On May 13, 2020 An Upstate Medical University urology professor reported that it has been awarded a grant from the Department of Defense (DOD) to continue and advance his research on kidney cancer (Press release, SUNY Upstate, MAY 13, 2020, View Source [SID1234557898]).

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The grant will support work by Mehdi Mollapour, PhD, vice chair for translational research for the department of urology, and his lab as it continues a decade-long research project into understanding kidney cancer biology and to develop novel therapeutic strategies to treat patients. Mollapour, professor of urology, molecular biology and biochemistry, is also the director of kidney cancer biology at Upstate.

His work, published in high-impact-factor journals (Dushukyan et al, 2017, Cell Reports & Oberoi et al, Proceedings of the National Academy of Sciences, 2016) identified a prosurvival role for PP5 protein in kidney cancer. Mollapour’s lab is currently funded by several grants from the National Institutes of Health and the National Cancer Institute. He applied for this DOD grant last fall and was notified of the award this spring.

"It’s always exciting when any grant is funded," he said. "From small amounts to big amounts, to have the funds to be able to continue our work and pay students and pay researchers is exciting."

About 74,000 Americans will be diagnosed with kidney cancer in 2020, according to the American Cancer Society. The disease is more common in men and kills nearly 15,000 people in the U.S. each year, according to the ACS.

In the application for the DOD grant, Mollapour’s lab cites a higher risk for developing kidney cancer among military families because of environmental exposures. The application also talks about what a difficult disease it can be to treat, highlighting the need to seek biomarkers for early detection and new therapies like those being developed in Mollapour’s lab. Traditional radiation and chemotherapies are ineffective in patients with kidney cancer and when presenting with large or locally advanced tumors, about 50 percent develop metastatic disease, for whom the five-year survival rate is less than 20 percent, according to the application.

The most recent grant – Mollapour’s first from the DOD – will propel the lab’s work and continue to open doors for additional funding.

"The grant allows us to better understand this disease and new ways of treating it. Naturally, data generated here will enable us to obtain further funding," he said. The $400,000 grant will support research staff, including students, working in the lab for two years. He and his staff are actively applying for additional funding from the National Institutes of Health.

Mollapour credits the work of everyone in his lab for obtaining this grant. After learning the good news about the DOD funding, Mollapour said he does what he always does when he is notified of new grant funding – he calls Upstate Chair of Urology Gennady Bratslavsky, MD, on the phone and plays the song "We Are The Champions," by Queen over the phone.

"When he hears that he knows what happened," Mollapour said laughing. "We have a secret code and Bratslavsky gets equally excited because he appreciates the importance of research and that is why he is fully committed in supporting research."

Mollapour and Bratslavsky worked together before coming to Upstate.

"Dr. Mollapour is a brilliant scientist and I take great pride in being able to recruit him from the National Cancer Institute where we both worked in urologic oncology studying kidney cancer," Bratslavsky said. "I respect Dr. Mollapour’s talent in research, his perseverance and his ability to be a mentor for many of my students and residents."

Mollapour said this grant is exciting and important because of its direct connection to patient care and its potential to extend the lives of kidney cancer patients.

"I know whatever we are going to do in terms of research will directly impact the kidney cancer patient," he said. "This is not one of those types of research that is 10 steps away from helping the patient. This is so gratifying and very exciting. The patient is always on my mind. It might be cliché but I really think we will help the patients with this. We are going to make it happen one way or another."

On May 13, 2020 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported positive results from two studies from the company’s leading lung cancer research program (Press release, Merck & Co, MAY 13, 2020, View Source [SID1234557914]). Initial results from the Phase 2 KEYNOTE-799 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, plus concurrent chemoradiation therapy (CCRT) demonstrated an objective response rate (ORR) of 67.0% in Cohort A (squamous and nonsquamous non-small cell lung cancer [NSCLC] patients who received paclitaxel plus carboplatin) and 56.6% in Cohort B (nonsquamous NSCLC patients who received cisplatin plus pemetrexed) in untreated patients with unresectable, locally advanced stage III NSCLC. Additionally, new and updated data from the final analysis of the pivotal Phase 3 KEYNOTE-189 trial showed that 45.7% of patients with metastatic nonsquamous NSCLC treated with KEYTRUDA in combination with chemotherapy were alive at two years versus 27.3% of patients treated with chemotherapy alone.

