On April 21, 2020 Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a biotechnology company developing novel immunotherapy treatments for cancer and autoimmune diseases, reported an update on the ongoing development of its product candidates, eftilagimod alpha ("efti" or "IMP321") and IMP761, as well as its response to the COVID-19 pandemic and its potential business impact (Press release, Immutep, APR 21, 2020, View Source [SID1234556461]).

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COVID-19 update

Immutep has welcomed recent guidance from the United States Food and Drug Administration ("FDA"), European Medicines Agency ("EMA") and other regulators on how to continue ongoing clinical trials during the COVID-19 pandemic. Cancer patients have been recognised by regulators as at risk and vulnerable to COVID-19 infection due to their weakened immune system. The FDA and other regulators are actively helping trial sponsors and hospitals continue critical clinical trials through the pandemic.

For Immutep, the safety and wellbeing of its clinical trial participants and investigators are its absolute priority. The Company is working closely with the clinical sites and regulators to monitor the situation, with the impact to date on treatment of patients being limited. Immutep also continues to work with its Clinical Research Organisation (CRO) partners to verify data remotely and review clinical trial processes according to the new guidance.

The Company anticipates that trial recruitment may slow down for its two actively recruiting trials, TACTI-002 and INSIGHT-004 over the coming months, due to the closure of hospitals in certain countries that have been most affected, such as Spain and the United Kingdom. However, INSIGHT has already recruited 91% of total patients and TACTI-002 has recruited 70% of total patients. Both its AIPAC and TACTI-mel trials are fully recruited.

Immutep is also implementing strategies to account for any impact of the pandemic on its ongoing trial data, related to potential patient infection. These strategies are under constant re-evaluation. As COVID-19 response restrictions are lifted, the Company will conduct an impact analysis to evaluate the overall effects of the pandemic.

Immutep Limited, Level 12, 95 Pitt Street, Sydney NSW 2000

ABN: 90 009 237 889

LOGO

The Company’s own operations are minimally affected with increased home office work and less travel for the staff.

Eftilagimod alpha Clinical Update

TACTI-002-Phase II clinical trial

In mid-February, Immutep reported highly encouraging first data from its ongoing TACTI-002 study of efti in combination with pembrolizumab, an anti-PD-1 therapy. The data showed an Overall Response Rate (ORR)of 47% for patients in Part A, first line non-small cell lung cancer (NSCLC) patients who are receiving the combination treatment of efti with pembrolizumab. This compared very favorably to patients in Part A who are receiving pembrolizumab monotherapy and reported an initial ORR of approximately just 20%.

Trial recruitment continues to progress well, with 76 patients out of up to 109 already enrolled at 12 clinical sites across Australia, Europe, the UK and US. Details of recruitment for each Part are below.

Study—Part* Stage 1 (N)
Actual/target Stage 2 (N)
target
Part A—1st line NSCLC

17/17 17/19
Part B—2nd line NSCLC

18/23 -/13
Part C—2nd line met. HNSCC

18/18 6/19
Immutep was selected to provide a poster short talk presentation of new TACTI-002 data as part of the high- impact paper presentation program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting, scheduled for 27 and 28 April. In addition, further data will be reported throughout 2020.

AIPAC-Phase IIb clinical trial

In March 2020, Immutep reported first results from its randomised, placebo controlled AIPAC trial in metastatic breast cancer. Patients receiving efti showed a positive trend in Progression Free Survival (PFS) rate at the 6-month landmark, with 63% of those who received paclitaxel plus efti being progression-free. This compared favourably to 54% of patients who received paclitaxel plus placebo. The ORR in the efti group was 48.3%, compared to 38.4% in the placebo group.

