Treatment Cost Not Tied to Survival in Breast Cancer

The monthly cost of treating disease is not associated with a patient with breast cancer surviving or the disease worsening, according to new research.

A key focus of new therapies for breast cancer should be improving overall survival (OS) rates and quality of life (QoL) for patients, stressed first author Julia Caroline Michaeli, MD, and colleagues in their paper published on September 25 in Breast Cancer. Michaeli, a physician at LMU University Hospital, LMU Munich, Munich, Germany, also presented her research in a poster at the European Society for Medical Oncology (ESMO) Breast Cancer 2024 in Berlin, Germany, in May.

The study, “Breast cancer drugs: FDA approval, development time, efficacy, clinical benefits, innovativeness, trials, endpoints, and price,” analyzed 26 new breast cancer drugs approved by the US Food and Drug Administration (FDA). Its authors specifically focused on the development, benefits, trials, and prices of these new therapies, collecting data from FDA labels, Medicare, Medicaid, and clinicaltrials.gov. Meta-analysis was done on OS and progression-free survival (PFS), hazard ratios (HRs), and tumor response’s relative risk (RR) alongside objective response rate (ORR).

“Our analysis shows that the monthly treatment costs of new breast cancer drugs were not associated with their OS or PFS benefit,” said Co-author Daniel T. Michaeli, MSc, MSc, BSc, in an interview. “This suggests that, in the US, we do not pay higher prices for drugs that provide a greater benefit to patients, but conversely, it also suggests that we could (maybe should) pay lower prices for drugs with only a marginal benefit. The ESMO-MCBS [Magnitude of Clinical Benefit Scale] scale shows a similar result.”

Here are some key results of the new research:

• New drugs’ HRs were 0.78 for OS (95% CI, 0.74-0.82) and 0.59 for PFS (95% CI, 0.54-0.64), with an RR for tumor response of 1.61 (95% CI, 1.46-1.76). Median improvements in OS were 2.8 months (interquartile range [IQR], 1.8-5.8), and PFS were 4.4 months (IQR, 2.2-7.1). In single-arm trials, objective rate response was 31% (95% CI, 10-53).
• There was a low correlation between OS/PFS (P = .031).
• Sixty percent of treatments had a “high-value” ESMO-MCBS score, with 14% demonstrating improvements in QoL.
• Drugs cost an average of $16,013 per month in 2023. There was no association between prices and OS/PFS benefit nor the ESMO-MCBS. The median value per life year gained was $62,419 (IQR, 25,840-86,062) for OS.

Let’s delve further into how results were determined looking at specific areas of the research process.

Drugs Approved and How Researchers Identified Them

The researchers accessed the Drugs@FDA database and identified all new drug listings. They included both New Drug Applications and Biologics License Applications. The timeline for FDA approval fell between January 1, 2000, and June 30, 2023.

One example of a drug in the study is bevacizumab, which received accelerated approval to treat advanced breast cancer by the FDA in 2008. This approval was withdrawn by the FDA in 2011, said Daniel T. Michaeli, who is also a physician at the National Center for Tumor Diseases in Heidelberg, Germany.

Next, the researchers broke down the listings to a sample of only anticancer drugs. They did not include non-oncology, supportive care, or diagnostic agents, meaning that gene and cell therapies were excluded. They checked each drug for all anticancer indications that were approved until June 30, 2023.

Finally, the researchers restricted the sample further to solely include indications approved for the treatment of early (perioperative) breast cancer and metastatic breast cancer.

The breast cancer drugs’ indications were then categorized by treatment type, either monotherapy vs combination therapy; biomarker status (hormone receptor–positive vs human epidermal growth factor receptor 2–positive vs other vs none); and line of therapy (first-line vs second-line vs ≥ third-line).

The researchers also focused on clinical novelty and innovativeness, which were determined on an indication level on the basis of a previously reported definition of indication novelty. Specifically, they evaluated the drugs for new indications (first-in-indication); drugs for known indications with a major benefit as exhibited by FDA priority review (advance-in-indication); and drugs for known indications without FDA priority review (addition-to-indication).

How Outcomes Leading to Approvals Factored Into Research

The researchers looked at pivotal clinical trials. The trial for each indication was marked by how many patients were enrolled, whether the trial was phase 2 or phase 3, whether the trial was randomized controlled or single-arm, whether the trial was open-label or double-blind, and the number of arms.

Other markings for each indication were whether the trial was direct comparator between active and inactive cancer drugs, whether the trial was placebo or no treatment, primary endpoint (OS vs PFS vs tumor response), randomization ratio (equal vs skewed), and crossover (specific vs nonspecific).

Single-arm trials were calculated using ORR on the basis of how many responders and patients were in the trial. The researchers calculated median improvements in OS, PFS, and duration of tumor response with IQRs as the difference between median survival in the treatment and control arm.

In terms of clinical benefit and QoL evaluation, the researchers used the ESMO-MCBS in 2023. For metastatic disease, an ESMO-MCBS of 4-5 was termed “high-value”; an ESMO-MCBS of 1-3 was qualified as “lower-value.” For curative purposes, an ESMO-MCBS of “A” and “B” was considered “high-value”; an ESMO-MCBS of “C” was judged “low-value.”

The researchers also compiled data on indications’ improvement in QoL as listed by the ESMO-MCBS.

