On September 10, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the European Commission has approved KEYTRUDA, the company’s anti-PD-1 therapy, in combination with pemetrexed (ALIMTA) and platinum chemotherapy for the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC) in adults whose tumors have no EGFR or ALK positive mutations (Press release, Merck & Co, SEPT 10, 2018, View Source [SID1234529376]). This approval, the first in Europe for an anti-PD-1 therapy in combination with chemotherapy, is based on data from the pivotal Phase 3 KEYNOTE-189 trial in patients with metastatic nonsquamous NSCLC regardless of PD-L1 tumor expression status, which demonstrated a significant survival benefit for the combination of KEYTRUDA with chemotherapy as compared with standard-of-care chemotherapy alone – reducing the risk of death in these patients by half (HR=0.49 [95% CI, 0.38-0.64]; p<0.00001).

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"We are very pleased that the European Commission has approved KEYTRUDA in combination with chemotherapy based on the significant survival benefit demonstrated in the KEYNOTE-189 trial," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "This approval is a first in Europe and adds to the rapidly growing role of KEYTRUDA as a foundation for the treatment of lung cancer."

The approval allows marketing of the KEYTRUDA combination in all 28 EU member states plus Iceland, Lichtenstein and Norway, at the approved dose of 200 mg every three weeks until disease progression or unacceptable toxicity. KEYTRUDA is also approved in Europe as a monotherapy for the first-line treatment of metastatic squamous or nonsquamous NSCLC in patients whose tumors have high PD-L1 expression (tumor proportion score [TPS] of 50 percent or more) with no EGFR or ALK positive tumor mutations (KEYNOTE-024) and for previously-treated patients with locally advanced or metastatic NSCLC whose tumors express PD-L1 (TPS of 1 percent or more) and who have received at least one prior chemotherapy regimen (KEYNOTE-010).

"Lung cancer is the leading cause of cancer death in Europe, and we are committed to doing everything in our power to help address it," said Frank Clyburn, president, Merck Oncology. "Today KEYTRUDA is now approved across Europe for the treatment of appropriate patients with metastatic nonsquamous non-small cell lung cancer as both a monotherapy and in combination with chemotherapy."

Data Supporting the Approval

The approval was based on data from KEYNOTE-189, a Phase 3, multicenter, randomized, active-controlled, double-blind trial. Key eligibility criteria were metastatic nonsquamous NSCLC, no prior systemic treatment for metastatic NSCLC, and no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within two years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

Patients were randomized to receive KEYTRUDA 200 mg, cisplatin or carboplatin, and pemetrexed intravenously every three weeks for four cycles followed by KEYTRUDA 200 mg for up to 24 months and pemetrexed every three weeks (n=410); or placebo with cisplatin or carboplatin and pemetrexed intravenously every three weeks for four cycles followed by pemetrexed every three weeks (n=206). Treatment continued until progression of disease or unacceptable toxicity, or a maximum of 24 months. For patients who completed 24 months of therapy or had a complete response, treatment with KEYTRUDA could be reinitiated for disease progression and administered for up to one additional year.

Primary efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central review (BICR) using RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). Secondary efficacy outcome measures were overall response rate (ORR) and duration of response (DOR). Patients receiving placebo plus chemotherapy who experienced disease progression could cross over to receive KEYTRUDA as monotherapy. The KEYNOTE-189 study was conducted in collaboration with Eli Lilly and Company, the makers of pemetrexed (ALIMTA).

In KEYNOTE-189, there was a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared with pemetrexed and platinum chemotherapy alone – with a reduction in the risk of death by 51 percent (HR=0.49 [95% CI, 0.38-0.64]; p<0.00001) and a 48 percent reduction in the risk of progression or death (HR=0.52 [95% CI, 0.43-0.64]; p<0.00001). The ORR was 48 percent (95% CI, 43-53) for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared to 19 percent (95% CI, 14-25) for patients randomized to pemetrexed and platinum chemotherapy alone (p<0.0001). The median DOR for patients randomized to receive KEYTRUDA in combination with pemetrexed and platinum chemotherapy was 11.2 months (range, 1.1+ to 18.0+ months) compared to 7.8 months (range, 2.1+ to 16.4+ months) for patients randomized to receive pemetrexed and platinum chemotherapy alone.

The safety of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was evaluated in 488 patients with nonsquamous NSCLC receiving 200 mg, 2 mg/kg or 10 mg/kg pembrolizumab every three weeks, in two clinical studies (KEYNOTE-189 and KEYNOTE-021). In this patient population, the most frequent adverse reactions were nausea (47%), anemia (37%), fatigue (38%), neutropenia (22%), decreased appetite (21%), diarrhea (20%) and vomiting (19%). Incidences of Grade 3-5 adverse reactions were 47 percent for KEYTRUDA combination therapy and 37 percent for chemotherapy alone.

