 HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which measures the amount of HER2 protein on a cancer cell, and/or an ISH test which counts the copies of the HER2 gene in cancer cells.2,3 HER2-positive cancers are defined as IHC 3+ or IHC 2+/ISH+, and HER2-negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.2

Approximately half of all patients with breast cancer have tumours with a HER2 IHC score of 1+, or 2+ in combination with a negative ISH test, a level of HER2 expression not currently eligible for HER2-targeted therapy.4-7 Low HER2 expression occurs in both HR-positive and HR-negative disease.8

HER2 testing is routinely used to determine appropriate treatment options for patients with metastatic breast cancer. Targeting the lower range of expression in the HER2 spectrum may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.9 Currently, patients with low HER2 expression with HR-positive tumours have limited treatment options following progression on endocrine (hormone) therapy.10 Few targeted options are available for those who are HR-negative.11

DESTINY-Breast04
DESTINY-Breast04 is a global, randomised, open-label, registrational Phase III trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive or HR-negative HER2-low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomised 2:1 to receive either Enhertu or chemotherapy.

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive disease based on blinded independent central review (BICR). Key secondary endpoints include PFS based on BICR in all randomised patients (HR-positive and HR-negative disease), OS in patients with HR-positive disease and OS in all randomised patients (HR-positive and HR-negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety.

DESTINY-Breast04 enrolled approximately 557 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 the US and Israel for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy, based on results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is also approved in approximately 40 countries 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 based on the results from the DESTINY-Breast01 trial.

Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) 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.

Regulatory applications for Enhertu are currently under review in China, Europe, Japan and several other countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2 based regimen based on the results from the DESTINY-Breast03 trial.

Enhertu was granted Breakthrough Therapy Designation in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy, based on the results of the DESTINY-Breast04 trial. Patients with hormone receptor (HR) positive breast cancer should additionally have received or be ineligible for endocrine therapy.

Enhertu is also currently under review in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have a HER2 (ERBB2) mutation and who have received a prior systemic therapy, based on the DESTINY-Lung01 trial, and in Europe for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2-based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as 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 the 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 selective oestrogen receptor degrader (SERD) and potential new medicine camizestrant.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in HER2-negative early and 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 initial approvals 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, evaluating 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 June 5, 2022 Amgen (NASDAQ:AMGN) and Takeda Pharmaceutical Company (TSE: 4502) reported that new data from the Phase 3 PARADIGM clinical trial of Vectibix (panitumumab) in Japanese patients with previously untreated unresectable wild-type RAS metastatic colorectal cancer (mCRC) are being featured during the June 5 Plenary Session (Abstract #LBA1) of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held in Chicago and online (Press release, Amgen, JUN 5, 2022, View Source [SID1234615558]).

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PARADIGM is a randomized trial conducted in Japan comparing the efficacy and safety of Vectibix plus mFOLFOX6 compared to bevacizumab plus mFOLFOX6 in chemotherapy-naive patients with unresectable advanced mCRC (n=823). This trial was conducted by Takeda. This is the first prospective trial to evaluate treatment options for patients with wild-type RAS mCRC and left-side primary tumor (descending colon, sigmoid colon, and rectum).

"Data from the PARADIGM study demonstrate the superiority of Vectibix over bevacizumab, both with chemotherapy, further establishing this Vectibix combination regimen as a standard of care for first-line treatment of wild-type RAS metastatic colorectal cancer," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "These study results build on the long history of Vectibix in the treatment of advanced colorectal cancer and reinforce the importance of comprehensive biomarker testing to identify all eligible patients."

The results of the trial showed that the mFOLFOX6 + Vectibix combination provides a statistically significant improvement in overall survival (OS) over the mFOLFOX6 + bevacizumab combination in patients with a left-sided primary tumor or regardless of tumor locations (median OS for left-sided tumors: 37.9 vs. 34.3 months, HR=0.82 [95.798% CI: 0.68-0.99], p=0.031, overall median OS: 36.2 vs. 31.3 months, HR=0.84 [95% CI: 0.72-0.98], p=0.030). The safety profile of Vectibix in this study was similar to clinical study results previously published.

