publication date: Nov. 16, 2018

Drugs & Targets

Using review pilot program, FDA takes two weeks to approve first-line treatment for peripheral T-cell lymphoma

FDA has expanded the approved use of Adcetris (brentuximab vedotin) injection in combination with chemotherapy for adult patients with certain types of peripheral T-cell lymphoma.

This is the first FDA approval for treatment of newly diagnosed PTCL.

To process the sBLA, FDA used the Real-Time Oncology Review, a pilot program launched this July to expedite the availability of potentially life-saving cancer treatments. RTOR is granted to treatments likely to demonstrate substantial improvements over available therapy; ADCETRIS is only the fourth treatment to receive a RTOR.

“The Real-Time Oncology Review program allows the FDA to access key data prior to the official submission of the application allowing the review team to begin their review earlier and communicate with the sponsor prior to the application’s actual submission,” Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products, said in a statement. “When the sponsor submits the completed application, the review team will already be familiar with the data and be able to conduct a more efficient, timely and thorough review. RTOR allowed the FDA to approve this indication within two weeks of the completed application’s submission.”

FDA granted the approval of Adcetris to Seattle Genetics.

PTCLs are rare, fast-growing non-Hodgkin lymphomas that develop from white blood cells called T-cells. The T-cells often spread quickly throughout the body and are hard to treat.

Adcetris is a monoclonal antibody that binds to a protein (called CD30) found on some cancer cells. Adcetris is now approved to treat previously untreated systemic anaplastic large cell lymphoma (ALCL) and other CD30-expressing PTCLs in combination with chemotherapy. Adcetris was previously approved by the FDA to treat adult patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant when a patient is at a high risk of relapse or progression, systemic ALCL after failure of other treatment, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after failure of other treatment.

The new approval was based on a clinical trial of 452 patients with certain PTCLs who received either Adcetris plus chemotherapy or a standard chemotherapy (CHOP) as first-line treatment. Progression-free survival (the amount of time a patient stays alive without the cancer growing) was significantly longer (hazard ratio 0.71, P-value 0.01) in the Adcetris arm (median 48 months, compared to 21 months with CHOP). Overall survival and overall response rates were also significantly better in the Adcetris arm.

The most common side effects of Adcetris plus chemotherapy included nerve damage (peripheral neuropathy), nausea and vomiting, diarrhea, low white blood cell counts, fatigue, mouth sores, constipation, hair loss, fever and low red blood cell count (anemia).

Health care providers are advised to monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications and infections. Patients should also be monitored for tumor lysis syndrome (a complication from many tumor cells being killed off at the same time), serious skin reactions, lung side effects (pulmonary toxicity) and liver damage (hepatotoxicity).

The prescribing information for Adcetris includes a boxed warning to advise health care professionals and patients about the risk of a fatal or life-threatening infection of the brain (progressive multifocal leukoencephalopathy) in patients receiving Adcetris.


FDA accepts novel clinical trial endpoint in approving Erleada for prostate cancer

FDA approved Erleada (apalutamide) for the treatment of non-metastatic castration-resistant prostate cancer. This is the first FDA-approved treatment for this indication.

“This approval is the first to use the endpoint of metastasis-free survival, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment,” said Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products, said in a statement. “In the trial supporting approval, Erleada had a robust effect on this endpoint. This demonstrates the agency’s commitment to using novel endpoints to expedite important therapies to the American public.”

The FDA granted the approval of Erleada to Janssen Pharmaceutical Companies, a unit of Johnson & Johnson.

Erleada works by blocking the effect of androgens, a type of hormone, on the tumor. These androgens, such as testosterone, can promote tumor growth.

The safety and efficacy of Erleada was based on a randomized clinical trial of 1,207 patients with non-metastatic, castration-resistant prostate cancer. Patients in the trial either received Erleada or a placebo. All patients were also treated with hormone therapy, either with gonadotropin-releasing hormone (GnRH) analog therapy or surgical castration. The median metastasis-free survival for patients taking Erleada was 40.5 months compared to 16.2 months for patients taking a placebo.

Common side effects of Erleada include fatigue, high blood pressure (hypertension), rash, diarrhea, nausea, weight loss, joint pain (arthralgia), falls, hot flush, decreased appetite, fractures and swelling in the limbs (peripheral edema).

Severe side effects of Erleada include falls, fractures and seizures.

Erleada’s sponsor is the first participant in the FDA’s recently-announced Clinical Data Summary Pilot Program, an effort to provide stakeholders with more usable information on the clinical evidence supporting drug product approvals and more transparency into the FDA’s decision-making process. Soon after approval, information from the clinical summary report will post with the Erleada entry on Drugs@FDA and on the new pilot program landing page.


