Article Content

Pembrolizumab Plus Chemotherapy Approved for Metastatic Nonsquamous NSCLC

The FDA approved pembrolizumab in combination with pemetrexed and platinum as first-line treatment of patients with metastatic, non-squamous non-small cell lung cancer (NSqNSCLC), with no EGFR or ALK genomic tumor aberrations.

FDA; oncology. FDA; ... - Click to enlarge in new windowFDA; oncology. FDA; oncology

Pembrolizumab was previously granted accelerated approval for this indication in May 2017 based on improvements in overall response rate and progression-free survival (PFS) for patients randomized to pembrolizumab administered with pemetrexed and carboplatin as compared with pemetrexed and carboplatin alone in the KEYNOTE-021 study.


This approval represents fulfillment of a postmarketing commitment demonstrating the clinical benefit of this treatment. This action is based on the results of KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active controlled study enrolling 616 patients receiving first-line treatment for metastatic NSqNSCLC. Patients were randomized (2:1) to receive pembrolizumab (or placebo) in combination with pemetrexed, and investigator's choice of either cisplatin or carboplatin every 3 weeks for four cycles followed by pembrolizumab (or placebo) and pemetrexed. Treatment with pembrolizumab continued until disease progression, unacceptable toxicity, or a maximum of 24 months.


The primary efficacy outcome measures were overall survival (OS) and PFS, as assessed by a blinded independent committee review (RECIST 1.1.)


The trial demonstrated a statistically significant improvement in OS for patients randomized to pembrolizumab and chemotherapy (HR 0.49; 95% CI: 0.38, 0.64; p<0.00001) in a pre-specified interim analysis. The median OS was not reached at the time of the data cutoff in the pembrolizumab plus chemotherapy arm and was 11.3 months for those in the chemotherapy arm.


The trial also demonstrated an improvement in PFS for patients randomized to pembrolizumab plus chemotherapy (HR 0.52; 95% CI: 0.43, 0.64; p<0.00001). The median PFS was 8.8 months for patients receiving pembrolizumab plus chemotherapy and 4.9 months for those receiving chemotherapy alone. The overall response rate was significantly higher (48% vs. 19%; p=0.0001) for those in the pembrolizumab plus chemotherapy arm and the median response duration was 11.2 months and 7.8 months, respectively.


The most common adverse reactions reported in >=20 percent of patients in KEYNOTE-189 were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.


The recommended pembrolizumab dose and schedule for NSqNSCLC is 200 mg as an IV infusion over 30 minutes every 3 weeks.


This is the second FDA approval using the Real-Time Oncology Review pilot program that enabled the FDA review team to begin analyzing data before the application submission.


Treatment for Two Rare Types of Non-Hodgkin Lymphoma Approved

The FDA approved mogamulizumab-kpkc injection for IV use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sezary syndrome (SS) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for SS.


"Mycosis fungoides and Sezary syndrome are rare, hard-to-treat types of non-Hodgkin lymphoma and this approval fills an unmet medical need for these patients," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "We are committed to continuing to expedite the development and review of this type of targeted therapy that offers meaningful treatments for patients."


Mogamulizumab-kpkc is a monoclonal antibody that binds to a protein (called CC chemokine receptor type 4 or CCR4) found on some cancer cells. The approval was based on a clinical trial of 372 patients with relapsed MF or SS who received either mogamulizumab-kpkc or vorinostat. Progression-free survival was longer for patients taking mogamulizumab-kpkc (median 7.6 months) compared to patients taking vorinostat (median 3.1 months).


The most common side effects of treatment with mogamulizumab-kpkc included rash, infusion-related reactions, fatigue, diarrhea, musculoskeletal pain, and upper respiratory tract infection.


Serious warnings of treatment with mogamulizumab-kpkc include the risk of dermatologic toxicity, infusion reactions, infections, autoimmune problems, and complications of stem cell transplantation that uses donor stem cells after treatment with the drug.


The FDA granted this application Priority Review and Breakthrough Therapy designation. Mogamulizumab-kpkc also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.


Nivolumab Approved for Certain Patients With Previously Treated SCLC

Nivolumab received approval from the FDA as the first and only immuno-oncology treatment option for patients with metastatic small cell lung cancer (SCLC) whose cancer has progressed after platinum-based chemotherapy and at least one other line of therapy.


Approval for this indication has been granted under accelerated approval based on overall response rate and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.


