On September 25, 2018 BerGenBio ASA (OSE:BGBIO) reported its clinical data from its phase II programme with bemcentinib, a first-in-class highly selective oral AXL inhibitor, in non-small cell lung cancer (NSCLC) at the 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada (23-26 September 2018) (Press release, BerGenBio, SEP 25, 2018, View Source [SID1234529585]).

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Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "We are extremely encouraged by the data presented at WCLC today. The expanded results from our study combining bemcentinib with the blockbuster immunotherapy KEYTRUDA were particularly promising. In this study, we saw increased response rates in tumours that were positive for AXL versus those that were not. Importantly, we also saw positive responses in tumours that had low or no PD-L1 expression, where we would expect to see little or no effect from KEYTRUDA therapy alone. We are now advancing this study into the second expansion stage.

"Lung cancer remains the largest cancer killer and, despite recent advances with immune-, targeted and combination therapies, many patients are still not benefitting from these treatments. By selectively inhibiting AXL activity with bemcentinib, we aim to block a fundamental survival mechanism that enables cancer cells to evade the immune system and become resistant to therapy. We believe that this approach has the potential to improve patient outcomes to treatment with established and emerging therapies. The encouraging clinical data presented at WCLC investigating bemcentinib with the three major treatment approaches in advanced lung cancer strengthens our belief in bemcentinib and we look forward to providing further updates at leading medical conferences."

The posters presented at WCLC are available on the BerGenBio website in the Investors / Presentations section and a summary of key findings is provided below.

Ph II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with Pembrolizumab in Patients with Advanced NSCLC
(BerGenBio study reference: BGBC008), James Lorens et al

The BGBC00B study is investigating whether adding bemcentinib to KEYTRUDA (pembrolizumab) in previously treated, PD-L1 unselected and immunotherapy naive patients with advanced adenocarcinoma of the lung is well tolerated and improves patient outcomes. The study will also assess the combination in the subset of PD-L1 negative patients for whom KEYTRUDA is not indicated. A total of 48 patients across two stages will be enrolled.

The first stage is fully enrolled with 24 patients, of which 7 remain on treatment or in follow-up
The biomarker analysis revealed that:
10 of 21 evaluable patients were AXL positive (48%)
Of 20 patients evaluated for PD-L1 expression, 11 (55%) were PD-L1 negative, 7 (35%) were weakly positive and 2 (10%) were strongly positive
40% overall response rate (ORR) was reported in AXL-positive patients with a disease control rate (DCR) of 70%
7 of 10 patients with no PD-L1 expression showed clinical benefit, of which there were 3 PRs (ORR 30%) and 4 SD (DCR70%). This compares with an ORR of 9% in the Keynote-001 study of KEYTRUDA monotherapy in PD-L1 negative patients

Ph I/II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with Erlotinib in Patients with EGFRm NSCLC
(BerGenBio study reference: BGBC004), Lauren Byers et al

TARCEVA (erlotinib) is indicated for NSCLC that is driven by a mutation in the EGFR gene, the most common mutation in NSCLC. Although response rates to TARCEVA are high initially, nearly all patients develop resistance over time. The BGBC004 study is designed to test if adding bemcentinib to TARCEVA in first- or second-line EGFR mutation-driven NSCLC may prevent or reverse acquired resistance to TARCEVA, respectively.

Patient recruitment into BGBC004 is complete, with 39 patients enrolled across three arms
Arm A – a safety cohort – confirmed a bemcentinib phase II dose (200mg daily) that was well tolerated in combination with full dose TARCEVA over extended periods of time (over two years and ongoing)
Arm B is designed to test whether the addition of bemcentinib to TARCEVA in second line may reverse disease progression in patients whose cancer has become resistant to erlotinib treatment. Arm B met its first primary endpoint, with tumour shrinkage and objective response observed in patients who were negative for the T790M resistance mutation and thus not eligible for any approved targeted therapy (ORR of 20% and a DCR of 40% including 1 PR and 1 SD out of five T790M negative patients)
Arm C is designed to evaluate the ability of bemcentinib to prevent acquired resistance to TARCEVA and improve outcomes in patients who had been responding/stable to first-line TARCEVA therapy. Arm C reported tumour shrinkage in 6 of 9 patients (67%). Importantly, median Progression-Free Survival (PFS), while not mature, had already surpassed median PFS for TARCEVA monotherapy given as a first-line treatment of 10 months.
A Ph I/II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) with Docetaxel in Patients with Previously Treated NSCLC
(BerGenBio study reference: BGBIL005), David Gerber et al

Single agent chemotherapy is the last treatment option for NSCLC patients if they fail targeted, immune- and platinum-based chemotherapy regimes. Around 10% of patients show responses to docetaxel single agent chemotherapy with a median PFS of 3-4 months commonly reported. The investigator-sponsored study BGBIL005 is designed to evaluate if combining bemcentinib with docetaxel chemotherapy is safe and can improve outcomes in up to 30 NSCLC patients who have failed up to three lines of therapy.

