‘Like a coin flip’: Assay denies some cancer patients new drug


In December, at a major breast cancer conference, some attendees couldn’t find a seat and were told to leave an overcrowded session on immunotherapy for metastatic triple-negative breast cancer (TNBC). They refused, and pushed in to hear what was being said.

The crowd might have been surprised to learn that the main draw of the event, a successful new drug, was not all it might have been for women with the disease, being handicapped by a test that determines who is eligible for it.

“That room was overpacked ― there were five people deep against the wall. ... It was amazing,” said Janice Cowden of Bradenton, Florida. She attended the meeting, the San Antonio Breast Cancer Symposium, as a patient advocate.

Cowden lives with metastatic TNBC, which is known for poor prognoses, aggressiveness, and a lack of targeted treatment options. “Stage IV is a state of desperation. We just want something to work,” she said.

That’s why the conference room was packed – the session was focused on something that had been found to work – the immunotherapy atezolizumab (Tecentriq, Genentech/Roche).

Atezolizumab had recently been conditionally approved for first-line use in advanced TNBC, having been shown to significantly slow disease progression and, in some patients, to possibly improve survival. A pair of medical oncologists reviewed the clinical trial data during the session.

One important point from the trial data was that the benefit was greater in patients whose tumors had the biomarker PD-L1, and so the Food and Drug Administration approval of the drug specified that it should be used only in those patients.

The drug approval was accompanied by approval of a companion diagnostic test used to identify this PD-L1-positive subgroup of patients, the Ventana SP142 Assay (Roche Diagnostics).

At the meeting, pathologist David Rimm, MD, of Yale University, New Haven, Connecticut, discussed the biomarker PD-L1 and the test. Rimm had a subtle but unsettling message about the crucial test: that the SP142 diagnostic assay, when used by increasing numbers of pathologists, resulted in increasing rates of PD-L1 scores that were not concordant.

A related meeting poster, presented the next day with Rimm as senior author, was more explicit and concluded that “more than half of the pathologists in real-world situations may mis- assign” patient scores with SP142 (and another Roche assay) because of wide variability in readouts.

“They’ve made a test that is inadequate – it just doesn’t work. It’s like flipping a coin,” he told Medscape Medical News about Roche’s SP142 assay in everyday practice.

The general problem is not a new one – for some years there have been problems with the use of PD-L1 as a biomarker for immunotherapy and with assays for that biomarker, with many groups questioning both accuracy and reproducibility. But the problems with SP142 are “the most egregious,” said Rimm, who has served as a paid consultant to Roche Diagnostics in the past.

In clinical practice, Rimm’s overall message is that because of the difficulty of reading SP142 assay results, some TNBC patients who were PD-L1-positive would not get the drug, and some who were not positive would get the drug.

Patient advocate Cowden was not worried about overtreatment. She was concerned about patients who “might die without receiving a potentially life-extending treatment.”

In an essay in the Pathologist, Rimm echoed that sentiment about undertreatment (as well as overtreatment) with atezolizumab for breast cancer: “In all cases, the patients are the potential victims, but this appears to be completely under the radar of the hype surrounding this new drug.”

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