Real-World Results With Checkpoint Inhibitors Inferior to CT Data

Mark L. Fuerst

November 02, 2020

Real-world survival outcomes for cancer patients on immune checkpoint inhibitors (ICIs) are inferior to outcomes reported in patients on clinical trials of ICIs, according to research published in JCO Clinical Cancer Informatics.

However, the research also suggests that real-world patients who receive ICIs achieve longer survival than patients on standard-of-care medications.

"Patients receiving ICIs in real-world practice may differ from those enrolled in trials in a variety of ways, including age, race, performance status, and comorbidity burden," said study author Jerry S.H. Lee, PhD, of the University of Southern California, Los Angeles.

Lee noted that only 3%-4% of cancer patients participate in clinical trials. In fact, more than half of patients with melanoma and nearly three-quarters of those with non-small cell lung cancer (NSCLC) do not meet criteria for eligibility in clinical trials, he said.

To examine the discrepancies between real-world practice and clinical trials and to better understand which patients receive ICIs in clinical practice, Lee and colleagues conducted a retrospective analysis using electronic health record data from Veterans Administration (VA) facilities nationwide.

The researchers identified 11,888 cancer patients who were treated with ICIs. The cohort included patients who are underrepresented in pivotal clinical trials, including older, non-White, and/or higher disease-burdened patients.

The majority of patients were treated for NSCLC (51.1%), followed by melanoma (14.4%), renal cell carcinoma (RCC; 8.1%), squamous cell carcinoma of the head and neck (6.8%), urothelial cancer (6.4%), hepatocellular carcinoma (4.5%), and other less common cancer types (8.8%).

Overall Survival by Indication

In general, median overall survival (OS) in the VA cohort was inferior to median OS reported in clinical trials. However, patients treated with first-line nivolumab for melanoma and second-line pembrolizumab or nivolumab for NSCLC had similar OS in the real-world and trial data.

The researchers did not report exact OS numbers from clinical trials. However, they did report the exact numbers from the VA cohort and show OS differences between the VA cohort and clinical trials graphically.

Among patients in the VA cohort, the median OS was:

  • 25.5 months in melanoma patients on first-line nivolumab

  • 16.3 months in RCC patients receiving nivolumab in the second line or higher

  • 14 months in RCC patients on first-line ipilimumab and nivolumab

  • 10.6 months in NSCLC patients on first-line pembrolizumab

  • 9.9 months in NSCLC patients receiving pembrolizumab or nivolumab in the second line or higher

  • 9.1 months in NSCLC patients on first-line pembrolizumab and platinum-based chemotherapy

  • 6.7 months in urothelial cancer patients receiving ICIs in the second line or higher.

A number of factors may have contributed to the shorter OS observed in the VA cohort, according to the researchers. The VA cohort is predominantly male, is older, and has a higher degree of comorbidity, compared with patients in clinical trials.

In addition, no data are available to determine the cause for discontinuation of therapy, and VA patients may have received ICIs after failing multiple lines of previous therapy, while clinical trials may limit patients to only one or two previous lines of therapy.

After stratifying VA patients by frailty status, the OS among non-frail patients was more similar to the OS reported in clinical trials.

"Real-world outcomes from the VA were more similar when adjusted for frailty, which shows the importance of patient diversity in clinical trials," Lee said. He added that the definition of frailty among VA patients included potential injury during combat and therefore differs from a generic frailty definition.

ICIs vs. Standard Care

The researchers also found that VA patients treated with ICIs had longer OS, compared with a cohort of VA patients receiving standard-of-care therapies.

The median OS was as follows:

  • In melanoma patients on first-line treatment – 39.29 months with nivolumab and 5.75 months with chemotherapy (P < .001).

  • In RCC patients on first-line treatment – 14.01 months with ipilimumab plus nivolumab and 8.63 months with targeted therapy (P = .051).

  • In RCC patients on second-line or greater treatment – 12.43 months with nivolumab and 8.09 months with everolimus (P < .001).

  • In NSCLC patients on first-line therapy – 8.88 months with pembrolizumab and 6.38 months with a platinum doublet (P < .001).

  • In NSCLC patients on first-line combination therapy – 10.59 months with pembrolizumab plus platinum chemotherapy and 6.38 months with a platinum doublet (P < .001).

  • In NSCLC patients on second-line or greater therapy – 10.06 months with pembrolizumab or nivolumab and 6.41 months with docetaxel (P < .001).

  • In urothelial cancer patients on second-line or greater therapy – 7.66 months with an ICI and 6.31 months with chemotherapy (P = .043).

Help for Treatment Decisions

"The real-world survival outcomes not only indicate the breadth of indications but also represent patients who tend not to be eligible for immunotherapy trials, based on their health status," Lee said. "We hope this dataset of national-level experience provides practicing oncologists evidence to help patients and family members in the process of decision-making about therapy."

Real-world data can also inform oncologists who face decisions on whether to prescribe or withhold ICIs and patients who face the financial burden of paying for ICIs, he said.

This dataset will be continually updated. The researchers have already added another 10,000 VA patients who have received immunotherapies in the year since the trial began.

"In a longitudinal way, we plan to examine what causes differences in outcomes and continue to find ways to extend care to veterans with a balance of high quality of life," Lee said.

"Patients who participate in clinical trials are, on average, younger and healthier than the general population," said Bora Youn, PhD, a senior biostatistician at Biogen in Cambridge, Mass., who was not involved in this study.

"In the case of immunotherapies, those with poor performance status and autoimmune conditions are often excluded from trials," Youn added. "In the real world, these patients can also receive treatments, and clinicians often need to extrapolate the results from clinical trials. It is therefore important to collect real-world data to understand the effectiveness and safety of these therapies in patients with limited evidence."

Youn led a real-world study, published in Cancer, of 1,256 Medicare recipients who were diagnosed with NSCLC and received ICI therapy.

"We found that factors associated with poor prognosis in general, such as squamous histology and failure of aggressive prior treatment, are also predictive of decreased survival among those who initiated immunotherapies. Yet, OS of older patients was relatively comparable to those observed in clinical trials," Youn said.

"Understanding the real-world effectiveness of these treatments will help improve the evidence base, especially for those underrepresented in clinical trials. These studies can also help identify patients who are most likely to benefit from immunotherapies," Youn added.

This study was supported by the VA Office of Research and Development Cooperative Studies Program. Lee and Youn disclosed no conflicts of interest.

SOURCE: Jennifer La et al. JCO Clinical Cancer Informatics. 2020:4:918-28.

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