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"KEYTRUDA has become a standard of care in metastatic non-small cell lung cancer based on the strength of clinical data showing a survival benefit as monotherapy or in combination with chemotherapy," said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. "New data from KEYNOTE-799 demonstrate the potential of KEYTRUDA plus concurrent chemoradiation therapy in earlier stages of lung cancer, while the long-term survival data from KEYNOTE-189 add to the strong body of evidence supporting the use of KEYTRUDA in combination with chemotherapy for appropriate patients with metastatic non-small cell lung cancer."

"Approximately 20-30% of patients with unresectable stage III non-small cell lung cancer have disease progression after initially receiving chemoradiation," said Salma K. Jabbour, radiation oncologist, professor, vice chair of clinical research, Rutgers Cancer Institute of New Jersey. "The encouraging results from KEYNOTE-799 demonstrate that combining KEYTRUDA with concurrent chemoradiation therapy has the potential to address a significant unmet medical need."

Merck is a leader in lung cancer, with an extensive clinical development program evaluating KEYTRUDA, in combination or as monotherapy, for the treatment of lung cancer across all stages of disease and lines of therapy in over 200 trials with more than 10,000 patients. In addition to KEYNOTE-799, Merck has initiated the Phase 3 KEYLYNK-012 study (ClinicalTrials.gov, NCT04380636), which will evaluate KEYTRUDA plus CCRT followed by one year of KEYTRUDA alone or in combination with LYNPARZA (olaparib) post-CCRT in patients with unresectable, locally advanced stage III NSCLC. KEYLYNK-012 is one of three new pivotal Phase 3 trials evaluating KEYTRUDA in combination with LYNPARZA for NSCLC. Additional studies include KEYLYNK-006 (nonsquamous patients; ClinicalTrials.gov, NCT03976323) and KEYLYNK-008 (squamous patients; ClinicalTrials.gov, NCT03976362), evaluating KEYTRUDA and maintenance LYNPARZA for the first-line treatment of metastatic NSCLC.

Results from KEYNOTE-799 (Abstract #9008) and KEYNOTE-189 (Abstract #9582) are being presented during the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. As announced, more than 80 abstracts in nearly 20 types of solid tumors and blood cancers will be presented from Merck’s broad oncology portfolio and investigational pipeline. Follow Merck on Twitter via @Merck and keep up to date with ASCO (Free ASCO Whitepaper) news and updates by using the hashtag #ASCO20.

First Presentation of Data from KEYNOTE-799 in Stage III NSCLC (Abstract #9008)

KEYNOTE-799 (ClinicalTrials.gov, NCT03631784) is a Phase 2, non-randomized, open-label study of 216 untreated patients with unresectable, locally advanced stage IIIA–C NSCLC designed to evaluate the efficacy of KEYTRUDA plus CCRT. All patients received KEYTRUDA, standard thoracic radiotherapy and investigator’s choice of two chemotherapy regimens. Cohort A included patients across NSCLC histologies who received paclitaxel plus carboplatin and Cohort B included only nonsquamous NSCLC patients who received cisplatin plus pemetrexed. Primary endpoints are ORR and rate of Grade ≥3 pneumonitis. Secondary endpoints include progression-free survival (PFS), overall survival (OS) and safety.

