On May 5, 2021 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma (Press release, Merck & Co, MAY 5, 2021, View Source [SID1234579191]). This indication is approved under accelerated approval based on tumor response rate and durability of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. This approval is based on data from the ongoing Phase 3 KEYNOTE-811 trial, in which KEYTRUDA in combination with trastuzumab and either 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin demonstrated a statistically significant objective response rate (ORR) of 74% (95% CI, 66-82) for patients who received the regimen with KEYTRUDA versus 52% (95% CI, 43-61) for those who received trastuzumab and chemotherapy alone (p<0.0001). For patients who received the regimen with KEYTRUDA, the complete response rate was 11% and the partial response rate was 63%. For patients who received trastuzumab and chemotherapy alone, the complete response rate was 3.1% and the partial response rate was 49%.

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Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see "Selected Important Safety Information" below.

"Today’s approval marks an important milestone, as this is the first time an anti-PD-1 therapy has been approved in combination with anti-HER2 therapy and chemotherapy as a first-line treatment for these patients," said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. "From the start of KEYTRUDA’s development, we have thoughtfully pursued novel combinations to help more patients with cancer. We are pleased to bring a new first-line combination regimen with KEYTRUDA that has shown meaningful improvement in ORR over standard treatment to patients with HER2-positive gastric and GEJ cancer."

This submission was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program.

Data Supporting the Approval

The approval was based on data from KEYNOTE-811 (ClinicalTrials.gov, NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial that was designed to enroll 692 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Randomization was stratified by PD‑L1 expression (Combined Positive Score [CPS] ≥1 or CPS <1), chemotherapy regimen (5-fluorouracil [5-FU] plus cisplatin [FP regimen] or capecitabine plus oxaliplatin [CAPOX regimen]), and geographic region (Europe/Israel/North America/Australia, Asia or Rest of the World). Patients were randomized (1:1) to receive one of the following treatment arms:

KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to six cycles and 5-FU 800 mg/m2/day for five days (FP) or oxaliplatin 130 mg/m2 up to six to eight cycles and capecitabine 1,000 mg/m2 bid for 14 days (CAPOX). KEYTRUDA was administered prior to trastuzumab and chemotherapy on Day 1 of each cycle; or
Placebo, trastuzumab, followed by investigator’s choice of chemotherapy regimen: FP regimen or CAPOX regimen, dosed as above
All study medications, except oral capecitabine, were administered as an intravenous infusion for every three-week cycle. Treatment with KEYTRUDA continued until RECIST v1.1‑defined progression of disease as determined by blinded independent central review (BICR), unacceptable toxicity or a maximum of 24 months. In an interim efficacy analysis, major outcome measures assessed were ORR and duration of response (DOR) by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

At the time of the interim analysis, ORR and DOR were assessed in the first 264 patients randomized. Among the 264 patients, the population characteristics were: median age of 62 years (range, 19 to 84), 41% age 65 or older; 82% male; 63% white, 31% Asian and 0.8% Black; 47% Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, and 53% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (stage IV), and 3% had locally advanced unresectable disease. Eighty-seven percent had tumors that expressed PD‑L1 with a CPS ≥1. Ninety-one percent (n=240) had tumors that were not microsatellite instability-high (MSI‑H), 1% (n=2) had tumors that were MSI‑H, and in 8% (n=22), the status was not known. Eighty-seven percent of patients received CAPOX.

A statistically significant improvement in ORR was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. Efficacy results showed:

Endpoint

KEYTRUDA + Trastuzumab
+ Fluoropyrimidine and
Platinum Chemotherapy
(n=133)

Placebo + Trastuzumab +
Fluoropyrimidine and
Platinum Chemotherapy
(n=131)

ORR

ORR* (95% CI)

74% (66, 82)

52% (43, 61)

Complete response rate

11%

3.1%

Partial response rate

63%

49%

p-value†

<0.0001

DOR

n=99

n=68

Median in months (range)

10.6 (1.1+, 16.5+)

9.5 (1.4+, 15.4+)

% with duration ≥ 6 months

65%

53%

* Response: Best objective response as confirmed complete response or partial response

† p-value based on stratified Miettinen and Nurminen method (compared to an alpha boundary of 0.002)

The safety analysis of the study included 217 patients with HER2-positive gastric cancer who received KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every three weeks, compared to 216 patients who received placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every three weeks. The median duration of exposure to KEYTRUDA was 5.8 months (range, 1 day to 17.7 months). KEYTRUDA and placebo were discontinued due to adverse reactions in 6% of patients in each arm. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased aspartate aminotransferase (AST) (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased alanine aminotransferase (ALT) (2.3%) and vomiting (2.3%).

