Keytruda receives second biomarker-based indication from FDA, regardless of tumor type – The Cancer Letter

publication date: Jun. 19, 2020

Keytruda was approved by FDA as monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

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 TMB-H central nervous system cancers have not been established.

FDA also approved the FoundationOne CDx test as the companion diagnostic to identify patients with solid tumors that are TMB-H (10 mutations/ megabase) who may benefit from immunotherapy treatment with KEYTRUDA monotherapy.

These approvals stem from years of research into how TMB levels may influence a patients response to immunotherapy, Brian Alexander, chief medical officer of Foundation Medicine said in a statement. Its critical that healthcare professionals have access to a validated genomic test to measure TMB in clinical tumor assessments and pinpoint those who are more likely to respond. Were proud to be collaborating with Merck to help match appropriate patients to this important treatment.

The accelerated approval was based on data from a prospectively-planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with TMB-H, who were enrolled in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label trial evaluating KEYTRUDA (200 mg every three weeks).

The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease, or a medical condition that required immunosuppression. TMB status was assessed using the FoundationOne CDx assay and pre-specified cutpoints of 10 and 13 mut/Mb, and testing was blinded with respect to clinical outcomes. Tumor response was assessed every nine weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) in the patients who received at least one dose of KEYTRUDA as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

In KEYNOTE-158, 1,050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB 10 mut/Mb. The study population characteristics of these 102 patients were: median age of 61 years (range, 27 to 80); 34% age 65 or older; 34% male; 81% White; and 41% Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 and 58% ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy.

In the 102 patients whose tumors were TMB-H, KEYTRUDA demonstrated an ORR of 29% (95% CI, 21-39), with a complete response rate of 4% and a partial response rate of 25%. After a median follow-up time of 11.1 months, the median DOR had not been reached (range, 2.2+ to 34.8+ months). Among the 30 responding patients, 57% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer.

In a pre-specified analysis of patients with TMB 13 mut/Mb (n=70), KEYTRUDA demonstrated an ORR of 37% (95% CI, 26-50), with a complete response rate of 3% and a partial response rate of 34%. After a median follow-up time of 11.1 months, the median DOR had not been reached (range, 2.2+ to 34.8+ months). Among the 26 responding patients, 58% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer. In an exploratory analysis in 32 patients whose cancer had TMB 10 mut/Mb and <13 mut/Mb, the ORR was 13% (95% CI, 4-29), including two complete responses and two partial responses.

FoundationOne CDx receives FDA approval as companion diagnostic with Keytruda

FoundationOne CDx has received FDA approval as a companion diagnostic for Keytruda (pembrolizumab), Mercks anti-PD-1 therapy.

FoundationOne CDx was also approved under accelerated approval for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

FoundationOne CDx is sponsored by Foundation Medicine.

FoundationOne CDx is the first and only FDA-approved companion diagnostic to measure TMB and help identify patients who may be appropriate for treatment with Keytruda, regardless of solid tumor type.

FoundationOne CDx, Foundation Medicines comprehensive genomic profiling assay approved for all solid tumors, enables oncologists to identify TMB-H patients ( 10 mutations/megabase) with unresectable or metastatic solid tumors across all tumor types who could potentially benefit from Keytruda.

FoundationOne CDx is the first FDA-approved CGP test that is clinically and analytically validated for all solid tumors and incorporates multiple companion diagnostic claims. It is currently approved as the companion diagnostic test for more than 20 therapies across multiple cancer types.

Lurbinectedin receives accelerated approval by FDA for metastatic SCLC

Lurbinectedin (Zepzelca) was granted accelerated approval by FDA for adult patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy.

Zepzelca is sponsored by Pharma Mar S.A.

Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. Patients received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity.

The main efficacy outcome measures were confirmed overall response rate, determined by investigator assessment using RECIST 1.1 and response duration. Among the 105 patients, the ORR was 35% (95% CI: 26%, 45%), with a median response duration of 5.3 months (95% CI: 4.1, 6.4). The ORR as per independent review committee was 30% (95% CI: 22%, 40%) with a median response duration of 5.1 months (95% CI: 4.9, 6.4).

Gemtuzumab ozogamicin receives extended indication for CD33-positive AML in pediatric patients

Gemtuzumab ozogamicin (Mylotarg) was granted an extended indication by FDA for newly-diagnosed CD33-positive acute myeloid leukemia to include pediatric patients 1 month and older.

Mylotarg is sponsored by Wyeth Pharmaceuticals LLC.

Efficacy and safety in the pediatric population were supported by data from AAML0531 (NCT00372593), a multicenter randomized study of 1,063 patients with newly-diagnosed AML ages 0 to 29 years. Patients were randomized to five-cycle chemotherapy alone or with gemtuzumab ozogamicin (3 mg/m2) administered once on day 6 in Induction 1 and once on day 7 in Intensification 2.