In all patients from Cohort A (n=112) and Cohort B (n=53) with a minimum of 15 weeks of follow-up, KEYTRUDA plus CCRT showed an ORR of 67.0% (90% CI, 58.9-74.3) and 56.6% (90% CI, 44.4-68.2) for Cohort A (2.7% complete response [CR]) and Cohort B (3.8% CR), respectively. The median duration of response (DOR) was not reached in either Cohort A (range, 1.6+ to 10.5+) or Cohort B (range, 1.7+ to 10.5+) as of data cutoff. Additionally, 91.1% and 100% of patients in Cohort A and B, respectively, had a response lasting six months or longer. In Cohort A, the six-month PFS rate was 81.4% and the six-month OS rate was 87.2%. In Cohort B, the six-month PFS rate was 85.2% and the six-month OS rate was 94.8%.

The incidence of adverse events (AEs) among patients who received KEYTRUDA plus CCRT was consistent with the established toxicity profiles of CCRT for stage III NSCLC and KEYTRUDA monotherapy. All-cause Grade ≥3 pneumonitis occurred in 8.0% (n=9) of patients in Cohort A and 5.5% (n=4) of patients in Cohort B; four deaths (Grade 5 pneumonitis) occurred in Cohort A. Observed rates of Grade ≥3 pneumonitis were within the expected range for immunotherapy combined with CCRT. The incidence of treatment-related Grades 3-5 AEs was 64.3% (n=72) in Cohort A and 41.1% (n=30) in Cohort B. Treatment-related AEs leading to discontinuation of any treatment component occurred in 28.6% (n=32) of patients in Cohort A and 12.3% (n=9) in Cohort B.

New Two-Year Survival Data from KEYNOTE-189 in Metastatic NSCLC (Abstract #9582)

New and updated data from the protocol-specified final analysis of KEYNOTE-189 (ClinicalTrials.gov, NCT02578680) continue to show that KEYTRUDA in combination with chemotherapy maintained a sustained, long-term survival benefit over chemotherapy alone after 31.0 months of median follow-up. The pivotal Phase 3 KEYNOTE-189 trial evaluated KEYTRUDA in combination with pemetrexed (ALIMTA) and platinum (cisplatin or carboplatin) chemotherapy for the first-line treatment of metastatic nonsquamous NSCLC compared with pemetrexed plus platinum alone in patients with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA in combination with chemotherapy reduced the risk of death by 44% (HR=0.56 [95% CI, 0.46-0.69]) compared with chemotherapy alone, with a median OS of 22.0 versus 10.6 months. The two-year OS rate was 45.7% for KEYTRUDA in combination with chemotherapy versus 27.3% with chemotherapy alone. KEYTRUDA in combination with chemotherapy also reduced the risk of disease progression or death by half (HR=0.49 [95% CI, 0.41-0.59]) compared with chemotherapy alone, with a median PFS of 9.0 versus 4.9 months. The two-year PFS rate was 22.0% for KEYTRUDA in combination with chemotherapy versus 3.4% for chemotherapy alone. The ORR was 48.3% for KEYTRUDA in combination with chemotherapy versus 19.9% for chemotherapy alone.

Among the 56 patients who completed two years of treatment with KEYTRUDA, the ORR was 85.7%. Median OS was not reached.

The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with metastatic NSCLC. Grades 3-5 AEs occurred in 72.1% of patients who received KEYTRUDA in combination with chemotherapy and 66.8% of patients who received chemotherapy alone. KEYNOTE-189 was conducted in collaboration with Eli Lilly and Company, the makers of ALIMTA (pemetrexed).

Merck Investor Event

Merck will hold a virtual investor event in conjunction with the ASCO (Free ASCO Whitepaper) Annual Meeting on Tuesday, June 2 at 2 p.m. ET. Details will be provided at a date closer to the event at View Source

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. The five-year survival rate for patients diagnosed in the U.S. with NSCLC and SCLC is estimated to be 5% and 6%, respectively.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA 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 1 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 Squamous Cell Cancer

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

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

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (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 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 [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 confirmatory trials.

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

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

Microsatellite Instability-High (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 (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

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

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

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 Grades 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 adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). 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 adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or 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 classical Hodgkin lymphoma, 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-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

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%).