In addition, analysis on the trial subgroups showed that patients with a low monocyte count at baseline received a remarkable benefit from efti, with a median PFS of 7.29 months, compared to just 5.45 months in the placebo group (Hazard Ratio 0.61). Similarly, patients with a more aggressive, more immunogenic luminal B type also benefitted from efti with a median PFS of 7.29 months, compared to just 5.45 months in the placebo group (Hazard Ratio 0.65). Patients with lower general performance status at baseline also had a median PFS of 7.13 months compared to of 6.67 months in the placebo group (Hazard Ratio 0.76). These interesting subgroups are being discussed with the Company’s clinical advisory board as well as other partners and will be investigated further.

Immutep Limited, Level 12, 95 Pitt Street, Sydney NSW 2000

ABN: 90 009 237 889

LOGO

Further building upon efti’s strong safety profile to date, the combination of efti and paclitaxel chemotherapy was overall safe and well tolerated. For further information please also view the webcast available at www.immutep.com.

Immutep expects to report Overall Survival (OS) and immuno-monitoring results from AIPAC later in 2020. Together with the already reported data, this will inform the Company’s future strategy for efti in metastatic breast carcinoma.

In early March 2020, Immutep received approval for its second Investigational New Drug ("IND") application from the United States FDA for efti. The IND enables the Company to initiate a clinical study in metastatic breast cancer patients. It also enables Immutep to further interact with the FDA regarding the use of efti in metastatic breast cancer.

INSIGHT-004 -Phase I clinical trial

Patient recruitment is continuing for Cohort 2 (30 mg efti) of the INSIGHT-004 study with 5 out of 6 patients participating. Cohort 1 is already fully recruited, bringing total recruitment to 11 out of 12 patients. As previously reported, the study is showing encouraging, positive initial activity.

The INSIGHT-004 is being conducted as the 4th arm of the INSIGHT trial and evaluates the combination of efti with avelumab in 12 patients with advanced solid malignancies.

TACTI-mel-Phase I clinical trial

Immutep is preparing a clinical study report for its TACTI-mel trial which reported positive final efficacy data in late 2019. The study showed deep and durable responses to the combination of efti and pembrolizumab in patients with metastatic melanoma. 12 patients (50%) reported a decrease of ³ 75% in the target lesions and 9 patients (38%) were treated for ³ 12 months.

IMP761 Preclinical Update

Since the end of the quarter, Immutep has reported significant progress in the cell line development of its IMP761 immunosuppressive product candidate. A pharmaceutical-grade, stable CHO cell line has been developed that produces significantly high product yields of IMP761. Immutep will complete its preparations for the Good Manufacturing Practice (GMP) process compliance development phase, ahead of potential clinical testing of the compound in autoimmune disease.

Partner Updates

EOC Pharma

Following the recent APIAC results, Immutep discussed the analysis of the reported PFS data (including subgroup analysis) with its Chinese partner for efti, EOC Pharma. Subsequently, EOC confirmed it plans to continue advancing efti (designated as EOC202 in China) in metastatic breast cancer.

Immutep Limited, Level 12, 95 Pitt Street, Sydney NSW 2000

ABN: 90 009 237 889

CYTLIMIC

At the end of the quarter, Immutep’s partner, CYTLIMIC reported positive results from its YNP01 phase I clinical trial which is evaluating the combination immunotherapy of a HSP70 derived peptide, a GPC3 derived peptide, Immutep’s IMP321 (efti) and Hiltonol in patients with advanced or metastatic solid cancer.

The results showed that approximately 70% of patients showed an immune response to each peptide. Further notable results were observed at the recommended dose (which has been adopted in CYTLIMIC’s Investigator-Initiated Phase I Trial CRESCENT1), including a significant reduction of lymphocyte population expressing an exhaustion marker in the peripheral blood and an overall survival of 18 months or more in 5 out of 11 patients.

The results were published in the scientific peer-reviewed journal, Cancer Immunology, Immunotherapy.

Financials

Cash receipts for the quarter were $0.22 million, compared to $7.28 million in Q2 FY2020. Q2 FY2020 was boosted by a milestone payment of £4 million from GSK related to the first patient being dosed in GSK’S Phase II clinical trial evaluating GSK2831781 in ulcerative colitis.

