AstraZeneca Advances the Science of Cancer Medicine With Practice-Changing Data at the ASCO20 Virtual Scientific Program

AstraZeneca will present ground-breaking new results across its broad portfolio of cancer medicines during the 2020 American Society of Clinical Oncology ASCO20 Virtual Scientific Program, May 29 to May 31, 2020. AstraZeneca will present 98 abstracts, including 19 oral presentations with one plenary and 10 late-breakers.

Presentations will showcase the Company’s leadership in the treatment of early lung cancer with a late-breaking plenary presentation of the unprecedented results from the Phase III ADAURA trial for TAGRISSO®(osimertinib) in the adjuvant treatment of patients with Stage IB, II and IIIA epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Data from the DESTINY program will highlight the transformative potential of ENHERTU® (trastuzumab deruxtecan) across HER2-driven tumors, including in lung, breast, gastric and colorectal cancers.

José Baselga, Executive Vice President, Oncology R&D, said: “AstraZeneca continues to deliver results with the goal of transforming clinical practice. Our science at ASCO this year shows the potential for treatment of early-stage EGFR-mutated lung cancer, where we aim to provide the hope of cure with TAGRISSO; to rewrite the rules on the treatment of patients with HER2-positive tumors with ENHERTU across a range of cancer settings; and to advance our next wave of pipeline medicines focused on treating patients earlier and overcoming resistance.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “One constant throughout these uncertain times is our unwavering commitment to changing the practice of medicine for patients living with cancer. Our new oncology medicines TAGRISSO, IMFINZI, LYNPARZA, and ENHERTU are demonstrating incredible momentum at ASCO, building on their established benefits for patients by delivering powerful data in new settings and bending cancer survival curves. This year’s data at ASCO reinforce our belief that we can one day eliminate cancer as a cause of death.”

Leadership in lung cancer across stages of disease

As AstraZeneca continues to advance lung cancer research and development from early to late-stage settings, the Company will present new data for TAGRISSO, IMFINZI® (durvalumab), ENHERTU, and potential new medicine savolitinib. Beyond ADAURA, an oral presentation of the final analysis of the Phase III CASPIAN trial confirms the sustained, clinically meaningful overall survival (OS) benefit of IMFINZI for patients with extensive-stage small cell lung cancer (ES-SCLC). Another oral presentation reinforces the potential of ENHERTU for patients with HER2-mutant NSCLC(see below). Results from a Phase II trial of savolitinib in patients with mesenchymal-epithelial transition (MET) exon 14 skipping mutations will also be presented.

Transforming treatment across HER2-driven cancers

AstraZeneca, in collaboration with Daiichi Sankyo Company, Limited (Daiichi Sankyo) will present new data from several trials highlighting the transformative potential of ENHERTU, includingdetailed results from the Phase II DESTINY-Gastric01 trial which showed a statistically significant and clinically meaningful improvement in objective response rate and OS for patients with HER2-positive metastatic gastric cancer. ENHERTU was recently granted Breakthrough Therapy Designation in the US for patients in this setting. Phase II data will also be presented for HER2-positive colorectal cancer and HER2-mutant NSCLC, two cancer settings for which there are currently no approved HER2-targeted medicines. Additionally, subgroup analyses from the Phase II DESTINY-Breast01 trial will reinforce the durable and consistent responses seen with ENHERTUin HER2-positive metastatic breast cancer.

Advancing treatment in other cancer types with high unmet need

AstraZeneca will present data from several trials highlighting how the Company’s leading research is progressing treatment in other cancers where a high unmet medical need remains, including:

• An oral presentation of results from Study 22 for the IMFINZI plus tremelimumab combination using a novel regimen in advanced liver cancer
• Final OS results from the Phase III SOLO2 trial for LYNPARZA® (olaparib) maintenance treatment in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in an oral presentation. LYNPARZA is developed and commercialized in collaboration with Merck & Co., Inc. (Merck: known as MSD outside the US and Canada)
• Multiple trials underscoring the impressive profile of CALQUENCE®(acalabrutinib), including data from the Phase II ACE-CL-001 trial with more than four years of follow up. The presentations represent the most mature safety and efficacy data to date with CALQUENCE monotherapy in patients with chronic lymphocytic leukemia