Among 11 patients evaluated, the combination was generally well tolerated and 2 PRs (18%) and 6 SDs (55%) were reported
A Phase II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with Pembrolizumab in Patients with Malignant Mesothelioma
(trial not active yet), Dean Fennell et al

The poster described a proposed design for an investigator-sponsored trial (MiST3) evaluating bemcentinib in combination with KEYTRUDA in patients with relapsed malignant mesothelioma. Mesothelioma is a cancer that develops from the thin layer of tissue that covers many of the internal organs and most commonly affects the lining of the lungs and chest wall.

About WCLC
The 19th World Conference on Lung Cancer (WCLC 2018) is the leading meeting on Thoracic Oncology. It is organised by the International Association for the Study of Lung Cancer and will gather more than 7,000 international delegates. WCLC 2018 will take place in Toronto Canada, 23 – 26 September 2018. View Source

About the BGBC008 trial
The BGBC008 trial is a phase II multi-centre open-label study of bemcentinib in combination with KEYTRUDA (pembrolizumab) in previously treated, immunotherapy naive, patients with advanced adenocarcinoma of the lung, the most common form of non-small cell lung cancer (NSCLC). The objective of the trial is to determine the anti-tumour activity of this novel drug combination and responses will be correlated with biomarker status (including AXL kinase and PD-L1 expression).

For more information please access trial NCT03184571 at www.clinicaltrials.gov.

About the BGBC004 trial
The BGBC004 trial is a phase I/II multi-centre open-label study of bemcentinib in combination with TARCEVA (erlotinib) in patients with EGFR mutation driven (EGFRm) Stage IIIb or Stage IV NSCLC. The trial is designed to evaluate reversal of resistance to EGFR targeted therapy in later line patients who are negative for the T790M resistance mutation (arm B) as well as prevention of resistance to TARCEVA in patients receiving the EGFR inhibitor first line (arm C).

For more information please access trial NCT02424617 at www.clinicaltrials.gov.

About the BGBIL005 trial

The BGBIL005 trial is an investigator-led phase I/II study of bemcentinib in combination with docetaxel chemotherapy in previously treated, relapsed / resistant NSCLC patients.

For more information please access trial NCT02922777 at www.clinicaltrials.gov.

About the MiST3 trial
The MiST3 trial is an investigator-led phase II study of bemcentinib in combination with KEYTRUDA in patients with relapsed mesothelioma. The trial, which is not active as of September 2018, is sponsored by the University of Leicester (Leicester, UK), and funded by the British Lung Foundation with support from Merck Sharp and Dohme Limited and BerGenBio. Up to 25 patients are planned to be enrolled at 3
clinical research sites in the UK.

On September 25, 2018 Aduro Biotech, Inc. (NASDAQ: ADRO) reported that Stephen T. Isaacs, chairman, president and chief executive officer of Aduro, will present at the following upcoming investor conferences (Press release, Aduro Biotech, SEP 25, 2018, View Source;p=RssLanding&cat=news&id=2368930 [SID1234529583]):

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Cantor Fitzgerald 2018 Global Healthcare Conference in New York, NY on Tuesday, October 2, 2018 at 3:25pm Eastern Time
Leerink Partners Roundtable Series: Rare Disease & Oncology in New York, NY on Wednesday, October 3, 2018 at 8:00am Eastern Time
To access the live webcast and subsequent archived recording of this and other company presentations, please visit Aduro’s website at www.aduro.com.

On September 25, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sanky) reported that the first patients have been dosed in DESTINY-Breast03 and DESTINY-Breast02, two global phase 3 studies evaluating the safety and efficacy of [fam-] trastuzumab deruxtecan (DS-8201), an investigational HER2 targeting antibody drug conjugate (ADC), in patients with previously-treated HER2 positive unresectable and/or metastatic breast cancer (Press release, Daiichi Sankyo, SEP 25, 2018, View Source [SID1234529580]). DESTINY-Breast03 will be a head-to-head comparison of [fam-] trastuzumab deruxtecan versus ado-trastuzumab emtansine (T-DM1), also a HER2 targeting ADC, while DESTINY-Breast02 will assess [fam-] trastuzumab deruxtecan in patients previously treated with standard of care HER2 therapies including T-DM1.

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Current treatment guidelines for patients with HER2 positive metastatic breast cancer recommend the combination of trastuzumab, pertuzumab and a taxane as first-line therapy.1,2 For patients whose cancer progresses after initial treatment, T-DM1 is an anti-HER2 agent specifically approved for second-line therapy.1 For cancers that progress after HER2 targeted agents trastuzumab, pertuzumab and T-DM1, there is no specific standard of care. Options for these patients are standard chemotherapy with or without continued anti-HER2 therapy and consideration of palliative care.1

"The DESTINY-Breast03 trial is a key element of our comprehensive development strategy to determine the potential of [fam-] trastuzumab deruxtecan as a second-line therapy in patients with HER2 positive metastatic breast cancer," said Gilles Gallant, BPharm, PhD, Vice President, DS-8201 Global Team Leader, Oncology Research and Development, Daiichi Sankyo. "DESTINY-Breast03 will also help assess whether our investigational and proprietary ADC linker and payload technology used in [fam-] trastuzumab deruxtecan demonstrates clinical relevance when compared to another HER2 targeting ADC currently approved in this setting."

