On September 10, 2019 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that first-line treatment with KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemotherapy demonstrated improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in a pooled analysis of a subgroup of patients with advanced nonsquamous and squamous non-small cell lung cancer (NSCLC) whose tumors do not express PD-L1 (tumor proportion score [TPS] <1%) from three randomized trials. Patients with nonsquamous NSCLC with EGFR or ALK genomic tumor aberrations were ineligible (Press release, Merck & Co, SEP 10, 2019, View Source [SID1234539398]). Results – from KEYNOTE-189, KEYNOTE-407 and KEYNOTE-021 (Cohort G) – were consistent with those observed in the overall study populations across all three trials. Findings were featured in an oral presentation at the IASLC 2019 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer in Barcelona, Spain (Abstract #MA25.01).

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"The goal of our robust lung cancer clinical development program has always been to extend survival for patients who are diagnosed with this deadly and aggressive disease," said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. "In this pooled analysis of three randomized KEYNOTE studies in advanced non-small cell lung cancer, KEYTRUDA in combination with chemotherapy demonstrated an improvement in overall survival compared to chemotherapy alone among newly diagnosed patients whose tumors do not express PD-L1."

Findings from the pooled subgroup analysis of 428 patients showed that KEYTRUDA in combination with chemotherapy reduced the risk of death by 44% (HR=0.56 [95% CI, 0.43-0.73]) compared to chemotherapy alone. The KEYTRUDA-chemotherapy combinations also reduced the risk of disease progression or death by 33% (HR=0.67 [95% CI, 0.54-0.84]) compared to chemotherapy alone. The ORR was 46.9% for patients treated with the KEYTRUDA-chemotherapy combinations versus 28.6% for those treated with chemotherapy alone. The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with advanced NSCLC.

"KEYTRUDA in combination with chemotherapy has become an important first-line therapy for appropriate patients with advanced non-small cell lung cancer based on the overall survival benefit observed in clinical trials," said Dr. Hossein Borghaei, chief, Division of Thoracic Oncology, Fox Chase Cancer Center. "It is encouraging to see that in this subgroup analysis, first-line KEYTRUDA in combination with chemotherapy reduced the risk of death by 44% in patients with nonsquamous or squamous advanced non-small cell lung cancer whose tumors do not express PD-L1."

Additional Data from Pooled Subgroup Analysis of KEYNOTE-189, KEYNOTE-407 and KEYNOTE-021 (Cohort G)

Data presented at WCLC are from a pooled subgroup of 428 previously untreated patients whose tumors do not express PD-L1 (TPS <1%) from the KEYNOTE-189 (nonsquamous NSCLC; n=190), KEYNOTE-407 (squamous NSCLC; n=194) and KEYNOTE-021 (nonsquamous NSCLC; n=44 [Cohort G]) trials. Patients were randomized to receive KEYTRUDA 200 mg every three weeks plus chemotherapy (n=243) or chemotherapy alone (n=185). Patients with nonsquamous NSCLC received pemetrexed (ALIMTA) and platinum chemotherapy; patients with squamous NSCLC received carboplatin and either paclitaxel or nab-paclitaxel. Patients with nonsquamous NSCLC with EGFR or ALK genomic tumor aberrations were ineligible. Key efficacy outcome measures include OS, PFS and ORR.

With a median follow-up of 10.2 months, KEYTRUDA in combination with chemotherapy reduced the risk of death by 44% (HR=0.56 [95% CI, 0.43-0.73]) compared to chemotherapy alone. Estimated 12-month OS rates were 66% with the KEYTRUDA-chemotherapy combinations compared to 47% with chemotherapy alone; the 18-month OS rates were 52% and 29%, respectively. Median OS was 19.0 months (95% CI, 15.2-24.0) with the KEYTRUDA-chemotherapy combinations compared to 11.0 months (95% CI, 9.2-13.5) with chemotherapy alone.

The KEYTRUDA-chemotherapy combinations also reduced the risk of disease progression or death by 33% (HR=0.67 [95% CI, 0.54-0.84]) compared to chemotherapy alone. Estimated 12-month PFS rates were 29% with the KEYTRUDA-chemotherapy combinations compared to 17% with chemotherapy alone; the 18-month PFS rates were 22% and 9%, respectively. Median PFS was 6.5 months (95% CI, 6.2-8.5) with the KEYTRUDA-chemotherapy combinations compared to 5.4 months (95% CI, 4.7-6.2) with chemotherapy alone.

