COAST Phase II trial showed oleclumab or monalizumab in combination with IMFINZI significantly delayed disease progression and increased objective response rate

First effectiveness data from PACIFIC-R reinforced long-term benefit of IMFINZI in the real-world setting

Results from the large, randomized COAST Phase II trial showed oleclumab, an anti-CD73 monoclonal antibody, or monalizumab, an anti-NKG2A monoclonal antibody, in combination with IMFINZI^® (durvalumab) improved progression-free survival (PFS) and objective response rate (ORR) compared to IMFINZI alone in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) who had not progressed after concurrent chemoradiation therapy (CRT).

After a median follow-up of 11.5 months, the results of an interim analysis showed IMFINZI in combination with oleclumab reduced the risk of disease progression or death by 56% (hazard ratio [HR] of 0.44; 95% confidence interval [CI] 0.26-0.75), and in combination with monalizumab by 35% (HR of 0.65; 95% CI 0.49-0.85), when compared to IMFINZI alone in Stage III NSCLC patients following CRT. The 10-month PFS rate was 64.8% for the durvalumab plus oleclumab combination and 72.7% for durvalumab plus monalizumab, versus 39.2% with durvalumab alone.

The results, presented during the European Society for Medical Oncology (ESMO) Congress 2021 today, also showed an increase in the primary endpoint of confirmed ORR for IMFINZI plus oleclumab over IMFINZI alone (30% vs. 18%) and for IMFINZI plus monalizumab over IMFINZI alone (36% vs. 18%).

One in four patients with NSCLC are diagnosed at Stage III, where the majority of tumors are unresectable (cannot be removed with surgery).^1,2 IMFINZI after CRT is the global standard of care for patients in this setting, based on the PACIFIC Phase III trial.^3-5

Roy S. Herbst, MD, PhD, Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT and Chair of the COAST Steering Committee said: “IMFINZI is the established standard of care for patients with unresectable, Stage III NSCLC, but solutions are still needed for patients who do not benefit from currently available therapies. The remarkable improvement observed with the addition of oleclumab or monalizumab to IMFINZI, along with the strong safety profile, suggests these novel combinations could further redefine outcomes for these patients.”

Susan Galbraith, Executive Vice President, Oncology R&D, said: “IMFINZI has transformed the treatment of patients with unresectable, Stage III NSCLC, and we’re excited by the promise of extending its benefit through novel combinations with two potential first-in-class monoclonal antibodies demonstrating strong clinical activity. Based on the stand-out results from COAST, we plan to start a registrational trial with the hope of bringing these new treatment options to patients that further increase the potential for cure in this setting.”

Safety was similar across treatment arms with no new safety signals identified for either IMFINZI combination. Incidence of Grade 3 or higher treatment-emergent adverse events (TEAE; all cause) were 39.4% with IMFINZI, 40.7% with IMFINZI plus oleclumab, and 27.9% with IMFINZI plus monalizumab.

The most common Grade 3/4 TEAE was dyspnea (reported in 3.0%, 1.7% and 1.6% of patients, respectively). Grade 3/4 pneumonitis was only reported for one patient (1.6%), who received IMFINZI plus monalizumab.

PACIFIC-real world observational study (PACIFIC-R) demonstrated benefit of IMFINZI in real-world setting at the ESMO Congress 2021

Data from a planned analysis of real-world PFS (rwPFS) from the PACIFIC-R observational study was also presented during ESMO, showing the first effectiveness data from over a thousand patients with unresectable, Stage III NSCLC who were treated with IMFINZI in the real-world setting as part of AstraZeneca’s global PACIFIC Early Access Program. The analysis showed a median rwPFS of 21.7 months in the real-world setting.

In comparison, a median PFS of 16.9 months was observed among patients treated with IMFINZI in the randomized, double-blinded, placebo-controlled PACIFIC Phase III trial. These results demonstrate the long-term effectiveness of IMFINZI in this real-world patient population and reinforce the PACIFIC regimen as the established standard of care today following platinum-based CRT.