The net cash used in G&A activities in the quarter was $0.49 million compared to $1.43 million in Q2 FY2020. The decrease reflected a return to normalised levels, after the Company prepaid some annual corporate expenses related to the 2020 calendar year in Q2. G&A costs for the quarter includes $136K in payment of Non-Executive Director’s fees and Executive Director’s salary.

Total net cash outflows related to operating activities in the quarter was $6.09 million. In comparison, total net cash inflows in Q2 FY2020 were $1.22 million.

The net cash used in Research and Development activities in the last quarter was $4.71 million, compared to $6.19 million in Q2 FY2020. R&D expenditure is expected to continue to decline further over the remaining three quarters of this calendar year as almost all patients in the AIPAC Phase IIb clinical trial have completed the treatment and moved into the follow-up phase.

The cash balance as at 31 March 2020 was $16.1 million compared to a balance of $20.5 million as at 31 December 2019. Immutep’s cash position gives the Company an expected cash runway beyond multiple upcoming data catalysts in 2020 and into the beginning of CY 2021.

A copy of the Appendix 4C – Quarterly Cash Flow Report for the quarter is attached.

On April 21, 2020 Idera Pharmaceuticals, Inc. (NASDAQ: IDRA) (the Company) reported final topline data from the ILLUMINATE-204 trial investigating intratumoral tilsotolimod, Idera’s investigational toll-like receptor 9 (TLR9) agonist (Press release, Idera Pharmaceuticals, APR 21, 2020, View Source [SID1234556460]).

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ILLUMINATE-204 is a multi-center, two-arm phase 1/2 trial in patients with anti-PD-1 refractory advanced melanoma. The phase 1 portion of the trial tested the safety and efficacy of increasing doses of tilsotolimod in combination with either Yervoy* (ipilimumab) or Keytruda± (pembrolizumab). The phase 2 expansion of the trial enrolled additional patients at the recommended phase 2 dose (RP2D) of 8 mg of tilsotolimod in combination with Yervoy, which is the treatment regimen being evaluated for the same indication in the Company’s registrational trial, ILLUMINATE-301.

"The clinical benefit suggested for these anti-PD-1 refractory melanoma patients with limited treatment options includes stabilization of disease and even responses, which is creating hope that this combination might be of benefit to patients in the PD-1 refractory setting," stated Joseph Markowitz, M.D., Ph.D., from the H. Lee Moffitt Cancer Center & Research Center in Tampa, Florida. "We eagerly await the outcome of the ongoing phase 3 trial to see whether this combination treatment with ipilimumab will represent an additional option for patients with advanced melanoma."

ILLUMINATE-204 Key Findings:

The study included 52 patients treated with 8 mg of tilsotolimod in combination with Yervoy.

·49 patients were evaluable for efficacy.
·Median overall survival (OS) was 21.0 months (95% confidence interval (CI): 9.8 months-not reached (NR)).
·The overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) was 22.4%, including 2 complete responses (95% CI: 11.8-36.6%).

oThe disease control rate (stable disease or better) was 71.4% (95% CI: 56.7%-83.4%).
oMedian duration of response was 11.4 months (95% CI: 3.3 months-NR).
o7 of 11 RECIST v1.1 responses were durable for greater than 6 months.
oTumor reduction was observed in both injected and noninjected tumors.
·The combination regimen was generally well tolerated among the 62 patients receiving tilsotolimod at any dose in combination with Yervoy.
o48% of patients reported a maximum Grade 3 or 4 treatment emergent adverse event (TEAE).
oThe most common serious TEAEs were autoimmune hepatitis, hyponatremia, and hypophysitis (n=2 for each).
o26% of patients reported immune-related toxicities, suggesting that tilsotolimod + Yervoy does not add immune-related toxicity versus Yervoy alone.
oThere were no TEAEs leading to discontinuation or death.