The ORR was 46.9% (n=114) for patients who received the KEYTRUDA-chemotherapy combinations and 28.6% (n=53) for those who received chemotherapy alone. Median DOR was 7.9 months (range, 1.1+ to 28.4+) with the KEYTRUDA-chemotherapy combinations and 6.7 months (range, 1.4+ to 30.1+) with chemotherapy alone. For patients receiving the KEYTRUDA- chemotherapy combinations, 42.4% experienced a response lasting 12 months or longer compared to 35.3% of those receiving chemotherapy alone.

Among patients who received KEYTRUDA in combination with chemotherapy, 68% (n=165) experienced a Grade 3-5 adverse event (AE) compared to 72% (n=131) of those who received chemotherapy alone. Grade 3-5 AEs that led to death occurred in 9% (n=23) of patients who received the KEYTRUDA-chemotherapy combinations and 6% (n=11) of those who received chemotherapy alone. Grade 3-5 immune-mediated AEs and infusion reactions occurred in 11% (n=27) of patients who received the KEYTRUDA-chemotherapy combinations compared to 3% (n=5) of those who received chemotherapy alone. Deaths resulting from immune-mediated AEs and infusion reactions occurred in 1% (n=2) of patients who received the KEYTRUDA-chemotherapy combinations compared to no deaths among patients who received chemotherapy alone.

The KEYNOTE-021 (Cohort G) and KEYNOTE-189 studies were conducted in collaboration with Eli Lilly and Company, the makers of pemetrexed (ALIMTA).

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon and breast cancers combined. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. Small cell lung cancer (SCLC) accounts for about 10 to 15% of all lung cancers. Between 2008 and 2014, the five-year survival rate for patients diagnosed in the U.S. with advanced NSCLC was only 5%.

About KEYTRUDA (pembrolizumab) Injection, 100mg

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 1,000 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.

KEYTRUDA (pembrolizumab) Indications

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.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of 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 confirmatory trials.

Head and Neck 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 and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of 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.

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. 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 confirmatory trials. KEYTRUDA is not recommended for the 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 the 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.

Microsatellite Instability-High (MSI-H) 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.

Gastric Cancer

KEYTRUDA 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 Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

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. 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).

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grade 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination with Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes 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.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%), receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including cHL, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

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 a PD-1 or PD-L1 blocking antibody 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%).

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

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-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% included 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%).

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

Adverse reactions occurring in patients with esophageal cancer 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 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 of which (≥1%) included 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 adverse reactions (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib or the combination were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). When KEYTRUDA was used in combination with axitinib, 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%).

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

There is limited experience in pediatric patients. In a trial, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with various cancers, including unapproved usages, were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%), and hyponatremia (18%).

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.

On September 10, 2019 GSK reported that data from its growing oncology pipeline will be presented at the in European Society for Medical Oncology Congress Barcelona, Spain, September 27 – October 01, 2019 (Press release, GlaxoSmithKline, SEP 10, 2019, View Source [SID1234539397]). Data spans nine tumour types, including ovarian and head and neck cancers, and highlight a diverse portfolio of potentially transformational medicines for cancer patients in immuno-oncology, cancer epigenetics, cell therapy and synthetic lethality.

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Results from the Phase 3 PRIMA (ENGOT-OV26/GOG-3012) study of Zejula (niraparib) maintenance treatment for patients with newly diagnosed advanced ovarian cancer will be presented in a Presidential Symposium. In July, positive headline results from the study demonstrated that niraparib could benefit women in the first line maintenance setting independent of biomarker status in a statistically significant and clinically meaningful way, with a safety and tolerability profile consistent with previous clinical trials. Niraparib is not currently approved by regulators in this indication.

"Our presentations at ESMO (Free ESMO Whitepaper) represent the first wave of data across the four focus areas of our new oncology pipeline and show the significant progress we have made in accelerating these potentially transformational medicines," said Dr. Axel Hoos, Senior Vice President and Head Oncology R&D. "We are particularly pleased with the promising data from our late-breaking PRIMA study, which enrolled women with first-line ovarian cancer who were at high risk for recurrence."

