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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Thursday, November 8, 2018

The FDA recently approved pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel as first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC).

Approval was based on KEYNOTE-407 (NCT02775435), a randomized, multi-center, double-blind, placebo-controlled trial in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease.

Patients were randomized (1:1) to pembrolizumab 200 mg or placebo in combination with carboplatin, and investigator's choice of either paclitaxel every 3 weeks or nab-paclitaxel weekly on a 3-week cycle for 4 cycles followed by pembrolizumab or placebo. Patients continued pembrolizumab or placebo until disease progression, unacceptable toxicity, or a maximum of 24 months.   

The main efficacy outcome measures were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) as assessed by blinded independent review. The trial demonstrated statistically significant improvements in OS, PFS, and ORR for patients receiving pembrolizumab plus chemotherapy compared with those randomized to placebo plus chemotherapy. The median OS was 15.9 and 11.3 months for the pembrolizumab plus chemotherapy and placebo plus chemotherapy arms, respectively (HR 0.64; 95% CI: 0.49, 0.85; p=0.0017). The median PFS was 6.4 and 4.8 months for the pembrolizumab plus chemotherapy and placebo plus chemotherapy arms, respectively (HR 0.56; 95% CI: 0.45, 0.70; p<0.0001). The analysis of ORR was limited to the initial 204 patients randomized. The ORRs were 58 percent and 35 percent, favoring the pembrolizumab-containing arm (difference of 23.6%; 95% CI: 9.9, 36.4; p=0.0008). The estimated median response durations were 7.2 and 4.9 months, respectively.

The most common adverse reactions in at least 20 percent of patients who received pembrolizumab on KEYNOTE-407 were fatigue/asthenia, nausea, constipation, diarrhea, vomiting, pyrexia, decreased appetite, rash, cough, dyspnea, alopecia, and peripheral neuropathy.

The recommended pembrolizumab dose for metastatic squamous NSCLC is 200 mg intravenously every 3 weeks, prior to chemotherapy when given on the same day, until disease progression, unacceptable toxicity, or 24 months after initiation.

"The results that support this approval from the KEYNOTE-407 trial demonstrate the potential of [pembrolizumab] in combination with chemotherapy in patients with squamous non-small cell lung cancer, regardless of PD-L1 expression," said Dr. Balazs Halmos, Director of the Multidisciplinary Thoracic Oncology Program at the Montefiore Einstein Center for Cancer Care and Director of Cinical Cancer Genomics at the Albert Einstein College of Medicine. "With this important approval, more patients will have the opportunity to benefit from immunotherapy."

Pembrolizumab 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 pembrolizumab-based regimen as their first-line treatment option.

Thursday, November 8, 2018

The FDA has approved elotuzumab injection for IV use in combination with pomalidomide and dexamethasone (EPd) for the treatment of adult patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. 

In ELOQUENT-3, a randomized, open-label, phase II trial, EPd demonstrated benefit in patients with relapsed or refractory multiple myeloma, doubling both median progression-free survival (PFS) and overall response rate (ORR) versus pomalidomide and dexamethasone (Pd).

Following priority review by the FDA, EPd is the first triplet combination to be approved based on a randomized clinical trial using Pd as a comparator.