In the KEYTRUDA arm versus placebo, there was a difference of ≥5% in the incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs. 44%) and nausea (49% vs. 44%). There were no clinically meaningful differences in the incidence of Grade 3-4 toxicity between the two arms.

There was a difference of ≥5% in the incidence between patients treated with KEYTRUDA versus standard of care for increased ALT (34% vs. 29%) and increased creatinine (20% vs. 10%). There were no clinically meaningful differences in the incidence of Grade 3-4 toxicity between the two arms.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. 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 confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, and fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

in combination with platinum- and fluoropyrimidine-based chemotherapy, or
as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD L1 (CPS ≥10) as determined by an FDA approved test.
Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. 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 KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 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 adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus 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 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. 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, including 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, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).

The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, and weight loss.

Adverse reactions occurring in patients with gastric cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).

Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

Adverse reactions occurring in patients with cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC (n=596) who had not been previously treated with chemotherapy in the metastatic setting, fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy, the most common were: pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common adverse reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were: fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

Pediatric Use

In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months).

Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About the Merck Access Program for KEYTRUDA

At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help appropriate patients who are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The Merck Access Program provides reimbursement support for patients receiving KEYTRUDA, including information to help with out-of-pocket costs and co-pay assistance for eligible patients. More information is available by calling 855-257-3932 or visiting www.merckaccessprogram-keytruda.com.

About Merck’s Patient Support Program for KEYTRUDA

Merck is committed to helping provide patients and their caregivers support throughout their treatment with KEYTRUDA. The KEY+YOU Patient Support Program provides a range of resources and support. For further information and to sign up, eligible patients may call 85-KEYTRUDA (855-398-7832) or visit www.keytruda.com.

On May 5, 2021 bluebird bio, Inc. (NASDAQ: BLUE) reported financial results and business highlights for the first quarter ended March 31, 2021 and shared recent operational progress (Press release, bluebird bio, MAY 5, 2021, View Source [SID1234579190]).

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"Undoubtedly the highlight of last quarter at bluebird was the approval of Abecma, the first and only CAR T therapy approved for the treatment of relapsed or refractory multiple myeloma," said Nick Leschly, chief bluebird. "We and our colleagues at BMS are now full speed ahead and on track to begin treating patients this quarter. It has been an amazing journey and in many ways, we’re just getting started. While the oncology team has been delivering on Abecma, the severe genetic disease team met the moment. We quickly completed an investigation of the SUSAR of AML in our HGB-206 study of LentiGlobin gene therapy for SCD and determined that it was highly unlikely to be due to BB305 lentiviral vector. With these data and the other event changed from an MDS diagnosis to transfusion-dependent anemia, we are now quickly moving to engage with regulators with a goal of lifting the clinical holds in mid-2021. Amidst these challenges and work towards the planned separation, I want to commend and thank all birds for truly demonstrating anti-fragility and continuing to keep patients at the center of everything we do."

BUSINESS SEPARATION UPDATE

Today, bluebird bio is providing additional detail regarding the company’s planned business separation, which is targeted for completion by year-end 2021.

bluebird bio

bluebird bio is announcing that Tom Klima will join the company as chief commercial officer. Tom brings a track record of success across multiple commercial roles in oncology and rare diseases, most recently at Gamida Cell Ltd., where he served as chief commercial officer.

Additional members of the bluebird bio leadership team focused on severe genetic diseases will include:

Andrew Obenshain, chief executive officer (previously-disclosed)
Jason Cole, chief business officer
Rich Colvin, interim chief medical officer
Anne-Virginie Eggiman, senior vice president, regulatory science
"As we move towards separation, I’m pleased to have key leadership team members in place that are poised to bring bluebird bio to its next phase of success," said Andrew Obenshain. "With the addition of Tom Klima to lead our commercial efforts, we are rounding out our team of experts with a deep level of expertise from early stage clinical development to commercial delivery. I’m excited about our path forward and look forward to continuing to expand the bluebird team to bring gene therapy to patients with severe genetic diseases."

