Neoadjuvant Cemiplimab in CSCC Can Reduce Treatment Burden in Adjuvant Setting, Says Dr Neil D. Gross

Patients with resectable stage II to IV cutaneous squamous cell carcinoma (CSCC) who received neoadjuvant cemiplimab followed by surgery had a disease-free survival rate of 12 months, indicating a treatment regimen addressing an area of substantial unmet need. The results were presented at ESMO Congress 2023 and simultaneously published in Lancet Oncology.^1,2

The phase 2 study enrolled a total of 79 patients who received neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgery. In the adjuvant portion, treatment was left up to investigator’s discretion and patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation.

Neil D. Gross, MD, FACS, head and neck surgeon and director of clinical research in the Department of Head and Neck Surgery at MD Anderson.

Image credit: MD Anderson

At the 2022 ESMO Congress,³ Neil D. Gross, MD, FACS, head and neck surgeon and director of clinical research in the Department of Head and Neck Surgery at MD Anderson, had presented on the primary analysis of the study, which showed a 51% pathological complete response rate. This analysis, with a median follow-up of 18.7 months, showed 12-month overall survival was 92% and the 12-month event-free survival was 89%.

During an interview with The American Journal of Managed Care^® (AJMC^®), Gross discussed the phase 2 findings presented at the 2023 conference, as well as next steps as the trial moves into phase 3.

This has been edited lightly for clarity.

AJMC: Last year, you presented at ESMO Congress 2022. What has changed between then and now, when you presented data based on 18 months of follow-up?

Gross: Last year, we presented the primary end point of the phase 2 nonrandomized multicenter trial of 79 patients with stage II to IV cutaneous squamous cell carcinoma that's resectable. In the study, all the patients received up to 4 doses of neoadjuvant cemiplimab before curative-intent surgery. What we reported then, and published in the New England Journal of Medicine,⁴ was a very high pathologic response rate: 51% of patients in the trial had a complete pathologic response and another 13% had major pathologic response. So, there's a lot of excitement around that, and everybody wanted to know, well, how these patients do? And that's what we presented this year. As you mentioned, with the median follow up of 18.7 months, and a data cut-off of December 1, 2022, we presented the secondary end points of event-free survival, disease-free survival, and overall survival, as well as a post hoc analysis that included the category of partial pathologic response.

Importantly, for this, we included the adjuvant portion of the trial and in the adjuvant portion, patients were eligible to receive adjuvant treatment at the investigator’s discretion based on local pathology review. Patients can receive up to 48 weeks of adjuvant cemiplimab or adjuvant radiation or observation. That's the update this year: presenting both what happened to the patients in the adjuvant setting, as well as their survival with 18 months of follow-up.

AJMC: The study found that no patient who had a pathological complete response had disease recurrence. What can we take away from this information, and how can we use it to inform decisions or research going forward?

Gross: This is really meaningful. I mean, there's been a lot of uncertainty. Well, what does it mean if a patient has a pathologic response? Does that translate to them doing well? And I think this helps to give us at least an early answer to that question. Again, none of the patients who had a complete pathologic response have had disease recurrence, despite the fact that only 1 of the patients received adjuvant radiation, and this is really meaningful. We couple this with the experience from the pilot trial, where there were 11 patients out of 20 who had a complete pathologic response, and those patients now have follow-up approaching 4 years, and none of those patients have recurred as well. So, it's a very strong signal that pathologic response can predict outcome, and that allows us to deintensify adjuvant treatment safely.

AJMC: How might these findings change what we do in the adjuvant setting regarding treatment options vs observation? Can cut out that adjuvant treatment for these patients or do something a little bit less burdensome for them?