CHMP gives positive opinion for Kisqali combination therapy for all women with HR+/HER2- locally advanced or metastatic breast cancer

The Committee for Medicinal Products for Human Use of the European Medicines Agency has adopted a positive opinion recommending an expanded indication for Kisqali (ribociclib), the CDK4/6 inhibitor with the largest body of first-line clinical trial evidence demonstrating consistent, superior and sustained efficacy compared to endocrine therapy alone.

The drug is sponsored by Novartis.

CHMP recommended Kisqali for the treatment of women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) locally advanced or metastatic breast cancer in combination with fulvestrant as initial endocrine-based therapy and in women who have received prior endocrine therapy. The positive opinion also recommended approval of Kisqali in combination with endocrine therapy and a luteinising hormone-release hormone agonist (LHRH) for pre- and perimenopausal women.

This positive CHMP opinion is based on data from the Phase III MONALEESA-7 and MONALEESA-3 trials. These trials demonstrated prolonged progression-free survival (PFS) for Kisqali-based regimens compared to endocrine therapy alone and showed improvements as early as eight weeks after start of treatment with Kisqali combination therapy.
In MONALEESA-7, Kisqali plus an aromatase inhibitor and goserelin nearly doubled the median PFS compared to an aromatase inhibitor and goserelin alone in pre- or perimenopausal women (27.5 months compared to 13.8 months; HR=0.569; 95% CI: 0.436-0.743)[3]. In MONALEESA-3, Kisqali plus fulvestrant demonstrated a median PFS of 20.5 months compared to 12.8 months for fulvestrant alone (HR=0.593; 95% CI: 0.480-0.732) across the overall population of first-line and second-line postmenopausal women. Across the two trials, the most common adverse reactions (incidence >=20%) were neutropenia, nausea, infections, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash and cough.
The European Commission will review the CHMP recommendation and usually delivers its final decision within two months. The decision will be applicable to all 28 European Union member states plus Iceland, Norway and Liechtenstein. Additional regulatory filings are underway with other health authorities worldwide.

Kisqali is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali was initially approved by FDA in March 2017 and by the European Commission in August 2017, as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor based on findings from the pivotal MONALEESA-2 trial[12]. In July 2018, Kisqali was approved by the FDA for the treatment of pre-, peri- or postmenopausal women in the US, and indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women.


FDA grants priority review for Tecentriq + Abraxane for metastatic triple-negative breast cancer

FDA has granted priority review for Genentech’s supplemental Biologics License Application for Tecentriq (atezolizumab) plus chemotherapy, Abraxane (albumin-bound paclitaxel; nab-paclitaxel) for the first-line treatment of unresectable locally advanced or metastatic triple-negative breast cancer in people whose disease expresses the PD-L1 protein, as determined by PD-L1 biomarker testing.

FDA is expected to make a decision on approval by March 12, 2019. A

The sBLA is based on data from the phase III IMpassion130 study, which was presented at the European Society for Medical Oncology Congress and published in the New England Journal of Medicine in October 2018. Results demonstrate Tecentriq plus nab-paclitaxel as an first-line treatment for unresectable locally advanced or metastatic TNBC significantly reduced the risk of disease worsening or death (progression-free survival) compared with nab-paclitaxel alone in all randomized patients (intention-to-treat) (median PFS=7.2 vs. 5.5 months; hazard ratio [HR]=0.80, 95% CI: 0.69-0.92, p=0.0025) and the PD-L1-positive population (median PFS=7.5 vs. 5.0 months; HR=0.62, 95% CI: 0.49-0.78, p<0.0001), a subgroup determined by PD-L1 biomarker testing.

At this interim analysis, statistical significance was not met for overall survival in the ITT population (median OS=21.3 vs. 17.6 months; HR=0.84, 95% CI: 0.69-1.02, p=0.0840), but the combination showed a clinically meaningful OS improvement in the PD-L1-positive population (median OS=25.0 vs. 15.5 months; HR=0.62, 95% CI: 0.45-0.86).

Due to the hierarchical statistical design, results in the PD-L1-positive population were not formally tested for statistical significance. Follow-up will continue until the next planned analysis. Safety in the Tecentriq plus nab-paclitaxel arm appeared consistent with the known safety profiles of the individual medicines, and no new safety signals were identified with the combination. Serious adverse events were reported in 23 percent of people who received Tecentriq plus nab-paclitaxel compared to 18 percent of people who received nab-paclitaxel alone.

Currently, Genentech has seven ongoing phase III studies investigating Tecentriq in TNBC, including early and advanced stages of the disease. If approved, this Tecentriq combination would be the first cancer immunotherapy regimen for the treatment of PD-L1-positive, metastatic TNBC.

The IMpassion130 study is a phase III, multicenter, randomized, double-blind study evaluating the efficacy, safety and pharmacokinetics of Tecentriq plus nab-paclitaxel compared with placebo plus nab-paclitaxel in people with unresectable locally advanced or metastatic TNBC who have not received prior systemic therapy for metastatic breast cancer. The study enrolled 902 people who were randomized equally (1:1). The co-primary endpoints are PFS per investigator assessment (RECIST 1.1) and OS. PFS and OS were assessed in all randomized patients (ITT) and in the PD-L1-positive population. Secondary endpoints include objective response rate, duration of response and time to deterioration in Global Health Status/Health-Related Quality of Life.