Data being presented at ESMO (Free ESMO Whitepaper) include:

Zejula (niraparib)

Niraparib Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer (PRIMA/ENGOT-OV26/GOG 3012)
A Gonzalez, #LBA1, Sep 28, 2019, 16:30 – 18:20, Barcelona Auditorium (Hall 2)
Immune-Related Gene Expression Profiling after Neoadjuvant Chemotherapy (NACT) of Ovarian High-Grade Serous Carcinoma
L M Manso, #1017P, Sep 29, 2019, 12:00 – 13:00, Poster Area (Hall 4)
Clinical Confirmation of Higher Exposure to Niraparib in Tumor vs Plasma in Patients With Breast Cancer
L Spring, #211P, Sep 29, 2019, 12:00 – 13:00, Poster Area (Hall 4)
Evaluation of Niraparib 200 mg/d as Maintenance Therapy in Recurrent Ovarian Cancer and Associated Thrombocytopenia in a Real-World US Setting
P Thaker, #1005P, Sep 29, 2019, 12:00 – 13:00, Poster Area (Hall 4)
GSK3359609: ICOS

Inducible T cell co-stimulatory (ICOS) receptor agonist, GSK3359609 (GSK609) alone and combination with pembrolizumab (pembro): preliminary results from INDUCE-1 expansion cohorts in head and neck squamous cell carcinoma (HNSCC)
D Rischin, #1119PD, Sep 28, 2019, 08:45 – 09:45, Bilbao Auditorium (Hall 5)
Pharmacokinetic/pharmacodynamic (PK/PD) exposure-response characterization of the ICOS agonist mAb GSK3359609 (GSK609) from INDUCE-1, a phase I open-label study
M Maio, #1971P, Sep 30, 2019, 12:00 – 13:00, Poster Area (Hall 4)
Belantamab mafodotin: BCMA

Trials in progress: DREAMM 4: A phase I/II single arm open-label study to explore safety and clinical activity of belantamab mafodotin (GSK2857916) administered in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM)
S Trudel, #1105TiP, Sep 28, 2019, 12:00 – 13:00, Poster Area (Hall 4)
GSK3326595: PRMT5

METEOR-1: A Phase I Study of GSK3326595, a First-In-Class Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor, in Advanced Solid Tumors
L Siu, #438O, Sep 29, 2019, 16:30 – 18:00, Malaga Auditorium (Hall 5)
GSK3377794: NY-ESO-1

Epidemiology of synovial sarcoma in EU28 countries
N Joseph, #1728P, Sep 28, 2019, 12:00 – 13:00, Poster Area (Hall 4)
Trials in progress: Safety and tolerability of autologous T cells with enhanced T-cell receptors specific to NY ESO 1/LAGE 1a (GSK3377794) alone, or in combination with pembrolizumab, in advanced non-small cell lung cancer: A phase 1b/2a randomized pilot study
K L Reckamp, #1590TiP, Sep 28, 2019, 12:00 – 13:00, Poster Area (Hall 4)
NY-ESO-1 and LAGE1A – an emerging target for cell therapies in solid tumours
I Eleftheriadou, #1229P, Sep 30, 2019, 12:00 – 13:00, Poster Area (Hall 4)
GSK1795091: TLR4

Trial in progress: A phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumors
A R Hansen, #511TiP, Sep 28, 2019, 12:00 – 13:00, Poster Area (Hall 4)
Bintrafusp alfa (M7824):

Trials in Progress: Bintrafusp alfa (M7824) and Eribulin Mesylate in Treating Patients With Metastatic Triple Negative Breast Cancer (TNBC)(NCT03579472)
J Litton, 383TiP, Sep 29, 2019, 12:00 – 13:00, Poster Area (Hall 4)
Alliances with ZEJULA (niraparib)

A Prospective Evaluation of Tolerability Of Niraparib Dosing Based on Baseline Body Weight (BW) and Platelet (Plt) Count: Blinded Pooled Interim Safety Data from the NORA Study
X Wu, #1004P, Sep 29, 2019, 12:00 – 13:00, Poster Area (Hall 4)
Trials in progress: A phase 3 randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (NCT03748641)
K Chi, #897TiP, Sep 30, 2019, 12:00 – 13:00, Poster Area (Hall 4)
Pre-specified interim analysis of GALAHAD: A phase 2 study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD)
M R Smith, #LBA50, Sep 29, 2019, 8:30 – 9:45, Malaga Auditorium (Hall 5)
Indication and Usage for ZEJULA