"This is the first prospective Phase 3 study of treatment in patients with wild-type RAS, unresectable metastatic colorectal cancer and left-sided primary tumor," said Dr. Takayuki Yoshino, chief for the Department of Gastrointestinal Oncology, and deputy director at the National Cancer Center Hospital East. "These results provide further evidence of the benefits Vectibix provides for treatment in wild-type RAS, left-sided mCRC."

"These results further our understanding of the value Vectibix plus chemotherapy as a first-line treatment may provide for this patient population," said Takafumi Horii, head of the Japan Oncology BU, Global Oncology Unit at Takeda Pharmaceutical. "We are grateful to the patients, families and physicians in Japan who have contributed to this trial as we strive to deliver new therapeutic options for patients with unmet needs around the world."

For more detailed results of the study, please refer to ASCO (Free ASCO Whitepaper).org.

The PARADIGM Trial

Trial overview

The aim of the trial was to evaluate the efficacy of mFOLFOX6 + bevacizumab versus mFOLFOX6 +
panitumumab in the first-line treatment of
chemotherapy-naive patients with metastatic colorectal cancer and the wild-
type RAS gene (KRAS/NRAS gene).

Trial design

Multicenter, randomized, open label

Number of patients enrolled

823

Primary endpoint

Overall survival (OS)

Secondary endpoints

Progression-free survival (PFS), response rate (RR), duration of response (DOR), curative resection rate, safety

Place of study

Japan

Ancillary study

Analysis of circulating tumor DNA from tumor and blood samples to identify predictors of treatment response and mechanisms of treatment resistance.

About Vectibix (panitumumab)

Vectibix is the first fully human monoclonal anti-EGFR antibody approved by the FDA for the treatment of mCRC. Vectibix was approved in the U.S. in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

In May 2014, the FDA approved Vectibix for use in combination with FOLFOX, as first-line treatment in patients with wild-type KRAS (exon 2) mCRC. With this approval, Vectibix became the first-and-only biologic therapy indicated for use with FOLFOX, one of the most commonly used chemotherapy regimens, in the first-line treatment of mCRC specifically for patients with wild-type KRAS mCRC.

In June 2017, the FDA approved a refined indication for Vectibix for use in in patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) mCRC.

INDICATION AND LIMITATION OF USE

Vectibix is indicated for the treatment of patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) metastatic colorectal cancer (mCRC): as first-line therapy in combination with FOLFOX, and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS mutant mCRC or for whom RAS mutation status is unknown.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: DERMATOLOGIC TOXICITY

Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

In Study 20020408, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.
Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune- related effects (e.g., Stevens Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix concerning dermatologic toxicity are provided in the product labeling.
Vectibix is not indicated for the treatment of patients with colorectal cancer that harbor somatic RAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as "RAS."
Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents. Additionally, in Study 20050203, 272 patients with RAS-mutant mCRC tumors received Vectibix in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix and FOLFOX versus FOLFOX alone.
Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 20080763) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix treatment, periodically during Vectibix treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.
In Study 20020408, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.
Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy.
Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. In the event of acute onset or worsening of pulmonary symptoms interrupt Vectibix therapy. Discontinue Vectibix therapy if ILD is confirmed.
In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix versus the risk of pulmonary complications must be carefully considered.
Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.
Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix for acute or worsening keratitis.
In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).
NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.
Vectibix can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 months after the last dose of Vectibix.
In monotherapy, the most commonly reported adverse reactions (≥ 20%) in patients with Vectibix were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.
The most commonly reported adverse reactions (≥ 20%) with Vectibix + FOLFOX were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. The most common serious adverse reactions (≥ 2% difference between treatment arms) were diarrhea and dehydration.
To see the Vectibix Prescribing Information, including Boxed Warning visit www.vectibix.com.

About Colorectal Cancer

Colorectal cancer is the second most common cancer in women worldwide and the third most common cancer in men. Approximately 1.2 million cases of colorectal cancer are expected to occur globally. With more than 630,000 deaths worldwide per year, it is the third leading cause of cancer-related death in the Western world. The highest incidence rates are found in Japan, North America, parts of Europe, New Zealand, and Australia, and rates are low in Africa and Southeast Asia.[1] Using molecular approaches to identify unique genetic signatures in mCRC has the potential to help improve treatment outcomes.[2]

About Amgen Oncology

At Amgen Oncology, our mission to serve patients drives all that we do. That’s why we’re relentlessly focused on accelerating the delivery of medicines that have the potential to empower all angles of care and transform lives of people with cancer.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company’s history, moving with great speed to advance those innovations for the patients who need them.