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

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

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

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

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%).

Please see Prescribing Information for KEYTRUDA at View Source and Medication Guide for KEYTRUDA at View Source

About LYNPARZA (olaparib)

LYNPARZA is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. LYNPARZA is being tested in a range of tumor types with defects and dependencies in the DDR.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab

Most common adverse reactions (Grades 1-4) in ≥10% of patients treated with LYNPARZA/bevacizumab compared to a ≥5% frequency for placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%) and leukopenia (18%). In addition, the most common adverse reactions (≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%), and headache (14%).

In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%), and decrease in platelets (35%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%), and dyspepsia (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

ADVERSE REACTIONS—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic Pancreatic Adenocarcinoma

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%).

DRUG INTERACTIONS

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

USE IN SPECIFIC POPULATIONS

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

INDICATIONS

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

First-Line Maintenance BRCAm Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance HRD Positive Advanced Ovarian Cancer in Combination with Bevacizumab

In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:

a deleterious or suspected deleterious BRCA mutation and/or
genomic instability
Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer

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

Advanced gBRCAm Ovarian Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

gBRCAm HER2-Negative Metastatic Breast Cancer

For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please click here for complete Prescribing Information, including Patient Information (Medication Guide).

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 May 13, 2020 DermTech, Inc. (NASDAQ: DMTK) ("DermTech" or the "Company"), a leader in precision dermatology enabled by a non-invasive skin genomics platform, reported business and unaudited financial results for the quarter ended March 31, 2020 and also provided a corporate update (Press release, DermTech International, MAY 13, 2020, View Source [SID1234557931]).

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First Quarter 2020 Financial Highlights

Billable sample volume of 5,811 was a 149% increase over the 2,338 recorded for the first quarter of 2019 and an 18% sequential increase over the fourth quarter of 2019.
Assay revenue of $0.8 million was a 238% increase from the first quarter of 2019 and a 60% sequential increase compared to the fourth quarter of 2019.
Contract revenue of $0.8 million was a 111% increase compared to the first quarter of 2019 and a 30% sequential decrease compared to the fourth quarter of 2019.
Cash and cash equivalents were $67.9 million at the end of the quarter.
"We are pleased with how our messaging and user-experience are resonating with clinicians and patients, which is reflected in the strong sample volume and revenue growth we experienced during the first two and a half months of the first quarter, before the initial effects of the coronavirus pandemic. While the coronavirus pandemic has impacted our business near term, our long-term growth prospects remain strong and we believe may be enhanced by the broad movement of healthcare toward telemedicine services," said John Dobak, M.D., chief executive officer of DermTech. "We recently introduced a telemedicine solution for remote, clinician-guided sample collection by the patient for our non-invasive genomic melanoma rule-out test (the DermTech Pigmented Lesion Assay or DermTech PLA). While we do not expect this telemedicine option to immediately make up for testing volume lost due to stay-at-home orders, we believe this is an important long-term business strategy. By informing dermatologists of the option to serve patients through remote, clinician-guided, sample collection, we leverage the ease of use of our platform and create a new driver for potential business growth."

Corporate Update on COVID-19 Effects and Responses

We have initiated a broad COVID-19 response to drive education and usage despite reduced patient office visits and in-person sales calls. Although most dermatology offices are currently closed, our lab is fully operational, and we are receiving and analyzing samples. In response to the closure of dermatology offices, our sales team has been utilizing virtual sales calls and client education, and we have introduced a telemedicine option for remote, clinician-guided sample collection by the patient for the DermTech PLA test. We have implemented additional safety measures and social distancing within our commercial laboratory operations and have transitioned our administrative functions to working remotely. Although it is still too early to estimate the speed or extent of a recovery, some dermatology practices are reopening, particularly in states that are beginning to relax stay-at-home orders. We expect these reopened dermatology practices may focus initially on essential and time-sensitive dermatology care needs, such as skin cancer assessment, though it is not clear how this will impact our sample volumes. Other activities and effects related to the COVID-19 crisis are detailed below.