Key AstraZeneca presentations during the ASCO20 Virtual Scientific Program

Lead author	Abstract title	Presentation details1
Immuno-Oncology
Paz-Ares, L	Durvalumab ± tremelimumab + platinum-etoposide in first-line ES-SCLC: Results from the Phase III CASPIAN study	Abstract #9002 Oral Abstract Session - Lung Cancer - Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers
Chen, Y	First-line durvalumab plus platinum-etoposide in ES-SCLC (CASPIAN): Impact of brain metastases on treatment patterns and outcomes	Abstract #9068 Poster #261 Poster Session - Lung Cancer - Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers
Naidoo, J	Non-pneumonitis immune-mediated adverse events with durvalumab in patients with unresectable, Stage III NSCLC (PACIFIC)	Abstract #9048 Poster #241 Poster Session - Lung Cancer - Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers
Kelley, RK	Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab in combination with durvalumab for patients with advanced hepatocellular carcinoma (Study 22)	Abstract #4508 Oral Abstract Session - Gastrointestinal Cancer - Gastroesophageal, Pancreatic, and Hepatobiliary
Oh, Do-Youn	Phase II study assessing tolerability, efficacy and biomarkers for durvalumab ± tremelimumab and gemcitabine/cisplatin in chemo-naïve advanced biliary tract cancer	Abstract #4520 Poster #128 Poster Session - Gastrointestinal Cancer: Gastroesophageal, Pancreatic, and Hepatobiliary
Lim, E	A Phase I, open-label multi-center study to assess the safety, pharmacokinetics, and the preliminary antitumor activity of AZD4635 both as monotherapy and in combination in patients with advanced solid malignancies: results from prostate cancer patients	Abstract #5518 Poster #99 Poster Session - Genitourinary Cancer - Prostate, Testicular, and Penile
DNA damage response
Poveda, A	Final overall survival results from SOLO2: a Phase III trial assessing maintenance olaparib in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation	Abstract #6002 Oral Abstract Session - Gynecologic Cancer
Cadoo, K	Olaparib treatment in patients with platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study	Abstract #6013 Poster #184 Poster Discussion - Gynecologic Cancer
Lee, J	Cediranib in combination with olaparib in patients without a germline BRCA1/2 mutation with recurrent platinum-resistant ovarian cancer: Phase IIb CONCERTO trial	Abstract #6056 Poster #227 Poster Session - Gynecologic Cancer
Poveda, A	Olaparib maintenance monotherapy for non-germline BRCA1/2-mutated platinum-sensitive relapsed ovarian cancer patients: Phase IIIb OPINION interim analysis	Abstract #6057 Poster #228 Poster Session - Gynecologic Cancer
Liu, J	A Phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer	Abstract #6003 Oral Abstract Session - Gynecologic Cancer
Gelmon, K	Real-world clinical effectiveness and safety of olaparib monotherapy in HER2-negative gBRCA-mutated metastatic breast cancer: Phase IIIb LUCY interim analysis	Abstract #1087 Poster #172 Poster Session - Breast Cancer - Metastatic
Tumor drivers and resistance
Herbst, R	Osimertinib as adjuvant therapy in patients with Stage IB–IIIA EGFRm NSCLC after complete tumor resection: ADAURA	Abstract #LBA5 Plenary Session Sunday 31 May, 1:00pm EDT
Lu, S	Phase II study of savolitinib in patients with pulmonary sarcomatoid carcinoma and other types of NSCLC harboring MET exon 14 skipping mutations	Abstract #9519 Poster #285 Poster Discussion - Lung Cancer - Non-Small Cell Metastatic
Choueiri, T	SAVOIR: A Phase III study of savolitinib vs. sunitinib in patients with MET-driven papillary renal cell carcinoma	Abstract #5002 Oral Abstract Session - Genitourinary Cancer - Kidney and Bladder
Julia, K	Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated NSCLC	Abstract # 9507 Oral Abstract Session - Lung Cancer- Non-Small Cell Metastatic
Piotrowska, Z	ECOG-ACRIN 5162: A Phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions	Abstract #9513 Poster #279 Poster Discussion - Lung Cancer - Non-Small Cell Metastatic
Hamilton, E	A Phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast cancer (SERENA-1)	Abstract #1024 Poster #109 Poster Discussion - Breast Cancer - Metastatic
Schmid, P	A Phase III trial of capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer (CAPItello­290)	Abstract #TPS1109 Poster #194 Poster Session - Breast Cancer - Metastatic
Hematology
Ghia, P	Acalabrutinib vs Idelalisib plus Rituximab or Bendamustine plus Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: ASCEND Final Results	Abstract #8015 Poster #348 Poster Discussion - Hematologic Malignancies - Lymphoma and Chronic Lymphocytic Leukemia
Byrd, C	Acalabrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia: Mature Results From Phase II Study Demonstrating Durable Remissions and Long-Term Tolerability	Abstract #8024 Poster #357 Poster Session - Hematologic Malignancies - Lymphoma and Chronic Lymphocytic Leukemia
Furman, R	Safety of Acalabrutinib Monotherapy in Hematologic Malignancies: Pooled Analysis From Clinical Trials	Abstract #8064 Poster #397 Poster Session - Hematologic Malignancies - Lymphoma and Chronic Lymphocytic Leukemia
Antibody drug conjugates
Smit, E	Trastuzumab deruxtecan in patients with HER2-mutated metastatic NSCLC: Interim results of DESTINY-Lung01	Abstract # 9504 Oral Abstract Session - Lung Cancer- Non-Small Cell Metastatic
Shitara, K	Trastuzumab deruxtecan in patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma: A randomized, Phase II, multicenter, open-label study (DESTINY-Gastric01)	Abstract #4513 Poster #121 Poster Session - Gastrointestinal Cancer - Gastroesophageal, Pancreatic, and Hepatobiliary
Siena, S	A Phase II, multicenter, open-label study of trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer: DESTINY-CRC01	Abstract #4000 Oral Abstract Session - Gastrointestinal Cancer - Colorectal and Anal
Modi, S	Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis	Abstract #1036 Poster #121 Poster Session - Breast Cancer- Metastatic