Enrollment into DESTINY-Breast01, the pivotal phase 2 trial evaluating [fam-] trastuzumab deruxtecan in HER2 positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 was completed in September 2018, with approximately 230 patients at more than 100 sites in North America, Europe, Japan and other countries in Asia.

About DESTINY-Breast03

DESTINY-Breast03 is a randomized, active-controlled, open-label, multicenter, two-arm, global phase 3 trial designed to compare the safety and efficacy of [fam-] trastuzumab deruxtecan 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 progression-free survival based on blinded independent central review. Secondary efficacy endpoints include overall survival, objective response rate, duration of response, clinical benefit rate and progression-free survival based on investigator assessment. Safety endpoints include serious adverse events, treatment-emergent adverse events and adverse events of special interest. Exploratory efficacy endpoints include duration of stable disease and time to response. Health economics and outcomes research endpoints as well as pharmacokinetic and biomarker endpoints will also be measured.

DESTINY-Breast03 will enroll approximately 500 patients at 150 study sites in North America, Asia and Europe. For more information about the study, visit ClinicalTrials.gov.

About DESTINY-Breast02

DESTINY-Breast02 is a randomized, active-controlled, open-label, multicenter, two-arm, global phase 3 trial designed to compare the safety and efficacy of [fam-] trastuzumab deruxtecan versus investigator’s choice (trastuzumab plus capecitabine or lapatinib plus capecitabine) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with standard of care HER2 therapies including T-DM1.

The primary efficacy endpoint of DESTINY-Breast02 is progression-free survival based on blinded independent central review. Secondary efficacy endpoints include overall survival, objective response rate, duration of response, clinical benefit rate and progression-free survival based on investigator assessment. Safety endpoints include serious adverse events, treatment-emergent adverse events and adverse events of special interest. Health economics and outcomes research endpoints as well as pharmacokinetic and biomarker endpoints will also be measured.

DESTINY-Breast02 will enroll up to 600 patients at approximately 160 study sites in North America, South America, Europe and Asia. For more information about the study, visit ClinicalTrials.gov.

About DESTINY-Breast01

DESTINY-Breast01 is a pivotal phase 2, open-label, global, multicenter, two-part study evaluating the safety and efficacy of [fam-] trastuzumab deruxtecan in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with T-DM1.

The primary endpoint of the study is objective response rate. Secondary objectives include duration of response, disease control rate, clinical benefit rate, progression-free survival and overall survival. The first part of the study includes a pharmacokinetic stage and a dose finding stage to identify the recommended dose of [fam-] trastuzumab deruxtecan to be evaluated in the second part of the study. The second part of the study enrolled patients into one of two cohorts: patients resistant or refractory to T-DM1 (part 2a) and patients who discontinued treatment with T-DM1 for reasons other than resistant or refractory disease (part 2b). For more information about this study, visit ClinicalTrials.gov.

Unmet Need in HER2 Positive Metastatic Breast Cancer

Breast cancer is the second most common cancer worldwide, responsible for approximately 1.67 million of 14.1 million new cases of cancer diagnosed each year.4 Despite improving survival rates over the past 25 years, breast cancer was the fifth leading cause of cancer death overall and was the number one cause of cancer death in women in 2012.3,4For patients diagnosed with metastatic breast cancer, five-year survival rates are low.5

About one in five breast cancers overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells, which is associated with aggressive disease.4Several unmet needs remain today in HER2 positive metastatic breast cancer. Many tumors advance to the point where no currently approved HER2 targeting treatment continues to control the disease, and there is no current standard of care for HER2 positive tumors after treatment with trastuzumab, pertuzumab and T-DM1.1,6

About [Fam-] Trastuzumab Deruxtecan

[Fam-] trastuzumab deruxtecan (DS-8201; [fam-] trastuzumab deruxtecan in U.S. only; trastuzumab deruxtecan in other regions of world) is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, [fam-] trastuzumab deruxtecan is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

A broad and comprehensive development program with [fam-] trastuzumab deruxtecan is underway in North America, Europe and Asia. In addition to DESTINY-Breast03 and DESTINY-Breast02 phase 3 trials, [fam-] trastuzumab deruxtecan is in pivotal phase 2 clinical development for HER2 positive metastatic breast cancer resistant or refractory to ado-trastuzumab emtansine (DESTINY-Breast01); pivotal phase 2 development for HER2 positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01); phase 2 development for HER2 expressing advanced colorectal cancer; phase 2 development for metastatic non-squamous HER2 overexpressing or HER2 mutated NSCLC; and, phase 1 development in combination with nivolumab for HER2 expressing metastatic breast and bladder cancer.