Final data from ILLUMINATE-204 is planned for submission to a medical meeting in the second half of 2020.

"The outcomes from this study encourage our belief that the combination of tilsotolimod and ipilimumab may provide a much-needed treatment option for advanced melanoma patients who have limited available therapies," stated Elizabeth Tarka, M.D., Idera’s Chief Medical Officer. "We are looking forward to completing our registrational trial for this indication, ILLUMINATE-301, where a comparator arm is included, and moving this potential therapy one step closer to patients in need."

Continued Dr. Tarka, "As with many of our peers, we are intently monitoring the COVID-19 pandemic and its potential effect on the ILLUMINATE-301 trial. We are working closely with our investigators and partners and taking proactive steps to help protect the safety of our study participants and clinical trial staff while also ensuring the scientific integrity of the trial data. Based on what we know today, and while recognizing the environment could rapidly change, we currently expect to achieve our target of sharing key topline data from the trial in the first quarter of 2021."

About ILLUMINATE-204

ILLUMINATE-204 is a multi-center, two-arm Phase 1/2 trial that tested the safety and effectiveness of tilsotolimod in combination with either Yervoy (ipilimumab) or Keytruda (pembrolizumab) in patients with anti-PD-1 refractory metastatic melanoma. For more information on ILLUMINATE-204, please refer to ClinicalTrials.gov (NCT02644967).

About ILLUMINATE-301

ILLUMINATE-301 is a randomized, phase 3 trial comparing the effectiveness of intratumoral tilsotolimod in combination with ipilimumab with ipilimumab alone in approximately 450 patients with anti-PD-1 refractory advanced melanoma, with a primary endpoint family of ORR per RECIST v1.1 and OS. Key secondary endpoints include durable response rate, time to response, progression-free survival, patient-reported outcomes, and safety. For more information on ILLUMINATE-301, please refer to ClinicalTrials.gov (NCT03445533).

About Anti-PD-1 Refractory Advanced Melanoma

Melanoma is a cancer that begins in a type of skin cell called melanocytes. While melanoma is the least common type of skin cancer, it has a poor prognosis when not detected and treated early. As is the case in many forms of cancer, melanoma becomes more difficult to treat once the disease has spread, or metastasized, beyond the skin to other parts of the body. According to the American Cancer Society, approximately 100,000 people in the US will be diagnosed with invasive melanoma this year. In recent years, pioneering immunotherapies known as checkpoint inhibitors (CPIs) have changed the treatment of advanced melanoma and have become the standard of care, with anti-PD-1 agents being the most commonly used immunotherapy in the first-line setting. These agents work by increasing the ability of the body’s immune system to help detect and fight cancer cells. However, due to primary or acquired resistance mechanisms that exclude or inhibit anti-tumor immune cells, as many as 60% of patients do not benefit from this type of therapy, and up to one-third of initial responders develop resistance to the therapy and ultimately experience disease progression. Today, these refractory patients are left with few options for further treatment, paving the way for novel investigational therapies such as tilsotolimod.

About Tilsotolimod (IMO-2125)

Tilsotolimod is an investigational, synthetic Toll-like receptor 9 agonist. Intratumoral injection of tilsotolimod has been shown to promote both innate and adaptive immune activation. Tumors with an active immune response appear to respond better to CPIs than those that exclude or inhibit anti-tumor immune cells. Tilsotolimod in combination with CPIs may cause regression of locally injected and distant tumor lesions and increase the number of patients who benefit from immunotherapy.

Tilsotolimod has received both Fast Track designation and Orphan Drug designation from the FDA and is being evaluated in multiple tumor types and in combination with multiple checkpoint inhibitors. For more information on tilsotolimod trials, please visit ClinicalTrials.gov.

On April 21, 2020 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that it will announce its first quarter 2020 financial results on Tuesday, May 5, 2020, after the close of the U.S. financial markets (Press release, Clovis Oncology, APR 21, 2020, View Source [SID1234556458]). Clovis’ senior management will host a conference call and live audio webcast at 4:30 p.m. ET to discuss the company’s results in greater detail.