Gross: I think that is the future, I believe. Now, it is contingent upon careful pathologic review. In this trial, we had central pathologic review of all the specimens. So, a very, very careful assessment to confirm a complete pathologic response. But if you know that there's nothing left with a pathologic response, then I feel very safe observing those patients and not giving adjuvant treatment. Now, I think a broader question is what's the role of adjuvant cemiplimab or immunotherapy in those patients? And I think that remains to be known and it's an area of interest, I think, moving forward, particularly for the patients who have a less than complete pathologic response.

AJMC: What about for patients who didn’t have a complete pathologic response?

Gross: What we what we found for the overall study cohort of 79 patients, the estimated 12-month event free survival was 89%. And for the patients who had a pathologic complete response, it was 95%. In fact, the estimated 12-month event-free survival was excellent for patients with any pathologic response, whether it be major pathologic or even a partial pathologic response. This compares very favorably to patients who either didn't have surgery for any reason or were nonresponders pathologically. It makes sense that those patients who don't respond need more treatment or would likely benefit from more treatment. And it's also important to recognize that the reason patients who had even a partial pathologic response did so well is the application of adjuvant treatment like adjuvant cemiplimab or adjuvant radiation. So, what we know is a complete pathologic response is very meaningful, and a nonresponse is very meaningful. I think the in-between space is still to be defined.

AJMC: As you move into a phase 3 trial, what changes will be made to the trial and what additional results do you want to see?

Gross: These data were published in Lancet Oncology in coordination with the presentation at ESMO. Also, these data served as the backbone for development of the phase 3 trial…set to launch in 2024. And [the phase 3 trial] is really designed to test this approach against the current standard of care with the primary end point being event-free survival. We have to show that we're able to improve survival in this disease. We think that the improvements in quality of life will follow as well, as we just discussed, but unless you can prove that you're saving lives, then it's hard to change the standard of care. So that's the goal now, to change the standard of care with the randomized phase 3 trial.

AJMC: This study is looking at patients who already have advanced disease. Is there potential for moving treatment into earlier stages based on the results seen here?

Gross: I think it's hard to know how much earlier we can get. Right? So, immunotherapy started in patients who are unresectable or had metastatic disease, and the responses were dramatic. And now we're moving it into patients with advanced resectable disease, and we hope to change the standard of care in that setting. Then what's next? What about earlier stage disease? And I think the bar gets higher and higher, as the stage gets earlier. Meaning, the patients with early-stage disease are often treated effectively with surgery or local therapy and have a high cure rate. So, the tolerance for any toxicity is just much lower in that situation, and we have to be careful. There are some patients who progress on treatment, so that's a risk, and patients can progress to inoperable. That's unlikely in early-stage disease, but it is a risk. There's also there are some toxicities. I mentioned that the patients are older and frail, and this is generally very well tolerated, but there can be toxicity.

As you think about treating patients with earlier stage disease, which is a huge volume of patients—cutaneous squamous cell carcinoma dwarfs all other cancers in terms of frequency—then that amount of exposure over a broad population carries some risks. It just has to be done carefully and thoughtfully. I think there's a real potential, particularly for high-risk patients, maybe patients who have innumerable skin cancers. It's not uncommon for patients to have 1, 2, 5, 10 cancers all over their body and there may be a role, particularly in patients who have early-stage but high-risk disease or just innumerable tumors.

References

1. Gross N, Miller DM, Khushalani NI, et al. A phase II study of neoadjuvant cemiplimab for stage II to IV cutaneous squamous cell carcinoma (CSCC): one-year follow-up. Ann Oncol. 2023;34(suppl 2):S651-S700. doi:10.1016/annonc/annonc1329

2. Gross N, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab and surgery for stage II-IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study. Lancet Oncol. 2023;24(11):1196-1205. doi:10.1016/S1470-2045(23)00459-X

3. Gross N, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab in patients (pts) with stage II–IV (M0) cutaneous squamous cell carcinoma (CSCC): primary analysis of a phase II study. Presented at: European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France. Abstract 789O.

4. Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. N Engl J Med. 2022;387(17):1557-1568. doi:10.1056/NEJMoa2209813