Oncology NewCo – 2seventy bio

Today, the company is announcing that Oncology NewCo will be named 2seventy bio and members of the leadership team will include:

Nick Leschly, chief executive officer (previously-disclosed)
Chip Baird, chief financial officer
Philip Gregory, chief scientific officer
Nicola Heffron, chief operating officer
"Two hundred seventy miles per hour is the maximum speed of human thought," said Nick Leschly, chief executive officer. "The name 2seventy was selected to signify this speed and our team’s translation of thought to action as we advance our next generation pipeline of transformative cell therapies to help cancer patients urgently in need."

RECENT HIGHLIGHTS

MULTIPLE MYELOMA

ABECMA FDA APPROVAL – On March 26, 2021, bluebird bio and Bristol-Myers Squibb announced that the U.S. Food and Drug Administration (FDA) approved Abecma (idecabtagene vicleucel; ide-cel) as the first B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Abecma is a personalized immune cell therapy approved as a one-time infusion with a recommended dose range of 300 to 460 x 106 CAR-positive T cells.
KARMMA NEJM PUBLICATION– On February 24, 2021, bluebird bio and Bristol-Myers Squibb announced that results from the pivotal Phase 2 KarMMa study were published in The New England Journal of Medicine. The KarMMa study met its primary endpoint of overall response rate and key secondary endpoint of complete response rate. The data from the study demonstrates deep and durable responses with ide-cel treatment in triple-class exposed RRMM patients (n=128).
SICKLE CELL DISEASE

CLINICAL STUDIES UPDATE – On April 20, 2021, bluebird bio announced a revised diagnosis for the previously reported case of myelodysplastic syndrome (MDS) in its Phase 1/2 study of LentiGlobin for sickle cell disease (SCD) (bb1111). Upon further assessment, the treating investigator concluded this is not a case of MDS and revised the diagnosis to transfusion-dependent anemia. In addition, on March 10, 2021, bluebird bio reported that it is very unlikely the suspected unexpected serious adverse reaction (SUSAR) of acute myeloid leukemia (AML) reported in the HGB-206 study of LentiGlobin for SCD was related to the BB305 lentiviral vector (LVV). bluebird bio continues to work with regulators to resume its clinical studies in sickle cell disease as well as to remove the clinical hold for HGB-207 and HGB-212 clinical studies of beti-cel for β-thalassemia, with potential lift of all clinical holds in mid-2021.
CEREBRAL ADRENOLEUKODYSTROPHY

ELI-CEL DATA AT EBMT– On March 15, 2021, bluebird bio presented new data suggesting durability of response and a strong safety profile post elivaldogene autotemcel (eli-cel, Lenti-D) gene therapy in patients with cerebral adrenoleukodystrophy (CALD) at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2021). Long-term results from the Phase 2/3 Starbeam study of eli-cel, showed that ninety percent of patients (27/30) are alive and free of major functional disabilities (MFDs) at 24 months or more of follow-up. In the 51 patients treated with eli-cel in clinical studies (ALD-102/LTF-304 and ALD-104) there were no reports of graft failure, graft rejection, GVHD, replication competent lentivirus or insertional oncogenesis.
PIPELINE

BILL & MELINDA GATES FOUNDATION GRANT TO EXPLORE IN-VIVO LVV APPLICATIONS – bluebird bio is announcing today that it has received a grant from the Bill & Melinda Gates Foundation to explore new, potentially transformative in vivo treatments for SCD using the Company’s proprietary lentiviral vector (LVV) platform. The funding will support the research and development of novel LVVs that target hematopoietic stem cells (HSCs) for in vivo administration to bring gene-based therapies for SCD and other potential indications to patients around the world who may have limited access to ex vivo and other emerging therapies. This research may also enable the application of in-vivo LVV approaches in other severe genetic diseases.
PSIOXUS PRE-CLINICAL DATA – On April 14, 2021, bluebird bio and PsiOxus Therapeutics presented preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021. The results showed synergistic activity between PsiOxus’ T-SIGn vector and bluebird bio’s CAR-T therapy in primary and metastatic solid tumors. A single IV cycle of PsiOxus’ T-SIGn vector enabled an otherwise non-effective dose of CAR-T cell therapy to clear primary and metastatic tumors in vivo.
COMPANY