ZEJULA is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Important Safety Information for ZEJULA

Myelodysplastic Syndrome/Acute Myeloid Leukaemia (MDS/AML), including some fatal cases, was reported in 1.4% of patients receiving ZEJULA vs 1.1% of patients receiving placebo in Trial 1 (NOVA), and 0.9% of patients treated with ZEJULA in all clinical studies. The duration of ZEJULA treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received prior chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

Hematologic adverse reactions (thrombocytopenia, anaemia and neutropenia) have been reported in patients receiving ZEJULA. Grade ≥3 thrombocytopenia, anaemia and neutropenia were reported in 29%, 25%, and 20% of patients receiving ZEJULA, respectively. Discontinuation due to thrombocytopenia, anaemia, and neutropenia occurred, in 3%, 1%, and 2% of patients, respectively. Do not start ZEJULA until patients have recovered from haematological toxicity caused by prior chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. If haematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a haematologist for further investigations.

Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA. Grade 3-4 hypertension occurred in 9% of patients receiving ZEJULA vs 2% of patients receiving placebo in Trial 1, with discontinuation occurring in <1% of patients. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Manage hypertension with antihypertensive medications and adjustment of the ZEJULA dose, if necessary.

Based on its mechanism of action, ZEJULA can cause foetal harm. Advise females of reproductive potential of the potential risk to a foetus and to use effective contraception during treatment and for 6 months after receiving their final dose. Because of the potential for serious adverse reactions from ZEJULA in breastfed infants, advise lactating women to not breastfeed during treatment with ZEJULA and for 1 month after receiving the final dose.

In clinical studies, the most common adverse reactions (Grades 1-4) in ≥10% of patients included: thrombocytopenia (61%), anaemia (50%), neutropenia (30%), leukopenia (17%), palpitations (10%), nausea (74%), constipation (40%), vomiting (34%), abdominal pain/distention (33%), mucositis/stomatitis (20%), diarrhoea (20%), dyspepsia (18%), dry mouth (10%), fatigue/asthenia (57%), decreased appetite (25%), urinary tract infection (13%), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation (10%), myalgia (19%), back pain (18%), arthralgia (13%), headache (26%), dizziness (18%), dysgeusia (10%), insomnia (27%), anxiety (11%), nasopharyngitis (23%), dyspnoea (20%), cough (16%), rash (21%) and hypertension (20%).

Common lab abnormalities (Grades 1-4) in ≥25% of patients included: decrease in haemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%) and increase in ALT (28%).

GSK in Oncology

GSK is focused on maximizing patient survival through transformational medicines for people living with cancer. GSK’s pipeline is focused on immuno-oncology, cell therapy, synthetic lethality and cancer epigenetics. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, antibody drug conjugates and cells, either alone or in combination.

On September 10, 2019 University of California, reported the U.S. Patent and Trademark Office (USPTO) granted a new CRISPR-Cas9 patent to the University of California (UC), University of Vienna, and Dr. Emmanuelle Charpentier covering single-molecule guide RNAs or nucleic acid molecules encoding the guide RNAs.

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Today’s patent (U.S. 10,407,697) is the 13th in the university’s U.S. CRISPR-Cas9 portfolio and follows the issuance of 10 other patents in the past six months. Continuing the momentum into the fall, UC expects to further expand its portfolio through the issuance of four additional patents in the near future. In total, the patents that have issued and those that are set to issue bring the university’s portfolio to 17 U.S. CRISPR-Cas9 patents covering various compositions and methods of targeting and editing genes in any setting, such as within plant, animal, and human cells, as well as modulating transcription.

"We are pleased by our recent trajectory that has significantly increased UC’s intellectual property protection of the Doudna-Charpentier team’s work on CRISPR-Cas9," said Eldora L. Ellison, Ph.D., lead patent strategist on CRISPR-Cas9 matters for UC and a Director at Sterne, Kessler, Goldstein & Fox. "We will continue pursuing claims for this pioneering gene-editing technology so we can ensure the methods are utilized for the benefit of society."

