Finding a Place for Immunotherapy for Advanced, Resectable Cutaneous Squamous Cell Carcinoma

Durvalumab has changed the game for stage III non-small cell lung cancer; pembrolizumab is potentially sparing MSI-high rectal cancer patients surgery, radiation, and chemotherapy; and trastuzumab is standard of care for all HER-2 positive breast cancers. Meanwhile, head and neck cancers are a little late to the game, with immunotherapy only being recommended (in combination with chemotherapy) in the recurrent or metastatic setting when there is no radiation or surgery option, per NCCN (National Comprehensive Cancer Network). Cutaneous head and neck cancers have had a bit of a break, however, with adjuvant immunotherapy being indicated in stage III or IV melanoma. For cutaneous squamous cell carcinoma (cSCC), cemiplimab has been on the bench, waiting until the disease is not amenable to radiation or surgery and needs palliation. But that paradigm might be shifting.

The concept of primary immunotherapy monotherapy (PRIMO) for locally advanced, resectable cSCC was recently debated at the Multidisciplinary Head and Neck Symposium in Phoenix, Arizona, held February 29 to March 2. The thought is that if upfront cemiplimab results in a complete response, the next step should be observation. If there is only a partial response or no response, then the patient undergoes surgery and/or radiation and possibly more immunotherapy. Thus far, phase II data has demonstrated pathologic complete response rates of up to 51% and major response rates of 13%, with none of the complete responders having a recurrence.1 So then the question is whether or not they even needed surgery.

Despite the excitement of treatment de-escalation, which should always be in our minds for the sake of our patients, the data are lacking. And the data and institutional experiences that exist raise more questions than answers.

Despite the excitement of treatment de-escalation, which should always be in our minds for the sake of our patients, the data are lacking. And the data and institutional experiences that exist raise more questions than answers. How long should we wait for a complete response? What do we do with patients who have a major partial response — do we give them more time to respond? Can we even rely on immunotherapy for a patient population that is often immunocompromised to begin with? If we proceed to surgery, how is the operation done? We don’t know if tumors are shrinking concentrically or multifocally, leaving residual tumor islands. We also don’t know what to do about questionable nerve involvement, which can have significant implications for patient quality of life depending on whether the nerve is spared or not. Plus, we have to consider the financial toxicity. How long should patients be left on immunotherapy? At what cost?

Neoadjuvant immunotherapy for other curative intent head and neck cancers has shown a pathologic complete response rate of only 10% after monotherapy.2 But do we need a complete response? One wonders what the benefit of neoadjuvant immunotherapy is: achieving a complete response or priming the immune system? How do we even evaluate whether an immune system is primed? Lung cancer data have shown that a better response correlates to overall survival, which, if extrapolated to head and neck cancers, raises further questions as to how to increase complete response rates. Ultimately, we need better predictors of response and more robust ways to risk-adapt treatment.

Certainly, strategies like PRIMO require careful patient selection and an experienced team of providers. And in the end, there need to be prospective phase III trials exploring the sea of questions surrounding immunotherapy for cSSC (NRG-HN014 activating July 2024) and for all head and neck cancers. The results of Keynote 689 exploring neoadjuvant pembrolizumab for locally advanced, resectable head and neck cancer are eagerly anticipated now that its accrual is complete. Perhaps that wheel is finally beginning to turn in the right direction to push head and neck cancers into the era of immunotherapy.


  1. 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)1557-1558. doi:10.1056/nejmoa2209813
  2. Pereira D, Martins D, Mendes F. Immunotherapy in head and neck cancer When, how, and why? Biomedicines. 2022;10(9)2151. doi:10.3390/BIOMEDICINES10092151

Kyra N. McComas, MD

PGY4 resident physician, Department of Radiation Oncology, Vanderbilt University Medical Center.