1. Beginning Friday, May 29 at 8:00 AM EDT oral presentations, poster discussions and poster sessions will be available on demand for 180 days including video and slide presentations, as well as discussant commentary

SELECT SAFETY INFORMATION FOR TAGRISSO® (osimertinib)

• There are no contraindications for TAGRISSO
• TAGRISSO is associated with several serious and sometimes fatal adverse reactions, including interstitial lung disease/pneumonitis, QTc interval prolongation, cardiomyopathy, keratitis, erythema multiforme and Stevens-Johnson syndrome, and embryo-fetal toxicity
• The most common adverse reactions (≥20%) were diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue, and decreased appetite

INDICATIONS

• TAGRISSO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test
• TAGRISSO is indicated for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy

Please see complete Prescribing Information, including Patient Information.

U.S. FDA-Approved Indication for ENHERTU

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

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.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms. Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications

None.

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.

Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Adverse Reactions

The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common adverse reactions (frequency ≥20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%).

Use in Specific Populations

• Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.
• Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
• Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
• Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
• Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were ≥65 years and 5% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (53%) as compared to younger patients (42%).
• Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed WARNING, and Medication Guide.

SELECT SAFETY INFORMATION for LYNPARZA® (olaparib) tablets

LYNPARZA is associated with serious, potentially fatal risks, including myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) and pneumonitis. LYNPARZA can also cause fatal harm.

Please see complete Prescribing Information, including Patient Information.

SELECT SAFETY INFORMATION for IMFINZI® (durvalumab) injection for intravenous use

• Serious, potentially fatal risks were seen with IMFINZI in the CASPIAN trial. 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%).
• Immune-mediated adverse reactions including immune-mediated pneumonitis, hepatitis, colitis, endocrinopathies (including thyroid disorders, adrenal insufficiency, type 1 diabetes, and hypophysitis), nephritis, dermatologic reactions, other immune-mediated adverse reactions, infection, and infusion-related reactions were reported in patients receiving IMFINZI in the CASPIAN trial.
• The most common adverse reactions (≥20%) were nausea, fatigue/asthenia and alopecia.
• Advise women not to become pregnant or breastfeed during treatment with IMFINZI and for at least 3 months after the last dose.
• The safety and effectiveness of IMFINZI have not been established in pediatric patients.

INDICATION

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 Patient Information.

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib) capsules

Serious and Opportunistic Infections

Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.

Second Primary Malignancies

Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.

Atrial Fibrillation and Flutter

Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manageas appropriate.

ADVERSE REACTIONS

The most common adverse reactions (≥ 20%) of any grade in patients with relapsed or refractory MCL were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).

*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.

Dose reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia,* neutropenia,* thrombocytopenia,* headache, upper respiratory tract infection, and diarrhea.

*Treatment-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils were based on laboratory measurements and adverse reactions.

In patients with previously untreated CLL exposed to CALQUENCE, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE plus obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Adverse events led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

In patients with relapsed/refractory CLL exposed to CALQUENCE, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.

Adverse reactions led to CALQUENCE dose reduction in 3.9% of patients (N=154), dose interruptions in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and discontinuation in 10% of patients, most frequently due to second primary malignancies followed by infection. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 1.3% of patients who received CALQUENCE.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.

Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE dose to 100 mg once daily.

Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg approximately every 12 hours.

Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2-receptor antagonist. Separate dosing with an antacid by at least 2 hours.

Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.

SPECIFIC POPULATIONS

Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.

Avoid administration of CALQUENCE in patients with severe hepatic impairment. Dose modifications are not required for patients with mild or moderate hepatic impairment.

Please see full Prescribing Information including Patient Information.

About the Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize ENHERTU worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for manufacturing and supply.

About the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize LYNPARZA, the world’s first PARP inhibitor, for multiple cancer types. Working together, the companies will develop LYNPARZA in combination with other potential new medicines and as monotherapies. Independently, the companies will develop LYNPARZA in combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients' lives and the Company's future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca's main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms - Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates - and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment 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, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal and Metabolism, and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

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