CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Dr. Gitlitz
The response rate was “quite low,” says Dr. Gainor, noting it was under five percent. “None of the ALK-positive patients responded, but it should be noted that the total number of ALK-positive patients in this study was quite small. Further prospective assessments are needed to better define this.” The response rates in a separate cohort of 30 EGFR wild-type and ALK wild-type patients were around 20 percent. “And this is more consistent with what we have seen in clinical trials of these drugs,” Dr. Gainor says.
The second part of the study investigated why that may be the case. The researchers examined paired biopsy specimens from 62 EGFR-mutant and 19 ALK-positive lung cancer patients in another cohort. The biopsies were obtained from the patients before they had targeted therapy and when they developed resistance to the therapy. “And what we found is that a subset of EGFR– and ALK-positive patients do express PD-L1, but what was noteworthy is the [tumors] tended not to be inflamed, so they lacked CD8-positive tumor infiltrating lymphocytes [TILs]” before and after targeted therapy, says Dr. Gainor, who is also an assistant professor at Harvard Medical School.
The authors wrote, “Concurrent PD-L1 expression (≥5%) and high levels of CD8 + TILs (grade ≥2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK-positive, pre- or post-TKI specimens.”
Dr. Gainor
“PD-L1 expression,” Dr. Gainor says, “is commonly just a surrogate for inflammation since PD-L1 is upregulated in response to interferon gamma from infiltrating immune cells. In this study, we found that ALK-positive tumors generally lacked CD8-positive TILs even when they had PD-L1 expression.” This led the study’s authors to hypothesize that PD-L1 expression in EGFR– and ALK-positive patients may be due to innate immune resistance. They concluded in their article, “This lack of an inflammatory microenvironment, despite PD-L1 expression, is suggestive of innate immune resistance, and may limit the effectiveness of PD-1/PD-L1 inhibitors in these patient populations.”
Returning to the case study, Dr. Levy decided to prescribe another ALK inhibitor, brigatinib, for his patient in lieu of immunotherapy. The patient’s cancer partially responded. Later, however, the disease advanced quickly and the man died. “He lived about three and a half years” after diagnosis, Dr. Levy said, adding that if the patient hadn’t progressed so rapidly on the last ALK inhibitor, he might have tried immunotherapy next. “But it’s tough to know. We don’t know how to use these drugs in patients who are ALK positive.” Multiple trials are being conducted now in hopes of answering the question: Is there a role prospectively for immunotherapy for these rare genotypes?
“Unfortunately,” says Dr. Gainor, “we have seen that lung cancers treated with targeted therapies almost universally develop resistance, but what that resistance looks like can differ substantially based upon the ALK inhibitor that is being used.” Dr. Gainor says research he and his colleagues conducted showed that “the first-generation inhibitor, crizotinib, and the three second-generation inhibitors—ceritinib, alectinib, and brigatinib—each have different selectivity profiles and, as a result, the spectrum of resistance differs across the four” (Gainor JF, et al. Cancer Discov. 2016;6[10]:1118–1133). “The hope is to use repeat biopsies complemented by circulating [tumor] DNA to actually guide the selection and sequencing of ALK inhibitors rather than just empirically picking one followed by the other.”
As for using ctDNA up front, Dr. Levy says that, in retrospect, the patient in the case study should have had a liquid biopsy sooner but the technology was just coming out at the time. “So I think in hindsight, if there wasn’t enough tissue up front, I would have just done it up front. You have made a diagnosis with the biopsy, and there’s not enough tissue to complete the genetic testing; that is where I think circulating tumor DNA can help aid you in the diagnosis and also an understanding of the tumor biology.”
Dr. Tafe surmises that ctDNA testing may in time be performed up front to complement tissue testing or detect and monitor for resistance. “Right now, there are really no guidelines as to how to best validate these assays for clinical use and what indications for testing we should have” for their use. The updated CAP, International Association for the Study of Lung Cancer, and Association for Molecular Pathology guideline for selection of lung cancer patients for treatment with targeted TKIs, published online Jan. 22, says in some clinical settings in which tissue is limited and/or insufficient for molecular testing, physicians may use a cell-free plasma DNA assay to identify EGFR mutations (Lindeman NI, et al. Arch Pathol Lab Med. Epub ahead of print Jan. 22, 2018. doi:10.5858/arpa.2017-0388-CP). “But tissue helps us also make the diagnosis, confirm cancer, and classify what type of cancer it is, so it’s incredibly informative,” Dr. Tafe says.
Although the ctDNA assays have high positive predictive values, she said, “we don’t exactly know what the false-negative rate is for these assays in terms of the ALK-specific mutations. We know for EGFR, it’s probably around 15 percent or so, depending on the assay.” Various factors affect whether tumors release DNA into the circulation: tumor size, stage, and location and tumor vascularity, metastasis, and previous treatment. Thus, a major question, Dr. Tafe said, is how to deal with a negative ctDNA assay result when there is a high suspicion of either recurrence or metastatic disease. “And often the answer is to go back and get another tissue biopsy because there can be false-negative ctDNA cases.”
Dr. Levy said it’s difficult to get a false-positive circulating tumor DNA test result. “Anything that is considered a primary driver—EGFR, ALK, BRAF—and pops up is probably going to be true.” But the medical oncologist does need to communicate with the pathologist because if the pathologist finds something different in the tissue than was found in the blood, “then you have a problem.”
Then, too, he adds, open communication between the pathologist and medical oncologist is essential across the continuum of lung cancer care.
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Karen Lusky is a writer in Brentwood, Tenn.