BUSINESS OPERATIONS – On April 20, 2021 bluebird bio announced its decision to withdraw ZYNTEGLO (betibeglogene autotemcel, beti-cel) for transfusion-dependent β-thalassemia (TDT) from the German market because reimbursement negotiations in Germany did not result in a price for ZYNTEGLO that reflects the value of this one-time gene therapy with potential life-long benefit for people living with TDT. Due in part to this decision, the company also announced a targeted reshaping of its workforce intended to enable the company to advance its late-stage gene therapy programs. This reduction and reallocation of resources will allow the company to focus on priority European markets and streamline global operations going forward to ensure its ability to deliver gene therapies to patients.
UPCOMING ANTICIPATED MILESTONES

Regulatory Outlook

SCD: The company is investigating the recently-reported safety events and plans to continue to work closely with the FDA in their review of these events to provide an update on the Company’s development plan and timeline for submission for regulatory approval by year end.
TDT: The company is on track to complete its rolling BLA submission to the U.S. FDA for beti-cel in mid-2021, contingent upon successful resolution of any U.S. FDA concerns applicable to the program arising out of the recently-reported safety events in the SCD program. This submission is anticipated to include adult, adolescent and pediatric patients with transfusion dependent β-thalassemia across all genotypes (including non-β0/β0 genotypes and β0/β0 genotypes).
CALD: The company is on track to complete its BLA submission to the U.S. FDA for eli-cel in mid-2021. The company plans to receive European approval for eli-cel in patients with CALD in mid-2021.
Clinical Updates and Milestones

Updated data from ongoing clinical study in patients with SCD by the end of 2021.
Updated data from ongoing clinical studies in patients with TDT in mid-2021.
Updated clinical data from the ongoing pivotal Phase 2 KarMMa study of Abecma (ide-cel, bb2121) in patients with relapsed and refractory multiple myeloma to be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 (ASCO21) Virtual Scientific Program on June 4.
bb21217 clinical data from the ongoing CRB-402 study in patients with multiple myeloma by the end of 2021.
Submission of 1 – 2 investigational new drug (IND) applications by the end of 2021.
Commercial and Foundation Building

Abecma first commercial patients treated in the first half of 2021.
Company

bluebird bio anticipates the separation of its severe genetic disease and oncology businesses into two independent, publicly traded companies (bluebird bio and 2seventy bio) to be completed by the end of 2021.
FIRST QUARTER 2021 FINANCIAL RESULTS

Cash Position: Cash, cash equivalents and marketable securities as of March 31, 2021 and December 31, 2020 were $1.09 billion and $1.27 billion, respectively. The decrease in cash, cash equivalents and marketable securities is primarily related to cash used in support of ordinary course operating activities.
Revenues: Total revenues were $12.8 million for the three months ended March 31, 2021 compared to $21.9 million for the three months ended March 31, 2020. The decrease was primarily driven by a decrease in ide-cel license and manufacturing services revenue and a decrease in revenue recognized in connection with treating patients in the Phase 1 CRB-402 study of bb21217 under our agreements with BMS.
R&D Expenses: Research and development expenses were $154.5 million for the three months ended March 31, 2021 compared to $154.1 million for the three months ended March 31, 2020. The increase was primarily driven by increased costs incurred through the amended BMS collaboration as well as an increase in employee compensation, benefit, and other headcount related expenses. These increased costs were partially offset by a decrease in manufacturing costs.
SG&A Expenses: Selling, general and administrative expenses were $86.9 million for the three months ended March 31, 2021 compared to $73.2 million for the three months ended March 31, 2020. The increase was primarily driven by increased employee compensation, benefit, and other headcount related expenses, as well as an increase in consulting fees associated with the ongoing project to separate the Company’s severe genetic disease and oncology programs into two independently traded companies. These increased costs were partially offset by a decrease in costs related to commercial readiness activities due to delays in commercialization as a result of the COVID-19 pandemic and in light of safety events in the HGB-206 study of LentiGlobin gene therapy for SCD.
Net Loss: Net loss was $205.8 million for the three months ended March 31, 2021 compared to $202.6 million for the three months ended March 31, 2020.

On May 5, 2021 Alector, Inc. (Nasdaq: ALEC), a clinical-stage biotechnology company pioneering immuno-neurology, reported business updates and financial results for the first quarter ended March 31, 2021 (Press release, Alector, MAY 5, 2021, View Source [SID1234579189]).