About Lung Cancer in Europe

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death in Europe and worldwide. In 2012, there were nearly 354,000 deaths from lung cancer in Europe. The two main types of lung cancer are non-small cell and small cell. NSCLC is the most common type of lung cancer, accounting for about 85 percent of all cases, the majority of which are of the nonsquamous type.

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 800 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 and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

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

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also 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.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin or cisplatin, as appropriate.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. 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. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

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 three 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. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

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.

In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

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 [Combined Positive Score (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 also 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.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

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.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

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 [Combined Positive Score (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. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

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. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.

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 receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). 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 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 for Grade 4 colitis.

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.

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 patients with HNSCC occurring in 15% (28/192) of patients. 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 anti-hyperglycemics 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 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 Allogenic 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 developed graft-versus-host disease (GVHD) (one fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (one 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 clinical 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 clinical trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

Adverse Reactions

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

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-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, 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; one from GVHD after subsequent allogeneic HSCT and one 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-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%).

Lactation

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Pediatric Use

There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile was similar to that seen in adults treated with KEYTRUDA. Toxicities 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%), hypertransaminasemia (28%), and hyponatremia (18%).

On September 10, 2018 Glythera Limited (Glythera), the next-generation Antibody Drug Conjugate (ADC) development company, reported that it has changed its name to Iksuda Therapeutics (Iksuda) and unveiled a new corporate brand (Press release, Glythera, SEPT 10, 2018, View Source [SID1234529375]). The new identity signifies the Company’s transition from technology licensing to drug development, focusing on cancer therapeutics and the treatment of solid tumours. To coincide with the rebranding, Iksuda Therapeutics has launched a new website: www.iksuda.com.

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Iksuda’s primary focus will be on the development of superior ADCs for treatment of difficult-to-treat cancers, but the Company will continue to support its partners’ portfolios with its advanced conjugation platform, PermaLink, and novel toxin payloads.

Iksuda anticipates that it will nominate two ADCs for clinical progression in Q4 2018, with first indications expected to be ovarian and lung cancers. To support its pre-clinical and clinical activities, the Company has significantly expanded its team over the past 12 months, including the appointment of Dr Robert Lutz’s as CSO in January 2018.

Dr Dave Simpson, Chief Executive Officer, Iksuda, said: "The name Iksuda is derived from the Sumerian word for ‘all conquering’ and was chosen to reflect our ambition of overcoming the issue of ADC instability to create a new generation of stable, effective ADCs for treating the most severe cancers and improving patient lives."

On September 10, 2018 Advaxis, Inc. (NASDAQ:ADXS), a late-stage biotechnology company focused on the discovery, development and commercialization of immunotherapy products, reported business highlights and financial results for the fiscal year 2018 third quarter, ended July 31, 2018 (Press release, Advaxis, SEPT 10, 2018, View Source [SID1234529374]).

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Recent key accomplishments include:

Dosing of the first patient in the Company’s Phase 1 trial with ADXS-NEO, a personalized immunotherapy approach targeting neoantigens identified by sequencing a patient’s own cancer cells, partnered with Amgen.
U.S. Food and Drug Administration (FDA) allowance of the Company’s Investigational New Drug (IND) application for its first ADXS-HOT drug candidate, ADXS-503, for non-small cell lung cancer. ADXS-HOT is an off-the-shelf cancer-type specific immunotherapy approach that leverages the Company’s proprietary Lm technology platform to target hotspot mutations and other tumor-associated antigens that commonly occur in specific cancer types.
Selecting prostate and bladder cancers as the second and third ADXS-HOT drug candidates to take into the clinic.
Granting of a license to OS Therapies for the use of ADXS31-164, also known as ADXS-HER2, for evaluation in the treatment of osteosarcoma, a rare and aggressive tumor that forms in the bone.
Pricing of its public offering of common stock and warrants. The planned underwritten public offering is expected to result in gross proceeds of approximately $20 million and close on or around September 11, 2018.
Management Commentary

"We are encouraged by the momentum achieved with both of our neoantigen-focused programs during our third fiscal quarter and continue on our path of achieving our goal of having five neoantigen-based product candidates in clinical evaluation by the end of 2019," said Kenneth A. Berlin, President and Chief Executive Officer of Advaxis. "We believe in the powerful impact neoantigens may have on the cancer treatment paradigm. Several of the unique attributes of our Lm platform including the capacity of our vector to contain a large number of neoantigens in each single drug construct, as well as the vector’s ability to generate strong T-cell responses to neoantigens as demonstrated in previously reported studies, provide us with an opportunity to lead in this potentially revolutionary field of cancer treatment.