Key findings from the trial include: 
  • PFS (primary endpoint, investigator-assessed): EPd reduced the risk of disease progression by 46 percent (hazard ratio [HR]: 0.54; 95% confidence interval [CI]: 0.34 to 0.86, p=0.0078), demonstrating a median PFS of 10.25 months (95% CI: 5.59 to non-estimable [NE]) versus 4.67 months (95% CI: 2.83 to 7.16) for Pd alone after a minimum follow-up of 9.1 months.
  • ORR (secondary endpoint, investigator-assessed): Response rates doubled in patients receiving EPd (53.3%; n=32/60 [95% CI: 40.0 to 66.3]) compared with patients receiving Pd alone (26.3%; n=15/57 [95% CI: 15.5 to 39.7]; p=0.0029), with very good partial responses or better seen in 20 percent of EPd-treated patients (n=12) and 8.8% of Pd-treated patients (n=5).
  • Safety: Serious adverse reactions were reported in 22 percent of patients treated with EPd and in 15 percent of patients treated with Pd. Discontinuation of any component of the treatment regimen due to adverse reactions occurred in 5.0 percent of patients in the EPd arm, compared to 1.8 percent of patients in the control arm.
“Despite remarkable recent innovations with novel therapies for the treatment of multiple myeloma, many patients still face poor outcomes, and particularly in the relapsed and relapsed, refractory setting,” said Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston. “This new regimen of elotuzumab combined with pomalidomide and dexamethasone not only extended the time to disease progression versus a standard of care but also doubled the response rate in some patients whose prior treatments had failed them. Thus to be able to offer an alternative with a meaningful clinical benefit is an important and significant milestone for our patients.”
Approximately 31,000 people in the U.S. will be diagnosed with multiple myeloma this year. A common characteristic for many patients is that they experience multiple relapses.

“Relapse can be overwhelming and extremely challenging for multiple myeloma patients, particularly after they have already tried several therapies,” said Paul Giusti, President and CEO of the Multiple Myeloma Research Foundation. “[Elotuzumab], in combination with pomalidomide and dexamethasone, is an exciting new option for patients with relapsed or refractory myeloma.”

Sunday, October 28, 2018

The FDA recently permitted marketing of ClonoSEQ assay, a next generation sequencing (NGS)-based test for minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma.

"At the FDA, we're continuing to maximize opportunities for innovation that can improve patient outcomes," said FDA Commissioner Scott Gottlieb, MD. "[This] approval is an important step forward for patients suffering from ALL and multiple myeloma. Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients' care.

"The FDA is applying novel regulatory approaches to make sure that these rapidly evolving NGS tests are accurate and reliable. At the same time, we're seeing more and more laboratory-developed tests seek marketing authorization from the FDA. We're doing as much as we can to advance these opportunities for patients under our current authorities," he continued. "But we believe that to more fully unlock these innovations, we need to modernize the regulatory framework for all in vitro clinical tests. We put forward one such plan. We believe such an approach can promote the development of safe, effective technologies that have the greatest potential to help us diagnose, treat and cure disease."

It is estimated that in 2018 approximately 6,000 people in the U.S. will be diagnosed with ALL and approximately 31,000 new cases of multiple myeloma will be diagnosed.

The ClonoSEQ assay is an in vitro diagnostic that uses multiplex PCR and NGS to identify and quantify certain gene sequences in DNA extracted from bone marrow from patients with ALL or multiple myeloma. The assay measures the amount of MRD and is capable of detecting MRD at levels below 1 in 1 million cells. This is a single site assay collected by the patient's provider and sent for evaluation.

The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma.

For patients with ALL, the assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival. Patients whose ClonoSEQ assay result was MRD negative have longer event-free survival, while patients with higher MRD assay results had lower event-free survival rates.

For patients with multiple myeloma, the assay demonstrated similar associations with progression-free survival—the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse—and disease-free survival—the length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer.

The FDA reviewed the test through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices of a new type. Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency's expectations in assuring the accuracy, reliability and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA's 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a predicate device.

Friday, October 19, 2018

​The FDA has accepted the supplemental New Drug Application (sNDA) for Priority Review for ibrutinib in combination with obinutuzumab in previously untreated adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

If the sNDA is approved, the use of ibrutinib with obinutuzumab could become the first chemotherapy-free, anti-CD20 combination approved by the FDA for the first-line treatment of CLL/SLL. Ibrutinib is currently FDA-approved to treat adults with CLL/SLL as a single-agent for all lines of therapy and in combination with bendamustine and rituximab (BR). Ibrutinib is a once-daily, first-in-class Bruton's tyrosine kinase (BTK) inhibitor that is administered orally.

