Targeted Therapies in Advanced Cutaneous Squamous Cell Carcinoma - Episode 6
Shubham Pant, MD:What’s the difference between locally advanced and metastatic?
Nikhil Khushalani, MD:I think it’s beauty in the eye of the beholder. Locally advanced is primarily, in clinical terminology, disease that has grown to a point where surgery either would not be recommended, or, if surgery were done, then it would be extraordinarily morbid, or cosmetically disfiguring, or unlikely to cure the patient. So, if it’s the same tumor that has recurred, for example, in the parotid area a couple of times, and we keep cutting and we keep excising this and it keeps coming back… You know, we all have patients in our practice with that. I think after 1 or 2 attempts at definitive surgery plus/minus adjuvant radiotherapy and if the tumor comes back but has not metastasized anywhere, those, in my mind, would be considered to be locally advanced and unresectable.
I think that’s where the true power of a multidisciplinary group comes into play, where we get input from really topnotch surgical oncologists, plastic surgeons, and then of course radiation oncology, and us, to try and decide if we don’t believe that surgery is going to cure this patient, what is the best pathway forward from a nonoperative standpoint?
In these trials that have been conducted so far, metastatic has included those patients with regional lymph node metastases. That was considered part of the metastatic cohort and then those with distant metastases as well, lung being the most common site.
Shubham Pant, MD:You said radiation doctors were a very important part of the multidisciplinary team. One part of radiation is you resect it and then you give radiation for adjuvant therapy to prevent recurrence.
Nikhil Khushalani, MD:Correct.
Shubham Pant, MD:But one of the other parts is before checkpoint inhibitors came into play, and you just said chemotherapy, which would maybe give a response but not for a long time. was radiation the first option?
Nikhil Khushalani, MD:Yes. So typically in those individuals with locally advanced disease, you really need to try and control the disease before it causes more symptoms, and that could include bleeding, necrosis, foul smelling discharge. Radiation can serve as an excellent palliative mechanism of treatment modality to help these patients. We tended to add, in the appropriate patient, chemotherapy to the radiation, both for direct cytotoxic effect as well as for radiosensitizing effects. So, yes, radiation is still a very big part in what we do with cutaneous squamous cell.
Shubham Pant, MD:In the phase I/phase II trial that you were talking about, locally advanced and metastatic both were involved. How many therapies did they get previously? Did they get radiation? Did they get prior chemotherapy, or were they not pretreated?
Nikhil Khushalani, MD:No, the vast majority of patients on the phase I/phase II trial for EMPOWER, which is the cemiplimab study, were pretreated. Most of them were actually heavily pretreated. More than 50% had received some form of systemic therapy previously, typically chemotherapy or EGFR-targeted therapy, and greater than 70% to 75% of them had seen radiation as some treatment modality at some point in their course. So these were heavily pretreated patients. There was a small percentage of patients that had not received previous systemic therapy, but the vast majority had. And that’s typical of the population. At the same time, being an early clinical trial, very appropriately so, patients who were immunosuppressed, patients who had concurrent chronic lymphocytic leukemia, patients who had previous organ transplant in their history or organ transplant recipients were excluded from participation in these trials. So the caveat there is certainly it’s a selected patient but still a patient that we see routinely in our clinical practice.
Shubham Pant, MD:So, you’re saying that the ones who had some immunosuppression or immune transplant, somebody with HIV, were excluded from the trials?
Nikhil Khushalani, MD:That’s correct.
Shubham Pant, MD:So these were patients who were not technically immune suppressed when they came into the trial, and they just had this chronic UV-A exposure. In the trial, was there any biomarker selection? Precision medicine is all about tumor agnostic. You have the microsatellite instability [MSI], which we pick up on in colorectal cancer. And that’s been approved for others, right? If you have MSI-high disease, you can get checkpoint inhibitors across the board. So, in this trial, was there any selection for microsatellite instability for tumor mutational burden? Because now certain tests can do tumor mutational burden, which is being used in lung cancer. So what about this trial?
Nikhil Khushalani, MD:In this trial, this was a completely unselected population. It was primarily histologic diagnosis. But, in my mind, that is where the field is headed, is biomarker-driven studies. That, to me, is really the Holy Grail of what we are doing with immunotherapy and trying to understand which patients benefit the most from immunotherapy, which patients are more likely to develop a response or no response, and are more likely to develop adverse effects. So one of the most common markers that we have utilized across skin cancers and in many other tumors as well with immunotherapy has been PD-L1 [programmed death-ligand 1] immunostaining. This is on the tumor itself, on the tumor block, the paraffin-embedded specimen, either on the tumor, or PD-L1 can also be expressed on lymphocytes.
One of the problems with that is the high variability in definitions. So, for a positive stain, depending on which particular PD-L1 test one uses, one could call 1% of cells being positive a positive result, or greater than 5%. And, in lung cancer, certainly greater than 50%. So in my mind that’s not been adequately standardized and definitely not so for cutaneous squamous cell. More importantly, what is critical and what we have learned now over 5 to 7 years of PD-L1 history is that patients who have a high PD-L1 expression in their tumors do potentially have a higher response to antiPD-1 [anti-programmed cell death protein 1] or PD-L1 agents. But the corollary is not necessarily true. That means patients who are PD-L1–negative by the test that you have used are not those who don’t respond. They can still respond, and, therefore, I would not deny a patient an anti–PD-1 agent when it’s indicated in a given case, simply because their PD-L1 status is 0%.
I think that’s one of the take-home messages that is critically important. And, if you look across the board in tumors where antiPD-1 agents have now been approvedso you’re looking at melanoma, kidney cancer, bladder cancer, lung cancer—if you average them out, and some publications have already come out, the response rate, on an average, is about 30%. It’s higher in melanoma. For example, for therapy-naive melanoma, it’s about a 40% response rate in the first-line setting, but it’s lower in kidney cancer. It’s about 22% there. So why is there a differential even between tumors? There has to be certain tumor-specific factors.
If you look at the ones in these cohorts who are PD-L1positive, the response rate sort of peaks up towards 50%. But for the ones who are PD-L1–negative, the response rate is still about 12% to 14%. So there is a substantial population of patients that would benefit. I don’t think this is the end-all, one-all biomarker from a PD-L1 standpoint. Even in the phase I trial with CSCC [cutaneous squamous cell carcinoma] where they looked at PD-L1 staining, it was not predictive of response or it did not correlate directly to response in that setting. If one combines these with other biomarkers, for example, CD8 density, or tumor mutational burden, maybe we’ll have a conglomerate of biomarkers that may allow us to better define which patients will and will not respond. And hopefully, the field is moving there very quickly.
Transcript edited for clarity.