This approval for nivolumab in patients with SCLC whose cancer has progressed after two or more prior lines of therapy was granted priority review.


The approval was based on data from the SCLC cohort of the ongoing phase I/II CheckMate-032 study evaluating nivolumab in patients who experienced disease progression after platinum-based chemotherapy. Of 109 patients receiving nivolumab after platinum-based chemotherapy and at least one other prior line of therapy, 12 percent (n=13/109; 95% CI: 6.5-19.5) responded to treatment based on assessment by a Blinded Independent Central Review, regardless of PD-L1 expression.


Twelve patients had a partial response (11%), and one patient had a complete response (0.9%). Among these responders, the median DOR was 17.9 months (95% CI: 7.9-42.1; range: 3.0-42.1 months). Nivolumab was discontinued in 10 percent of patients, and one dose was withheld in 25 percent of patients for an adverse reaction. Serious adverse reactions occurred in 45 percent of patients. The approved dosing for nivolumab in this indication is 240 mg administered every 2 weeks by IV infusion until disease progression or unacceptable toxicity.


Nivolumab is associated with the following warnings and precautions: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity.


"While immuno-oncology innovations have dramatically changed how oncologists approach certain cancers, we have had limited progress for patients with small cell lung cancer," said Leora Horn, MD, MSc, Associate Professor of Medicine, Ingram Associate Professor of Cancer Research, Director of the Thoracic Oncology Program and Assistant Vice Chairman for Faculty Development, Vanderbilt University Medical Center, Nashville. "[This] approval of nivolumab is particularly exciting considering it is the first checkpoint inhibitor approved for these specific patients, and now we can finally treat this devastating disease from a different angle."


"Small cell lung cancer can be a very challenging disease, particularly for those who have already been through multiple types of treatment, as most patients relapse within a year of diagnosis," noted Andrea Ferris, President and Chairman of LUNGevity Foundation. "This approval marks a major milestone for the patients touched by this unrelenting disease and may motivate them to pursue further treatment where there previously were no other approved options."


Ibrutinib Plus Rituximab Approved for Waldenstrom's Macroglobulinemia

The FDA approved ibrutinib in combination with rituximab for the treatment of Waldenstrom's macroglobulinemia (WM). The approval expands the label for ibrutinib in WM beyond its current approved use as a monotherapy to include combination use with rituximab. This approval represents the first approved non-chemotherapy combination option for the treatment of WM.


Ibrutinib first received FDA approval in WM as a monotherapy in January 2015 via the Breakthrough Therapy Designation pathway, making it the first FDA-approved therapy for the disease.


"The combination of ibrutinib and rituximab provides health care professionals with a new treatment option for patients living with this serious blood cancer," said Lia Palomba, MD, hematologist-oncologist at Memorial Sloan Kettering Cancer Center, New York City, and iNNOVATE study investigator. "Before ibrutinib, there were no FDA-approved treatment options for patients with Waldenstrom's macroglobulinemia, a disease first acknowledged nearly 75 years ago. Today, ibrutinib continues to provide an important therapeutic approach in the treatment of this complex disease."


This approval is based on results from the randomized, double-blind, placebo-controlled iNNOVATE study (PCYC-1127), the largest phase III study of a non-chemotherapy combination in WM patients. The iNNOVATE study evaluated ibrutinib in combination with rituximab versus placebo plus rituximab in 150 patients with either relapsed/refractory (r/r) disease or previously untreated WM.


At a median follow-up of 26.5 months, a significant improvement in the Independent Review Committee-assessed primary endpoint of progression-free survival (PFS) was seen with ibrutinib plus rituximab when compared with placebo plus rituximab (30-month PFS rates were 82% vs. 28%, respectively). Patients in the ibrutinib plus rituximab treatment arm experienced an 80 percent reduction in relative risk of disease progression or death compared with patients treated with placebo plus rituximab (HR=0.20; CI, 0.11-0.38, p<0.0001). The data were presented in an oral session at the 2018 ASCO Annual Meeting, selected for Best of ASCO 2018 Meetings, and simultaneously published in The New England Journal of Medicine (2018; doi:10.1056/NEJMoa1802917).