The Doudna-Charpentier team that invented the CRISPR-Cas9 DNA-targeting technology included Jennifer Doudna and Martin Jinek at the University of California, Berkeley; Emmanuelle Charpentier (then of Umea University); and Krzysztof Chylinski at the University of Vienna. The single-molecule guide RNAs covered by today’s patent, as well as the other compositions and methods claimed in UC’s previously issued patents and those set to issue, were included among the CRISPR-Cas9 gene editing technology work disclosed first by the Doudna-Charpentier team in its May 25, 2012 priority patent application.

Additional CRISPR-Cas9 patents in this team’s portfolio include 10,000,772; 10,113,167; 10,227,611; 10,266,850; 10,301,651; 10,308,961; 10,337,029; 10,351,878; 10,358,658; 10,358,659; 10,385,360; and 10,400,253. These patents are not a part of the PTAB’s recently declared interference between 14 UC patent applications and multiple previously issued Broad Institute patents and one application, which jeopardizes essentially all of the Broad’s CRISPR patents involving eukaryotic cells.

International patent offices have also recognized the pioneering innovations of the Doudna-Charpentier team, in addition to the 13 patents granted in the U.S. so far. The European Patent Office (representing more than 30 countries), as well as patent offices in the United Kingdom, China, Japan, Australia, New Zealand, Mexico, and other countries, have issued patents for the use of CRISPR-Cas9 gene editing in all types of cells.

University of California has a long-standing commitment to develop and apply its patented technologies, including CRISPR-Cas9, for the betterment of humankind. Consistent with its open-licensing policies, UC allows nonprofit institutions, including academic institutions, to use the technology for non-commercial educational and research purposes.

In the case of CRISPR-Cas9, UC has also encouraged widespread commercialization of the technology through its exclusive license with Caribou Biosciences, Inc. of Berkeley, California. Caribou has sublicensed this patent family to numerous companies worldwide, including Intellia Therapeutics, Inc. for certain human therapeutic applications. Additionally, Dr. Charpentier has licensed the technology to CRISPR Therapeutics AG and ERS Genomics Limited.

On September 10, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported the presentation of updated phase 1 data for U3-1402, an investigational HER3 targeting antibody drug conjugate (ADC), in 30 patients with metastatic EGFR mutated, TKI resistant non-small cell lung cancer (NSCLC) (Press release, Daiichi Sankyo, SEP 10, 2019, https://www.prnewswire.com/news-releases/updated-phase-1-data-for-daiichi-sankyos-u3-1402-in-patients-with-egfr-mutated-nsclc-presented-at-2019-world-conference-on-lung-cancer-300914515.html [SID1234539384]). The late-breaking data were featured today in a Mini Oral Session at the IASLC 2019 World Conference on Lung Cancer (#WCLC19) in Barcelona, Spain (#MA21.06, Abstract #1720).

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Updated efficacy results for 26 patients who received U3-1402 in one of four dose cohorts, and had baseline and at least one post-baseline tumor assessment, showed six confirmed partial responses across three dose levels. A reduction in tumor size was observed in 22 patients across all doses, with median best percentage change of -25.7 percent [range -82.6 percent to 13.3 percent]. Responses were reported in patients with and without a history of CNS metastases. All 30 patients in the trial had received prior treatment with an EGFR tyrosine kinase inhibitor (TKI) including 28 (93 percent) with osimertinib. Fifteen patients (50 percent) had also received prior chemotherapy. The median follow-up time was 4.5 months. At the time of data cut-off on May 3, 2019, a total of 17 patients remained on treatment.

Next-generation sequencing (NGS) and cfDNA analysis determined the presence of multiple resistance mechanisms to prior EGFR TKI therapies in patients who experienced partial responses and tumor reduction while being treated with U3-1402. Three patients with confirmed partial response harbored the EGFR resistance mutations T790M, which is the target of osimertinib, and C797S, which is associated with resistance to osimertinib. Additionally, all evaluable tumors demonstrated HER3 expression at various levels in retrospective immunohistochemistry (IHC) analysis (n=25).