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The conference call is being webcast and can be accessed from the Clovis Oncology website at www.clovisoncology.com. A replay of the webcast will be available for 30 days.

Conference Call Details

Clovis will hold a conference call to discuss fourth quarter and full year 2019 results on Tuesday, May 5 at 4:30 p.m. ET. The conference call will be simultaneously webcast on the Company’s web site at www.clovisoncology.com, and archived for future review. Dial-in numbers for the conference call are as follows: U.S. participants (866) 393-4306, International participants (734) 385-2616, conference ID: 1140127.

On April 21, 2020 Aptose Biosciences Inc. (Nasdaq: APTO; TSX: APS), a clinical-stage company developing highly differentiated therapeutics that target the underlying mechanisms of cancer, reported that it will release its financial results for the quarter ended March 31, 2020, on Tuesday, May 5, 2020, after the close of the market (Press release, Aptose Biosciences, APR 21, 2020, View Source [SID1234556456]).

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Conference Call & Webcast:

Date: Tuesday, May 5, 2020
Time: 5:00 PM Eastern Time
Dial In – Toll-Free: 1 844-882-7834
Dial In – International: 1 574-990-9707
Passcode: 6470926
Webcast: LINK

Replay available through May 19, 2020:

Dial In – Toll-Free: 1 855-859-2056
Dial In – International: 1 404-537-3406
Replay Passcode: 6470926
The live conference call can also be accessed through a link on the Investor Relations section of Aptose’s website at View Source An archived version of the webcast along with a transcript will be available on the company’s website for 30 days.

The press release, the financial statements and the management’s discussion and analysis for the quarter ended March 31, 2020 will be available on SEDAR at www.sedar.com and EDGAR at www.sec.gov/edgar.shtml.

On April 21, 2020 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) approved the use of IMBRUVICA (ibrutinib) in combination with rituximab for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (Press release, AbbVie, APR 21, 2020, View Source [SID1234556455]). This milestone marks the 11th FDA approval for IMBRUVICA since it was first approved in 2013 and the sixth in CLL, the most common form of leukemia in adults.1

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"The gold-standard first-line treatment option for many patients with chronic lymphocytic leukemia who were fit enough to tolerate an aggressive treatment course had been the intravenous chemoimmunotherapy of FCR – that is, until today," said Brian Koffman, M.D., C.M., Chief Medical Officer and Executive Vice President, CLL Society. "The FDA approval of ibrutinib and rituximab regimen is welcome news for these previously untreated patients who have been looking forward to a non-chemotherapy treatment option. The results from ECOG-ACRIN’s E1912 clinical trial in previously untreated, younger adult patients and today’s milestone represent a paradigm shift in how physicians can treat patients with CLL and may enable many to choose a non-chemotherapy treatment option."

The approval is based on positive results from the landmark Phase 3 E1912 study, which was designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). This is the third Phase 3 randomized study in the treatment of previously untreated CLL patients incorporated into the medicine’s U.S. prescribing information. In addition to the Real-Time Oncology Review (RTOR) pilot program and priority review, the approval was granted under the FDA’s recently established Project Orbis, an initiative of the FDA Oncology Center of Excellence, which provides a framework for submission and review of oncology medicine applications among multiple regulatory agencies worldwide.

"With eleven FDA approvals in six years, this latest CLL label update for IMBRUVICA further underscores the impact of this important medicine in the first-line setting," said Danelle James, M.D., M.A.S., IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie company. "IMBRUVICA enables long-term disease management and now has demonstrated superior progression-free survival compared to a standard chemoimmunotherapy regimen. Today, many patients who were previously considered appropriate for chemotherapy now have an alternative treatment option."