The sNDA submission is based on positive results from the phase III iLLUMINATE (PCYC-1130) trial announced in May 2018, which showed ibrutinib plus obinutuzumab was associated with significantly longer progression-free survival (PFS) versus chlorambucil plus obinutuzumab in adults with previously untreated CLL/SLL, as assessed by an Independent Review Committee.

iLLUMINATE (NCT 02264574) is a randomized, multi-center, open-label, phase III study of ibrutinib in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab in patients with previously untreated CLL/SLL. According to the study protocol, patients enrolled are age 65 years and older or if less than age 65 years must have had at least one of the following criteria: Cumulative Illness Rating Score (CIRS) >6 and Creatinine clearance estimated <70 mL/min using Cockcroft-Gault equation.

In the study, patients were randomized to receive ibrutinib 420 mg continuously in combination with obinutuzumab 1000 mg IV over 6 cycles or chlorambucil on Days 1 and 15 of each cycle plus obinutuzumab 1000 mg IV over 6 cycles. The primary endpoint is progression-free survival by Independent Review Committee (IRC), with secondary objectives including overall response rate and rate of minimal residual disease-negative responses. As previously reported, the study met its primary endpoint, showing significantly longer PFS was associated with adult CLL/SLL patients treated with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab, as assessed by an IRC.

The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year. CLL/SLL are predominately diseases of the elderly, with a median age diagnosis ranging from 65-70 years.

Tuesday, October 2, 2018

The FDA has approved the supplemental New Drug Application (sNDA) to expand the Prescribing Information for carfilzomib to include a once-weekly dosing option in combination with dexamethasone (once-weekly Kd70) for patients with relapsed or refractory multiple myeloma.

The approval is based on data from the phase III A.R.R.O.W. trial (RAndomized, Open-label, Phase III Study in Subjects with Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination with Dexamethasone, Comparing Once-Weekly versus Twice-weekly Carfilzomib Dosing), which demonstrated that carfilzomib administered once-weekly at 70 mg/m2with dexamethasone achieved superior progression-free survival (PFS) and overall response rates (ORR), with a comparable safety profile, versus twice-weekly carfilzomib administered at a dose of 27 mg/m2 in combination with dexamethasone (twice-weekly Kd27). Carfilzomib is not approved for twice-weekly 27 mg/m2 administration in combination with dexamethasone alone.

The FDA reviewed the application under its Oncology Center of Excellence Real-Time Oncology Review and Assessment Aid pilot programs, which aim to explore a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible. The FDA approved the application in just over one month after the final component of the application was submitted.

"While great progress has been made in the last decade, multiple myeloma remains an incurable disease characterized by a recurring pattern of remission and relapse, and it is important that patients have treatment options that meet their individual needs," said David S. Siegel, MD, PhD, Chief of the Division of Multiple Myeloma at John Theurer Cancer Center at Hackensack University Medical Center. "The availability of a more convenient once-weekly dosing regimen, with superior efficacy, comparable safety, and longer duration of therapy versus the twice-weekly regimen studied in the trial could allow patients to spend more time outside of the infusion center."

A.R.R.O.W. included 478 patients with relapsed and refractory multiple myeloma who received at least two or three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. Patients in the trial treated with once-weekly Kd70 achieved a statistically significant 3.7 month improvement in PFS compared to the Kd27 twice-weekly regimen (median PFS 11.2 months for once-weekly Kd70 versus 7.6 months for twice-weekly Kd27; HR=0.69; 95 percent CI: 0.54-0.88; one-sided p=0.0014).The ORR in patients treated with once-weekly Kd70 was 62.9 percent versus 40.8 percent for those treated with twice-weekly Kd27 (p<0.0001). In addition, 7.1 percent had complete responses or better in the once-weekly arm versus 1.7 percent in the twice-weekly arm in this refractory patient population.

The overall safety profiles of the two arms in A.R.R.O.W. were comparable, with no new safety risks identified in the once-weekly arm. Discontinuation rates due to adverse events were similar in the two arms. The most frequently reported treatment-emergent adverse events (greater than or equal to 20%) in either treatment arm were anemia, diarrhea, fatigue, hypertension, insomnia, and pyrexia.

The interim data were presented during an oral session at the 54th ASCO Annual Meeting and simultaneously published in The Lancet Oncology (2018;19(7):953-964).