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"Positive momentum continues to build throughout our early and late-stage product pipeline," said Arnon Rosenthal, Ph.D., co-founder and chief executive officer of Alector. "Our pivotal AL001 INFRONT-3 Phase 3 trial and AL002 INVOKE-2 placebo-controlled Phase 2 trial continue to enroll patients, and we look forward to sharing additional data from the AL001 Phase 2 clinical development program in people with FTD-GRN this summer at AAIC. In parallel, we continue to prepare for the initiation of a Phase 2 study evaluating AL001 in people with amyotrophic lateral sclerosis and advance our early-stage novel immuno-oncology candidates toward first-in-human studies. This is an exciting time for Alector and we look forward to continued execution on our clinical and corporate objectives."

Key Business Updates

Progranulin Portfolio:

Alector plans to present updated data from the ongoing AL001 Phase 2 open-label study at the upcoming Alzheimer’s Association International Conference (AAIC), taking place July 26-30, 2021.

Enrollment is ongoing in INFRONT-3, a randomized, placebo-controlled, pivotal Phase 3 trial evaluating AL001 in people at risk for or with frontotemporal dementia due to a progranulin gene mutation (FTD-GRN). The ongoing pivotal trial is evaluating the efficacy and safety of AL001 in at-risk and symptomatic participants with FTD-GRN. Participants in the trial will be given the option to continue receiving treatment in an open-label extension study.

The Company is on track to initiate a Phase 2 study evaluating AL001 in people with amyotrophic lateral sclerosis (ALS) caused by C9orf72 repeats, which share TDP-43 pathology with FTD-GRN in the second half of 2021.
Alzheimer’s Disease Portfolio:

Alector continues patient enrollment in INVOKE-2, a Phase 2 trial evaluating AL002 in people with early Alzheimer’s disease. The randomized, double-blind, placebo-controlled, dose-ranging, multi-center Phase 2 study is expected to enroll approximately 265 participants with early Alzheimer’s disease (AD) at up to 90 sites globally. The AL002 clinical program is being developed in collaboration with AbbVie.

Alector plans to present two posters highlighting AL002 at AAIC, taking place July 26-30, 2021. The first poster will include the results of the AL002 Phase 1 study in healthy volunteers and the second poster will highlight the study design of the ongoing INVOKE-2 trial in people with early AD.

Data from the Phase 1b study evaluating AL003 in participants with AD is expected in 2021. Alector initiated the Phase 1b study in January 2020 and completed enrollment in 2020. The AL003 clinical development program is being developed in collaboration with AbbVie. Preliminary results from the study are expected to be presented at a scientific medical meeting in the second half of 2021.
Early-Stage Pipeline with Potential in Neurodegenerative Diseases and Oncology

The Company continues to progress AL044, a first-in-class antibody targeting the MS4A4A receptor. MS4A4A is a major risk gene for AD that encodes a transmembrane receptor protein that is expressed selectively in microglia in the brain and is associated with control of microglia functionality and potential viability.

Planning is underway to initiate first-in-human studies for AL008 and AL009, two oncology programs, in 2022. AL008 is a novel, investigational, antibody product candidate with a dual mechanism of action that combines inhibition of the CD47-SIRP-alpha (SIRPα) pathway with stimulation of activating Fc receptors and has the potential to yield a best-in-class product. AL009 is a first-in-class multi-Siglec inhibitor that works to enhance the innate and adaptive immune system response by blocking a critical glycan checkpoint pathway that drives immune inhibition.
First Quarter 2021 Financial Results

Revenue. Collaboration revenue for the quarter ended March 31, 2021, was $4.1 million, compared to $7.2 million for the same period in 2020. Revenue is recognized as the program costs are incurred by measuring actual costs incurred to date compared to the overall total expected costs to satisfy the performance obligation. Changes in estimates for revenue recognized over time are recognized on a cumulative basis.

R&D Expenses. Total research and development expenses for the quarter ended March 31, 2021, were $45.7 million, compared to $34.6 million for the same period in 2020. This increase was mainly driven by an increase in expenses to support the advancement of clinical and pre-clinical programs across several therapeutic initiatives as well as an increase in personnel-related expenses.

G&A Expenses. Total general and administrative expenses for the quarter ended March 31, 2021, were $11.1 million, compared to $14.6 million for the same period in 2020. This decrease was primarily due to a decrease in legal fees related to the conclusion of our arbitration proceedings for certain intellectual property matters.

Net Loss. For the quarter ended March 31, 2021, Alector reported a net loss of $52.2 million, compared to a net loss of $40.0 million for the same period in 2020.

