Q&A: Ted Laetsch on Tumor-Agnostic Therapies

In August, GlaxoSmithKline's dostarlimab-gxly (Jemperli) earned the FDA's accelerated approval for recurrent or advanced cancers that are mismatch repair–deficient (dMMR). Dostarlimab-gxly, an immune checkpoint inhibitor (ICI) that modulates the PD-1 axis, is the second in this class to receive a tumor-agnostic nod from the agency, after pembrolizumab (Keytruda; Merck). Others with tumor-agnostic indications are larotrectinib (Vitrakvi; Bayer) and entrectinib (Rozlytrek; Genentech), TRK inhibitors targeting NTRK1/2/3 fusions.

These approvals have spurred oncologists to identify additional therapies and biomarkers with tumor-agnostic potential. Theodore Laetsch, MD, of Children's Hospital of Philadelphia in Pennsylvania, is well acquainted with larotrectinib, having collaborated closely with Loxo Oncology as the drug was developed, prior to Bayer acquiring its licensing rights. Laetsch also led the pediatric phase I/II SCOUT trial, “which contributed a significant component of the dataset used to seek larotrectinib's approval in [a] tumor-agnostic fashion.” Speaking with Alissa Poh for Cancer Discovery, he offered some thoughts on the field and its challenges.

Well, we've seen initial data from the NCI-MATCH and Pediatric MATCH trials testing tumor-agnostic treatments. There were positive results with nivolumab [Opdivo; Bristol Myers Squibb] in dMMR non-colorectal cancers; dabrafenib [Tafinlar; Novartis] and trametinib [Mekinist; Novartis] in BRAF V600E tumors; and capivasertib [AZD5363] in tumors with an AKT1 mutation, E17K. However, the remaining studies, including AZD4547 in cancers with FGFR pathway aberrations, were negative.

For now, at least. Kinase-activating fusions really do seem a somewhat unique class for which drugs can be histology-agnostic. Besides TRK as the poster child, ALK fusions come to mind; they occur in a range of cancers, including pediatric anaplastic large-cell lymphoma, for which crizotinib [Xalkori; Pfizer] was recently approved. We see ALK-positive infantile inflammatory myofibroblastic tumors too, and because a lot of what we do in pediatric oncology is off-label, these young patients are routinely treated with crizotinib and other next-generation ALK inhibitors—so far only indicated for adult non–small cell lung cancer—as well.

After pembrolizumab and larotrectinib, the hope was that we could quickly identify other potentially tumor-agnostic biomarkers and therapies, but I don't know that there are any clear front-runners; the field seems to have struggled.

I think the problem is multifaceted. Some of the emerging biomarkers are not as well validated; on the flip side, we don't yet have good drugs for some alterations. Then, too, it may be the case that some alterations are truly more relevant in one cancer than another. I'd say these three aspects, together, are probably why we haven't had further success.

A Pediatric MATCH trial that turned out negative was selumetinib [Koselugo; AstraZeneca] in tumor types harboring a variety of MAPK pathway alterations. Enrolled patients had RAF and RAS family mutations, for instance, but these are relatively far upstream of selumetinib's target, MEK. Blocking a single node, especially one at some distance along a highly convoluted signaling pathway, was likely not as effective as blocking one of the actual activated kinases directly. That's my perspective on why no efficacy was seen.

Yes, at least in the targeted therapy context. Pembrolizumab and other ICIs are broadly active because they act on the immune system, which can recognize tumors with a high mutation burden and lots of neoantigens. For a targeted therapy, I think the way to be successful is to be very specific in the biomarker. In other words, identify the patient population, or populations, with a molecular signature that's predicted to be highly responsive and study the drug in them, instead of looking for therapeutic activity—as with selumetinib—across a wide range of different MAPK-activating alterations.

I think so. The folks at Loxo Oncology [studied] larotrectinib in rare cancers with small patient populations, which will be critical for drug development models in which we hope to see further tumor-agnostic activity. As well, Loxo moved very quickly to assess larotrectinib in children—within 8 months of the first adult patient being treated. This was in part due to the overall rarity of NTRK1/2/3 fusions, but also driven by science: Such fusions are enriched in younger patients, especially infants. There's a lesson to be learned here, I believe, about following the science wherever it may lead.

Definitely. I think broad screening platforms will be especially useful—for instance, next-generation sequencing panels such as Foundation Medicine's [FoundationOne CDx]. These aren't tied to any specific drug or study sponsor, and you can screen patients for multiple biomarker-driven trials simultaneously. This way, not only do patients have better access to treatment options, but we might be able to accelerate the pace of tumor-agnostic drug development by identifying very rare populations with a biomarker of interest.