On June 4, 2022 Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a biotechnology company developing novel LAG-3 related immunotherapy treatments for cancer and autoimmune disease, reported that new data from 1st line NSCLC patients (Part A) of the Phase II TACTI-002 trial evaluating Immutep’s lead product candidate, eftilagimod alpha ("efti" or "IMP321") in combination with MSD’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in 114 patients (Press release, Immutep, JUN 4, 2022, View Source [SID1234615700]).

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The data was presented in an Oral Presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting.

TACTI-002 Principal Investigator, Dr Enriqueta Felip of Vall d’Hebron University Hospital Barcelona, Spain, said: "It is very encouraging to see the combination of efti plus pembrolizumab is showing favourable anti-tumour activity in patients with 1st line NSCLC. These responses were deep and durable and there has also been a low patient discontinuation rate. I believe the combination of efti plus pembrolizumab warrants late stage clinical investigation."

Immutep CSO and CMO, Dr Frederic Triebel, noted: "Our ORR by local read of 38.6% in 1st line NSCLC patients is comparing favourably to historical results from anti-PD-1 monotherapies where response rates in PD-L1 all-comer trials are typically around 20%. We are particularly pleased to see encouraging responses across all PD-L1 status groups, showing that efti may kick start an anti-tumour immune response even in patients with no or low PD-L1 expression. In addition, the combination of efti plus pembrolizumab has a safety profile consistent with that observed in previously reported studies for pembrolizumab monotherapy. We continue to believe that efti, with its unique mechanism of action, may ultimately provide a very meaningful benefit to diverse sets of cancer patients including those with more limited treatment options."

Immutep CEO Marc Voigt said: "We are delighted that patient outcomes are improved with the combination of efti plus pembrolizumab across different patient groups. The data is encouraging for patients, as there is an unmet medical need particularly for those with NSCLC with no or low PD-L1 expression. We enlarged this part of the study in order to see if the strong earlier results in a smaller group of patients are holding true in more than a hundred patients. By biotech standards, we consider this to be a large patient population for a Phase II trial."

"For Immutep, these highly favourable results are of strategic importance, as they support late stage development for an attractive and very large adressible market," he said.

Trial endpoints
The primary endpoint was ORR according to iRECIST and local read. The data announced today represents the primary analysis of mature data of this endpoint. Secondary endpoints include ORR by RECIST 1.1., DCR, Duration of Response (DoR), PFS, Overall Survival (OS), and Safety assessments.

Patient population and condition
A total of 114 patients with 1st line NSCLC were enrolled and treated with efti plus pembrolizumab in 6 countries across 19 trial sites throughout Europe, the United States, and Australia.

Importantly, the patients were enrolled without any selection for PD-L1 status (PD-L1 all-comers), a biomarker indicating the likelihood of response to pembrolizumab. The trial was confirmed as a "PD-L1 all-comer trial" with ~70% of patients having a Tumour Progression Score (TPS) of < 50%. 93% of patients had metastatic disease at study entry and the patients had an ECOG performance status of 0 (37.7%) or 1 (62.3%). Treatment prior to study start included radiotherapy (33%), surgery (20%) and systemic therapy (22%) for non-metastatic disease. The trial reflects a typical patient population for this indication, including a mix of squamous/non-squamous disease and male/female representation.

Key Findings from 1st line NSCLC patients in TACTI-002 – data cut-off date 15 April 2022
Primary analysis of primary endpoint by iRECIST – ORR

ORR of 38.6% in the intent to treat (ITT) group (44/114 patients) and 42.7% for evaluable patients (44/103) by local read, see Table 1
Responses across all PD-L1 status groups in this all-comer trial (by central lab assessment):
ORR of 28.1% (9/32) in PD-L1 negative patients
ORR of 41.7% (15/36) in patients with PD-L1 status of 1-49%
ORR of 45.5% (25/55) in patients with PD-L1 status of ≥ 1%
ORR of 52.6% (10/19) in patients with PD-L1 status of ≥ 50%
Comparable ORR in squamous (35%) or non-squamous (38.9%) tumour type
RECIST 1.1 results are comparable to the iRECIST results
ORR is favourable compared to historical trials of anti-PD-1 monotherapy for all-comer population and PD-L1 status groups1

