Roche Disputes Problems With Assay
Roche, manufacturer of both atezolizumab and the companion diagnostic test, disputes that there is a problem.
The FDA and multiple health authorities worldwide have approved atezolizumab and the companion diagnostic SP142 assay for use in TNBC, points out Eslie Dennis, MD, vice president of medical affairs at Roche Tissue Diagnostics.
“The role of a companion diagnostic assay is to discriminate between responders and non-responders for a specific therapeutic product in a specific indication, with a cut-off based on clinical outcomes,” she wrote in an email to Medscape Medical News.
Data from the pivotal IMpassion130 trial show that the assay was effective at that task. Among the 369 patients in the 902-patient trial whose tumors were ≥1% positive for PD-L1, those treated with atezolizumab (and nab-paclitaxel; n = 185) had a median progression-free survival (PFS) of 7.4 months, vs. 4.8 months among those treated with placebo (and nab-paclitaxel; n = 184) (P < .0001).
“Exploratory analysis showed no [PFS] benefit in PD-L1-negative patients as tested by the SP142 assay [in IMpassion130],” Dennis and three other physicians write in a reply to Rimm in a letter published in July 2019 in the Pathologist.
The same held true for overall survival in exploratory analysis – there was no benefit with atezolizumab among the PD-L1-negative patients, they write.
Notably, overall survival benefit for patients who were PD-L1 positive was about 10 months (at the first interim analysis; at the second analysis, the benefit dropped to 7 months and was not statistically significant).
But Rimm points out that the pivotal trial used only one pathologist in a central lab to determine PD-L1 status, who was undoubtedly an expert with the SP142 assay.
Further, Rimm observes that additional data submitted to the FDA to show that SP142 test results are reproducible outside of the pivotal trial setting were performed with only three pathologists and thus unsurprisingly yielded high rates of agreement – all above 90%.
The data from both of these circumstances are problematic, Rimm said, because in the real world, hundreds of pathologists will score the SP142 assay – all in the context of a busy day reading a variety of other tests for other diseases.
It’s one thing to get an FDA approval for an assay, and it’s another thing to be a reliable, well-functioning assay in the real world, he summarized.
Last year, Roberto Salgado, MD, PhD, a pathologist at the Université Libre de Bruxelles, Belgium, commented that “a positive phase III trial should not be taken as a guarantee that the assay used in the trial can be implemented in daily practice” in an opinion piece in the Pathologist.
SP142 Identifies the “Fewest Possible Patients”
The SP142 assay has been shown in multiple studies to have lower sensitivity for PD-L1 than other competing PD-L1 assays, said Rimm, citing examples such as a 2017 study and a 2018 study.
Angela DeMichele, MD, a medical oncologist at the University of Pennsylvania in Philadelphia, agreed and explained what that meant in practical terms for women whose tumors are tested with SP142. “It means that the test is going to identify the fewest possible PD-L1-positive patients [relative to the other available assays],” she said. “It [the SP142 assay] is far from a perfect test for this situation,” added DeMichele, an expert on biomarkers in breast cancer clinical trials.
She said that biomarker tests, like many products of science, tend to become dated with the passage of time, as more is learned about the target and new assays are developed. “Unfortunately, you can’t change assays midstream,” said DeMichele. She has received a grant from Roche and Stand Up to Cancer to study atezolizumab and another drug in a clinical trial among patients with metastatic TNBC who have minimal residual disease.
DeMichele also said that “David Rimm is one of the most knowledgeable people in the world about this issue.”
But DeMichelle also points out the practical: “We’re stuck as clinicians” because regulatory bodies and insurance companies only pay for atezolizumab when the SP142 assay indicates PD-L1 positivity. That’s not the case in Europe, where health authorities do not specify which PD-L1 assay is to be used with atezolizumab for breast cancer, pointed out Belgium’s Salgado last year.
