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DTC spending on ads for cancer drugs is a small part of the $5.2 billion the industry as a whole spent in 2015, but as Bristol-Myers Squibb and Merck battle for market share in immuno-oncology, that may be changing.

From June 2013 to February of this year, pharma companies spent an estimated $223 million on more than 42,000 airings for DTC ads for Bristol-Myers Squibb’s Opdivo, Merck’s Keytruda, Dendreon’s Provenge, and Amgen’s Neulasta, according to At least half of that spending is for Opdivo ads that aired during the last year.

Before 2013, when the first Provenge DTC aired, it was unheard of for brands to use direct-to-consumer advertising for oncology drugs. DTC was a marketing play for the blockbuster consumer brands, the Lipitor’s and Viagra’s of the world.

See also: Merck’s Keytruda wins approval in first-line lung cancer

Four years later, there are now two dueling immunotherapy ads on primetime TV promoting Keytruda and Opdivo for certain lung-cancer patients. Immunotherapies represents some of the most innovative cancer advancements of the past decade, and with as many 44 active PD-1 combination drugs in development, experts say the industry may be nearing a massive splurge on national TV ads for new cancer medicines.  

DTC is often the go-to strategy for the drug with the most to gain, such as when brand teams are trying to create awareness of a new market or new type of drug, or if the therapy has a stronger clinical profile than its competitors.

“DTC is a blunt instrument,” explained Matt Arnold, principal analyst for Decision Resources Group. “What it does very well is build that initial awareness for a launch brand, especially in an emerging class, like immunotherapy.”

See also: Merck outspends Bristol-Myers Squibb on journal ads for Keytruda

Bristol-Myers Squibb launched the first DTC ad for Opdivo, called Longer Life, in September 2015. Opdivo was approved by the FDA to treat advanced non-small cell lung cancer in the second line, regardless of the patient’s PD-L1 expression, a claim Merck couldn’t make for Keytruda. At the time, Keytruda was only approved to treat patients whose tumors had high expression of PD-L1.

Merck’s campaign kicked off more than a year later, on January 30. Three months prior, the FDA granted Keytruda approval as a standalone therapy in the first-line setting for advanced non-small cell lung cancer patients, an indication that Opdivo does not have. Bristol-Myers Squibb’s plans to secure a first-line indication for Opdivo may be further away than expected since Opdivo failed its monotherapy Phase-III trial for first-line use in August.

To hear Jill DeSimone, SVP of commercial operations for Merck’s oncology business, tell it, the company knew Keytruda’s latest approval represented an innovative step forward for lung-cancer patients, and one that Merck intended to capitalize on. “We wanted to go forward when we had something really significant to say patients and caregivers,” she said. “Up until this point there hadn’t been a lot of innovation in first-line lung cancer.”

See also: Merck launches DTC campaign for Keytruda

In 2016 Opdivo generated nearly three times the revenue that Keytruda did, with sales of $3.7 billion, compared to Keytruda’s $1.4 billion. In the first nine months of last year, BMS doled out $108 million in ad spend for Opdivo, while Merck spent $24 million on Keytruda in the same timeframe, according to Kantar Media. Up to this point, Merck had targeted oncologists through professional journal ads — outspending BMS two-to-one ($2 million from Merck vs. $863,000 from BMS) in the first half of 2016, also according to data from Kantar. 

Now that Merck kicked off its new campaign, that figure is expected to rise. Merck has its own story to tell for Keytruda, Arnold said. “TV is a great way to tell that story and build that initial awareness, especially with an older population,” he said. “It’s expensive. It’s a shotgun approach, and it’s not very targeted, but we know that it works for awareness.”

See also: Infographic: Merck’s Keytruda versus Bristol-Myers Squibb’s Opdivo

Promoting brands that treat lung cancer can be challenging compared to other forms of the disease. Bristol had to overcome stigmas in marketing Opdivo, since its prescribed after patients have already failed another form of treatment, said Teresa Bitetti, SVP of U.S. oncology for Bristol-Myers Squibb.

“Lung cancer is often an aggressive, highly-stigmatized, difficult-to-treat disease with a high mortality rate,” she said in an email. “Unfortunately we know that some patients with lung cancer declined additional treatment after progressing on a previous therapy, and this decision is often made because there is a lack of awareness and understanding of additional treatment options beyond chemotherapy.”

Gil Bashe, managing partner of global health for Finn Partners, said it’s difficult for patients undergoing treatment to be aware of new options.

See also: Merck kicks off lung-cancer campaign

“Unlike other disease states where we’ve grown accustomed to [different] types of therapy, like heart disease, for example, the area of cancer therapy has so many new breakthrough medicines that it’s very hard for patients to stay in tune with what’s happening and what’s new,” he said.

All awareness is not created equal, however, and the Opdivo ad faced criticism. When it debuted, detractors argued that Bristol blurred the line of hope and hype in its promotion of the immunotherapy.

Dr. Lowell Schnipper, an oncologist at Beth Israel Deaconess Medical Center in Boston, argued in an op-ed in JAMA Oncology, published in August, that the ad does not facilitate a productive conversation between patients and doctors. “It is difficult to conceive that a medical oncologist would fail to discuss the potential use of [Opdivo] or another immunomodulatory agent for second-line therapy of squamous non-small cell lung cancer,” he wrote.

See also: Marketers take a new approach to lung-cancer campaigns, and why that matters

Another op-ed in The New York Times criticized the ad, saying that the drug’s “velvet-voice narrator” and “actors portraying lung cancer patients playing with babies and watching Little League games” would be uplifting “if it weren’t so utterly misleading and exploitative.” Matt Jablow, the author, lost his wife to stage 4 lung cancer. Opdivo was one of the drugs she took in her treatment regimen.

Even investors have questioned the utility of DTC for a cancer drug. During an earnings call in January 2016, Deutsche Bank analyst Gregg Gilbert questioned the usefulness of the tactic, saying that he expected adoption of immunoncology drugs like Opdivo to grow whether or not the company promoted the drug to patients.

Decision Resource Group’s Arnold said that DTC is “a reasonable first step for a launch brand as long as there’s follow-up online,” but there are diminishing returns for individual brands as more pharma brands turn to TV. “The more brands you cram into the category, the thinner each wedge of that pie is going to be, and the outlays for these campaigns are substantial,” he said.