"As more patients are treated on study, the findings continue to demonstrate activity with U3-1402, including ongoing confirmed partial responses, in patients with EGFR-mutant metastatic non-small cell lung cancer that is no longer responding to EGFR TKI therapy," said Helena Yu, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, and a trial investigator. "These data suggest that targeting HER3 with U3-1402 may be an effective treatment strategy irrespective of mechanism of resistance identified in the setting of EGFR TKI resistance, where new precision treatments are needed."

Preliminary safety data for 30 patients who received U3-1402 in one of four doses indicated a manageable safety profile for U3-1402 at a median treatment exposure of 3.2 months. The recommended dose for expansion has been established at 5.6 mg/kg. The most common treatment-emergent adverse events (TEAEs) of any grade, occurring in ≥30 percent of patients, included nausea (63.3 percent), fatigue (43.3 percent), vomiting (36.7 percent) and platelet count decrease (30 percent). One TEAE grade ≥3 occurred in more than 10 percent of patients (platelet count decrease, 20 percent). The following dose-limiting toxicities were observed in four patients: four grade 4 platelet count decrease and one grade 3 febrile neutropenia. One patient experienced a TEAE associated with treatment discontinuation (3.3 percent). Nine patients (30 percent) experienced treatment-emergent serious adverse events regardless of causality. Four patients (13.3 percent) experienced treatment-emergent serious adverse events that were drug-related.

"HER3 is frequently overexpressed in non-small cell lung cancers as well as other types of solid tumors, but no HER3 targeting therapies are approved for NSCLC or any cancer," said Dalila Sellami, MD, Vice President, U3-1402 Global Team Leader, Global Oncology Research and Development, Daiichi Sankyo. "U3-1402 is a potential first-in-class ADC designed to target and deliver treatment directly to HER3 expressing tumors, and based on these results, we will advance to dose expansion and broaden the scope of the trial to include patients with squamous or non-squamous NSCLC."

About the Study
The global, phase 1, open label, two-part study is enrolling patients with metastatic or unresectable EGFR mutated NSCLC whose disease has progressed while taking an EGFR TKI. The first part of the study includes patients who either experienced disease progression on erlotinib, gefitinib, dacomitinib or afatinib and tested negative for the T790M mutation or who experienced disease progression on osimertinib regardless of T790M status. The primary objectives of the study are to assess the safety and tolerability of U3-1402. Secondary study objectives are to evaluate preliminary efficacy by measuring antitumor activity of U3-1402 and to characterize the pharmacokinetics of U3-1402. Part one (dose escalation) assesses U3-1402 at four doses (3.2 mg/kg to 6.4 mg/kg) to determine a recommended dose for expansion. Part two (dose expansion) will evaluate U3-1402 at the recommended dose for expansion of 5.6 mg/kg and include an additional cohort of patients with metastatic squamous or non-squamous NSCLC without EGFR mutation whose disease has progressed after chemotherapy and anti-PD-L1 regimens. The study is expected to enroll more than 100 patients at approximately 17 sites globally. For more information, visit ClinicalTrials.gov.

About U3-1402
Part of the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise, U3-1402 is an investigational and potential first-in-class HER3 targeting ADC. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, U3-1402 is comprised of a human anti-HER3 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

U3-1402 is one of three Daiichi Sankyo ADCs in clinical development for NSCLC in addition to DS-1062 and [fam-] trastuzumab deruxtecan (DS-8201), which is being co-developed and co-commercialized globally in collaboration with AstraZeneca. U3-1402 is also being evaluated in a phase 1/2 study in patients with HER3 positive metastatic breast cancer.

U3-1402, DS-1062 and DS-8201 are investigational agents that have not been approved for any indication in any country. Safety and efficacy have not been established.

Unmet Need in Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide; there were an estimated 2.1 million new cases of lung cancer in 2018 and 1.8 million deaths.1 Most lung cancers are diagnosed at an advanced or metastatic stage.2 Non-small cell lung cancer (NSCLC) accounts for 80 to 85 percent of all lung cancers.3 The introduction of targeted therapies and checkpoint inhibitors in the past decade has improved the treatment landscape for patients with advanced or metastatic NSCLC; however, for those who are not eligible for current treatments, or whose cancer continues to progress, new therapeutic approaches are needed.4