Table 1 – Primary endpoint (ORR) results for 1st line NSCLC patients from TACTI-002

Tumour Response2
(data cut-off 15 April 2022) Part A
1st line NSCLC (N=114)
ORR as per iRECIST by local read
(primary endpoint) n (%) [95% confidence interval]3
ORR (ITT, N=114) 44 (38.6%) [29.6-48.2]
ORR (evaluable patients, N=103) 44 (42.7%) [33.0-52.9]
Analysis by iRECIST – DCR, DoR and PFS

Responses are deep, see Chart 1
Responses are also durable, with only 8.6% of confirmed responses having a progression ≤ 6 months and median DoR not yet reached
Interim median PFS (ITT, PD-L1 all-comers) is 6.9 months
Interim median PFS increases to 8.4 months for ≥ 1% PD-L1 status group and to 11.8 months for ≥ 50% PD-L1 status group. Remains favourable compared to historical trials of anti-PD-1 monotherapy4
DCR (ITT) of 73.7% (84/114) and 81.6% (84/103) for evaluable patients
DCR comparable across all PD-L1 status groups with a range of 68.8-79.0%
Chart 1 – Change in lesion size from baseline for 1st line NSCLC patients from TACTI-002

Safety

The combination of efti plus pembrolizumab is safe and well-tolerated, continuing efti’s good safety profile to date. Part A reports a low discontinuation rate, with only 9.6% of patients discontinuing due to study treatment related adverse events. The safety profile to date is consistent with that observed in previously reported studies for pembrolizumab monotherapy except for local injection site reactions (erythema).

Conclusion
The combination of efti plus pembrolizumab is showing favourable efficacy in 1st line NSCLC in the PD-L1 all-comer population and in all PD-L1 status groups, and with a low treatment discontinuation rate. The data support continued late stage development in this indication.

Webcast Details
The Company will host a global webcast to discuss the new data from 1st line NSCLC patients participating in its Phase II TACTI-002 trial including an analyst Q&A.

Date & Time: 8.00 am AEST (Sydney) Tuesday 7 June 2022 /
5.00 pm CDT (Chicago) Monday 6 June 2022 /
12.00 am midnight CEST (Berlin) Tuesday 7 June 2022
Speakers: Immutep CEO Marc Voigt, CMO/CSO Dr Frederic Triebel and Christian Mueller, Vice President Strategic Development
Register: View Source
Questions: Investors are invited to submit questions in advance via [email protected].

A replay of the webcast will be available after the event at www.immutep.com.

Next results
Immutep expects to report further results from TACTI-002 in H2 calendar year 2022.

About the TACTI-002 Trial
TACTI-002 (Two ACTive Immunotherapies) is being conducted in collaboration with Merck & Co., Inc., Rahway, NJ, USA (known as "MSD" outside the United States and Canada). The study is evaluating the combination of eftilagimod alpha (efti) with MSD’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with second line head and neck squamous cell carcinoma or non-small cell lung cancer in first and second line.

The trial is a Phase II, Simon’s two-stage, non-comparative, open-label, single-arm, multicentre clinical study that is taking place in study centres across Australia, Europe, and the US.

Patients participate in one of the following:
• Part A – first line Non-Small Cell Lung Cancer (NSCLC), PD-X naïve
• Part B – second line NSCLC, PD-X refractory
• Part C – second line Head and Neck Squamous Cell Carcinoma (HNSCC), PD-X naïve

TACTI-002 is an all-comer study in terms of PD-L1 status, a well-known predictive marker for response to pembrolizumab monotherapy especially in NSCLC and HNSCC.

On June 4, 2022, Candel Therapeutics, Inc. presented an investor presentation (Presentation, Candel Therapeutics, JUN 4, 2022, View Source [SID1234615637]).

