publication date: Jun. 14, 2019

Drugs & Targets

FDA approves chemoimmunotherapy regimen in diffuse large B-cell lymphoma

FDA granted accelerated approval to Polivy (polatuzumab vedotin-piiq), a novel antibody-drug conjugate, in combination with the chemotherapy bendamustine and rituximab product, to treat adult patients with diffuse large B-cell lymphoma that has progressed or returned after at least two prior therapies.

FDA granted the approval of Polivy to Genentech. It granted the application Breakthrough Therapy and Priority Review designations. Polivy also received Orphan Drug designation.

Polivy is an antibody that is attached to a chemotherapy drug. Polivy binds to a specific protein (CD79b) found only on B cells, then releases the chemotherapy drug into those cells. Efficacy was evaluated in a study of 80 patients with relapsed or refractory DLBCL who were randomized to receive Polivy with BR or BR alone.

Efficacy was based on complete response rate and duration of response, defined as the time the disease stays in remission. At the end of treatment, the complete response rate was 40% with Polivy plus BR compared to 18% with BR alone. Of the 25 patients who achieved a partial or complete response to Polivy plus BR, 16 (64%) had a DOR of at least six months and 12 (48%) had a DOR of at least 12 months.


FDA approves two indications for Keytruda

FDA has approved Merck’s Keytruda as monotherapy in patients whose tumors express PD-L1 (Combined Positive Score ≥1) or in combination with platinum and fluorouracil for the first-line treatment of patients with metastatic or unresectable, recurrent head and neck squamous cell carcinoma.

The approval is based on results from pivotal phase III KEYNOTE-048 trial, where Keytruda demonstrated a significant improvement in overall survival compared with the EXTREME regimen (cetuximab with carboplatin or cisplatin plus FU) as monotherapy in patients whose tumors expressed PD-L1 (CPS ≥1) (HR=0.78 [95% CI, 0.64-0.96]; p=0.0171) and in combination with chemotherapy in the total study population (HR=0.77 [95% CI, 0.63-0.93]; p=0.0067).

With these new indications, Keytruda is the first anti-PD-1 therapy approved in the first-line setting as monotherapy in patients whose tumors express PD-L1 (CPS ≥1) or in combination with chemotherapy regardless of PD-L1 expression for patients with metastatic or unresectable, recurrent HNSCC and the first anti-PD-1 therapy to demonstrate a statistically significant improvement in OS in these patients.

Keytruda was initially approved for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy in 2016 under the FDA’s accelerated approval process based on objective response rate data from the phase Ib KEYNOTE-012 trial.

In accordance with the accelerated approval process, continued approval was contingent upon verification and description of clinical benefit, which has now been demonstrated in KEYNOTE-048 and has resulted in the FDA converting the accelerated approval to a full approval.

This approval is based on data from the prespecified interim analysis of the phase III KEYNOTE-048 trial, a randomized, multi-center, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy and who were considered incurable by local therapies.

Randomization was stratified by tumor PD-L1 expression (Tumor Proportion Score ≥50% or <50%) according to the PD-L1 IHC 22C3 pharmDx kit, HPV status according to p16 IHC (positive or negative), and ECOG Performance Status (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms:

  • Keytruda 200 mg intravenously every three weeks;

  • Keytruda 200 mg intravenously every three weeks, carboplatin AUC 5 mg/mL/min intravenously every three weeks or cisplatin 100 mg/m2 intravenously every three weeks and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every three weeks (maximum of six cycles of platinum and FU);

  • Cetuximab 400 mg/m2 intravenously as the initial dose then 250 mg/m2 intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every three weeks or cisplatin 100 mg/m2 intravenously every three weeks and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every three weeks (maximum of six cycles of platinum and FU).

Among the 882 patients, the study population characteristics were: median age of 61 years (range, 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian, and 2.4% Black; 61% had ECOG PS of 1; and 79% were former or current smokers. Twenty-two percent of patients’ tumors were HPV positive; 23% had PD-L1 TPS ≥50%; and 95% had stage IV disease (19% were stage IVA, 6% were stage IVB, and 70% were stage IVC). Eighty-five percent of patients’ tumors had PD-L1 expression of CPS ≥1, and 43% had CPS ≥20.

Treatment with Keytruda continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. A retrospective re-classification of patients’ tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor specimens used for randomization.

The main efficacy outcome measures were OS and progression-free survival as assessed by blinded independent central review according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ) sequentially tested in the subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1 and the overall population.

In KEYNOTE-048, the safety of Keytruda, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in patients with previously untreated, recurrent, or metastatic HNSCC.

The median duration of exposure to KEYTRUDA 200 mg every three weeks was 3.5 months (range, 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range, 3 days to 24.2 months) in the combination arm.

Keytruda was discontinued for adverse reactions in 12% of patients in the Keytruda single agent arm. The most common adverse reactions resulting in permanent discontinuation of Keytruda were sepsis (1.7%) and pneumonia (1.3%).


FDA approves PD-L1 IHC 22C3 pharmDx assay in HNSCC

FDA has approved Agilent Technologies Inc.’s PD-L1 IHC 22C3 pharmDx assay for expanded use.

The assay is now approved as an aid in identifying patients with head and neck squamous cell carcinoma for treatment with Keytruda (pembrolizumab), anti-PD-1 therapy manufactured by Merck.

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

PD-L1 IHC 22C3 pharmDx is the only companion diagnostic FDA-approved to aid in the identification of HNSCC patients for treatment with KEYTRUDA. HNSCC is the fifth cancer type for which PD-L1 IHC 22C3 pharmDx has gained FDA approval in the U.S.

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

Agilent developed PD-L1 IHC 22C3 pharmDx in partnership with Merck & Co. PD-L1 IHC 22C3 pharmDx also helps physicians identify non-small cell lung cancer, cervical cancer, gastric or GEJ adenocarcinoma, and urothelial carcinoma patients for treatment with Keytruda.

PD-L1 expression in NSCLC tissues is interpreted using Tumor Proportion Score. PD-L1 expression in HNSCC, urothelial carcinoma, cervical cancer, and gastric or GEJ adenocarcinoma tissues is interpreted using Combined Positive Score.


Cofactor Genomics joins FNIH Biomarkers Consortium

Cofactor Genomics said it has become a member of the Foundation for NIH Biomarkers Consortium with the goal of advancing the adoption of multidimensional biomarkers in cancer and immune-related diseases.

Formally launched in 2006, the FNIH Biomarkers Consortium is a major public-private biomedical research partnership managed by the FNIH with broad participation from stakeholders across biomedical research, including government, industry, academia, patient advocacy, and other not-for-profit organizations.

In addition to the FNIH, founding members include NIH, FDA, the Pharmaceutical Research and Manufacturers of America, the Centers for Medicare & Medicaid Services, and BIO.

The FNIH Biomarkers Consortium brings together expertise and resources of various partners to rapidly identify, develop, and seek qualification of potential high-impact biomarkers particularly to enable improvements in drug development, clinical care, and regulatory decision-making.

Cofactor’s success in demonstrating the utility of Predictive Immune Modeling with their ImmunoPrism assay positions them to add value to a number of the initiatives of the FNIH Biomarkers Consortium, specifically in the area of inflammation, immunity, and cancer.

Cofactor’s technical teams will participate in the FNIH Biomarkers Consortium and offer expertise in ImmunoPrism reagents and services to achieve advanced profiling of immune response.

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