[Fam-] trastuzumab deruxtecan has been granted Breakthrough Therapy designation for the treatment of patients with HER2 positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2 positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2 targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). [Fam-] trastuzumab deruxtecan has received SAKIGAKE Designation for the treatment of HER2 positive advanced gastric or gastroesophageal junction cancer by the Japan Ministry of Health, Labour and Welfare (MHLW).

[Fam-] trastuzumab deruxtecan is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

On September 25, 2018 Takeda Pharmaceutical Company Limited (TSE: 4502) reported results from the Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial, demonstrating that ALUNBRIG reduced the risk of disease progression or death, known as progression-free survival (PFS), as assessed by a blinded independent review committee (BIRC), by more than fifty percent compared to crizotinib in adults with anaplastic lymphoma kinase-positive (ALK+) locally advanced or metastatic non-small cell lung cancer (NSCLC) who had not received a prior ALK inhibitor (Press release, Takeda, SEP 25, 2018, View Source [SID1234529579]). Findings from the first interim analysis of the ALTA-1L trial will be presented during the Presidential Symposium at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer (WCLC) in Toronto on Tuesday, September 25, 2018. The data were also simultaneously published online in The New England Journal of Medicine. ALUNBRIG is currently not approved as first-line therapy for advanced ALK+ NSCLC.

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ALTA-1L is a global, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor but may have received up to one prior regimen of chemotherapy in the advanced setting. Patients were eligible for study entry on the basis of locally determined ALK testing. Patients received either ALUNBRIG, 180 mg once daily with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily. Treatment with ALUNBRIG resulted in superior PFS compared to crizotinib as assessed by a blinded independent review committee (hazard ratio = 0.49 [95 percent confidence interval (CI), 0.33 to 0.74]; log-rank p=0.0007), corresponding to a 51 percent reduction in the risk of disease progression or death. The safety profile associated with ALUNBRIG was generally consistent with the existing U.S. prescribing information.

"The ALK+ NSCLC treatment landscape has experienced tremendous change over the last decade, and the ALTA-1L trial demonstrates that brigatinib has the potential to be a key player in the first-line setting," said D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center and the lead investigator of ALTA-1L. "The ALTA-1L trial offers unique aspects, including the real-world applicability of the data. The study’s design offered enrollment to a broader population by allowing patients to participate even if they had received prior chemotherapy and enrolled patients based on local standard of care ALK testing as opposed to mandating confirmation at a central lab. We look forward to further follow-up, which will provide even better understanding of the role of brigatinib in the evolving landscape."

"We are thrilled to share these highly anticipated results with the lung cancer community," said David Kerstein MD, Global Clinical Lead for Brigatinib and Lung Cancer Clinical Portfolio Strategy Lead, Takeda. "The ALTA-1L data demonstrate that ALUNBRIG is superior to crizotinib in the first-line setting, reducing disease progression or death by more than half, with particularly pronounced activity in the brain. We would like to thank all the investigators, and especially the patients and their caregivers who participated in this important clinical research."

Brigatinib vs Crizotinib in Patients with ALK Inhibitor-Naïve Advanced ALK+ NSCLC: First Report of a Phase 3 Trial (ALTA-1L) (Presidential Symposium on Tuesday, September 25, 8:30 a.m. ET at the Metro Toronto Convention Centre North Building, Plenary Hall)

Key findings, which will be presented by D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center and lead investigator of ALTA-1L, include:

A total of 275 patients were randomized to either brigatinib (n=137) or crizotinib (n=138). The median age was 59 years (brigatinib, 58; crizotinib, 60) and 55% of patients in the trial were female (brigatinib, 50%; crizotinib 59%). Twenty-nine percent had brain metastases at baseline (brigatinib, 29%; crizotinib, 30%), with comparable pre-enrollment CNS radiotherapy rates. Overall, 27% of patients had prior chemotherapy in the locally advanced or metastatic setting (brigatinib, 26%; crizotinib, 27%).
At the data cutoff for the first interim analysis (February 19, 2018), at a median follow-up period of 11.0 and 9.3 months in the brigatinib arm and crizotinib arm, respectively, 95 patients (69%) in the brigatinib arm and 59 patients (43%) in the crizotinib arm remained on study treatment.
The trial has met the pre-specified threshold for superiority in the primary endpoint at the first interim analysis. With a total of 99 events, BIRC-assessed PFS with brigatinib was superior to crizotinib (hazard ratio, 0.49 [95% confidence interval (CI), 0.33 to 0.74]; log-rank p=0.0007).
Additional efficacy outcomes are presented in the table below:

ALTA-1L Efficacy Results

Efficacy Endpoint Brigatinib Crizotinib
Intention-to-treat population n=137 n=138