IMFINZI is approved in the curative-intent setting of unresectable, Stage III NSCLC after CRT in the US, Japan, China, across the EU and in many other countries with more than 80,000 patients treated with IMFINZI in this setting since its first approval in February 2018. IMFINZI is also approved for the 1st-line treatment of extensive-stage small cell lung cancer (ES-SCLC) in combination with etoposide and either carboplatin or cisplatin in more than 55 countries, including the US, Japan, China and across the EU, based on the CASPIAN Phase III trial.

AstraZeneca has several ongoing registrational trials focused on evaluating IMFINZI in earlier stages of lung cancer, including in potentially curative settings (PACIFIC-2, 4 and 5, MERMAID-1 and 2, AEGEAN, ADJUVANT BR.31, and ADRIATIC Phase III trials). The Company is also testing novel combinations with IMFINZI in the Phase II NeoCOAST trial in the neoadjuvant early-stage setting.

IMPORTANT SAFETY INFORMATION

There are no contraindications for IMFINZI^® (durvalumab).

Immune-Mediated Adverse Reactions

Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC when in combination with chemotherapy.

Immune-Mediated Colitis

IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions.

Immune-Mediated Hepatitis

IMFINZI can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions.

Immune-Mediated Endocrinopathies

• Adrenal Insufficiency: IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
• Hypophysitis: IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI.
• Thyroid Disorders: IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.
• Thyroiditis: Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
• Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI.
• Hypothyroidism: Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
• Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Grade 3 immune-mediated type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI.

Immune-Mediated Nephritis with Renal Dysfunction

IMFINZI can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.

Immune-Mediated Dermatology Reactions

IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), have occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions.

Other Immune-Mediated Adverse Reactions

The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies.

• Cardiac/vascular: Myocarditis, pericarditis, vasculitis.
• Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.
• Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
• Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.
• Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.
• Endocrine: Hypoparathyroidism
• Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.

Infusion-Related Reactions

IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.

Complications of Allogeneic HSCT after IMFINZI

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT.

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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI 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.

Adverse Reactions

• In patients with Stage III NSCLC in the PACIFIC study receiving IMFINZI (n=475), the most common adverse reactions (≥20%) 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 reactions (≥3%) were pneumonitis/radiation pneumonitis (3.4%) and pneumonia (7%)
• In patients with Stage III NSCLC in the PACIFIC study receiving 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%) 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
• In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), the most common adverse reactions (≥20%) were nausea (34%), fatigue/asthenia (32%), and alopecia (31%). The most common Grade 3 or 4 adverse reaction (≥3%) was fatigue/asthenia (3.4%)
• In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy

The safety and effectiveness of IMFINZI have not been established in pediatric patients.

Indications:

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

IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

Please see complete Prescribing Information, including Medication Guide.

About Stage III NSCLC

In 2021, an estimated 235,760 new cases of lung cancer will be diagnosed in the United States.⁵ Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.⁶ 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.¹

Stage III (locally advanced) 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. ⁷ In contrast to Stage IV, when cancer has spread (metastasized), the majority of Stage III patients are currently treated with curative intent.^3,8

The majority of Stage III NSCLC patients are diagnosed with unresectable tumors.^1,2 Prior to the approval of IMFINZI in this setting, no new treatments beyond CRT had been available to these patients for decades.^3-4,9

About COAST

COAST is a Phase II, multi-arm, randomized trial investigating IMFINZI alone or in combination with either oleclumab (anti-CD73 monoclonal antibody) or monalizumab (anti-NKG2A monoclonal antibody) in 189 patients with locally advanced, unresectable Stage III NSCLC who had not progressed after CRT.

COAST is being conducted in 82 centers across 9 countries in North America, Europe and Asia. The primary endpoint of the trial is ORR as a measure of anti-tumor activity. Secondary endpoints include safety, duration of response, overall survival and PFS.

