The benefit of using immunotherapy for the treatment of CSCC and a review of cemiplimab in Study 1540.
Morgana Freeman, MD: The rationale behind the use of targeting PD-1 [programmed cell death protein 1] in CSCC [cutaneous squamous cell carcinoma] is the same rationale that we’ve applied to other solid tumor types. We know that cancer evades the immune system by engagement of the PD-L1 [programmed death-ligand 1] ligand with PD-1 receptors on T-cells, which are an inert programmed system to tell the immune system to back off when appropriate. Where cancer has successfully exploited this ligand is by exhausting those T-cells and then depleting them of their ability to fight cancer. When we interfere with that, we can actually reengage cytotoxic T-cells, re-energize the immune system, and as I explain to patients, reprogram the immune system to fight the cancer for them. This is really important not only because it reengages that initial anti-tumor immune response but then also allows for the population of immune memory T-cells—and therefore a cohort of cells—that will continue to remember what that cancer looks like even after it’s been eradicated. This is what we know contributes to the tail that is seen on survival and response curves and how patients can continue to respond to therapy even without continued infusions in some cases.
Where it’s important particularly in CSCC is that this disease is a very immune-rich tumor. We know that these cancers have very high tumor mutational burden because of the UV [ultraviolet] damage that’s been done and the signatures that it therefore generates. That makes it appetizing for those activated T-cells. What we don’t really know is whether PD-L1 expression is as important. There seems to be some relationship with PD-L1 expression and response, but it’s not as closely tied as what we’ve seen in lung cancers. In terms of what the greatest signal is for response right now in CSCC, that is something we don’t know. But we definitely see incredible responses, probably far more than what we’ve seen with single ORRs [objective response rates] compared to other tumor types. That’s what makes it a very appropriate candidate for immunotherapy.
Cemiplimab was evaluated in the Study 1540 trial, which is the pivotal study of locally advanced and metastatic CSCC. In about half of those patients, they were treatment naive, meaning their first-line treatment was with cemiplimab. In the other half, they had been previously treated with some other systemic therapy—in many cases either cisplatin- or Erbitux-based chemoradiation.
It was a comparatively small study, less than 100 patients, and the majority of those patients had received some prior cancer-related surgery. About two-thirds of them had distant metastatic disease. The other one-third had locally advanced CSCC. The outcomes primarily were to determine the objective response rate, but also to look at the duration of response along with the safety and tolerability profile.
What they found is that patients had very deep and clinically evident responses within the first few weeks of therapy. The median time to response was 1.9 months in the case of locally advanced disease. We saw an objective response rate of 48% in the pooled patient population, which again, comparatively speaking, the performance of PD-1 drugs as a single therapy across most tumor types is somewhere more in the 30% to 35% range.
What we also saw is that the majority of those patients had responses ongoing at the 6-month data interrogation mark. Greater than two-thirds of patients were continuing to respond, which again exceeded our historical expectations in CSCC. This is because most of the time when patients are treated with EGFR, with cisplatin-based chemotherapy, they typically progress at the 8-month to 10-month mark. So, we were very pleased not only with the number of patients that responded and how much they responded in terms of target lesion decrease, but then also that those responses were sustainable. What we also noticed is that the drug had a very favorable adverse effect profile, with 20% of patients experiencing hypothyroidism, rash, or diarrhea. This is very manageable compared to perhaps what we’ve had with other systemic therapies in the past.
Omid Hamid, MD: The long-term data available with cemiplimab are extraordinary. This shows that about 46% to 48% of our patients are having a partial or a complete response. About 70% of our patients are getting durable benefit, which includes partial response, complete response, and stability of disease. That means less morbidity and less mortality.
What we are also seeing is that about 80% of patients are having a durable response. When you look at those patients who are out past 6 months who initially had response, greater than 60% of them are still benefiting. As the data mature, we’re seeing that those durations of response can be significant, getting close to 2 years for patients who are on these initial trials.
What’s even more extraordinary is the rapidity of response. When you look at these studies that looked at cemiplimab in patients with locally advanced and metastatic cutaneous squamous cell carcinoma, the median time to response is under 2 months. That means that the patients are immediately receiving benefit. The depth of response is significant, with the majority of patients getting complete responses or near complete responses. Then, the durability is similar to those of other solid tumors that have responded and benefited from immunotherapy.