Cash Position. Cash, cash equivalents, and marketable securities were $362.7 million as of March 31, 2021.

On May 5, 2021 Emergent BioSolutions Inc. (NYSE: EBS) reported that members of the company’s senior management team will participate in the following investor conferences (Press release, Emergent BioSolutions, MAY 5, 2021, View Source [SID1234579188]):

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Goldman Sachs Credit and Leveraged Finance Conference
May 17, 2021
1-on-1 meetings only
Benchmark Company Healthcare House Call Conference
May 26, 2021
1-on-1 meetings only
Singular Research Spring Select Webcall
May 27, 2021
Company presentation scheduled at 8:00 am Pacific / 11:00 am Eastern
For conferences where a presentation is planned, the company’s webcast presentation may include a discussion of the company’s recent business developments as well as its financial results and guidance. The webcast will be available both live, if possible, and by replay, and will be accessible from the Emergent website.

On May 5, 2021 MorphoSys AG (FSE:MOR; NASDAQ:MOR) reported its financial results for the first quarter of 2021 (Press release, MorphoSys, MAY 5, 2021, View Source [SID1234579187]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"For 2021, our focus is on three key areas: executing on the Monjuvi launch; rapidly advancing the tafasitamab backbone strategy through additional clinical studies; and expanding our pipeline," said Jean-Paul Kress, M.D., Chief Executive Officer of MorphoSys. "While we experienced headwinds from the pandemic in the first quarter, we are cautiously optimistic that the COVID-19 impact in the U.S. will start to diminish in the second half of 2021. We are confident in the potential of Monjuvi given its broad second-line label and overall profile in the r/r DLBCL setting. We are also making important progress initiating key trials for both tafasitamab and felzartamab this year."

Tafasitamab Highlights

Monjuvi(R) (tafasitamab-cxix) U.S. net product sales of € 12.9 million (US$ 15.5 million).
Monjuvi was granted a product-specific HCPCS J-Code, effective April 1, 2021.
On January 5, 2021, MorphoSys and Incyte announced that the Swiss Agency for Therapeutic Products (Swissmedic) had accepted the marketing authorization application (MAA) for tafasitamab and on January 12, 2021, MorphoSys and Incyte announced that Health Canada had accepted the New Drug Submission (NDS) for tafasitamab. Both applications seek approval for tafasitamab, in combination with lenalidomide, followed by tafasitamab monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from low grade lymphoma, who are not eligible for, or refuse, autologous stem cell transplantation (ASCT).
Pipeline Highlights

Felzartamab:

M-PLACE study of felzartamab in autoimmune membranous nephropathy ongoing: the safety run-in phase was completed and the full enrollment phase opened.
In February 2021, the first patient with autoimmune membranous nephropathy was dosed with felzartamab in the New-PLACE study, a phase 2 study evaluating different treatment schedules to identify the regimen for the pivotal study.
Otilimab:

On March 2, 2021, we announced that our partner GSK reported preliminary results of the OSCAR study using otilimab for the treatment of severe pulmonary COVID-19 related disease. Given these data suggest an important clinical benefit in a pre-defined sub-group of high-risk patients and the urgent public health need, GSK has amended the OSCAR study to expand this cohort to confirm these potentially significant findings. The dosing of the first patient in the expanded study triggered milestone payments totaling € 16 million to MorphoSys.
MOR210:

On January 25, 2021, MorphoSys and I-Mab announced that the first patient has been dosed in a phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of MOR210/TJ210 monotherapy in patients with relapsed or refractory advanced solid tumors in the United States.
Corporate Updates

On January 6, 2021, MorphoSys announced the appointment of Sung Lee as Chief Financial Officer, effective as of February 2, 2021.
Significant Events After The Reporting Period

On April 19, 2021, MorphoSys and Incyte announced that the first patient has been dosed in the placebo-controlled Phase 3 inMIND study evaluating the efficacy and safety of tafasitamab or placebo in combination with lenalidomide and rituximab in patients with relapsed or refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL).

First Quarter 2021 Financial Results (IFRS)

Total revenues for the quarter ended March 31, 2021 were € 47.2 million compared to € 251.2 million for the comparable period in 2020. The year-over-year decline was driven by the upfront payment of the collaboration and license agreement with Incyte in the first quarter 2020 for the out-licensing of tafasitamab outside the USA.

Cost of Sales: In the first three months of 2021, cost of sales increased to € 5.0 million (3M 2020: € 3.3 million).