We estimate that the various stay-at-home orders implemented throughout the country beginning in March reduced our overall first quarter billable sample volume by approximately 200-300 tests.
April 2020 billable sample volume is down by approximately 80%, commensurate with the closure of dermatology offices, compared to the average monthly billable sample volume for January and February 2020 prior to the beginning of the stay-at-home orders. April 2020 billable sample volume decreased 56% compared to April 2019. Please note that while we are providing this additional information regarding April and first quarter 2020 volume impacts due to the pandemic in this update, we do not intend to continue to provide this type of data going forward.
In April, we announced that clinicians can choose to supervise remote sample collection by patients for the DermTech PLA. If, during a telemedicine visit, a clinician observes a pigmented lesion suspicious of melanoma, the clinician can request that we send the DermTech PLA collection kit to the patient’s home for a clinician-guided remote collection. We believe that our announcement of the availability of this teledermatology option comes at a critical time for patients and physicians, eliminating the need for unnecessary office visits during the COVID-19 pandemic.
Results from an institutional review board approved pilot study of seven cases undergoing clinician-guided remote collection were published in the peer-reviewed dermatology journal SKIN in May 2020. In addition, a larger ongoing internal validation effort has enrolled approximately 100 patients. Findings demonstrate that clinician-guided remote collection by patients is effective and equivalent to in-office collection, in terms of providing sufficient genomic material to generate a DermTech PLA test result.
We have initiated the development of a smartphone teledermatology app that enables the patient to take a picture of the suspicious lesion and securely forward it to a clinician for review. The smartphone teledermatology app also includes functionality to enable the clinician to efficiently order the DermTech PLA collection kits to be sent to patients’ homes for clinician-guided remote collection. We have also initiated a packaging redesign to simplify the sample collection process and clarify instructions for clinician-guided remote sample collection by the patient.
In April, we launched our DermTech PLA educational webinar series, which will occur periodically each month, and to date is being increasingly attended by practicing clinicians. In addition, our solution has been highlighted in several virtual dermatology educational meetings as a core solution for managing pigmented lesions remotely.
The launch of our second-generation product, the PLA plus, has been delayed until the resumption of normal office visits by dermatologists and the normalization of review cycle times by accreditation authorities. Our goal is to have this test available in the second half of the year. The PLA plus will replace our existing Nevome product.
We are continuing sales force recruiting and have several seasoned sales representatives slated to join DermTech in the coming quarters. We expect to have a sales force of 40-50 personnel in place by the end of 2020, with some incremental hires during 2021. The majority of the costs associated with these sales force additions in 2020 are now likely to occur in the second half of the year due to COVID-19.
We have not furloughed or terminated any employees as a result of the COVID-19 related slow down, but additional increases in headcount and spending associated with higher sample volumes and improving internal capabilities will be delayed until the recovery from the pandemic can be better predicted. We expect to continue our originally planned expenditures for research and development and for infrastructure enhancements, including capital equipment.
First Quarter 2020 Review