BIRC-assessed PFS
Median, months (95% CI) NR (NR to NR) 9.8 (9.0 to 12.9)
12-month estimate (95% CI) 67% (56% to 75%) 43% (32% to 53%)
Hazard ratio (95% CI) 0.49 (0.33 to 0.74)
Log-rank p-value 0.0007
Investigator-assessed PFS
Median, months (95% CI) NR (NR to NR) 9.2 (7.4 to 12.9)
12-month estimate (95% CI) 69% (59% to 76%) 40% (30% to 50%)
Hazard ratio (95% CI) 0.45 (0.30 to 0.68)
Log-rank p-value 0.0001
BIRC-assessed confirmed ORR (95% CI) 71% (62% to 78%) 60% (51% to 68%)
P-value 0.07
BIRC-assessed overall ORR (objective response at 1 or more assessments) (95% CI) 76% (68% to 83%) 73% (65% to 80%)

Patients with BIRC-assessed brain metastases at baseline
n=43 n=47
Intracranial PFS
Median, months (95% CI) NR (11.0 to NR) 5.6 (4.1 to 9.2)
12-month estimate (95% CI) 67% (47% to 80%) 21% (6% to 42%)
Hazard ratio (95% CI) 0.27 (0.13 to 0.54)
Log-rank p-value <0.0001

Patients with BIRC-assessed measurable brain metastases at baseline
n=18 n=21
Confirmed intracranial ORR (95% CI) 78% (52% to 94%) 29% (11% to 52%)
P-value 0.0028
Overall intracranial ORR (objective response at 1 or more assessments) (95% CI) 83% (59% to 96%) 33% (15% to 57%)
NR = Not reached

CI = Confidence Interval

PFS= Progression-Free Survival

ORR= Objective Response Rate

The safety profile associated with ALUNBRIG was generally consistent with the existing U.S. prescribing information.
Any grade treatment-emergent adverse events that occurred at a higher incidence with brigatinib than with crizotinib by more than five percentage points were increased blood creatine phosphokinase (brigatinib, 39% vs crizotinib, 15%), cough (25% vs 16%), hypertension (23% vs 7%), and increased lipase (19% vs 12%).
Any grade treatment-emergent adverse events that occurred at a higher incidence with crizotinib than with brigatinib by more than five percentage points were nausea (crizotinib, 56% vs brigatinib, 26%), diarrhea (55% vs 49%), constipation (42% vs 15%), peripheral edema (39% vs 4%), vomiting (39% vs 18%), increased alanine aminotransferase (32% vs 19%), decreased appetite (20% vs 7%), photopsia (20% vs 1%), dysgeusia (19% vs 4%), and visual impairment (16% vs 0).
Grade 3 to 5 treatment-emergent adverse events occurred in 61% of the patients in the brigatinib arm and 55% of the patients in the crizotinib arm. Most common grade 3 or greater treatment-emergent adverse events for brigatinib were increased blood creatine phosphokinase (16%), increased lipase (13%), hypertension (10%), and increased amylase (5%); and for crizotinib were increased alanine aminotransferase (9%), increased aspartate aminotransferase (6%), and increased lipase (5%).
Interstitial lung disease/pneumonitis at any time occurred in 4% (5/136) of patients in the brigatinib arm and 2% (3/137) in the crizotinib arm. Interstitial lung disease/pneumonitis with early onset (defined as within 14 days of treatment initiation) was observed in 3% of patients in the brigatinib arm (onset: Days 3 to 8) and was not observed in the crizotinib arm.
About the ALTA-1L Trial

The Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial of ALUNBRIG in adults is a global, ongoing, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor. Patients received either ALUNBRIG, 180 mg once daily with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily. Blinded Independent Review Committee (BIRC)-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, intracranial ORR, intracranial PFS, overall survival (OS), safety and tolerability. A total of approximately 198 PFS events are planned at the final analysis of the primary endpoint in order to demonstrate a minimum of six months PFS improvement over crizotinib. The trial is designed with two pre-specified interim analyses for the primary endpoint – one at approximately 50 percent of planned PFS events and one at approximately 75 percent of planned PFS events.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.

Takeda is committed to continuing research and development in NSCLC to improve the lives of the approximately 40,000 patients diagnosed with this serious and rare form of lung cancer worldwide each year.

About ALUNBRIG (brigatinib)

ALUNBRIG is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 2017, ALUNBRIG received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for ALK+ metastatic NSCLC patients who have progressed on or are intolerant to crizotinib. This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with ALK+ metastatic NSCLC who have progressed on or who were intolerant to an ALK inhibitor (crizotinib). The FDA and Health Canada approvals of ALUNBRIG were primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial.

ALUNBRIG received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.

The brigatinib clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with ALK+ NSCLC worldwide and the healthcare professionals who treat them. The comprehensive program includes the following clinical trials:

Phase 1/2 trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG
Pivotal Phase 2 ALTA trial investigating the efficacy and safety of ALUNBRIG at two dosing regimens in patients with ALK+ locally advanced or metastatic NSCLC who had progressed on crizotinib
Phase 3 ALTA-1L, a global randomized trial assessing the efficacy and safety of ALUNBRIG in comparison to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor
Phase 2 single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib
Phase 2 global, single-arm trial evaluating ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib
Phase 3 global randomized trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+ NSCLC who have progressed on crizotinib
For additional information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION (U.S.)