EGFR mutation is a well-established oncogenic target for management of advanced stage NSCLC.5 For patients with advanced EGFR mutated NSCLC, targeted therapy with EGFR TKIs offers higher response rates and progression-free survival compared to chemotherapy.5 However, most patients eventually develop resistance to the drugs, at which point treatment options become more limited.6 Clinical resistance to EGFR TKIs has been linked to multiple gene-based mechanisms, and in many cases, the underlying cause remains unknown.7,8,9 At the same time, a majority of EGFR mutant NSCLCs show some level of HER3 expression.10,11

HER3 is a member of the human epidermal growth factor receptor (EGFR) family of tyrosine kinase receptors, which are associated with aberrant cell growth.12 HER3 expression has been associated with increased metastases and reduced survival in patients with non-small cell lung cancer, where frequency has been reported as high as 75 percent.13 HER3 is overexpressed in several types of cancers.14 In recent years, researchers have recognized potential for HER3 as a therapeutic target.12 Currently, no HER3 targeting agents are approved for NSCLC or any cancer.

About Daiichi Sankyo Cancer Enterprise
The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. For more information, please visit: www.DSCancerEnterprise.com.

On September 10, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported the presentation of updated phase 1 clinical results and new biomarker data for DS-1062, an investigational TROP2 targeting antibody drug conjugate (ADC), in 52 unselected patients with heavily pretreated advanced non-small cell lung cancer (NSCLC). The data were featured today in a Mini Oral Session at the IASLC 2019 World Conference on Lung Cancer (#WCLC19) in Barcelona, Spain (#MA25.10, Abstract #3854) (Press release, Daiichi Sankyo, SEP 10, 2019, https://www.prnewswire.com/news-releases/updated-clinical-results-and-new-biomarker-analyses-presented-for-daiichi-sankyos-ds-1062-in-patients-with-advanced-nsclc-at-2019-world-conference-on-lung-cancer-300914513.html [SID1234539383]).

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Updated efficacy results for 46 evaluable patients who received DS-1062 at one of eight doses (0.27 mg/kg to 10.0 mg/kg) showed 12 partial responses (10 confirmed, 2 early) observed in a dose-dependent manner. Five of the confirmed partial responses were observed among seven patients (71.4 percent) receiving DS-1062 at 8 mg/kg, the recommended dose for expansion. The other two patients receiving the 8 mg/kg dose experienced stable disease, and six of the seven are continuing on trial. Patients had received prior treatments, including immune checkpoint inhibitors (86.5 percent), EGFR inhibitors and ALK inhibitors. The data cut-off was July 3, 2019. Thirty-five patients were ongoing in the trial as of August 20, 2019.

Thirty-five patients were evaluable for TROP2 expression by immunohistochemistry (IHC) analysis. TROP2 expression trended higher in patients who experienced a partial response. Gene analysis suggested SLFN11 expression, which has previously been associated with response to topoisomerase I inhibitors, trended higher in patients with tumor reduction.1 In addition, data showed a decrease in cfDNA in patients who experienced partial response and stable disease.

"There is a need for new treatment options to help patients with advanced non-small cell lung cancer that continues to progress on standard therapies, and these findings with DS-1062 in heavily pretreated patients are encouraging," said Rebecca S. Heist, MD, MPH, Medical Oncologist, Massachusetts General Hospital, Cancer Center, and a study investigator. "Further study in more patients at the recommended expansion dose will help further assess the potential for targeting TROP2 with DS-1062 in NSCLC."

Updated data for 52 patients evaluable for safety as of July 3, 2019 showed that DS-1062 was well-tolerated in doses up to 8 mg/kg, which is defined as the maximum tolerated dose and the recommended dose for expansion. The most common treatment-emergent adverse events (any grade, occurring in ≥ 30 percent of patients) included fatigue (36.5 percent) and nausea (36.5 percent). Twenty-two patients (42.3 percent) experienced at least one treatment emergent adverse event (TEAE) ≥ grade 3. Dose-limiting toxicities occurred in two patients at the 10 mg/kg dose (one mucosal inflammation and one stomatitis) and in one patient at the 6 mg/kg dose (rash maculopapular). TEAEs led to discontinuation in two patients (3.8 percent). Serious TEAEs were reported in 14 patients (26.9 percent) regardless of causality. One patient (1.9 percent) with disease progression treated with the 6.0 mg/kg dose developed an adverse event of special interest (respiratory failure, grade 5). Any pulmonary events suspected of being interstitial lung disease (ILD) or pneumonitis are considered adverse events of special interest and evaluated by an independent adjudication committee. The case was adjudicated and determined not to be ILD. Since the data cutoff, four potential cases of ILD have been reported and are pending adjudication: one grade 2 pneumonitis [6.0 mg/kg], one grade 2 organizing pneumonia [8.0 mg/kg], one grade 2 pneumonitis [8.0 mg/kg] and one grade 5 respiratory failure in a patient with disease progression [8.0 mg/kg].