In January 2020, the Company contracted with a regional health plan to make the DermTech PLA for the early detection of melanoma available to the regional health plan’s commercial and Medicare Advantage membership.
In February 2020, the Company entered into a lease amendment to expand the size of its existing headquarters by approximately 13,300 square feet from approximately 15,355 square feet to approximately 28,655 square feet. The Company plans to use this additional lease space to expand lab operations for higher sample volume and efficiency, and to support the growth of all functions during the scale-up process.
On March 4, 2020, the Company closed a private placement resulting in aggregate gross proceeds to the Company of $65.0 million, with participation from leading healthcare-focused investors and mutual funds, along with strong support from existing stockholders.
In March 2020, the Company announced that the Journal of Drugs and Dermatology published the results of a large registry study confirming the clinical utility of the DermTech PLA. The study also confirmed the value of the Company’s adhesive patch by demonstrating that community-based clinicians using the DermTech PLA were able to reduce unnecessary biopsies by over 90%, to lower healthcare costs and rule out melanoma via a genomics approach that elevates pigmented lesion management beyond what the eye can see.
In the first quarter of 2020, the Company began receiving regular reimbursement payments from Noridian, our local Medicare Administrative Contractor, at the rate of $760, less 2% for sequestration. In addition, the Company began receiving payments from commercial payors under our new CPT code 0089U. While payments from commercial payors remain inconsistent, they have improved over prior quarters, specifically for those commercial payors that have Medicare Advantage plans.
TRUST study enrollment exceeded 50% prior to COVID-19 related stay-at-home orders. The TRUST study is the first of its kind for the Company to provide repeat clinical assessments and genomic testing on pigmented lesions suspicious for melanoma that were initially tested negative with the DermTech PLA. The Company will continue to enroll this study as patients begin to return for in-office visits, though the timeline to completion is currently unclear.
First Quarter 2020 Financial Results

Assay revenue increased 238% to $0.8 million for the three months ended March 31, 2020, compared to $0.2 million for the same period of 2019. Assay revenue for the three months ended March 31, 2020 increased due to higher billable sample volume and revenue recognition of Medicare samples related to the final local coverage determination effective February 10, 2020, compared to the same period of 2019. Contract revenue increased 111% to $0.8 million for the three months ended March 31, 2020, compared to $0.4 million for the same period of 2019. Contract revenue can be highly variable as it is dependent on the pharmaceutical customers’ clinical trial progress, which can be difficult to forecast due to variability of patient enrollment, drug safety and efficacy and other factors. Total revenues increased 161% to $1.6 million for the three months ended March 31, 2020, compared to $0.6 million for the same period in 2019.

Gross margin for the three months ended March 31, 2020 was 23%, compared to -6% for the same period of 2019. The increase in gross margin was largely driven by the increase in the Company’s contract revenue during the three months ended March 31, 2020. Assay gross margin for the three months ended March 31, 2020 was -46%.

Sales and marketing expense increased 241% to $2.9 million for the three months ended March 31, 2020, compared to $0.9 million for the same period of 2019. The increase was primarily attributable to sales force expansion to drive the adoption of the DermTech PLA and additional marketing investment to increase awareness of the DermTech PLA as a non-invasive genomic based diagnostic for melanoma.

Research and development expense increased 57% to $0.9 million for the three months ended March 31, 2020, compared to $0.6 million for the same period of 2019. The increase was primarily attributable to higher compensation and recruiting costs related to expanding the research and development team as well as increased laboratory supplies.

General and administrative expense increased 130% to $3.5 million for the three months ended March 31, 2020, compared to $1.5 million for the same period of 2019. The increase was primarily due to additional public company costs, including higher audit and legal costs related to filings with the Securities and Exchange Commission, higher compensation costs from expanding the general and administrative team and higher insurance costs.

Net loss for the three months ended March 31, 2020 was $7.0 million, which included $1.0 million of non-cash stock-based compensation, compared to a net loss of $5.2 million for the same period of 2019, which included $0.3 million of non-cash stock-based compensation.

Cash and cash equivalents totaled $67.9 million as of March 31, 2020.

On May 13, 2020 VolitionRx Limited (NYSE AMERICAN: VNRX) ("Volition"), an epigenetics company developing simple, easy to use and cost effective blood tests to help diagnose a range of cancers, reported that it will present three abstracts at the 2020 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, VolitionRX, MAY 13, 2020, View Source [SID1234557947]).

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

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ASCO Abstract e20078 "Circulating nucleosomes in hematological malignancy"
The first abstract presented announces initial data demonstrating the ability of Volition’s sample-enrichment tool, Nu.Q Capture, to separate short and long nucleosomes in clinical colorectal cancer samples to enable the concentration of tumor-derived nucleosomal markers prior to analysis. The other two abstracts presented provide new performance data for Volition’s Nucleosomics Nu.Q technology in the early detection of lung cancer and blood cancer.