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension: In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia: Bradycardia can occur with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance: In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hyperglycemia: In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90→180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.

CYP3A Substrates: Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.

USE IN SPECIFIC POPULATIONS

Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.

Females and Males of Reproductive Potential:

Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.

Infertility: ALUNBRIG may cause reduced fertility in males.

Pediatric Use: The safety and efficacy of ALUNBRIG in pediatric patients have not been established.

Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 and younger patients.

Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild hepatic impairment or mild or moderate renal impairment. The safety of ALUNBRIG in patients with moderate or severe hepatic impairment or severe renal impairment has not been studied.

On September 25, 2018 AstraZeneca and MedImmune, its global biologics research and development arm, have presented data on overall survival (OS) in the Phase III PACIFIC trial of IMFINZI (durvalumab) during the Presidential Symposium of the IASLC 19th World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer in Toronto, Canada. Results were published simultaneously in the New England Journal of Medicine (Press release, AstraZeneca, SEP 25, 2018, View Source [SID1234529578]).

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Results from the Phase III PACIFIC trial in patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease had not progressed following chemoradiation showed that IMFINZI significantly improved OS, the second primary endpoint of the trial, compared to placebo regardless of PD-L1 expression, reducing the risk of death by 32% (HR 0.68, 99.73% CI 0.47-0.997; p=0.0025). See data table below.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer, said: "These data establish IMFINZI as the first immunotherapy to demonstrate an overall survival benefit for patients with unresectable, Stage III non-small cell lung cancer following chemoradiation therapy. Today’s announcement brings new hope to patients in a setting where survival rates have not changed in decades."

Scott J. Antonia, MD, Ph.D., chair of the Thoracic Oncology Department at Moffitt Cancer Center in Tampa, Florida, USA and principal investigator in the PACIFIC trial said: "The five-year survival rate in this setting has historically been around 15% after concurrent chemoradiation therapy. The significant survival benefit observed using the PACIFIC regimen provides confidence and clear rationale for a new standard of care."

Summary of primary endpoints:

IMFINZI
(n=476)

Placebo
(n=237)

OS (primary endpoint)1
Number of deaths (%) 183 (38.4%) 116 (48.9%)
Hazard ratio
(99.73% CI)2,3

0.68 (0.47, 0.997)
p-value2-4 0.0025
Median in months NR(5) 28.7
(95% CI) (34.7, NR) (22.9, NR)
PFS (primary endpoint)1,6
Number (%) of patients with event
243 (51.1%)

173 (73.0%)
Hazard ratio
(95% CI)2,7

0.51 (0.41, 0.63)

Median in months 17.2 5.6
(95% CI) (13.1, 23.9) (4.6, 7.7)
1The data cut-off date for first-planned OS analysis and updated PFS analysis was March 22, 2018.
2Stratified by sex, age, and smoking history.
3Confidence interval adjusted for interim analysis.
4Criteria for statistical significance at the interim analysis of OS was a p-value ≤ 0.00274 for OS (using Lan DeMets spending function approximating O’Brien Fleming boundary).
5Not Reached (NR).
6Assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1.
7No formal statistical comparison was made because the study had achieved significance for PFS at the first planned interim analysis (data cutoff of Feb 13, 2017).

The safety and tolerability profile for IMFINZI was consistent with that reported at the time of the previous progression-free survival (PFS) analysis. IMFINZI can cause serious, potentially fatal adverse reactions. In the updated analysis, the most common adverse reactions (greater than or equal to 20% of patients) among patients on IMFINZI versus placebo were cough (35.2% vs 25.2%), fatigue (24.0% vs 20.5%), dyspnea (22.3% vs 23.9%) and radiation pneumonitis (20.2% vs 15.8%). 30.5% of patients experienced a grade 3 or 4 adverse event (AE) with IMFINZI vs 26.1% with placebo, and 15.4% of patients discontinued treatment due to AEs with IMFINZI vs 9.8% of patients on placebo.

IMFINZI is currently approved in the US for the treatment of patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy, based on the PACIFIC trial. It is also approved in the EU, Canada, Switzerland, India, Japan and Brazil. Other global health authority reviews and submissions are ongoing.

IMPORTANT SAFETY INFORMATION

There are no contraindications for IMFINZI (durvalumab).

IMFINZI can cause serious, potentially fatal adverse reactions including immune-mediated pneumonitis, hepatitis, colitis or diarrhea, endocrinopathies, nephritis, rash or dermatitis, other immune-mediated adverse reactions, infection, and infusion-related reactions. Please refer to the full Prescribing Information for important dosage modification and management information specific to adverse reactions.

Immune-Mediated Pneumonitis

IMFINZI can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids. Fatal cases have been reported. Monitor patients for signs and symptoms of pneumonitis and evaluate with radiographic imaging when suspected. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold IMFINZI for Grade 2 pneumonitis; permanently discontinue for Grade 3 or 4 pneumonitis.