"ADXS-NEO, partnered with Amgen, takes a personalized approach to therapy and has the potential to make an important contribution among underserved cancer patient populations with few or no treatment options," he added. "Similarly, the IND allowance by the FDA of our ADXS-HOT drug candidate for non-small cell lung cancer enables us to finalize our Phase 1 trial design and dose our first patient by the end of the year. The ADXS-HOT program, in general, is focused on shared hotspot mutations and other cancer antigens commonly found in cancers with large patient populations such as non-small cell lung cancer and prostate cancer."

"We are also excited about the licensing transaction executed with OS Therapies to evaluate our HER-2 therapy for the treatment of human osteosarcoma. This is a product candidate we believe in, although it falls outside our neoantigen focus. The transaction supports continued clinical development by a team of experts exclusively focused on finding new treatments for osteosarcoma and allows us to remain dedicated to our corporate strategy," he added.

Financial Results for Third Quarter Fiscal Year 2018

The net loss for the third quarter ended July 31, 2018 was $14.0 million or $0.27 per share. This compares with a net loss for the third quarter of fiscal year 2017 of $32.6 million or $0.80 per share. The $18.6 million reduction in the net loss compared to prior year was primarily a result of the significant reduction in spending in research, development and administrative areas.

Research and development expenses for the third quarter of fiscal year 2018 were $10.8 million, compared with $17.8 million for the third quarter of fiscal year 2017. The decrease is primarily attributable to a decrease in laboratory costs, drug manufacturing process validation and drug stability studies supporting the MAA, which we withdrew in July 2018.

General and administrative expenses for the third quarter of fiscal year 2018 were $4.5 million, compared with $18.0 million for the third quarter of fiscal year 2017. The decrease is primarily attributable to a decrease in stock-based compensation of approximately $11.4 million related to the resignation of the Company’s Chief Financial Officer and Chief Executive Officer in April 2018 and July 2017, respectively, two Board members who did not seek re-election in March 2018, a reduction in headcount and the elimination of stock-based compensation paid to consultants.

Balance Sheet Highlights

As of July 31, 2018, the Company had approximately $40.4 million in cash, restricted cash and cash equivalents on its balance sheet. The Company is anticipating closing on an underwritten public offering of its common stock and warrants on or around September 11, 2018 which is expected to result in gross proceeds of approximately $20 million to the Company.

On September 10, 2018 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted therapeutics for cancer, wet age-related macular degeneration and fibrotic diseases, reported the publication of results from a Phase 1b clinical trial combining TRC105 with Inlyta (axitinib) in patients with advanced or metastatic renal cell carcinoma (RCC) (Press release, Tracon Pharmaceuticals, SEPT 10, 2018, View Source [SID1234529373]). Dr. Toni Choueiri of the Dana Farber Cancer Institute and colleagues published these results in the peer-reviewed journal, The Oncologist (Epublication ahead of print is available at PubMed.gov through PubMed ID number 30190302), and Dr. Andrew Hahn of the Huntsman Cancer Institute and co-authors published an accompanying editorial (Epublication ahead of print is available at PubMed.gov through PubMed ID number 30139834). These data were previously presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen, Denmark.

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The open-label dose escalation and expansion Phase 1b study enrolled a total of 18 patients (17 of whom were evaluable for response) who had received at least one prior line of therapy with a VEGF receptor tyrosine kinase inhibitor (VEGFR TKI). The median number of prior therapies in the group was three, with a range of one to six. All patients in the trial received a combination of TRC105 and Inlyta. The data are summarized in the table below.

For comparison, in a separate trial, the objective response rate (ORR) seen in the large subgroup of VEGFR TKI-refractory patients treated with Inlyta (n=194) in the Inlyta AXIS Phase 3 study in second-line clear cell RCC patients was 11.3%, and median progression-free survival (PFS) was 4.8 months.

The publication also notes that plasma levels of TGF-β receptor 3 (betaglycan) at baseline were significantly higher in patients who experienced a partial response, while levels of osteopontin were significantly lower at baseline for patients that achieved a partial response. Both markers correlated with time on study and their potential prognostic value are being investigated in the ongoing Phase 2b TRAXAR study. TRACON’s Phase 2b TRAXAR clinical trial of TRC105 in combination with Inlyta completed enrollment of 150 patients with advanced or metastatic RCC in Q3 2017 and top-line data are expected to be available in December 2018.

About the TRAXAR Phase 2b Clinical Trial in RCC

The Phase 2b TRAXAR clinical trial is a multicenter, open-label, randomized clinical trial of TRC105 in combination with Inlyta versus Inlyta in patients with advanced or metastatic RCC. The primary endpoint of the Phase 2b study is progression-free survival. Patients may have also failed one prior mTOR inhibitor and one prior immunotherapy. For additional information on this clinical trial, please visit www.clinicaltrials.gov, identifier NCT01806064.

