Derm Advances: Insights From Dr Hamid on the Phase 3 C-POST Trial Results

Dr Omid Hamid discusses how the C-POST phase 3 trial findings with adjuvant Libtayo (cemiplimab) signal a shift in the treatment paradigm for high-risk cutaneous squamous cell carcinoma (CSCC), highlighting the growing importance of dermatologists in initiating multidisciplinary care pathways that may reduce recurrence, spare radiation, and guide personalized immunotherapy decisions.

Dr Omid Hamid: Hi, this is Omid Hamid. I'm a medical oncologist at the Angeles Clinic and Research Institute in Los Angeles, California. We are a Cedars-Sinai affiliate. My expertise is in cutaneous malignancies, immunotherapy, and clinical trial design. And today we're going to talk about the benefits seen in the C-POST study in the adjuvant setting for patients with high-risk cutaneous squamous cell carcinoma.

Reactions to the C-POST Data 

Question 1: What are your general impressions of the C-POST trial data published in The New England Journal of Medicine? 

Dr Omid Hamid: And so the C-Post trial is a paradigm-shifting trial for patients with cutaneous squamous cell carcinoma and high risk. I find it to be paradigm shifting, bringing up questions about the appropriate time to give adjuvant therapy. And I would say that it is a call to action for dermatologists, medical oncologists, and internal medicine physicians who see these patients to work in a collaborative fashion to evaluate whether a patient is a good candidate for adjuvant immunotherapy.   

This was a phase III randomized trial, which is the gold standard, and patients with local or regional cutaneous squamous cell carcinoma after resection and postoperative radiotherapy—so after standard therapies—high-risk patients were randomized between getting immunotherapy with a checkpoint inhibitor, in this case it was a cemiplimab, for 1 year versus not. 

And what they found was strikingly similar to what we've seen with adjuvant therapy for other solid tumors—that there was a significant disease-free survival benefit, so recurrence benefit. And it is indicating lower risks of locoregional recurrence and morbidity and also indicating distant recurrence that has been, that risk has been decreased.  So, it is now being looked at as a standard and is leading to further discussions about what the right thing to do with these high-risk patients are. 

And I'll just touch on who we think is high risk. I don't think it's as important for dermatologists and internal medicine physicians, but it should indicate, in any patient that is maybe at this risk, that there should be a referral to medical oncology. So, these are high-risk, so nodes that are big or have extranodal expansion, there are more than 3, or non-nodal features of in-transit metastases, that's like tumor from the primary moving onwards, locally recurrent, at deep lesions with bone or perineural invasion. Some people may say that that's also head and neck squamous cell carcinoma. 

Question 2: Libtayo demonstrated a 24-month disease-free survival of 87.1% compared to 64.1% with placebo, with benefits observed for both locoregional and distant recurrence. From your perspective, how clinically meaningful are these results for post-surgical management of patients with CSCC?

Dr Omid Hamid: The demonstration of a 24-month disease-free survival advantage and a distant metastases-free survival advantage is significant for these patients. As you can tell, these patients have a high risk of recurrence, and the majority of these lesions are in very sensitive areas. So this respects the morbidity of recurrence and the need for repetitive surgical or radiation procedures that can be disfiguring. 

In the adjuvant setting, recently for many solid tumors, these approvals have come without an overall survival advantage that has been seen. And for this data, I would say that it's very early to discuss overall survival. You need at least 3 years of follow-up or further. But when you start looking at the data, the Kaplan-Meier curves that have been looked at with cemiplimab and placebo for disease recurrence, you start to see these curves that have been consistent with any type of immunotherapy that there's a early divergence, and then around 3 years there's a plateau, and that benefit begins to become more significant and more durable. 

When you look at the breakdown and the hazard ratio for disease recurrence, that favored cemiplimab in all cohorts. And when you look at the confidence intervals, that is, if the confidence interval does not cross one, that's significant. The majority of these factors, the confidence interval was significant, whether it was a PD-L1 score, history of prior immune suppression, geographic region. 

When you look at the anatomical region, the head and neck space was very significant, because those are high risk of recurrence. The non-head and neck, that was, it didn't cross—it did cross one, sorry—it was not as significant, but the numbers were much, much less in those patients, and you'll have to wait longer to see that. And as I've said, the freedom from distant recurrence begins to mimic that curve.  

So I think there are still, when you look at these curves, lots of censored events that have yet to happen, and I look forward to further delineation of that as this data matures. 

Question 3: How does this efficacy data compare to what you currently observe in patients managed with surgery and observation alone?

Dr Omid Hamid: This data has to be taken on its own in comparison to what we see with radiation and surgery alone. What you have built in here is a placebo group, and you'll see what happens on recurrence and what morbidities show up and what then the long-term survival becomes. They've looked at patient satisfaction and quality of life here, and I look forward to more data.  

So they did the EORTC quality of life 30 score for global health. And one of the things is, across all time points, there was no meaningful difference. So, the quality of life, even on this therapy, remained well. And then I think what you'll need to see is, down the line when there's more recurrence, what happens there. 

The data has to be taken with a grain of salt in that most of these trials, the placebo arm is a control to see if you can salvage patients upon recurrence, whether early versus late utilization is important. So it does not change how I treat my locally recurrent and how I manage those patients who are in surveillance. But it does tell me now that there is a need for multidisciplinary discussion of patients who fit this paradigm. 

There are newer studies coming out that may indicate that we may not need radiation in a subset of patients, and that's the neoadjuvant protocol. So this is the march from showing benefit in the adjuvant and then looking at the neoadjuvant and giving patients with disease in place some induction therapy and then considering whether the morbidity of radiation is unnecessary in those patients who respond with a complete response. So, the paradigm is shifting and we may need to utilize immune checkpoint inhibition earlier in care to prevent the morbidity of recurrence. 