In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, pneumonitis occurred in 5% of patients, including Grade 3 (0.8%), Grade 4 (<0.1%), and Grade 5 (0.3%) pneumonitis. Pneumonitis led to discontinuation of IMFINZI in 1.5% of the 1889 patients. In the PACIFIC study, the incidence of pneumonitis (including radiation pneumonitis) was 34%, including Grade 3 (3.4%) and Grade 5 (1.1%) pneumonitis in the IMFINZI arm. In the PACIFIC study, pneumonitis led to discontinuation of IMFINZI in 6% of patients.

Immune-Mediated Hepatitis

IMFINZI can cause immune-mediated hepatitis, defined as requiring use of corticosteroids. Fatal cases have been reported. Monitor patients for signs and symptoms of hepatitis during and after discontinuation of IMFINZI, including clinical chemistry monitoring. Administer corticosteroids for Grade 2 or higher elevations of ALT, AST, and/or total bilirubin. Withhold IMFINZI for ALT or AST greater than 3 but less than or equal to 8 times the ULN or total bilirubin greater than 1.5 but less than or equal to 5 times the ULN; permanently discontinue IMFINZI for ALT or AST greater than 8 times the ULN or total bilirubin greater than 5 times the ULN or concurrent ALT or AST greater than 3 times the ULN and total bilirubin greater than 2 times the ULN with no other cause.

In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, hepatitis occurred in 12% of patients, including Grade 3 (4.4%), Grade 4 (0.4%), and Grade 5 (0.2%) hepatitis. Hepatitis led to discontinuation of IMFINZI in 0.7% of the 1889 patients.

Immune-Mediated Colitis

IMFINZI can cause immune-mediated colitis, defined as requiring use of corticosteroids. Administer corticosteroids for Grade 2 or greater colitis or diarrhea. Withhold IMFINZI for Grade 2 colitis or diarrhea; permanently discontinue for Grade 3 or 4 colitis or diarrhea.

In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, colitis or diarrhea occurred in 18% of patients, including Grade 3 (1.0%) and Grade 4 (0.1%) colitis. Diarrhea or colitis led to discontinuation of IMFINZI in 0.4% of the 1889 patients.

Immune-Mediated Endocrinopathies

IMFINZI can cause immune-mediated endocrinopathies, including thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis/hypopituitarism. Monitor patients for clinical signs and symptoms of endocrinopathies.

Thyroid disorders—Monitor thyroid function prior to and periodically during treatment. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Withhold IMFINZI for Grades 2–4 hyperthyroidism, until clinically stable. Continue IMFINZI for hypothyroidism. In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, hypothyroidism occurred in 11% of patients, while hyperthyroidism occurred in 7% of patients. Thyroiditis occurred in 0.9% of patients, including Grade 3 (<0.1%). Hypothyroidism was preceded by thyroiditis or hyperthyroidism in 25% of patients.
Adrenal insufficiency—Administer corticosteroids as clinically indicated and withhold IMFINZI until clinically stable for Grade 2 or higher adrenal insufficiency. In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, adrenal insufficiency occurred in 0.7% of patients, including Grade 3 (<0.1%) adrenal insufficiency.
Type 1 diabetes mellitus—Initiate treatment with insulin as clinically indicated. Withhold IMFINZI for Grades 2–4 type 1 diabetes mellitus, until clinically stable. In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, type 1 diabetes mellitus occurred in <0.1% of patients.
Hypophysitis—Administer corticosteroids and hormone replacement as clinically indicated and withhold IMFINZI until clinically stable for Grade 2 or higher hypophysitis. Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in <0.1% of 1889 patients with various cancers who received IMFINZI.
Immune-Mediated Nephritis

IMFINZI can cause immune-mediated nephritis, defined as evidence of renal dysfunction requiring use of corticosteroids. Fatal cases have occurred. Monitor patients for abnormal renal function tests prior to and periodically during treatment with IMFINZI. Administer corticosteroids as clinically indicated. Withhold IMFINZI for creatinine greater than 1.5 to 3 times the ULN; permanently discontinue IMFINZI and administer corticosteroids in patients with creatinine greater than 3 times the ULN.

In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, nephritis (reported as any of the following: increased creatinine or urea, acute kidney injury, renal failure, decreased glomerular filtration rate, tubulointerstitial nephritis, decreased creatinine clearance, glomerulonephritis, and nephritis) occurred in 6.3% of the patients including Grade 3 (1.1%), Grade 4 (0.2%), and Grade 5 (0.1%) nephritis. IMFINZI was discontinued in 0.3% of the 1889 patients.

Immune-Mediated Dermatologic Reactions

IMFINZI can cause immune-mediated rash. Bullous dermatitis and Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) have occurred with other products in this class. Administer corticosteroids for Grade 2 rash or dermatitis lasting for more than 1 week or for Grade 3 or 4 rash or dermatitis. Withhold IMFINZI for Grade 2 rash or dermatitis lasting longer than 1 week or Grade 3 rash or dermatitis; permanently discontinue IMFINZI in patients with Grade 4 rash or dermatitis.