The main efficacy outcome measure was event-free survival measured from the date of trial entry until induction failure, relapse, or death by any cause. The EFS hazard ratio was 0.84 (95% CI: 0.71-0.99). The estimated percentage of patients free of induction failure, relapse, or death at five years was 48% (95% CI: 43%-52%) in the gemtuzumab ozogamicin + chemotherapy arm versus 40% (95% CI: 36%45%) in the chemotherapy alone arm. No difference between treatment arms in overall survival was demonstrated.

City of Hope signs licensing agreement with Scopus BioPharma to develop novel, targeted IO gene therapy

City of Hope has signed an exclusive worldwide licensing agreement with Scopus BioPharma Inc. to develop and commercialize a City of Hope first-in-class, targeted immuno-oncology gene therapy.

A first in-human phase I clinical trial for B cell lymphoma patients that uses the licensed gene therapy drug, CpG-STAT3siRNA, a STAT3 inhibitor, is expected to commence at City of Hope in the second half of this year.

Growing evidence links B cell non-Hodgkin lymphomas to persistent activation of STAT3, a gene that drives tumor cell growth and anti-tumor immune suppression. The STAT3 inhibitor is a highly selective and targeted therapy that silences the activity of the STAT3 gene by way of RNA interference. It also stimulates the TLR9 receptors to activate the bodys immune defense to recognize and kill cancer cells.

In preclinical testing at City of Hope, the STAT3 inhibitor has successfully reduced growth and metastasis of various preclinical tumor models, including melanoma, and colon and bladder cancers, as well as leukemia and lymphoma.

City of Hopes Hua Yu, Billy and Audrey L. Wilder Professor in Tumor Immunotherapy, associate chair/professor in the Department of Immuno-Oncology, and co-leader of the Cancer Immunotherapeutics Program, and Marcin Kortylewski, associate professor in the Department of Immuno-Oncology, who are both leading experts in the role of STAT3 in tumor angiogenesis and tumor immune evasion and in oligonucleotide-based cancer immunotherapies, developed the STAT3 inhibitor.

The strategy was developed based on seminal discoveries by Yus team defining the key role of STAT3 in cancer cell survival and immune tolerance, combined with pioneering work by Kortylewskis team on STAT3 targeting using TLR9-targeted delivery of siRNA oligonucleotide therapeutics into immune cells.

STAT3 is critical for the survival and metastasis of cancer cells, and for suppressing anti-tumor immune responses, Yu said in a statement.

Our laboratories were the first to demonstrate that successful cancer immunotherapy needs to be two-step since TLR9 immunostimulation is only effective when STAT3 in the tumor microenvironment is no longer active, Kortylewski said in a statement. It is exciting to see this technology approaching clinical application with a strong ally in biopharma.

Royal Philips and MD Anderson to facilitate personalized oncology treatments and clinical trial matching based on genomic markers

The University of Texas MD Anderson Cancer Center and Royal Philips are providing oncologists with evidence-based therapy and clinical trial guidance through Philips oncology informatics solutions and MD Andersons Precision Oncology Decision Support system.

This collaboration will allow physicians around the world to personalize therapy based on the patients genomic profile, with the aim of improving patient care.

MD Anderson developed the PODS system as an evidence-based tool to facilitate therapeutic decision-making at the point of care. The system provides actionable clinical information, including approved therapies and available clinical trials, based upon genetic alterations within the tumor. Through the Philips solutions, clinicians receive a unified view of therapies and clinical trials in the context of their patients unique tumor, helping them make an evidence-based decision for their patients treatment.

Philips and MD Anderson aim to help pathologists and oncologists serve their patients and provide them with therapeutic options and relevant clinical trials based on tumor markers.

Isoray, University of Cincinnati physicians company sign research agreement to study head and neck cancers

Isoray Inc. has entered a research grant agreement with the University of Cincinnati Physicians Company for a study on treatment of recurrent head and neck cancers.

University of Cincinnati Physicians Company is the multispecialty practice group for University of Cincinnati College of Medicine and UC Health.

The planned trial will evaluate the safety and early effectiveness of the addition of Keytruda (pembrolizumab) to the regimen of Cesium-131 with surgical resection. A total of 50 patients whose head and neck cancers have recurred and who are eligible for surgical resection are planned to be enrolled.

The study, a trial combining Keytruda and Cesium-131 brachytherapy with salvage surgery in head and neck squamous cell carcinoma, will be carried out under the direction of principal investigators Shuchi Gulati and Chad Zender at the University of Cincinnati Medical Center. There is potential for other centers to participate in the study.

A previous multi-institutional study has provided evidence that the use of Cesium-131 with surgical resection is well-tolerated in the treatment of recurrent head and neck cancers.

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Keytruda receives second biomarker-based indication from FDA, regardless of tumor type - The Cancer Letter