Targetable Mutations in CSCC

Shubham Pant, MD:Dr Khushalani, you know just like different cancers, we talked about skin cancer, we talked about basal cell cancer, it was recognized almost a decade back I think that you have the hedgehog pathway.

Nikhil Khushalani, MD:Correct.

Shubham Pant, MD:Which is one of the main pathways in basal cell cancer. And we have these hedgehog inhibitors that are out there for basal cell cancer. Can you tell me a little bit about the mutational landscape, and if there’s any precision medicine, targeted therapy options for patients with cutaneous squamous cell carcinoma [CSCC]? Do you do next-generation sequence testing in these patients? If you do, what targets do you hope to find?

Nikhil Khushalani, MD:I don’t think we have reached that point in precision medicine yet with CSCC. And one of the problems is primarily related to the vast number of mutations that one automatically detects when one looks at this from a molecular profile, specifically CSCC, which is very different from basal cell carcinoma, where it is 1 pathway that is primarily involved that is the driver mutation in basal cell carcinoma.

Shubham Pant, MD:Just like CML? So similar to that?

Nikhil Khushalani, MD:Exactly. The hedgehog pathway in basal cell has been identified as a pathway of great importance. And as you correctly pointed out, we already have drugs that can target that pathway. We have vismodegib and sonidegib, and both of them have excellent response rates and duration of control. We are now recognizing what the escape mechanisms of those pathways are, and continue to treat those patients with those drugs.

Now, counter that to CSCC, which primarily being a UV light-related damage to the skin type of pathway with chronic sun exposure, the number of mutations that one sees is extraordinarily high. In fact, with CSCC it is the highest known amongst all solid tumors, with melanoma a close second, and then colorectal cancer, which is microsatellite [instability-high], or MSI-high, being part of that spectrum as well.

Shubham Pant, MD:Right, so those are the higher ones.

Nikhil Khushalani, MD:Right.

Shubham Pant, MD:That’s almost as high as microsatellite unstable cancer.

Nikhil Khushalani, MD:Exactly.

Shubham Pant, MD:So a lot of mutations, a really hot tumor.

Nikhil Khushalani, MD:Exactly.

Shubham Pant, MD:A lot of mutations.

Nikhil Khushalani, MD:The problem there is that even though we find all these mutations, for example, the most common mutated gene isTP53. The problem, as you very well know, is that it’s hard to target p53, and folks are looking at other proteins within the p53 pathway that could potentially be actionable. Other mutations includeNOTCH1, NOTCH2, HRAS. The problem, again, is that none of these are truly actionable. But more importantly we don’t know, because there’s such a heterogeneity in these mutations, we really don’t know which is the driver here.

Shubham Pant, MD:It’s like a bus with 20 people. You don’t know who’s driving.

Nikhil Khushalani, MD:Exactly. So it becomes a little difficult to specifically identify which one of these is the true target. But what is unique about this, because of the number of mutations that we see, is that there’s a higher propensity to developing neoantigen expression, which in turn allows this tumor to be potentially manipulated by immunotherapy. What we have learned from other diseases, including melanoma, is that tumors with high mutational burden have a higher propensity of response to checkpoint inhibitors, specifically targeting the PD-1/PD-L1 [programmed cell death protein 1/programmed death-ligand 1] pathway, and that’s eventually what has now achieved success in CSCC as well.

Shubham Pant, MD:So tell me a little bit about targeting the PD-1/PD-L1 pathway. Can you tell us more about these drugs? There are different drugs that are targeting PD-L1 and PD-1. How are they different?

Nikhil Khushalani, MD:As you know, the program death receptor is one of our immune checkpoints. The way I tend to explain it to patients is, think of it as one of the normal breaks in the immune system. And now certainly this came very close on the heels of CTLA-4 [cytotoxic T-lymphocyte—associated protein 4], which has now gone on to claim great fame with Nobel Prize laureates as well from [The University of Texas] MD Anderson [Cancer Center].

Shubham Pant, MD:Right.

Nikhil Khushalani, MD:But I think this is all part of the immune checkpoint pathway. We’ve identified multiple other checkpoints as well. But PD-1 is very unique. It has 2 ligands—PD-L1 and PD-L2. And PD-L1, at least right now, appears to be the more dominant driver of that PD-1/PD-L1 interaction. As I tend to explain it in laymen terms to patients, think of this as though you’re driving on the road and looking at a signal light ahead. You’re in your car. And what exactly happens when you see that red light ahead? Your brain sends a signal to your legs, through your motor neuron, saying you need to get off the accelerator to get on to the brake. Hit the brake and hit it just enough so you stop right behind the car in front of you.

Shubham Pant, MD:Right.

Nikhil Khushalani, MD:What would happen if I take off that signal between your brain and your legs? You’re really not going to get off the accelerator, and you’ll just keep going. Now you may get lucky and just keep going unscathed.

Shubham Pant, MD:Right.

Nikhil Khushalani, MD:But you may also get unlucky and meet with an accident right at the cross street. So that’s exactly how these drugs work. Or at least in simplistic terms, these drugs release the brakes on the immune system, allow the immune system to hopefully get reinvigorated and relieve the state of what’s called exhaustion of T cells, and then allow them to recognize the tumor cells as being foreign and try to destroy those tumor cells. The problem is, where you actually meet with an accident is, what happens when there’s too much upregulation of the immune system? You can actually develop adverse effects that are related to that. So the autoimmune type of adverse effects include colitis, thyroiditis, pneumonitis, and basically any ‘itis’ that can occur. So that’s in very simplistic terms so that patients understand what exactly they’re getting.

The development of cemiplimab, which as we mentioned earlier, is a human antibody to PD-1, was in some ways serendipitous from the standpoint of cutaneous squamous cell carcinoma. In the phase I expansion study that was conducted, there was 1 particular patient with advanced disease that was treated and had a rapid and deep clinical and radiographic response, which, in turn, led to further development. This led to expanding the cohorts to both locally advanced as well as metastatic cutaneous squamous cell carcinoma in the phase I program, and then actually conducting a phase II portion of that study, specifically looking again at 2 cohorts, the locally advanced and the metastatic disease cohorts.

Transcript edited for clarity.