In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, 26% of patients developed rash or dermatitis and 0.4% of the patients developed vitiligo. Rash or dermatitis led to discontinuation of IMFINZI in 0.1% of the 1889 patients.

Other Immune-Mediated Adverse Reactions

IMFINZI can cause severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. While immune-mediated reactions usually manifest during treatment with IMFINZI, immune-mediated adverse reactions can also manifest after discontinuation of IMFINZI. For suspected immune-mediated adverse reactions, exclude other causes and initiate corticosteroids as clinically indicated. Withhold IMFINZI for Grade 3 immune-mediated adverse reactions, unless clinical judgment indicates discontinuation; permanently discontinue IMFINZI for Grade 4 adverse reactions.

The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in 1889 patients who received IMFINZI: aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity, including uveitis and keratitis. Additional clinically significant immune-mediated adverse reactions have been seen with other products in this class (see Warnings and Precautions Section 5.7 of IMFINZI full Prescribing Information).

Infection

IMFINZI can cause serious infections, including fatal cases. Monitor patients for signs and symptoms of infection and treat as clinically indicated. Withhold IMFINZI for Grade 3 or 4 infection, until clinically stable.

In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, infections occurred in 43% of patients, including Grade 3 (8%), Grade 4 (1.9%), and Grade 5 (1.0%). In patients with Stage III NSCLC in the PACIFIC study, the most common Grade 3 or higher infection was pneumonia, which occurred in 5% of patients.

Infusion-Related Reactions

IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of an infusion-related reaction. Interrupt or slow the rate of infusion for Grades 1–2 infusion-related reactions; permanently discontinue for Grades 3–4 infusion-related reactions.

In clinical studies enrolling 1889 patients with various cancers who received IMFINZI, infusion-related reactions occurred in 2.2% of patients, including Grade 3 (0.3%).

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. There are no data on the use of IMFINZI in pregnant women. Advise pregnant women of the potential risk to a fetus and advise women of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of IMFINZI.

Lactation

There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for at least 3 months after the last dose.

Most Common Adverse Reactions

In patients with Stage III NSCLC in the PACIFIC study (IMFINZI n=475), the most common adverse reactions (≥20% of patients) were cough (40%), fatigue (34%), pneumonitis or radiation pneumonitis (34%), upper respiratory tract infections (26%), dyspnea (25%), and rash (23%). The most common Grade 3 or 4 adverse reaction (≥3%) was pneumonia (7%).
In patients with Stage III NSCLC in the PACIFIC study (IMFINZI n=475), discontinuation due to adverse reactions occurred in 15% of patients in the IMFINZI arm. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions (≥2% of patients) were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in <2% of patients and were similar across arms.
The safety and effectiveness of IMFINZI have not been established in pediatric patients.

Indication

IMFINZI is indicated for the treatment of patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

Please see complete Prescribing Information, including Medication Guide.

NOTES TO EDITORS

About Stage III NSCLC

Stage III (locally advanced) non-small cell lung cancer (NSCLC) is commonly divided into three sub-categories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally and the possibility of surgery. Stage III disease is different from Stage IV disease, when the cancer has spread (metastasized) to distant organs, as Stage III is currently treated with curative intent.

Approximately one in four patients with NSCLC in the United States present with Stage III disease, which is estimated to affect over 43,000 patients. The majority of Stage III NSCLC patients are determined to have unresectable tumors. Until recently, the standard of care beyond CRT was active surveillance to monitor for progression as there had been no FDA approved treatments following CRT.

About PACIFIC

The PACIFIC trial is a Phase III, randomized, double-blinded, placebo-controlled, multi-center trial of IMFINZI (durvalumab) as treatment in "all-comer" patients (i.e. regardless of PD-L1 status) with unresectable Stage III NSCLC whose disease has not progressed following platinum-based chemotherapy concurrent with radiation therapy (CRT).

The trial is being conducted in 235 centers across 26 countries involving 713 patients. The primary endpoints of the trial are progression-free survival (PFS) and overall survival (OS), and secondary endpoints include landmark PFS and OS, overall response rate (ORR) and duration of response (DoR).

About IMFINZI (durvalumab)

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 tumor’s immune-evading tactics and releasing the inhibition of immune responses.

IMFINZI is approved for unresectable Stage III NSCLC in the US, EU, Canada, Switzerland, India, Japan, and Brazil based on the Phase III PACIFIC trial.

As part of a broad development program, IMFINZI is also being tested as a monotherapy and in combination with chemotherapy, radiation therapy, small molecules and tremelimumab, an investigational anti-CTLA4 monoclonal antibody, as a first- or second-line treatment for patients with NSCLC, small cell lung cancer, locally advanced or metastatic urothelial carcinoma, head and neck cancer and other solid tumors.