"Results from iNNOVATE showed significant improvement in progression-free survival at 30 months and demonstrated the superiority of ibrutinib plus rituximab over rituximab monotherapy in Waldenstrom's macroglobulinemia," said Meletios A. Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Greece, and iNNOVATE lead study investigator. "Based on these results, ibrutinib in combination with rituximab may be considered as a first- and second-line option for appropriate people diagnosed and living with WM."


The most common adverse reactions (occurring in 20% or more of patients) of all grades in patients treated with ibrutinib plus rituximab in the iNNOVATE study were bruising (37%), musculoskeletal pain (35%), hemorrhage (32%), diarrhea (28%), rash (24%), arthralgia (24%), nausea (21%), and hypertension (20%). Grade 3 or 4 infusion-related reactions were observed in 1 percent of patients treated with ibrutinib plus rituximab.


The recommended dose of ibrutinib for WM is 420 mg orally once daily until disease progression or unacceptable toxicity as a single agent or in combination with rituximab. When administering ibrutinib in combination with rituximab, consider administering ibrutinib prior to rituximab when given on the same day.


Magnetic Device System Approved for Guiding Sentinel Lymph Node Biopsies

The FDA approved a magnetic device system for guiding lymph node biopsies in patients with breast cancer undergoing mastectomy. The Magtrace and Sentimag Magnetic Localization System (Sentimag System) uses magnetic detection during sentinel lymph node biopsy procedures to identify sentinel lymph nodes for surgical removal.


"Sentinel lymph node biopsies are crucial for determining whether a patient's breast cancer has spread and helping the provider determine the most appropriate course of treatment," said Binita Ashar, MD, Director of the Division of Surgical Devices in the FDA's Center for Devices and Radiological Health (CDRH). "Currently, a sentinel lymph node biopsy is performed after injection of radioactive materials and/or blue dye. This magnetic system [we've approved] will offer patients undergoing mastectomy an option for their sentinel lymph biopsy procedure that does not require the injection of radioactive materials."


The Sentimag System uses magnetic materials to guide the sentinel lymph node biopsy procedure. The system is comprised of a sensitive magnetic sensing probe and base unit designed to detect small amounts of Magtrace, the magnetic tracer drug that is injected into breast tissue. The Magtrace particles travel to lymph nodes and become physically trapped in them, facilitating magnetic detection of the lymph nodes. Following the injection of Magtrace, the Sentimag probe is applied to the patients' skin in areas closest to the tumor site containing the lymph nodes. The sensing of the magnetic particles is indicated by changes in audio and visual alerts from the base unit, enabling the surgeon to move the hand-held probe around the area of the lymph nodes, and locate the sentinel lymph node or nodes (if there are more than one). The surgeon then makes a small incision and removes the node, which is checked by a pathologist for the presence of cancer cells.


A negative sentinel lymph node biopsy result suggests that cancer has not spread to nearby lymph nodes. A positive result may indicate that cancer is present in the sentinel lymph node and may be present in other nearby lymph nodes and, possibly, other organs. This information can help a doctor determine the stage of the cancer and develop an appropriate treatment plan.


The FDA evaluated data from a trial of 147 patients with breast cancer to compare the Sentimag System to the control method of injecting patients with blue dye and radioactive materials together and using a gamma probe to identify the sentinel lymph node. Patients were administered both methods to compare lymph node detection rates. The lymph node detection rate for the Sentimag System was 94.3 percent while the control method detection rate was 93.5 percent. Overall, 98.0 percent of patients had the same detection rate with both the Sentimag System and the control method.


The most common adverse event reported include breast discoloration, which is reported to disappear after 3 months in patients who underwent mastectomy, bradycardia, and potential allergic reaction to the magnetic materials. The Sentimag System is contraindicated in any patient with hypersensitivity to iron oxide or dextran compounds. It is also not recommended for patients with iron overload disease or with a metal implant in the axilla or in the chest.


Magtrace may travel to regions away from the injection site such as liver or spleen, if injected directly into the bloodstream. In such cases, the presence of Magtrace may cause image artifacts during MRI. Magtrace residues have not been reported to produce artifacts affecting imaging in X-ray, PET scans, CT scans, PET/CT scans, or ultrasound studies.


The FDA reviewed the Sentimag System application using a coordinated, cross-agency approach. The clinical review was conducted by the FDA's CDRH in consultation with the Center for Drug Evaluation and Research and with support from the FDA's Oncology Center of Excellence, while all other aspects of review and the final product approval determination was conducted by the FDA's CDRH.