Method Used for Calculating Drug Prices

Using the Centers for Medicare and Medicaid Services (CMS) and Medicare’s plan finder, drug prices were identified. The researchers then used the same price calculation they had worked with for two previous studies: “Launch and Post-Launch Prices of Injectable Cancer Drugs in the US: Clinical Benefit, Innovation, Epidemiology, and Competition” and “Cancer Drug Prices in the United States: Efficacy, Innovation, Clinical Trial Evidence, and Epidemiology.” The method was as follows.

The researchers accessed the CMS’ quarterly average sales price data files to obtain drug pricing data. Next, they calculated monthly treatment costs based on the dosing regimen defined in FDA labels for the average US patient. This was done using a body weight model of 70 kg and a body surface area of 1.7 m², focusing on patients with normal liver and kidney function. Using this method, treatment costs include drug price only, not including doctor’s fees, delivery or administrative costs, and any support care that would be needed for some patients with cancer.

Analysis of Monthly Cost vs Patient Benefit

The researchers determined that the new drugs cost an average of $16,013 per month in 2023 and that no significant benefit was found between the new drugs’ clinical benefit (OS, PFS, or ESMO-MCBS) and their prices.

In terms of how the researchers determined this in further detail, they “correlated them to OS/PFS/ESMO-MCBS,” Daniel T. Michaeli explained. “None of these associations were of significant magnitude,” indicating that “breast cancer drugs are not priced-based on these new drugs’ benefits for patients.”

The researchers concluded that there is misalignment between new cancer drugs’ value and price. They also pointed out the importance of value frameworks like the ESMO-MCBSm, which can serve as a price negotiation guide and could help identify high-value treatments that patients with breast cancer could quickly take advantage of.

“Breast cancer drugs are not priced-based on these new drugs’ benefits for patients,” Daniel T. Michaeli said.

Outside Clinician’s Perspective

One question that the research brings up is to what extent is the low OS/PFS ratio problematic, and what might be the potential problems with many drugs receiving expedited approval based on PFS, rather than OS.

“PFS is a ‘surrogate endpoint’ that should reasonably predict a clinical endpoint, which is either OS or quality of life,” said Daniel T. Michaeli. “In other words, cancer drugs should aim to prolong or improve the quality of patients’ lives. With tumor response and PFS, you simply measure if the tumor shrinks or increases in size. For certain tumor entities and drugs — and this has to be verified for every drug — PFS is a great predictor of OS. Under this specific assumption, the FDA often expedites the approval of new drugs. Note that we can measure PFS a lot quicker than OS and need to study the drug only in smaller trials — this means it’s less costly to conduct these trials.”

“However, there are some cases that show that these special approval drugs cannot live up to their expectations. There’s a list by the FDA of these withdrawn drugs,” Daniel T. Michaeli continued.

From the standpoint of Jesus D. Anampa Mesias, MD, a clinician not involved in the research, “the OS/PFS correlation of 0.34 in the ESMO poster is a weak correlation.”

“This is because several clinical trials are designed based on improvement in PFS as the primary objective, and OS is a secondary endpoint,” said Anampa Mesias, a breast cancer medical oncologist and hematologist at Montefiore Einstein Comprehensive Cancer Center in Bronx, New York.

“Most trials are designed with the idea that PFS is a surrogate of OS. So, if a trial shows improvement in PFS, the study may conclude that the drug actually works; however, based on a weak PFS/OS correlation, that might not be true because what we really want is a drug that improves OS and/or quality of life,” he continued.

Another point that could be explored is how outcomes based on breast cancer drug approvals from the period covered in the poster should be characterized.

The current study does not specify the number of drug approvals by measured outcome (OS, PFS, or ORR), Anampa Mesias noted. “However, the outcomes that we want to see would be improvement in [overall] survival or improvement in quality of life,” he elaborated.

“There is some pooled data suggesting an improvement in OS of 2.8 months; however, a very important outcome is about the quality of life that patients experienced. We need to make sure that patients also have a better quality of life with new drugs. Otherwise, it might not be really impactful to prolong life.”

The Bigger Picture

Overall, in terms of this poster’s content, “the outcomes used for approval are adequate — OS, PFS, ORR,” Anampa Mesias concluded. But he said it’s important to highlight that some drugs may require specific outcomes; “for instance, studies evaluating immunotherapy have shown improvement in OS despite no improvement in PFS. Therefore, studies for such drugs may be better evaluated by OS rather than PFS.”

“Studies that are based on measurement of early tumor-based endpoints (PFS, ORR) should have a statistical plan to analyze OS as well. Moreover, evaluation of quality of life should also be included in such trials,” he continued.

In a wider context, some drugs with expedited approvals are based on studies that show an improvement on PFS, without data on OS, Anampa Mesias also pointed out.

“Those drugs may not improve OS, or even worse, [they] may also have toxicities that could lead to late deaths, which may actually be detrimental in OS, despite an early improvement in PFS,” Anampa Mesias said. “Furthermore, the expedited approval of a drug that does not have a true clinical benefit leads to financial toxicity for our patients with cancer, who are already struggling with all the other costs of cancer treatment.”

In terms of future research, OS may not be a feasible endpoint in all clinical trials, Anampa Mesias concluded. “Early tumor-based endpoints can be reasonable endpoints in some scenarios.”

“Regardless of the primary endpoints used, OS evaluation should be incorporated with all the mature data, and also quality of life evaluation should be reported,” he said.

Michaeli and Daniel T. Michaeli had no disclosures to the report, but one of the authors reported several conflicts of interest, which are available in the new paper. Anampa Mesias had no disclosures to report.