Research and Development (R&D) Expenses: In the first three months of 2021, research and development expenses were € 33.3 million (3M 2020: € 21.5 million). Growth over 2020 reflects the increased investment to support the advancement of proprietary programs and consisted primarily of expenses for external laboratory services and personnel expenses.

Selling, General and Administrative (SG&A) Expenses: Selling expenses increased in the first three months of 2021 to € 28.2 million (3M 2020: € 12.8 million) and general and administrative expenses remained almost unchanged at € 10.3 million (3M 2020:€ 10.1 million). The year-over-year increase in selling expenses was primarily driven by the full quarter impact of the expenses for services provided by Incyte as part of the joint U.S. marketing activities for Monjuvi.

Operating Loss: Operating loss amounted to € 29.6 million in the first three months of 2021 (3M 2020: operating profit of € 203.5 million).

Consolidated Net Loss: For the first three months of 2021, consolidated net loss was € 41.6 million (3M 2020: consolidated net profit of € 195.5 million).

Cash and Investments: As of March 31, 2021, the Company had cash and investments of € 1,215.0 million compared to € 1,244.0 million on December 31, 2020.

Number of shares: The number of shares issued remained unchanged since year-end 2020 and totaled 32,890,046.

Financial Guidance and Operational Outlook for 2021

*Group revenues includes the announced € 16 million milestone payments from GSK, but excludes other potential significant milestones from development partners and/or licensing partnerships. This revenue guidance is subject to a number of uncertainties including the potential for variability from the first full year of the Monjuvi product launch, the limited visibility that MorphoSys has on the Tremfya royalty stream as well as the ongoing COVID-19 pandemic and the impact on our as well as our partner’s business operations.

**Operating expenses is comprised of R&D and SG&A, inclusive of Incyte’s share of Monjuvi selling costs in the USA.

MorphoSys expects for Tafasitamab the following events and activities in 2021:

Continuation of the phase 1b trial with tafasitamab in previously untreated DLBCL (firstMIND);
Initiation of a pivotal phase 3 trial of tafasitamab in previously untreated DLBCL (frontMIND);
Continuation of the phase 3 inMIND trial of tafasitamab in patients with relapsed or refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL);
Investigation of tafasitamab, plamotamab and lenalidomide in patients with relapsed or refractory DLBCL, first-line DLBCL and relapsed or refractory follicular lymphoma (r/r FL) jointly with Incyte and Xencor;
Continuation of the L-MIND study of tafasitamab and evaluate the long-term efficacy and safety data;
Continuation of the phase 3 B-MIND study of tafasitamab in combination with bendamustine for r/r DLBCL;
Presentation of data from the 3-year follow up of L-MIND as well as other abstracts at several scientific conferences (e.g. ASCO (Free ASCO Whitepaper), EHA (Free EHA Whitepaper));
Decision on the European Marketing Authorization Application (MAA), seeking approval of tafasitamab in combination with lenalidomide, followed by tafasitamab monotherapy, for the treatment of adult patients with r/r DLBCL which is currently under review;
Support of Incyte in submitting marketing authorization applications in other markets.
MorphoSys will hold its conference call and webcast tomorrow, May 6, 2021, to present the results for the first quarter of 2021 and the further outlook for 2021.

A live webcast and slides will be made available at the Media and Investors section under Conferences on MorphoSys’ website at View Source and after the call, a slide-synchronized audio replay of the conference will be available at the same location.

The interim statement for the first quarter of 2021 (IFRS) is available online:
View Source/Reports

About tafasitamab
Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb(R) engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

Monjuvi(R) (tafasitamab-cxix) is approved by the U.S. Food and Drug Administration in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In January 2020, MorphoSys and Incyte entered into a collaboration and licensing agreement to further develop and commercialize tafasitamab globally. Monjuvi(R) is being co-commercialized by Incyte and MorphoSys in the United States. Incyte has exclusive commercialization rights outside the United States.

A marketing authorization application (MAA) seeking the approval of tafasitamab in combination with lenalidomide in the EU has been validated by the European Medicines Agency (EMA) and is currently under review for the treatment of adult patients with relapsed or refractory DLBCL, including DLBCL arising from low grade lymphoma, who are not candidates for ASCT.

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in a number of ongoing combination trials.

Monjuvi(R) is a registered trademark of MorphoSys AG.
XmAb(R) is a registered trademark of Xencor, Inc.