The E1912 study demonstrated previously untreated patients (aged 70 or younger) with CLL lived longer without disease progression – as measured by statistically significant progression-free survival (PFS) – with IMBRUVICA plus rituximab compared to those treated with the potent chemoimmunotherapy regimen comparator of fludarabine, cyclophosphamide and rituximab (FCR). At a median follow-up of 37 months, IMBRUVICA plus rituximab significantly improved PFS compared to FCR (hazard ratio [HR] 0.34; 95% confidence interval [CI]: 0.22-0.52; p<0.0001). With a median follow-up time of 49 months, median overall survival was not reached with a total of 23 deaths: 11 (3%) in the IMBRUVICA plus rituximab and 12 (7%) in the FCR treatment arms. Extended follow-up results from the E1912 study were most recently presented in an oral session at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

In the E1912 study, the most common adverse reactions (occurring in 30% or more of patients) of all Grades in patients treated with IMBRUVICA plus rituximab compared to patients treated with FCR were fatigue (80% vs. 78%), musculoskeletal pain* (61% vs. 35%), diarrhea (53% vs. 27%), rash* (49% vs. 29%), hypertension* (42% vs. 22%), arthralgia (41% vs. 10%), nausea (40% vs. 64%), headache (40% vs. 27%), bruising* (36% vs. 4%), cough (32% vs. 25%) and hemorrhage* (31% vs. 8%).

The recommended dosage of IMBRUVICA for CLL/SLL is 420 mg orally once a day until disease progression or unacceptable toxicity. For adults with CLL/SLL, IMBRUVICA can be administered as a single agent, in combination rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR). When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.

*Includes multiple adverse drug reaction terms.

About the E1912 Study2
The Phase 3 E1912 study evaluated 529 previously untreated CLL patients ages 70 or younger (median age of 58) who were randomly assigned in a 2:1 fashion to receive IMBRUVICA plus rituximab (N=354) or the chemoimmunotherapy FCR (N=175). The primary endpoint was PFS.

The study was led by ECOG-ACRIN with study site participation by groups in the NCI’s National Clinical Trials Network (Alliance for Clinical Trials in Oncology, ECOG-ACRIN, NRG Oncology and SWOG), and was sponsored by the NCI. Pharmacyclics LLC supported the study through a Cooperative Research and Development Agreement with the NCI.

About IMBRUVICA
IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics, LLC, an AbbVie Company and Janssen Biotech, Inc. The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.3,4 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.5

Since its launch in 2013, IMBRUVICA has received 11 FDA approvals across six disease areas: chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström’s macroglobulinemia (WM); previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.6

IMBRUVICA is now approved in 95 countries and has been used to treat more than 195,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

In early 2019, the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and it is the only Category 1 treatment for treatment-naïve patients without deletion 17p. In February 2020, the NCCN Guidelines were updated to elevate IMBRUVICA with or without rituximab from other recommended regimens to a preferred regimen for the treatment of relapsed/refractory MCL.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. For more information, visit www.IMBRUVICA.com.

*Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA in 27 clinical trials. Bleeding events, including bruising and petechiae, occurred in 39% of patients who received IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

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

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients who received IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: In 645 patients with B?cell malignancies who received IMBRUVICA as a single agent, Grade 3 or 4 neutropenia occurred in 23% of patients, Grade 3 or 4 thrombocytopenia in 8% and Grade 3 or 4 anemia in 3%, based on laboratory measurements.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,476 patients who received IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%), including non-skin carcinomas (4%), occurred among the 1,476 patients who received IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA 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 IMBRUVICA and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥30%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (54.5%)*, diarrhea (43.8%), fatigue (39.1%), musculoskeletal pain (38.8%), neutropenia (38.6%)*, rash (35.8%), anemia (35.0%)*, and bruising (32.0%).

The most common Grade ≥ 3 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (20.7%)*, thrombocytopenia (13.6%)*, pneumonia (8.2%), and hypertension (8.0%).

Approximately 9% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce recommended IMBRUVICA dose and monitor more frequently for adverse reactions of IMBRUVICA.