About PACIFIC-R

PACIFIC-Real World (PACIFIC-R) is an observational study of 1,399 patients with unresectable, Stage III NSCLC previously treated with IMFINZI as part of an early access program (EAP) between September 2017 and December 2018. Patients were enrolled in the PACIFIC-R study after discontinuation of the EAP in participating countries. Eligible patients had not progressed after CRT and were enrolled regardless of PD-L1 status at trial initiation.

About IMFINZI^® (durvalumab)

IMFINZI 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.

In addition to approvals in unresectable, Stage III NSCLC and ES-SCLC, IMFINZI is also approved for previously treated patients with advanced bladder cancer in several countries.

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

About Oleclumab

Oleclumab is a potentially first-in-class, anti-CD73 monoclonal antibody that selectively binds to and inhibits the activity of CD73. CD73 is a cell surface enzyme which is overexpressed in the tumor microenvironment and promotes tumor growth by limiting anti-tumor immunity via the adenosine receptor pathway.

Preclinical studies have demonstrated that CD73 blockade improved anti-tumor activity in combination with radiotherapy, chemotherapy and immunotherapy. Oleclumab is also being examined in various Phase II trials for solid tumor malignancies.

About Monalizumab

Monalizumab is a potentially first-in-class, anti-NKG2A antibody. NKG2A is a checkpoint receptor expressed on tumor-infiltrating cytotoxic T-cells and natural killer cells that inhibits their anti-cancer functions.

Monalizumab is also being studied in the ongoing INTERLINK-1 Phase III trial, evaluating monalizumab in combination with cetuximab for the treatment of patients with previously-treated recurrent or metastatic head and neck squamous cell carcinoma.

Monalizumab is being developed in collaboration with Innate Pharma. AstraZeneca obtained full oncology rights to monalizumab in October 2018 through a co-development and commercialization agreement initiated in 2015.

About AstraZeneca Support Programs

AstraZeneca strives to ensure that appropriate patients and their oncologists have access to IMFINZI and relevant support resources. These include educational resources, an Oncology Nurse Educator program and affordability and reimbursement programs, such as Access 360™.

Additionally, AstraZeneca has launched Lighthouse, a program that provides support to patients during any immune-mediated adverse events they may encounter during treatment, through medically trained Lighthouse Advocates. The program aims to make patients’ treatment experience as comfortable as possible. Find out more about Lighthouse at LighthouseProgram.com or call 1-855-LHOUSE1(1-855-546-8731).

About AstraZeneca in lung cancer

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

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

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

About AstraZeneca in immunotherapy

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

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

About 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 catalyze 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.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

References

1. EpiCast Report: NSCLC Epidemiology Forecast to 2025. GlobalData. 2016.
2. Provencio M, et al. Inoperable Stage III Non-Small Cell Lung Cancer: Current Treatment and Role Of Vinorelbine. J Thorac Dis. 2011;3:197-204.
3. Cheema PK, et al. Perspectives on Treatment Advances for Stage III Locally Advanced Unresectable Non-Small-Cell Lung Cancer. Curr Oncol. 2019;26(1):37–42.
4. Curran WJ, et al. Sequential vs Concurrent Chemoradiation for Stage III Non–Small Cell Lung Cancer: Randomized Phase III Trial RTOG 9410. J Natl Cancer Inst. 2011;103(19):1452-1460.
5. American Cancer Society. Key Statistics for Lung Cancer. Available at https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html.Accessed September 2021.
6. American Cancer Society. What is Lung Cancer. Available at https://www.cancer.org/cancer/lung-cancer/about/what-is.html. Accessed September 2021.
7. Anthonia SJ et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377:1919-1929.
8. ASCO. Cancer.net. Lung Cancer – Non-Small Cell. Available at https://www.cancer.net/cancer-types/lung-cancer/view-all. Accessed September 2021.
9. Hanna N, et al. Current Standards and Clinical Trials in Systemic Therapy for Stage III Lung Cancer: What is New? Am Soc Clin Oncol Educ Book. 2015:e442-447.

US-57740 Last Updated 9/21

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