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Low response rate for checkpoint inhibitors underscores ‘unrealistic expectations’ about their effectiveness
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An increase in the number of immune checkpoint inhibitors approved by the FDA, along with more indications, means that 43% of patients with cancer in the United States are eligible to receive these drugs, according to an analysis published in JAMA Network Open.
Nevertheless, researchers estimated that fewer than 13% of patients with cancer respond to checkpoint inhibitors.
“There is often a lot of excitement and sometimes hype about novel cancer drugs, and sometimes this hype is unjustified since it is built upon results from studies done on animals,” Alyson Haslam, PhD, an epidemiologist with Knight Cancer Institute at Oregon Health & Science University and co-author of the study, told HemOnc Today. “Because of this enthusiasm, patients and sometimes physicians develop unrealistic expectations about the benefit of these drugs in the real world.”
Haslam and her colleague, Vinay Prasad, MD, MPH, an associate professor of medicine at Oregon Health and Sciences University and a HemOnc Today Next Gen Innovator, conducted the study to determine the number of patients eligible for and who could actually benefit from this class of novel cancer drugs.
“Prior studies estimated low eligibility and response for genome-driven therapy, which are other hyped cancer therapies, and so we decided to calculate estimates for checkpoint inhibitor drugs,” Haslam said.
The cross-sectional analysis included checkpoint inhibitors approved by the FDA for a cancer indication from January 2011 through August 2018. The researchers used publicly available data from FDA drug labels and cancer death statistics between 2011 and 2018 from the American Cancer Society.
Researchers divided the number of deaths from cancers for which a checkpoint inhibitor had been FDA approved by the total number of cancer deaths to determine the proportion of people eligible for checkpoint inhibitor therapy. They estimated the number of people who could benefit from checkpoint inhibitors by multiplying the number of people estimated to be eligible for each cancer type by the overall response rate reported on the FDA drug label for each year a specific indication was approved.
The results showed that six checkpoint inhibitors received FDA approval for 14 indications between March 25, 2011, and Aug. 17, 2018.
The investigators found that the estimated percentage of patients with cancer eligible for treatment with checkpoint inhibitors increased markedly over the study period, starting at 1.54% (95% CI, 1.51-1.57) in 2011 and increasing to 26.86% (95% CI, 26.75-26.98) in 2015 and 43.63% (95% CI, 43.51-43.75) in 2018.
The estimated response rate was 0.14% (95% CI, 0.13-0.15) in 2011 and increased to 5.86% (95% CI, 5.8-5.92) by 2015 as additional checkpoint inhibitors were approved for more indications. The estimated percentage of responders reached 12.46% (95% CI, 12.37-12.54) by 2018.
“Most of the increases in eligibility and response are seen in patients with non-small cell lung cancer,” Haslam told HemOnc Today.
Indications that added the most to the eligibility estimate included NSCLC (21.48%), hepatocellular carcinoma (4.95%) and small cell lung cancer (3.79%). The highest contributors to the estimated response rate included NSCLC (7.09%), renal cell carcinoma (1.02%) and melanoma (0.92%).
The ratio of percentage benefit to percentage of cancers among FDA-approved checkpoint inhibitors increased over the study period, from 0.09 in 2011 to 0.28 in 2018, but has decreased from its peak of 0.32 in 2014.
The study’s results are limited because it used the highest response rate reported on FDA labels, which means researchers’ estimates should be considered as an upper boundary of normal. In addition, their estimates were based on clinical trial results, which Haslam and Prasad noted “often include younger patients with fewer comorbidities.”
“We hope that the results of our study will have an impact on clinical practice, mainly with how physicians approach and communicate the benefit of treatment with their patients,” Haslam said.
The study and its results hopefully will lead to more realistic discussions about the effectiveness of checkpoint inhibitors, not only among patients and providers, but in the media as well, according to the researchers.
“The media has certainly had a role in creating hype for immunotherapy drugs. ...Terms such as ‘game-changer,’ ‘winning,’ ‘revolutionary’ and ‘end of cancer’ have been used to describe [them],” Haslam told HemOnc Today.
“The use of these terms suggests that these drugs are nothing but successes, but that is not always the case,” Haslam added. “While the durable response among some people can be considered ‘game-changing’ for them, these outcomes are more often the exception rather than the rule. We need to approach clinical practice and policy with these results in mind.”
Daniel V.T. Catenacci, MD, director of the gastrointestinal oncology program at The University of Chicago, and colleagues mirrored Haslam’s sentiment in an accompanying editorial highlighting the hype vs. the reality of checkpoint inhibitor efficacy.
“Approvals and expanded indications for [immune checkpoint inhibitors] are occurring routinely, but lay excitement does not always align with clinical data,” Catenacci and colleagues wrote.
“The observations in this article are sobering and remind us to keep expectations of [immune checkpoint inhibitors] realistic,” they added. “As the dust settles and the wave of hysteria ebbs, studies like this lend support to physicians as they attempt to explain to most of their patients with cancer the reason they are not receiving [immune checkpoint inhibitors] — because these drugs are not appropriate for them.”
Catenacci and colleagues also highlighted discouraging changes in benefit ratios over time despite the study being limited by its underestimation of checkpoint inhibitor eligibility and overestimation of those who may benefit.
“This study quantitates the disturbing trend that, despite the expansion in the number of patients eligible for expensive and potentially toxic [immune checkpoint inhibitors], the ratio of those benefiting is decreasing,” they wrote. “As responsible and informed oncologists, it is vital that we use [immune checkpoint inhibitors] judiciously with an eye to maximizing benefit, as difficult as this may be while patients demand [immune checkpoint inhibitors] based on the press, the current buzz and patient-directed advertising.” – by Drew Amorosi
Disclosures: Haslam reports no relevant financial disclosures. Prasad reports royalties from his book Ending Medical Reversal; funding from the Laura and John Arnold Foundation; honoraria for Grand Rounds and lectures from several universities, medical centers, nonprofit groups and professional societies; serving as a writer for Medscape; and making the podcast Plenary Session, which has Patreon backers. Catenacci reports personal fees from Astellas, Bristol-Myers Squibb, Eli Lilly, Five Prime, Foundation Medicine, Genentech/Roche, Guardant Health, Merck, Taiho and Tempus. Please see the accompanying editorial for all other authors’ relevant financial disclosures.
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