Question 4: What are your impressions of the disease-free survival (DFS) benefit across patient subgroups?

Dr Omid Hamid: Again, when you look at the patient subgroups—the clinical characteristics and the demographics of these patients—and look at the disease-free survival according to pre-specified subgroups, the cemiplimab arm, the active intervention arm, hazard ratios are significant for the majority of groups, and where they aren't, the number of patients involved is small, so you would not expect to see that. 

So what am I saying? It was significant for age group, old or young. It was significant for sex, male, female. Race, the majority of patients with cutaneous squamous cell carcinoma are Caucasian, so there was only about 40 patients that were non-White. But in the Caucasian cell group, it was significant. Geographical region. And of course, one of the things we talk about is anatomical region. We know that the head and neck area is the higher-risk area. And in that place, clearly more significant for our disease recurrence or death. The non-head and neck patients, those numbers were very small, so it's hard to see a difference or you'd need to wait longer. But even with performance score and history of immune suppression, it was significant. And then one of the de facto predictive markers that we're using is PD-L1 status, and in both of those subgroups it was significant.  

So, these high-risk patients are getting distant metastases-free survival and relapse-free survival. It's very early to talk about overall survival benefits, and we'll look and see.  

Question 5: How do you view the safety profile of Libtayo from a dermatology standpoint, especially when balancing treatment risk in older or comorbid patients?

Dr Omid Hamid: When you look at this data, you see that discontinuation and adverse events differed. And it was about 10% of patients discontinued for adverse events. But this class of agents, we're very familiar with these checkpoint inhibitors, these PD-1 inhibitors, have become standard for over 40 different indications, and we utilize them for melanomas and non-melanomatous skin cancers in a locoregional and metastatic and in the adjuvant/neoadjuvant settings these days, especially for melanoma. 

So what I find is that we're all very comfortable in the medical oncology field giving these for our patients regardless of age. I think more important is to look at comorbidities, which are probably organ specific. The majority of side effects from this class of agents is manageable, and the majority of side effects resolve either with symptomatic therapy or the initiation of steroids.  So, I think this is very safe for patients. The majority of physicians who give it are comfortable with recognizing and treating the adverse events. So I believe that this will become a standard in the community. 

Broader Therapeutic Context and Future Directions

Question 6: If approved, how might adjuvant Libtayo change your post-operative workflow or referral patterns in managing high-risk CSCC?

Dr Omid Hamid: If this is approved for us, I believe that it creates a greater need for multidisciplinary discussion about these patients. Cutaneous squamous cell carcinoma is a malignancy that's somewhat overlooked. The majority of patients get surgery and, depending on risk, postoperative radiation and never really do see a medical oncologist and never really are discussed. This is a push to do that for these patients given the magnitude of benefit in recurrence seen. 

It will also change because the benefits early that we saw in our utilization in the local advanced and the metastatic setting pushed us to do these adjuvant and neoadjuvant trials, and now more and more combinatorials are coming forward here. There's some indication that cetuximab, which is a different type of agent, may have greater efficacy when given either concurrently or after. So this is going to change how we utilize therapy for those who recur that have seen this agent. The clinical trials that we create to increase the level of benefit in the adjuvant and the neoadjuvant setting, so it is a clear push for greater therapies for this subgroup of patients that may have been overlooked in the past.  

Question 7: What role do you see for dermatologists in leading or coordinating immunotherapy care in the adjuvant setting, particularly in community practice or non-oncology settings?

Dr Omid Hamid: So this data only serves to cement the important role of the dermatologist as a patient advocate here. Clearly, in the adjuvant setting, it would prevent recurrence and distant recurrence and leads to a better long-term quality of life for patients. The neoadjuvant paradigm requires dermatologists to be able to refer patients prior to doing a surgical intervention, whether it's a resection or a Mohs procedure, and may obviate the need for radiation. 

That person who would initiate the care plan and the journey for our patients with cutaneous squamous cell carcinoma is the dermatologist. The dermatologist serves to educate not only the patient about the role and the importance of a multidisciplinary view of their current status but also serves as a educator to the peer group. And that peer group are the internal medicine physicians who refer, they're the radiation oncologists who may not have been exposed to this data, and the medical oncologists who require some collaborative discussion about treatment and the patient's data. So, very important, probably the most important person in initiating the care plan for patients. 

Question 8: What additional data would help you feel confident about integrating adjuvant immunotherapy into dermatologic care pathways?

Dr Omid Hamid: The data that we're looking to cement our confidence in this pathway are similar to the data that we're looking forward to in other solid tumors that are treated the same way. That is, we know that there is a relapse-free survival benefit with this data. We don't know whether that lends itself to a long-term benefit in survival for our patients, and that only comes with following this data longer. We also don't have an idea of which patients would never recur even with their high-risk features. And therefore, we would obviate the need for a therapy that does come with some toxicity. And I look forward to some of the correlative work that's been done on blood and tissue here.  

And then the data from the neoadjuvant setting, which could help us understand who responds the best and help us have some predictive markers that would help us avoid toxicity and would help us with prospective design. 

I think this is the beginning of our journey in adjuvant therapy for patients with cutaneous squamous cell carcinoma. The immunotherapy is a revolution and a revelation for these patients who were previously treated with therapeutics that had shown efficacy in head and neck cutaneous, I’m sorry, in head and neck squamous cell carcinoma, a completely different entity, and really did not have a therapeutic paradigm with significant benefit. We now have seen that. We now have cemented its benefits in the locally advanced and metastatic and are moving it into the adjuvant. So, the data that could help us identify the subgroup of patients in a molecular and a predictive way is what I look forward to.