About Carotuximab (TRC105)

TRC105 is a novel, clinical stage antibody to endoglin, a protein overexpressed on proliferating endothelial cells that is essential for angiogenesis, the process of new blood vessel formation. TRC105 is currently being studied in a pivotal Phase 3 trial in angiosarcoma and multiple Phase 2 clinical trials, in combination with VEGF inhibitors, as well as in a Phase 1 trial with Opdivo. TRC105 has received orphan designation for the treatment of soft tissue sarcoma in both the U.S. and EU. The ophthalmic formulation of TRC105, DE-122, is currently in a randomized Phase 2 trial for patients with wet AMD. For more information about the clinical trials, please visit TRACON’s website at www.traconpharma.com/clinical_trials.php.

On September 10, 2018 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a biotechnology company discovering and developing innovative immuno-oncology protein therapeutics, reported that the company completed the Phase 1 safety lead-in portion and has initiated the Phase 3 portion of the FIGHT Phase 1/3 clinical trial of bemarituzumab (FPA144), an isoform-selective anti-FGF receptor 2b antibody, in combination with chemotherapy in patients with previously untreated, advanced gastric cancer (GC) or gastroesophageal junction (GEJ) cancer (Press release, Five Prime Therapeutics, SEPT 10, 2018, View Source [SID1234529372]).

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"We are very pleased to have completed the safety lead-in and move into the Phase 3 registrational portion of the bemarituzumab trial in patients with gastric cancer," said Helen Collins, M.D., Senior Vice President and Chief Medical Officer of Five Prime. "Patients with advanced gastric cancer are in dire need of new treatment options. Bemarituzumab is a targeted therapy and we are using state-of-the-art diagnostic tools to help us identify patients with FGFR2b overexpression, which is associated with a worse prognosis. Bemarituzumab has demonstrated encouraging monotherapy activity as a late-line treatment for gastric cancer and we believe that combining with chemotherapy in the front-line setting should provide the greatest patient benefit."

In December 2017, Five Prime initiated the Phase 1 portion (NCT03343301) of the Phase 1/3 FIGHT (FGFR2b Inhibition in Gastric and Gastroesophageal Junction Cancer Treatment) global registrational trial. The Phase 1 portion tested bemarituzumab doses of 6 mg/kg and 15 mg/kg in combination with modified FOLFOX6 (mFOLFOX6) with no overlapping toxicities identified.

The randomized, controlled, double-blinded Phase 3 portion of the FIGHT trial will evaluate bemarituzumab plus mFOLFOX6 versus placebo plus mFOLFOX6 in approximately 550 patients with gastric cancer (GC) or gastroesophageal junction (GEJ) cancer whose tumors overexpress FGFR2b. The Phase 3 trial will include approximately 250 sites in the U.S., Europe and Asia, including China, South Korea and Japan, where the incidence of gastric cancer is high. Zai Lab will manage the Phase 3 portion of the FIGHT trial in China.

The primary endpoint of the FIGHT trial is overall survival (OS) with secondary endpoints of progression-free survival (PFS), objective response rate (ORR), safety and pharmacokinetic (PK) parameters.

Unmet Need in GC and GEJ

GC, including GEJ cancer, is the fifth most common cancer worldwide and third leading cause of cancer death.

Current first-line chemotherapy treatment delays progression by approximately 6 months compared to best supportive care, but median OS remains poor with literature-reported ranges of approximately 10 to 11 months and PFS of approximately 6 months. The presence of FGFR2b overexpression is present in approximately 10% of patients with GC/GEJ and is associated with a worse prognosis. Few treatment options following progression are available after first-line chemotherapy and a significant unmet need remains in the treatment of GC/GEJ.

Five Prime is developing companion diagnostics to identify FGFR2b overexpression using an IHC test and FGFR2 gene amplification using ctDNA analysis. Five Prime will use both assays to select patients for the FIGHT trial.

About Bemarituzumab

Bemarituzumab is a first-in-class, isoform-selective, humanized monoclonal antibody in clinical development as a targeted immunotherapy for tumors that overexpress FGFR2b, a splice variant of a receptor for some members of the fibroblast growth factor (FGF) family. Bemarituzumab blocks FGFs 7, 10 and 22 from binding to FGFR2b, and has been engineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) to increase direct tumor cell killing by recruiting natural killer (NK) cells. Clinical results to date suggest that the specificity of bemarituzumab avoids the dose-limiting toxicities that have been seen with less selective pan-FGFR tyrosine kinase inhibitors that act on multiple FGFRs, including FGFR2.

In December 2017, Five Prime and Zai Lab announced a strategic collaboration for the development and commercialization of bemarituzumab in Greater China.