Is a PFS Benefit Alone Really Worth $10,000 a Month?

In the field of lung cancer, and more broadly in oncology, many of our biggest advances in 2021 have come as clinically meaningful improvements in surrogate endpoints — disease-free survival, progression-free survival, and sometimes even pathologic complete response rate.

I have historically been most compelled to consider new findings to be practice-changing when they improve overall survival or quality of life — the endpoints that translate to direct benefits for patients. However, I also feel it is appropriate to call surrogate endpoints practice-changing when they can predict improvements in overall survival or quality of life.

Take the PACIFIC trial, which assessed maintenance durvalumab after concurrent chemoradiation for unresectable stage III non–small cell lung cancer (NSCLC).

Back in 2017, I was initially unconvinced by the interim phase 3 data that were presented in a press release that highlighted the disease-free survival benefit. However, after examining additional data more closely, I saw the dramatic improvement in time to distant relapse or death was overwhelmingly likely to predict an improvement in overall survival — a benefit that the data subsequently bore out.

More recently, the disease-free survival results for adjuvant osimertinib in resected endothelial growth factor receptor mutation–positive NSCLC and adjuvant atezolizumab in resected programmed death-ligand 1–positive stage II-IIIA NSCLC have led to excitement about US Food and Drug Administration approvals for these therapies. Although there is reason to be cautious about the likelihood of an overall survival benefit with either therapy — particularly for patients with low programmed death-ligand 1 who receive atezolizumab — I think that the results are promising enough to discuss these treatment options with appropriate patients.

Some argue, however, that overall survival is not necessarily a critical goal and that certain surrogate endpoints are inherently beneficial. Patients and oncologists may, for instance, view delaying disease progression as a win, even if overall survival remains the same.

I appreciate the view that favorable scan results are an achievement, even without a survival benefit. Patients appreciate the good news, and it is gratifying for us to deliver it. However, what remains unspoken is whether the benefit can be provided at a reasonable value given the financial costs associated with the new treatment.

In the United States, we consider the physician-patient relationship to be autonomous and even revered, but we conveniently ignore the fact that both are deciding on treatments that are funded by people who are not represented in the room. And in a healthcare system that fails to cover basic cancer care needs as well as other critical, high-value interventions for both the uninsured and underinsured, we should acknowledge that our decisions redirect limited resources from others.

Is it the best use of $10,000 per month for a new drug that improves disease-free survival but not overall survival? Given the cost of so many of these newer treatments, we should expect more than indirect, inferred benefits for patients.

At the same time, we also have to remain vigilant and reflect on whether we are echoing the marketing messages of the companies selling these treatments. Having recently watched the excellent Hulu series, Dopesick, which realistically portrays the medical community's egregious overuse of oxycontin at the behest of Purdue Pharmaceuticals, it is striking to see how effectively the pharmaceutical industry can co-opt stakeholders. Very few physicians or patients

have expertise in healthcare policy with broad societal perspective, yet subspecialists offer edicts as if society should dedicate unlimited resources first and foremost to our career focus or personal cause.

I certainly appreciate the appeal of surrogate endpoints in a world in which we hope to offer novel therapies to patients in a timely fashion. In the next few years, some of our most promising data in oncology will demand that we consider whether surrogate endpoints are practice-changing. We are facing a fundamental question: Are we using these surrogate endpoints to predict overall survival or quality of life or do these endpoints stand on their own as practice-changing metrics?

We need to acknowledge that our primary clinical focus is not the only one that deserves our attention, particularly when our treatment decisions are, in fact, spending other people's money. We should be asking not whether we prefer to deliver good news after a scan, but whether that alone is enough to justify the high cost of a new treatment without an overall survival benefit.

H. Jack West, MD, associate clinical professor and executive director of employer services at City of Hope Comprehensive Cancer Center in Duarte, California, regularly comments on lung cancer for Medscape. Dr West serves as web editor for JAMA Oncology, edits and writes several sections on lung cancer for UpToDate, and leads a wide range of continuing education programs and other educational programs, including hosting the audio podcast, West Wind.

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