"These findings support DS-1062 as a potential TROP2 targeting therapy for NSCLC and further reinforce the strength and flexibility of our DXd ADC platform, which enables each of our ADCs to be custom designed to potentially provide an optimal balance of safety and efficacy," said Eric Slosberg, PhD, Head, Global Translational Development, Oncology Research and Development, Daiichi Sankyo. "As the study advances, we will continue with our translational research to help uncover underlying factors contributing to patient response and identify patients most likely to respond to DS-1062."

DS-1062 was designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver chemotherapy inside cancer cells that express TROP2 as a cell surface antigen. The DXd ADC technology provides flexibility to adapt the drug-to-antibody ratio (DAR) or the number of DXd molecules conjugated per antibody. DS-1062 has a DAR of four, which is based on initial preclinical research into the construct necessary for intended safety and efficacy in TROP2 expressing tumors. Preclinical studies have demonstrated that DS-1062 selectively binds to the TROP2 receptor on the surface of a tumor cell. It is proposed that DS-1062 is then brought inside the cancer cell where lysosomal enzymes break down the tetrapeptide-based linker and release the DXd payload.

About the Phase 1 Study
The phase 1, first-in-human open-label study is investigating the safety and tolerability of DS-1062 in patients with unresectable advanced NSCLC who are refractory to or have relapsed following standard treatment or for whom no standard treatment is available. The first part of the study (dose escalation) assesses the safety and tolerability of increasing doses of DS-1062 to determine the maximum tolerated dose and recommended dose for expansion. The second part of the study (dose expansion) will evaluate the safety and tolerability of DS-1062 at the recommended dose for expansion and will enroll 40 additional patients with advanced NSCLC. Study endpoints include safety, pharmacokinetics, objective response rate, duration of response, disease control rate, time to response, progression-free survival, overall survival, biomarker analysis and immunogenicity. The study is currently enrolling patients with unresectable advanced NSCLC in the United States and Japan. For more information about the study, visit ClinicalTrials.gov.

Unmet Need in Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide; there were an estimated 2.1 million new cases of lung cancer in 2018 and 1.8 million deaths.2 Most lung cancers are diagnosed at an advanced or metastatic stage.3 Non-small cell lung cancer (NSCLC) accounts for 80 to 85 percent of all lung cancers.4 The introduction of targeted therapies and checkpoint inhibitors in the past decade has improved the treatment landscape for patients with advanced or metastatic NSCLC; however, for those who are not eligible for current treatments, or whose cancer continues to progress, new therapeutic approaches are needed.5

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is highly expressed on several types of solid tumors, including NSCLC.6,7 Researchers have recognized TROP2 as a promising molecular target for therapeutic development in various types of malignancies, including NSCLC.7,8 Overexpression of TROP2 has been associated with increased tumor aggressiveness and decreased survival in several cancers.9 High TROP2 expression was identified in 64 percent of non-small cell adenocarcinomas and 75 percent of non-small cell squamous cell carcinomas in one study.6 Currently, no TROP2 targeting therapy is approved for NSCLC or any cancer.

About DS-1062
Part of the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise, DS-1062 is an investigational TROP2 targeting ADC. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, DS-1062 is comprised of a humanized anti-TROP2 monoclonal antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

DS-1062 is one of three Daiichi Sankyo ADCs in clinical development for NSCLC in addition to U3-1402 and [fam-] trastuzumab deruxtecan (DS-8201), which is being co-developed and co-commercialized globally in collaboration with AstraZeneca.

DS-1062, U3-1402 and DS-8201 are investigational agents that have not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise
The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. For more information, please visit: www.DSCancerEnterprise.com.