publication date: Nov. 2, 2018
Drugs & Targets
FDA approves Keytruda + carboplatin and either paclitaxel or nab-paclitaxel for first-line metastatic squamous NSCLC
Merck, known as MSD outside the United States and Canada, announced the FDA has approved Keytruda, Merck’s anti-PD-1 therapy, in combination with carboplatin and either paclitaxel or nab-paclitaxel, for the first-line treatment of patients with metastatic squamous non-small cell lung cancer based on results from the KEYNOTE-407 trial.
In the pivotal phase III trial of patients regardless of tumor PD-L1 expression status, KEYTRUDA in combination with chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) significantly improved overall survival, reducing the risk of death by 36 percent compared to chemotherapy alone (HR=0.64 [95% CI, 0.49, 0.85]; p=0.0017).
This approval marks the first time an anti-PD-1 regimen has been approved for the first-line treatment of squamous NSCLC regardless of tumor PD-L1 expression status.
Immune-mediated adverse reactions, which may be severe or fatal, can occur with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation.
Based on the severity of the adverse reaction, Keytruda should be withheld or discontinued and corticosteroids administered if appropriate. Keytruda can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman.
Keytruda is the first anti-PD-1 approved in the first-line setting as both combination and monotherapy in certain patients with metastatic NSCLC. With this approval, all appropriate patients with metastatic squamous NSCLC and all appropriate patients with metastatic nonsquamous NSCLC and no EGFR or ALK genomic tumor aberrations are now eligible for a KEYTRUDA-based regimen as their first-line treatment option.
The approval was based on data from KEYNOTE-407, a randomized, double-blind, multicenter, placebo-controlled study. The key eligibility criteria for this study were metastatic squamous NSCLC, regardless of tumor PD-L1 expression status, and no prior systemic treatment for metastatic disease.
Patients with autoimmune disease that required systemic therapy within two years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.
Patients were randomized to receive Keytruda 200 mg and carboplatin every three weeks for four cycles, plus paclitaxel every three weeks for four cycles or nab-paclitaxel on Days 1, 8 and 15 of every three-week cycle for four cycles, followed by Keytruda 200 mg every three weeks; or placebo and carboplatin every three weeks for four cycles, plus paclitaxel every three weeks for four cycles or nab-paclitaxel on Days 1, 8 and 15 of every three-week cycle for four cycles, followed by placebo every three weeks.
Treatment with Keytruda or placebo continued until progression of disease, unacceptable toxicity, or a maximum of 24 months. Patients in the placebo arm were offered Keytruda as a single agent at the time of disease progression.
Primary efficacy outcome measures were OS as well as progression-free survival and objective response rate as assessed by blinded independent central review using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. An additional efficacy outcome measure was duration of response.
In KEYNOTE-407, there was a statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or nab-paclitaxel compared with patients randomized to placebo with carboplatin and either paclitaxel or nab-paclitaxel.
In KEYNOTE-407, safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). The safety of KEYTRUDA in combination with carboplatin and either paclitaxel or nab-paclitaxel was investigated in 101 patients at the first interim analysis of KEYNOTE-407.
Keytruda was discontinued for adverse reactions in 15 percent of patients with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of Keytruda occurred in 43 percent of patients.
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.
FDA accepts sNDA for Lonsurf for metastatic gastric/gastroesophageal junction adenocarcinoma; grants Priority Review
Taiho Oncology, Inc. announced the FDA has accepted and granted priority review for the supplemental New Drug Application for Lonsurf (trifluridine/tipiracil, TAS-102) as a treatment for patients with previously treated, advanced or metastatic gastric adenocarcinoma, including cancer of the gastroesophageal junction.
The FDA has provided an anticipated Prescription Drug User Fee Act action date of February 24, 2019.
The sNDA is based on data from the global, randomized, double blind pivotal phase III trial evaluating LONSURF versus placebo and best supportive care in patients with heavily pretreated metastatic gastric/gastroesophageal junction adenocarcinoma that progressed or were intolerant to previous lines of therapy.
