Pembrolizumab for cSCC Testing Against Placebo In KEYNOTE-630 Trial

Shlomo Koyfman, MD

Shlomo Koyfman, MD

The standard treatment for high-risk, locally advanced, cutaneous squamous cell carcinoma (cSCC) is surgical resection and adjuvant radiation. However, 40% to 50% of cases have a recurrence or develop regional metastasis after these standards of care are implemented.

“Now that PD-1 inhibition or PD-L1 inhibition is becoming so effective in the metastatic recurrent setting, the thought is, can we bring it into the upfront curative setting for the highest-risk patients to try to prevent recurrence,” said Shlomo Koyfman, MD.

To address the high percentage of recurrence and metastatic cSCC, researchers are recruiting subjects for a phase III trial (KEYNOTE-630) using the programmed cell death protein-1 (PD-1) inhibitor pembrolizumab (Keytruda) as treatment and also testing the safety and efficacy of the drug for the target patient population.

In the double-blinded study, subjects (570 expected patients) will be randomized 1:1 and treated with either 400 mg of intravenous pembrolizumab every 6 weeks or up to 9 cycles of placebo. Based on biopsy results, those who experience recurrence in the placebo group can crossover for retreatment with pembrolizumab.

The primary trial objective is to first complete a biopsy-based comparison of recurrence-free survival (RFS) in pembrolizumab versus placebo for subjects with cSCC. The secondary aim is to compare overall survival (OS), safety and tolerability, and assess health-related quality of life of the patients in the trial.

In an interview withTargeted Oncology, Koyfman, the director of head and neck and skin cancer radiation at Cleveland Clinic, provides details about the current treatments for cSCC and how the new KEYNOTE-630 trial could improve practice for oncologists who treat cSCC.

TARGETED ONCOLOGY: What is the rationale for the KEYNOTE-630 trial?

Koyfman: The KEYNOTE-630 trial is looking at a patient population that we've never looked at in a randomized fashion. These are high-risk cutaneous squamous cell cancers which, historically, we manage with surgery, [or] maybe a little radiation. But, over the years we've discovered that there's a higher-risk subset of patients that despite bimodality therapy, having good surgery, and having radiation—they're still recurring at too high a rate. And with immunotherapy results in this patient population in the metastatic setting doing so well, there's a lot of excitement about incorporating immunotherapy upfront in the curative setting, and this is the first time that this is going to happen.

TARGETED ONCOLOGY:What is the reason for using immunotherapy in this patient population?

Koyfman: The impetus for this trial came from [2 facts]. Number one, all of us who treat skin cancer realize that patients whose immune systems don't work very well [like] transplant patients, lymphoma patients—they have terrible skin cancers, which was the first hint that something about the immune system is off and probably responsible for why sometimes this cancer that should be 90% curable is not going so well. And then, a couple of years ago at ASCO, we learned of cemiplimab (Libtayo), which is an immunotherapy agent that had the highest response rate of any agent in this disease and it revolutionized the field. So, now that PD-1 inhibition or PD-L1 inhibition is becoming so effective in the metastatic recurrent setting, the thought is, can we bring it into the upfront curative for the highest-risk patients to try to prevent recurrence.

TARGETED ONCOLOGY: Can you discuss the trial design?

Koyfman: The KEYNOTE-630 trial is an exciting trial. It will be the largest randomized study in skin cancer ever in a therapeutic setting. It's aiming to accrue over 500 patients, and it's a trial of everybody who had surgery and post-operative radiation and then afterward they're randomized to a year of pembrolizumab versus placebo. The goal is to try to see if we can reduce the number of events and improve the event-free survival in these highest-risk patients.

The eligibility would be locally advanced from a nodal perspective, a lot of extra-nodal extension, or locally advanced from a primary tumor perspective with either really large tumors [that are] invasive (involving skull base or nerves), [or] some of the biological features like poorly differentiated tumors, recurrent tumors, bad perennial invasion, and those kinds of features that portend a more aggressive biology.

[It's] somewhat of a complicated eligibility scheme because again, most of these skin cancers are low risk. So, the goal is to try and enrich the population with high-risk patients so we can understand it and try to help those people most.

TARGETED ONCOLOGY: What are some challenges with the current way that oncologists treat these patients?

Koyfman: A radiation oncologist probably knows best because usually the low-risk patient gets surgery and are fine. The higher-risk patients get sent to us—we give them radiation [and] we follow them, and we're seeing recurrences. There are previous data that shows when they recur; the outcomes aren't that great. Now in the immunotherapy era, there's reasonable salvage, but the salvage is unlikely to be curative. So, it gets frustrating as a radiation oncologist to keep treating these people and still see recurrences despite having radiated them. So, this is an opportunity to try to get it right the first time and try to intensify the upfront therapy so that we can maximize cure rates.

TARGETED ONCOLOGY: Are you planning to have any biomarker analyses?

Koyfman: Yes. Tissue is being collected. There's a lot of biomarker analysis that's going to be done. It's a fascinating area and really challenging because, as opposed to a lot of other cancers where PD-L1 expression, tumor mutational burden, or some of those other classic markers of responsiveness to immunotherapy—it's not clear whether that's going to pan out in skin cancer. We don't have any other good biomarkers with skin cancer. Remember, we haven't done large trial in these patients. So, we don't have history, years, and amount of tissue that we've had to mine to figure out the prognostic biomarkers. This is the first time that we're going to have that kind of tissue, and there's going to be a ton of biomarker discovery associated with it, and it's all brand new.

TARGETED ONCOLOGY: Do you foresee the role of pembrolizumab going even further and being explored in combination with other treatments?

Koyfman: I think that it depends on the setting. In the adjuvant setting, doing immunotherapy versus not [doing it] is the question. There's a lot of excitement about these agents in all settings. What happens if you have very large tumors where taking them out would be morbid—what about doing it in the pre-operative setting? It's a super exciting time [and] there are trials that are opening up like that.

What happens for that 50% of patients that don't respond to immunotherapy? What's going to be second-line, what about combinations, what about other things, and what are the predictors of that. [There are] tons of unanswered questions [because] this field is so new. We're like melanoma 10 years ago. So, it's just starting to be elucidated, and it'll be exciting in the years to come.

Reference:

Geiger JL, Daniels GA, Cohen EEW, et al. KEYNOTE-630: Phase 3 study of adjuvant pembrolizumab versus placebo in patients with high-risk, locally advanced cutaneous squamous cell carcinoma.J Clin Oncol. 2019