Immunomedics expands clinical collaboration with AstraZeneca to include metastatic NSCLC

The clinical collaboration between Immunomedics Inc. and AstraZeneca and MedImmune for the development of Imfinzi (durvalumab) and sacituzumab govitecan combination therapy has been broadened to include second-line metastatic non-small cell lung cancer, the companies said.

“The combination study with durvalumab, together with our internal efforts to further develop sacituzumab govitecan monotherapy, will help us define the best registration strategies in NSCLC within accelerated timelines,” said Robert Iannone, head of research & development and chief medical officer of Immunomedics.

As CPIs increasingly move into front-line therapy, either alone or in combination with chemotherapy, treatment options for second-line and beyond are limited to single agent chemotherapies, which have only very modest activity. Thus, there is a high unmet need in NSCLC for patients who don’t respond or have progressed after treatment with CPIs.

Sacituzumab govitecan as monotherapy has produced an overall response rate of 19 percent in 47 patients with pretreated metastatic NSCLC with a duration of response of 6.0 months. In a subgroup of patients (14 of 47 patients) who had previously been treated with CPIs as their last line of therapy, ORR was 14 percent (2/14).

This open-label, multi-center phase I/II study will enroll two cohorts of patients, one in CPI primary refractory, and one in acquired resistance to CPI.

Sacituzumab govitecan, Immunomedics’ most advanced product candidate, is a novel, first-in-class antibody-drug conjugate. It is currently under priority review by the FDA for accelerated approval as a treatment of patients with metastatic triple-negative breast cancer who have received two prior therapies for metastatic disease. If approved, sacituzumab govitecan would be the first and only ADC approved for the treatment of metastatic triple-negative breast cancer.

Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses.

As part of a broad development program, durvalumab is being investigated as monotherapy and in combination with IO, small molecules, and chemotherapies across a range of tumors and stages of disease.


Ziopharm Oncology announces Immuno-oncology Clinical Supply Agreement with Regeneron to evaluate combination therapy for brain cancer

Ziopharm Oncology Inc., announced a clinical supply agreement with Regeneron Pharmaceuticals Inc. to evaluate Ziopharm’s Ad-RTS-hIL-12 plus veledimex in combination with Regeneron’s PD-1 antibody Libtayo (cemiplimab-rwlc) to treat patients with recurrent glioblastoma.

Ad-RTS-hIL-12 plus veledimex is an investigational gene therapy designed to induce and control the production of human interleukin 12 that activates the immune system and recruits cancer-fighting T cells into tumors.

Libtayo has been approved in the U.S.  for the treatment of patients with metastatic cutaneous squamous cell carcinoma or locally advanced CSCC who are not candidates for curative surgery or curative radiation.

Under the agreement, Ziopharm and Regeneron will initiate a phase II study in the first half of 2019 in patients with rGBM to measure preliminary safety and efficacy of Ad-RTS-hIL-12 plus veledimex in combination with Libtayo.

Ziopharm will be responsible for the conduct and costs of the clinical trial, and Regeneron will supply Libtayo for the study. The companies potentially may explore the Ad-RTS-hIL-12 plus veledimex in combination with Libtayo in additional indications.

Regeneron, in collaboration with Sanofi, is developing Libtayo both alone and in combination with other therapies for the treatment of various cancers.

Ad-RTS-hIL-12 plus veledimex, within Ziopharm’s Controlled IL-12 platform, is a novel gene therapy candidate that conditionally expresses recombinant hIL-12 under the control of orally-administered veledimex.

This activator ligand acts via the proprietary RheoSwitch Therapeutic System gene switch to control transcription and thus expression of hIL-12. This cytokine is considered a master regulator of the immune system and has demonstrated an ability to activate and recruit killer T cells to sites of cancer resulting in anti-tumor responses.

A phase I study evaluating Ad-RTS-hIL-12 plus escalating amounts of veledimex administered to patients with rGBM revealed dose-dependent production of both hIL-12 as well as endogenous interferon gamma and biopsy data demonstrated an influx of CD3+CD8+ cytotoxic T cells and overexpression of PD-1/PD-L1 markers.

Data from this same trial showed a median overall survival of 12.7 months for patients treated with 20mg of veledimex (n=15) at a mean follow-up time of 12.9 months (as of May 4, 2018).

This compares favorably to the 5 to 8 months OS established in a similar patient population of historical controls with rGBM. Preclinical data from a mouse study evaluating Ad-RTS-mIL-12 plus veledimex to produce mouse IL-12 in combination with an anti-PD-1 are promising, including 100 percent survival in one dosing cohort.

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