Posts Tagged ‘interaction Blockade between PD-1 and its ligands’

First Drug in Checkpoint Inhibitor Class of Cancer Immunotherapies has demonstrated Superiority over Standard of care in the treatment of First-line Lung Cancer Patients: Merck’s Keytryda

Reporter: Aviva Lev-Ari, PhD, RN


A comprehensive classification of all Immunotherapy Molecules in Development is presented in

Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN



Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 270 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.


Merck’s KEYTRUDA® (pembrolizumab) Demonstrates Superior Progression-Free and Overall Survival Compared to Chemotherapy as First-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer

KEYNOTE-024 Studied Patients Whose Tumors Expressed High Levels of PD-L1

Thursday, June 16, 2016 6:45 am EDT
Press Release
KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the KEYNOTE-024 trial investigating the use of KEYTRUDA® (pembrolizumab), in patients with previously untreated advanced non-small cell lung cancer (NSCLC) whose tumors expressed high levels of PD-L1 (tumor proportion score of 50 percent or more), met its primary endpoint. In this trial, KEYTRUDA was superior compared to chemotherapy for both the primary endpoint of progression-free survival (PFS), and the secondary endpoint of overall survival (OS). Based on these results, an independent Data Monitoring Committee (DMC) has recommended that the trial be stopped, and that patients receiving chemotherapy in KEYNOTE-024 be offered the opportunity to receive KEYTRUDA.

“We believe that the KEYNOTE-024 results have the potential to change the therapeutic paradigm in first-line treatment of non-small-cell lung cancer,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “We look forward to sharing these data with the medical community and with regulatory authorities around the world.”

The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies in patients with advanced NSCLC. Results from KEYNOTE-024 will be presented at an upcoming medical meeting.

Merck currently has the largest immuno-oncology clinical development program across the industry and is advancing five registration-enabling studies for NSCLC with KEYTRUDA as a monotherapy and in combination.

About KEYNOTE-024

KEYNOTE-024 is a randomized, pivotal, phase 3 study (ClinicalTrials.gov, NCT02142738) evaluating KEYTRUDA (pembrolizumab) monotherapy compared to standard of care (SOC) platinum-based chemotherapies in the treatment of patients with advanced NSCLC. Patients enrolled were those who had received no prior systemic chemotherapy treatment for their advanced disease and whose tumors expressed high levels of PD-L1 (defined as a tumor proportion score of 50 percent or more) as determined by a central laboratory using an immunohistochemistry assay. The study randomized 305 patients to receive KEYTRUDA (200 mg every three weeks) or SOC platinum-based chemotherapies: paclitaxel+carboplatin, pemetrexed+carboplatin, pemetrexed+cisplatin, gemcitabine+carboplatin, or gemcitabine+cisplatin. Pemetrexed maintenance therapy was permitted for patients with non-squamous histologies. In addition, patients randomized to the control had the option of crossing over to pembrolizumab upon disease progression. The primary endpoint is PFS; secondary endpoints are OS and overall response rate (ORR).

About KEYTRUDA® (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA 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.

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

KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 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. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA®  (pembrolizumab)

Immune-mediated pneumonitis occurred in 19 (3.5%) of 550 patients, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis and occurred more frequently in patients with a history of asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic radiation (6.0%). 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 occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis. 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 occurred in patients receiving KEYTRUDA. 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.

Hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA (pembrolizumab) for Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in patients receiving KEYTRUDA. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA (pembrolizumab) for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. 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% of 550 patients: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

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.

KEYTRUDA was discontinued due to adverse reactions in 14% of 550 patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

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.

Safety and effectiveness of KEYTRUDA (pembrolizumab) have not been established in pediatric patients.



Dive Brief:

  • Merck’s cancer immunotherapy Keytruda beat out standard of care chemotherapy in extending time without worsening symptoms and overall survival among patients with previously untreated non-small cell lung cancer (NSCLC), the company said Thursday.
  • After reviewing the positive results, an independent data monitoring committee recommended halting Keytruda’s Phase 3 trial ahead of schedule.
  • These results mark the first time a checkpoint inhibitor has been proven more effective than standard of care in a first-line setting, according to The Street.



Merck Extends Cancer Immunotherapy Reach to First-Line Lung Cancer

Merck’s (MRK) flagship cancer immunotherapy Keytruda delayed the re-growth of tumors and prolonged survival in patients with newly diagnosed non-small cell lung cancer compared to chemotherapy, the company said Thursday.

The new phase III study results from Merck are significant because they represent the first time that a drug belonging to the so-called checkpoint inhibitor class of cancer immunotherapies has demonstrated superiority over standard of care in the treatment of first-line lung cancer patients.

Lung cancer is the most prevalent cancer globally, with more than 200,000 patients in the U.S. and 1.5 million patients globally diagnosed each year. As such, lung cancer is an important commercial market for the drug companies developing new therapies which harness the immune system to target and kill cancer cells.

Cancer immunotherapy sales will reach $34 billion to $35 billion by 2026, of which almost half will come from lung cancer, predicts Leerink, the health care investment bank.

Merck is the first of the Big Pharma companies to demonstrate the efficacy of a checkpoint inhibitor in newly diagnosed lung cancer, but it will likely have company soon.

Bristol-Myers Squibb (BMY) is expected to announce results from a phase III study of Opdivo in first-line lung cancer in the third quarter.Roche (RHHBY) is also making an aggressive push with its own checkpoint inhibitor into lung cancer.

For now, Merck is not saying much about how well Keytruda performed in the phase III, study known as Keyote-024. The study compared Keytruda against a doublet chemotherapy in patients with non-small cell lung cancer who had not yet received any systemic therapy.

Keytruda beat chemotherapy on the study’s primary endpoint of progression-free survival and the secondary endpoint of overall survival, the company said. The magnitude of Keytruda’s benefit was not disclosed Thursday, but Merck said the data are strong enough to support approval filings in the U.S. and Europe.

Importantly, the patients enrolled in Merck’s Keytruda study also had to have lung cancers that expressed high levels of the protein PD-L1, defined as a tumor proportion score of 50% or more.

Checkpoint inhibitors like Keytruda and Opdivo work by blocking the interaction between PD-L1, a protein found on the surface of tumor cells. with PD-1, a receptor found on immune cells. Blocking the PD-1/PD-L1 connection allows a patient’s immune system to recognize and kill cancer cells.

Bristol is enrolling a larger, more inclusive group of first-line lung cancer patients with tumors expressing lower levels of PD-L1 in its studies of Opdivo. Depending on the study results, this may give Bristol a competitive advantage in the commercial market.

That’s what has already happened in the treatment market for more advanced, second-line lung cancer, where Bristol enjoys a significant market share advantage over Merck.

Adam Feuerstein writes regularly for TheStreet. In keeping with company editorial policy, he doesn’t own or short individual stocks, although he owns stock in TheStreet. He also doesn’t invest in hedge funds or other private investment partnerships. Feuerstein appreciates your feedback; click here to send him an email.

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