We have seen HLA typing become more prominent in oncology clinical studies. Especially in the realm of immuno-oncology therapeutics including CAR T-cells, bi-specifics, and cancer vaccines. I suspected that HLA typing was headed for use as a companion diagnostic, but this first approval came much sooner than I expected. The first oncology approval tied to HLA status just came through at the beginning of the month.
From the package insert:
Select patients for treatment of unresectable or metastatic uveal melanoma with KIMMTRAK based on a positive HLA-A*02:01 genotyping test [see Clinical Studies (14)]. An FDA-approved test for the detection of HLA-A*02:01 genotyping is not currently available.
Lacking any formal training in immunology I will forgo any attempt to explain and instead refer to the attached illustration as to the mechanism of action for this one:
Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives.
Future Oncol. 2021 Nov; 17(33):4583-4606
Doi:10.2217/fon-2021-0318. Epub 2021 Aug 25
Schematic representation of the mechanism of action of tebentafusp
Left: natural interaction between a tumor cell presenting an antigen on HLA and TCR of a T lymphocyte. Right: tebentafusp (in blue) mimics a normal immune synapse between gp100 melanoma specific antigen (in red) presented by HLA-A*02:01 of melanoma cell (in green): the antiCD3 effector function of tebentafusp (reverse pentagon in blue) engages CD3 receptor (in pink) on T-cell surface, causing T-cell-mediated cancer cell death.
Based on the description, I would guess that development of an FDA-approved HLA test is a post-marketing commitment. I would further add that the requirement for HLA as a CDx was not determined until late phase in clinical development, and so launch of the FDA-approved diagnostic is decoupled from drug approval as a post-marketing commitment. Fortunately, HLA testing is broadly available from CLIA-accredited laboratories and I would not expect the lack of an FDA-approved diagnostic at this time to hinder the initial launch of tebentafusp.
This raises an interesting question. To what degree will an FDA-approved CDx be adopted when a broad testing ecosystem already exists for that biomarker? Oncologists are not strictly required to order an FDA-approved CDx. Furthermore, given that this approval is for an orphan indication that would most likely be treated exclusively at specialized academic medical centers, all with their own established HLA testing systems, will there be any appreciable uptake of an FDA-approved assay that will be a “one-off” solution? If HLA testing requirements and applicable CDx assays continue to grow, we could find ourselves in a PDL1-type situation, with multiple test options and platforms tied to different therapeutics. Unless payers move to a strict requirement for use of FDA-approved CDx, I would predict low commercial uptake with most testing provided by lab-developed tests or general HLA testing solutions. When combined with the FDA’s move towards requiring full development of a CDx, rather than relying on an ecosystem of established LDTs to support drug approvals, commercial launch strategies are becoming more complex.
In the meantime, at Neo we will be accelerating our investment in HLA typing technologies to keep pace with development.