E13534: Enrichment of circulating tumor DNA from cell free DNA of Hematopoietic origin

Data from this pilot study, the first published results for Volition’s Nu.Q Capture program, showed that Nu.Q Capture technology successfully demonstrated enrichment of circulating tumor nucleosomes and tumor DNA ("ctDNA"). The data clearly showed the separation of short and long nucleosomes from both cancer cell lines in a laboratory setting, and in clinical colorectal cancer patients versus healthy controls.

Dr. Mark Eccleston, Business Development Director and a founding scientist at Volition, said: "Effective removal of most ‘healthy/long’ nucleosomes creates an enriched sample allowing for more accurate measurement of cancer nucleosomes. Similarly, the removal of most ‘healthy/long’ nucleosome-associated DNA can also enhance detection of cancer using ctDNA technologies. These data are a really positive sign of the potential of Nu.Q Capture as a valuable tool to enable improved and earlier detection of cancer."

For more information about this abstract please watch this short video: View Source

E15542: Performance of a Nu.Q-H3.1 assay for lung cancer detection
This study, conducted in conjunction with Dr. Anne Sibille and team of Liege University Hospital, Belgium, aimed to assess the performance of a Nu.Q assay in discriminating both between lung cancer and healthy controls, and between lung cancer and Chronic Obstructive Pulmonary Disease ("COPD").

A pilot study of 142 subjects demonstrated that Nu.Q assays could not only discriminate lung cancer versus healthy controls with an Area Under the Curve ("AUC") of 88%, but also between lung cancer and COPD with an AUC of 85%. The AUC is an industry accepted measure of the effectiveness of an assay whereby 100% is the most accurate.

Commenting on this study, Dr. Marielle Herzog, Research and Development Director at Volition, said: "Lung cancer is not only the most prevalent cancer, but it is also the most deadly, responsible for over 1.75 million deaths worldwide each year. Its diagnosis currently relies on invasive methods and often occurs at a late stage of disease, explaining its poor outcome. Our hope is that a blood-based test could aid earlier diagnosis. Based on these encouraging results, we believe further studies with larger numbers of patients should be performed to confirm and validate the usefulness of these biomarkers and models."

E20078: Circulating nucleosomes in hematological malignancy
This pilot study investigated the circulating levels of intact nucleosomes containing the histone H3.1 isoform (Nu.Q-H3.1) in a variety of solid tumors including Non Hodgkin Lymphoma ("NHL"), Acute Myeloid Leukemia ("AML"), Acute Lymphocytic Leukemia ("ALL"), and in healthy subjects.

The results showed elevated levels of Nu.Q-H3.1 in patients diagnosed with cancers. Only 14 of 271 patients with a solid tumor had levels >200ng/ml. In contrast, the median Nu.Q-H3.1 levels observed for patients with NHL, AML and ALL were 276, 284 and 585ng/ml, respectively. The median nucleosome level in 62 healthy subjects was 40ng/ml and the highest level was 198ng/ml. The Area Under the Curve ("AUC") for all patients diagnosed with NHL, AML or ALL (n=54) vs healthy subjects was 91% with a sensitivity of 74% at 95% specificity.

Lead author, Dr. Jason Terrell, Chief Medical Officer at Volition, commented: "Elevated nucleosome levels have been reported for a number of diseases. These encouraging early results indicate that levels of Nu.Q-H3.1 are particularly elevated in haematological cancers. These data show that Nu.Q technology may be a useful diagnostic tool warranting further study."

For further information about this abstract please watch this video presentation:
View Source

Abstracts will be available to view starting at 5:00 pm ET on May 13, 2020 on the ASCO (Free ASCO Whitepaper) Meeting Library.