The trial met its primary endpoint of prolonged overall survival and secondary endpoint measures of progression-free survival as well as continuing to demonstrate LONSURF’s consistent safety and tolerability profile.
Full results from this study were recently presented at the European Society of Medical Oncology 2018 Congress in Munich and published simultaneously in The Lancet Oncology.
Lonsurf, in the U.S., is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy and, if RAS wild-type, an anti-EGFR therapy.
TAGS (TAS-102 Gastric Study) is a Taiho-sponsored pivotal phase III, multinational, randomized, double-blind study evaluating trifluridine/tipiracil, also known as TAS-102, plus best supportive care versus placebo plus BSC in patients with metastatic gastric cancer, including gastroesophageal junction cancer, refractory to standard treatments.
The primary endpoint in the TAGS trial is overall survival, and the main secondary endpoint measures include progression-free survival, and safety and tolerability, as well as quality of life.
TAGS enrolled 507 adult patients with metastatic gastric cancer who had previously received at least two prior regimens for advanced disease. The study was conducted in Japan, the United States, the European Union, Russia, Belarus, Israel, and Turkey.
Standard chemotherapy regimens for advanced gastric cancer include fluoropyrimidines, platinum derivatives, and taxanes (with ramucirumab), or irinotecan. The addition of trastuzumab to chemotherapy is standard of care for patients with HER2-neu-positive advanced gastric cancer. However, after failure of first- and second-line therapies, standard third-line treatments are limited.
Lonsurf (trifluridine/tipiracil) is an oral anticancer drug, which utilizes the combination of trifluridine and tipiracil, whose dual mechanism of action is designed to maintain clinical activity and differs from conventional fluoropyrimidines.
FTD is an antineoplastic nucleoside analogue, which is incorporated directly into the DNA, thereby interfering with the function of DNA. The blood concentration of FTD is maintained via TPI, which is an inhibitor of the FTD-degrading enzyme, thymidine phosphorylase.
In Japan, Taiho Pharmaceutical has been marketing Lonsurf for the treatment of unresectable advanced or recurrent colorectal cancer since 2014. In the United States, beginning in 2015, Taiho Oncology, Inc., a U.S. subsidiary of Taiho Pharmaceutical, began marketing the drug for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
In June 2015, Taiho Pharmaceutical and Servier entered into an exclusive license agreement for the co-development and commercialization of Lonsurf in Europe and other countries outside of the United States, Canada, Mexico and Asia. In parts of Asia outside of Japan, Taiho Pharmaceutical’s business partner TYY Biopharm launched Lonsurf in Taiwan in July 2018, and Jeil Pharmaceutical is preparing to bring the drug to market in South Korea.
As of October 2018, Lonsurf has been approved as a treatment for advanced mCRC in 61 countries and regions worldwide.
Lonsurf is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor, indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
Venclexta + Gazyva reduced risk of disease worsening or death in previously untreated CLL with co-morbidities
Genentech announced the randomized phase III CLL14 study, which evaluated fixed-duration Venclexta (venetoclax) in combination with Gazyva (obinutuzumab) in people with previously untreated chronic lymphocytic leukemia and co-existing medical conditions, met its primary endpoint and showed a statistically significant reduction in the risk of disease worsening or death (progression-free survival as assessed by investigator) compared to standard-of-care Gazyva plus chlorambucil.
Genentech is a member of the Roche Group.
The results showed that no new safety signals or increase in known toxicities of Venclexta or Gazyva were observed with the treatment combination, the company said.
Data from the CLL14 study will be submitted to global health authorities. Venclexta in combination with Rituxan (rituximab) has been approved by the FDA for the treatment of people with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy.
A supplemental New Drug Application is currently under review by FDA for Venclexta in combination with a hypomethylating agent or in combination with low dose cytarabine for the treatment of people with previously untreated acute myeloid leukemia who are ineligible for intensive chemotherapy, with a decision expected by end of year.
A clinical development program for Venclexta is ongoing in several types of blood cancer, including AML and multiple myeloma. Gazyva continues to be investigated in combination with approved and investigational molecules in CLL and follicular lymphoma.
