FDA Panel Says Necitumumab Has Benefit in Squamous NSCLC

Alicia Ault

July 09, 2015

SILVER SPRING, MD — A new drug for lung cancer, necitumumab (Lilly), received a nod from experts that is being interpreted as a positive sign, which could result in its approval in the United States before the end of the year.

Necitumumab was reviewed today by the Food and Drug Administration's (FDA) Oncologic Drugs Advisory Committee. A majority of the committee agreed that the drug shows some promise in the first-line treatment of locally advanced or metastatic squamous non-small cell lung cancer (NSCLC).

The Committee did not vote on whether necitumumab should be approved, but most said that it had a favorable risk-benefit profile despite safety concerns, including concern about what appeared to be slightly more sudden and unexplained deaths in patients taking the drug.

The FDA does not have to follow the recommendation of its advisory committees, but usually does.

Necitumumab is a monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor (EGFR) and blocks interaction between EGFR and its ligands. According to the manufacturer (Lilly), EGFR expression is high in NSCLC tumors, and is found in more than 95% of squamous NSCLC. Lilly is seeking approval of the drug to be used in combination with gemcitabine and cisplatin as a first-line therapy in squamous NSCLC.

In the pivotal study, SQUIRE, there was a 1.6-month improvement in median overall survival, and a 0.2-month improvement in median progression-free survival with the addition of necitumumab to gemcitabine and cisplatin (Neci + GC) when compared to the gemcitabine-cisplatin (GC) regimen. Median overall survival was 11.5 months for Neci + GC, compared with 9.9 months for GC alone, and the median progression-free survival was 5.7 months, compared with 5.5 months.

"This is a marginal benefit," said panel member James Liebmann, MD, assistant professor of medicine at the University of Massachusetts in Worcester. "But it's a marginal benefit in exactly the same range as everything else that's been approved for this disease," he said.

Panel chair Deborah K. Armstrong, MD, agreed. "I think the survival benefit is modest, but real," said Dr Armstrong, a professor of oncology at the Johns Hopkins University in Baltimore, Maryland.

She and other panel members agreed with Lilly's plans to highlight toxicities and ways to manage them in labeling, and also urged the company to state that the drug had not been proven to work definitively in tumors with EGFR protein expression. "It is very distressing that we're not seeing any correlation with the imputed target and the response to the therapy," said Dr Armstrong.

Necitumumab also was less effective in patients aged over 70 years. Lilly could not explain that result, and some panelists urged the company to recommend against use in those patients.

Panelist Tito Fojo, MD, PhD, said he was concerned that it appeared that patients in the GC arm received fewer cycles than those in the Neci + GC group. He thought that may have biased results in progression-free survival.

Coupled with safety issues, "at the end of the day, this trial doesn't provide me the comfort of saying the risk-benefit is a favorable one," said Dr Fojo.

VTEs More Common

The SQUIRE trial, conducted at 184 sites in 26 countries, involved 545 patients randomized to Neci + GC and 548 to GC alone. Almost all patients in each arm experienced an adverse event, and 72% of the Neci +GC arm and 62% of the GC arm had a grade 3 or greater event.

Thirty-one percent of Neci + GC patients had any grade hypomagnesemia and 79% had a skin rash. Fatal cardiopulmonary arrest and/or sudden death wereobserved in 12 of 538 (2.2%) Neci + GC patients compared with 3 of 541 (0.5%) patients in the GC arm. The FDA said that some of these deaths appeared to be due to untreated hypomagnesemia.

Agency officials asked the committee to discuss those deaths and also the higher incidence of thromboembolic events in the Neci + GC arm in the SQUIRE study and those seen in an earlier study (INSPIRE). That trial, in nonsquamous NSCLC, was stopped because of the thromboembolic events and a lower survival benefit.

In SQUIRE, 9% of patients in the Neci + GC arm had a grade 3 or greater thromboembolic event compared with 5% of the GC patients, said the FDA. Pulmonary emboli and deep vein thrombosis were the most common venous thromboembolic events (VTEs).

Lilly is proposing a number of risk-management strategies, including warning physicians to carefully consider use of necitumumab in patients with a history of coronary artery disease or arrhythmias, or a history of VTEs, and to also consider anticoagulation in high-risk patients.

Need for Options

Several patient advocates who spoke during the public portion of the meeting urged the panel to support approval of necitumumab, noting that there are few options for squamous NSCLC.

Squamous tumors make up about a third of all lung cancers, and are primarily due to heavy tobacco use, but not always. The majority of patients with the squamous form present with locally advanced or metastatic disease, said the FDA. Five-year survival is less than 5%, according to the agency.

David Gandara, MD, who spoke on behalf of Lilly, said that median overall survival in squamous NSCLC has barely budged since the early 2000s, with platinum-based therapy the mainstay. "All therapies are palliative — not curative," added Dr Gandara, director of the thoracic oncology program at University of California, Davis.

And, so far, targeted therapies have proven to be largely ineffective, with detrimental side effects, said Dr Gandara, who was not compensated by Lilly.

"We all need options," he said.

Dr Liebmann agreed, with an amendment. "You want good options. Not just options," he said.

In a statement after the meeting, Lilly Oncology senior vice president, product development and medical affairs Richard Gaynor, MD, said, "We are encouraged by the Committee's constructive discussion on the benefit-risk profile of necitumumab as few advances have been made over the past two decades in the first-line treatment of advanced squamous NSCLC, leaving a significant unmet medical need."

He said the company would continue to work with the FDA and that the agency is expected to make a decision on necitumumab "later this year."


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