As always, this year's American Society of Clinical Oncology (ASCO) meeting left me feeling hopeful about the future.
But this year it was mixed with a degree of concern about the way we are designing and conducting trials and what, as an oncology community, we are choosing to celebrate.
Two trials — SONIA and ADAURA — perfectly showcase these competing sentiments.
Let's start with SONIA, a nationwide, publicly funded trial in the Netherlands exploring first- vs second-line use of CDK4/6 inhibitors in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. These drugs have already been tested and approved in both first and second lines of treatment, but there was uncertainty as to whether second-line therapy offered similar outcomes to first-line. In other words, could patients do just as well without a CDK4/6 inhibitor in the first line and consequently delay the extra costs and toxicities associated with CDK4/6 inhibitors?
We needed a trial like SONIA to directly test that question because the initial first-line trials did not mandate control-arm patients to cross over and receive CDK4/6 inhibitors at the time of relapse. (Ideally, this question would have been answered already by mandating crossover in the first-line trials.) The primary endpoint of SONIA was progression-free survival (PFS) after the two lines of therapy, which is appropriate for a first- vs second-line comparison trial. Secondary endpoints included overall survival and quality of life.
The trial found that PFS after two lines of therapy was not significantly different between the two arms. Bottom line: SONIA found that it doesn't matter whether patients receive a CDK4/6 inhibitor in the first or second line. This conclusion was bolstered by the overall survival results, which found similar survival between the two arms.
However, there were major downsides for patients who received a CDK4/6 inhibitor in the first line. These patients took CDK4/6 inhibitors for an additional 16.5 months compared with patients who received CDK4/6 inhibitors in the second line — meaning an extra 16.5 months of more intense financial and physical toxicities. Drug expenditures increased by $200,000 per patient.
This trial also highlighted the financial feasibility of running trials from public funds. The cost of the trial was recouped by savings during the trial itself.
But, despite asking, and answering, an important, practice-changing question, the SONIA trial went largely unnoticed and uncelebrated.
By contrast, the ADAURA trial was widely celebrated at ASCO, on social media, and in press coverage. The trial was even selected for the plenary session (while SONIA was not).
In brief, ADAURA showed overall survival gains for osimertinib vs placebo for patients with resected EGFR-mutated lung cancers, with a hazard ratio of 0.49. While it's an impressive result, the trial represents a confirmatory overall survival study for a drug already FDA-approved for this indication. The results were not practice-changing; osimertinib has already been integrated into adjuvant therapy for the past 2 years since the FDA approval.
The ADAURA trial design, however, had issues. Jack West and I wrote two papers about these issues with the trial back in 2021, and West wrote one recently as well. In short, many of the control-arm patients did not get osimertinib at relapse. Of 205 patients who had disease recurrence, only 79 (38%) got osimertinib at relapse; 43 did not get any TKI, including 21 who did not get any treatment.
This is deeply problematic. I believe that receiving osimertinib at relapse should have been mandatory because it is standard of care. But because crossover in the control arm was not mandatory, this trial never clearly answered whether adjuvant osimertinib is better than osimertinib at relapse; it simply demonstrated that receiving osimertinib is better than not.
Still, ADAURA took center stage at ASCO. Highlighting this trial in the plenary sessions seemed like an odd choice — I don't believe that ASCO has ever offered its plenary stage before to a confirmatory overall survival study — and I'd argue that doing so meant that a more deserving, practice-changing trial like SONIA did not get the plenary stage.
Engagement with the trial was also problematic. Some top leaders and media outlets claimed that osimertinib cuts deaths by half, misinterpreting the hazard ratio as the overall survival difference, which was actually around 12% at 5 years.
The biggest surprise, however, was the reaction from key opinion leaders in the field. Many leaders were quick to dismiss the concerns raised about the trial's control arm — concerns which weren't meant to take away from the clinical utility of adjuvant osimertinib but rather to highlight a trial design that can lead to patient harm.
Calling out this kind of design issue is especially important because it can help prevent a repeat of the same problem in future trials. It is our responsibility to advocate for all patients, including those in the control arm.
Making the excuse that the trial was run outside the United States is a weak argument, emblematic of research parachutism in global oncology. If the trial could offer adjuvant osimertinib, it could also offer first-line osimertinib at relapse, irrespective of where the trial was conducted.
And while some key opinion leaders downplayed or defended issues with the control arm in ADAURA, others seemed to downplay the practice-changing implications of SONIA. SONIA's results are clear: CDK4/6 inhibitors can be given in the second line without compromising survival outcomes while also saving patients from toxicities and additional costs.
Some, however, interpreted this "less is more" or "de-escalation" trial as being applicable to old and frail patients only, despite the trial including all patients with good performance status. Some also said that CDK4/6 inhibitors should still be used in the first line, arguing that we need biomarkers to determine who can wait until the second line. But this argument should be reversed: Biomarkers would be needed only to identify who might benefit from a CDK4/6 inhibitor in the first line. In other words, oncologists should need a compelling reason to overtreat patients.
For more, I have recorded my thoughts on major trials from ASCO 2023 in a video and provided pointers on how to analyze clinical trials critically in an earlier post.
Overall, the purpose of this column is to encourage trial designs that answer important questions without limiting some patients access to the best care, as well as to encourage independent thinkers, community oncologists, and trainees to not just follow the hype and join the cheerleading bandwagon. At the latest ASCO, I noticed a lot more critical and thoughtful voices compared with previous years, and that gave me hope. But we still have a long way to go.
Bishal Gyawali, MD, PhD, is an associate professor in the Departments of Oncology and Public Health Sciences and a scientist in the Division of Cancer Care and Epidemiology at Queen's University in Kingston, Ontario, Canada, and is also affiliated faculty at the Program on Regulation, Therapeutics, and Law in the Department of Medicine at Brigham and Women's Hospital in Boston. His clinical and research interests revolve around cancer policy, global oncology, evidence-based oncology, financial toxicities of cancer treatment, clinical trial methods, and supportive care. He tweets at @oncology_bg.
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Lead image: Bishal Gyawali, MD, PhD
Image 1: Bishal Gyawali, MD, PhD
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Cite this: At ASCO, the Cancer Community Hyped the Wrong Trial - Medscape - Jun 29, 2023.
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