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On June 4, 2022 Everest Medicines (HKEX 1952.HK) announces today that its licensing partner, Gilead Sciences, Inc. (Nasdaq: GILD), reported positive results from the primary analysis of the Phase 3 TROPiCS-02 study of Trodelvy (sacituzumab govitecan) versus physicians’ choice of chemotherapy (TPC) in heavily pre-treated HR+/HER2- metastatic breast cancer patients who received prior endocrine therapy, CDK4/6 inhibitors and two to four lines of chemotherapy (Press release, Everest Medicines, JUN 4, 2022, View Source;metastatic-breast-cancer-patients-301561342.html [SID1234615598]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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The study met its primary endpoint of progression-free survival (PFS) with a statistically significant and clinically meaningful 34% reduction in the risk of disease progression or death (median PFS 5.5 vs. 4 months; HR: 0.66; 95% CI: 0.53-0.83; P<0.0003). The first interim analysis of the key secondary endpoint of overall survival (OS) demonstrated a trend in improvement. These data are immature, and patients will be followed for subsequent OS analysis. These findings will be featured in an oral session (Abstract #LBA1001) during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

The study demonstrated that at the one-year mark, three times as many patients were progression-free when treated with Trodelvy compared to those who received TPC (21% versus 7%). Improvements in PFS with Trodelvy were also consistent across key patient subgroups, including patients who had previously received three or more chemotherapy regimens for metastatic disease (HR: 0.70; CI: 0.52-0.95), patients with visceral metastases (HR: 0.66; CI: 0.53-0.83), and the elderly (≥65 years of age; HR: 0.59; CI: 0.38-0.93).

"For patients with HR+/HER2- metastatic breast cancer, resistance to endocrine therapy is inevitable in almost all cases. The standard of care is then limited to sequential single agent chemotherapy, with declining response rates, disease control and quality of life," said Dr. Hope Rugo, Professor of Medicine and Director, Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center, U.S. "In TROPiCS-02, we enrolled heavily pre-treated patients with metastatic breast cancer who had disease progression following multiple lines of chemotherapy. To observe a clinically meaningful reduction in the risk of disease progression or death in these patients with limited treatment options is remarkable. Sacituzumab govitecan will be an important potential future treatment option for these patients."

The safety profile for Trodelvy was consistent with prior studies, with no new safety concerns identified in this patient population. The most frequent Grade ≥3 treatment-related adverse reactions for Trodelvy compared to TPC were neutropenia (51% versus 38%), diarrhea (9% versus 1%), leukopenia (9% versus 5%), anemia (6% versus 3%), fatigue (6% versus 2%) and febrile neutropenia (5% versus 4%).

Everest Medicines is conducting a Phase 3 registrational Asian study EVER-132-002 evaluating Trodelvy versus physicians’ choice of chemotherapy in people with HR+/HER2− metastatic breast cancer, which is enrolling patients in China mainland, Taiwan and South Korea.

"Data from our partner’s Phase 3 TROPiCS-02 Study further demonstrate Trodelvy’s potential to benefit a larger portion of breast cancer patients," said Yang Shi, Chief Medical Officer for Oncology/Immunology at Everest Medicines. "We look forward to the results from our Asia clinical study."

About the TROPiCS-02 Study
The TROPiCS-02 study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate Trodelvy versus physician’s choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who were previously treated with endocrine therapy, CDK4/6 inhibitors and two to four lines of chemotherapy. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review for participants treated with Trodelvy compared to those treated with chemotherapy. Secondary endpoints include overall survival, duration of response, clinical benefit rate and overall response rate as well as assessment of safety and tolerability and quality of life measures. In the study, HER2 negativity was defined per American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the College of American Pathologists (CAP) criteria as immunohistochemistry (IHC) score of 0, IHC 1+ or IHC 2+ with a negative in-situ hybridization (ISH) test. More information about TROPiCS-02 is available at View Source

About HR+/HER2- Breast Cancer
Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common type of breast cancer and accounts for approximately 70% of all new cases, or nearly 400,000 diagnoses worldwide each year. Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is 30%. As patients with HR+/HER2- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. For patients treated with single-agent chemotherapy, the prognosis is poor.

About Trodelvy
Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2 directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

Trodelvy is approved in more than 35 countries, with multiple additional regulatory reviews underway worldwide, for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. Trodelvy is also approved in the U.S. under the accelerated approval pathway for the treatment of adult patients with locally advanced or metastatic urothelial cancer (UC) who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

Trodelvy is also being developed for potential investigational use in other TNBC and metastatic UC populations, as well as a range of tumor types where Trop-2 is highly expressed, including hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer, metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer.

Under a licensing agreement with Gilead Sciences, Inc., Everest Medicines has exclusive rights to develop, register, and commercialize Trodelvy for all cancer indications in Greater China, South Korea, and certain Southeast Asian countries.

The TRODELVY trademark is used under license from Gilead Sciences, Inc.