On May 13, 2020 Bristol Myers Squibb (NYSE: BMY) and bluebird bio, Inc. (Nasdaq: BLUE) reported that the companies received a Refusal to File letter from the U.S. Food and Drug Administration (FDA) regarding the Biologics License Application (BLA) for idecabtagene vicleucel (ide-cel; bb2121) for patients with heavily pre-treated relapsed and refractory multiple myeloma, which was submitted in March 2020 (Press release, Bristol-Myers Squibb, MAY 13, 2020, View Source [SID1234557878]).

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

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Upon preliminary review, the FDA determined that the Chemistry, Manufacturing and Control (CMC) module of the BLA requires further detail to complete the review. No additional clinical or non-clinical data have been requested or are required. Bristol Myers Squibb is planning to resubmit the BLA no later than the end of July 2020.

Bristol Myers Squibb Investor Call and Webcast

Bristol Myers Squibb will hold an investor conference call to discuss this update today at 8:00 a.m. EDT.

Investors are invited to listen to a live webcast of the call at bms.com/investors or by dialing toll free in the U.S. 877-257-8599 or international 1-631-291-4581, confirmation code: 5938714. Please dial in at least 15 minutes in advance to ensure a timely connection to the call.

bluebird bio Investor Call and Webcast
bluebird bio will hold an investor conference call to discuss the update today at 8:45 a.m. EDT.

Investors are invited to listen to a live webcast of the call on the investors page of www.bluebirdbio.com or by dialing toll free in the U.S. (844) 825-4408 or international (315) 625-3227, confirmation code: 2892826. Please dial in at least 15 minutes in advance to ensure a timely connection to the call.

For Holders of Contingent Value Rights (CVR), Ticker BMY-RT

U.S. FDA approval of ide-cel by March 31, 2021 is one of the required remaining milestones of the Contingent Value Rights issued upon the close of the Celgene acquisition in the fourth quarter of 2019. The other is U.S. FDA approval of liso-cel by December 31, 2020. The company is committed to working with FDA to progress both applications and achieve the remaining regulatory milestones required by the CVR.

About Ide-cel

Ide-cel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy. The ide-cel CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing BCMA, attached to a human CD8 α hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 4-1BB and CD3-ζ chain, in tandem. Ide-cel recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

In addition to the pivotal KarMMa trial evaluating ide-cel in patients with relapsed and refractory multiple myeloma, Bristol Myers Squibb and bluebird bio’s broad clinical development program for ide-cel includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-4) in earlier lines of treatment for patients with multiple myeloma, including newly diagnosed multiple myeloma. For more information visit clinicaltrials.gov.

Ide-cel was granted Breakthrough Therapy Designation (BTD) by the FDA and PRIority Medicines (PRIME) designation, as well as Accelerated Assessment status, by the European Medicines Agency for relapsed and refractory multiple myeloma.

Ide-cel is being developed as part of a Co-Development, Co-Promotion and Profit Share Agreement between Bristol Myers Squibb and bluebird bio.

Bristol Myers Squibb: Advancing Cancer Research

At Bristol Myers Squibb, patients are at the center of everything we do. The goal of our cancer research is to increase patients’ quality of life, long-term survival and make cure a possibility. We harness our deep scientific experience, cutting-edge technologies and discovery platforms to discover, develop and deliver novel treatments for patients.

Building upon our transformative work and legacy in hematology and Immuno-Oncology that has changed survival expectations for many cancers, our researchers are advancing a deep and diverse pipeline across multiple modalities. In the field of immune cell therapy, this includes registrational CAR T cell agents for numerous diseases, and a growing early-stage pipeline that expands cell and gene therapy targets, and technologies. We are developing cancer treatments directed at key biological pathways using our protein homeostasis platform, a research capability that has been the basis of our approved therapies for multiple myeloma and several promising compounds in early- to mid-stage development. Our scientists are targeting different immune system pathways to address interactions between tumors, the microenvironment and the immune system to further expand upon the progress we have made and help more patients respond to treatment. Combining these approaches is key to delivering potential new options for the treatment of cancer and addressing the growing issue of resistance to immunotherapy. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines a reality for patients.