Venclexta is being developed by AbbVie and Genentech. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the U.S.
CLL14 (NCT02242942) is a randomized phase III study evaluating the combination of fixed-duration Venclexta plus Gazyva compared to Gazyva plus chlorambucil in patients with previously untreated chronic lymphocytic leukemia with coexisting medical conditions.
432 patients with previously untreated CLL were randomly assigned to receive either Venclexta plus Gazyva (Arm A) or Gazyva plus chlorambucil (Arm B). The primary endpoint of the study is investigator-assessed progression free survival.
Secondary endpoints include PFS assessed by independent review committee, best overall response, complete response, duration of response, overall survival, event-free survival, time to next CLL treatment, minimal residual disease status and safety.
TESARO achieves Zejula prostate cancer development milestone by Janssen
TESARO Inc. announced the achievement of development milestones that trigger an $18 million payment from Janssen Biotech Inc.
The milestones are related to Janssen’s ongoing GALAHAD trial, which is assessing niraparib monotherapy for the treatment of men with metastatic castration-resistant prostate cancer and DNA-repair anomalies. Data from the trial are anticipated to support global regulatory filings in 2019.
In addition, data from the phase Ib BEDIVERE trial were recently presented at the European Society of Clinical Oncology and demonstrated the safety and tolerability of combining niraparib with abiraterone acetate + prednisone in men with mCRPC.
Data from the BEDIVERE trial will be used to inform the dosing regimen in a future phase III trial that will assess the clinical benefit of niraparib in combination with AA-P in mCRPC patients.
TESARO entered into a global prostate collaboration and license agreement with Janssen in 2016, through which Janssen received rights to develop and commercialize niraparib for patients with prostate cancer worldwide, except Japan. Under the terms of the agreement, TESARO is eligible to receive development, regulatory and commercial milestones, in addition to royalty payments.
GALAHAD is an ongoing phase II, open-label, single arm trial designed to evaluate the safety and efficacy of niraparib monotherapy (300mg daily) in men with metastatic castration-resistant prostate cancer and DNA-repair anomalies progressing on/after taxane-based chemotherapy and androgen receptor targeted therapy. Patients are enrolled in the study based on their DNA-repair deficiency status.
BEDIVERE is an ongoing phase Ib, open-label, dose-selection study with dose expansion designed to evaluate the safety of niraparib in combination with AA-P in men with metastatic castration-resistant prostate cancer who may or may not have had DNA-repair anomalies.
Niraparib is marketed in the U.S. and Europe under trade name Zejula.
Cofactor Genomics launches ImmunoPrism kit for use in clinical sequencing laboratories
Cofactor Genomics has launched an RNA-based immune profiling kit developed for laboratories wishing to derive the immune composition of tumor samples.
Using the ImmunoPrism Immune Profiling Kit, laboratories now have access to the same kit Cofactor Genomics uses to prep, sequence and analyze against Cofactor’s database of machine-learning optimized immune reference expression models.
The launch of the kit follows recent ImmunoPrism announcements on collaborations with The Fred Hutchinson Cancer Research Center and NCI, and most recently, the clinical accreditation of the assay by the College of American Pathologists within Cofactor’s CAP/CLIA lab.
Building on data from thousands of RNA expression profiles, the fully analyzed, proprietary, biomarker discovery report includes quantitative immune cell characterizations and enables intra- and inter-sample immune cell ratios and comparisons, which have been shown to have prognostic value. The report also includes statistics such as p-value, threshold for patient selection, predictive accuracy, and positive/negative predictive values, the company said.
Cofactor’s ImmunoPrism Immune Profiling Kit details the quantitative percentage for eight major immune cell types and expression levels of ten immune escape genes. This immune characterization can be obtained using FFPE, FNAs, CNBs, accommodating solid tumors with very limited amounts of tissue, in some cases as low as 20 nanograms. This includes pre-treatment clinical samples, which previously have been difficult to characterize, the company said.