Advanced squamous cell carcinoma threatened the patient’s eye. Although most cases of cutaneous squamous cell carcinoma can be effectively treated via simple excision, this patient’s cancer was large, disfiguring, and potentially life-altering, as surgical treatment would likely require enucleation.
“The standard of care for patients with locally advanced, resectable head and neck squamous cell carcinomas is surgery and radiation. But given the proximity of the pathology to critical structures, like the eye, ear, lips, and nose, surgery can be functionally devastating,” said Neil D. Gross, MD, professor and director of clinical research in the department of head and neck surgery at MD Anderson Cancer Center in Houston. “Some patients lose an eye, or an ear, or big parts of their scalp.”
Neoadjuvant immunotherapy may allow some patients with locally advanced squamous cell carcinoma to avoid disfiguring and functionally devastating surgeries. In 2017, Dr. Gross launched a small clinical trial testing immunotherapy prior to surgery and found that “with just two doses of the drug before surgery, the tumors started melting away,” he said. “For 11 out of 20 patients, by the time we went to surgery, there was no tumor left; it was completely gone. For another four patients, it was almost completely gone.” (Clin Cancer Res. 2021;27:4557–4565).
Dr. Gross and others have since conducted a phase two, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab, a PD-1/PD-L1 checkpoint inhibitor, as neoadjuvant therapy in patients with resectable stage II, III, or IV cutaneous squamous cell carcinoma of the head and neck. Again, results were positive. “There was nothing left of the cancers in just over half of the patients,” Dr. Gross said. “In another handful of patients, the cancer was almost completely gone.” (N Engl J Med. 2022;387:1557–1568). Some patients were able to keep their eyes (and vision).
Will neoadjuvant immunotherapy eventually become the standard of care for patients with locally advanced, resectable squamous cell carcinoma of the head and neck? Perhaps. Additional questions must be answered first.
Here’s what’s currently known—and not yet known—about neoadjuvant immunotherapy for advanced squamous cell carcinoma.
New Treatment Options for Previously Underserved Patients
Cutaneous squamous cell carcinoma is the second most common form of skin cancer worldwide, and approximately 2% to 5% of patients present with locally advanced cancers (Clin Cancer Res. 2021;27:4557–4565). Treatment is challenging— particularly because many patients are of advanced age and have other comorbid conditions—and may be disfiguring and disabling. Approximately 30% of patients with locoregionally advanced resectable cutaneous squamous cell carcinoma eventually die of the disease, despite treatment (Clin Cancer Res. 2021;27:4557–4565). “These patients have been underserved for a long time,” Dr. Gross said.
Previous attempts at neoadjuvant therapy weren’t particularly effective. Although physicians in the 1970s and 1980s tried shrinking tumors with chemotherapy prior to surgery, neoadjuvant chemotherapy “never really caught on for this type of cancer,” Dr. Gross said. Intra-arterial chemotherapy has been investigated as a neoadjuvant therapy for head and neck squamous cell carcinoma, but to date, “no obvious evidence for positive responses has been reported,” according to an article published in Frontiers of Oncology (2018;8:79).
Immunotherapy appears to be a game changer. Skin cancers are particularly sensitive to immunotherapy because most are caused by UV damage from the sun, which creates many DNA mutations in cancerous tumors. Administering immunotherapy in the neoadjuvant setting may be especially beneficial, because “when the bulk of the tumor is still present, a more profound and broader immune response can be induced,” said Nader Sadeghi, MD, professor and chair of the department of otolaryngology–head and neck surgery at McGill University Health Center in Montreal and director of the McGill Head and Neck Cancer Program. “This is because the cancerous tumor is composed of many heterogeneous colonies of cells, and broader antigen presentation from tumor cells can induce more robust tumor-specific T-cell response.” The hope, he said, is that this immune effect continues after surgery as well.
Though long-term progression-free survival data are not yet available, as neoadjuvant treatment of cutaneous squamous cell carcinoma is still a relatively novel approach, research to date suggests that neoadjuvant immunotherapy may indeed lead to good outcomes, at least for some patients.
“We now have long-term survival data from the 20 patients who participated in the initial pilot trial, and their responses have been very durable,” Dr. Gross said. “Every single one of the 15 patients who experienced a response to immunotherapy has remained disease-free for an average of 42 months.”
Neoadjuvant Immunotherapy for Advanced Cutaneous Squamous Cell Carcinoma
The first pilot study of neoadjuvant immunotherapy for advanced, resectable squamous cell carcinoma used cemiplimab. Patients received two cycles of intravenous cemiplimab every three weeks before surgical resection. Only two doses were given, because physicians (and patients) didn’t want to delay surgery any longer, according to Dr. Gross.
The initial plan called for all enrolled patients to undergo both surgery and adjuvant radiation. “Given the dramatic pathologic responses to neoadjuvant immunotherapy, however, the majority of patients (60%) did not receive adjuvant radiotherapy … None of these patients developed recurrence.” (Clin Cancer Res. 2021;27:4557–4565).
During the phase two confirmatory trial, physicians were allowed to administer up to four doses of neoadjuvant cemiplimab. “Patients would get two doses, undergo a scan and evaluation, and, if they were responding and not having significant side effects, they could get up to four doses,” Dr. Gross said. “The idea was that maybe we’d see more responses or push some partial responses to a more dramatic response. But we didn’t really see that.”
Seventy-eight percent of patients received all four doses. Disease progression was the most common reason patients did not receive four doses of neoadjuvant immunotherapy. Eighty-seven percent of treated patients reported adverse events; the most common were fatigue, diarrhea, nausea, and rash. Immune-related adverse events occurred in 15% of treatment patients, with grade 3 immune-related adverse events occurring in 4% of patients. Four patients died during the trial—two of heart attacks that “were not considered related” to treatment, according to Dr. Gross; one of COVID-19; and one, age 93, of heart failure that may have been exacerbated by immunotherapy.
Fifty-one percent of patients experienced a pathological complete response; another 13% experienced a pathological major response, and “several patients … were spared function-impairing surgery,” Dr. Gross said. Two patients who presented with bulky disease at baseline experienced progression to inoperable disease (N Engl J Med. 2022;387:1557–1568).
The 63.3% rate of pathologic complete or major pathologic response is “the highest achieved in a multi-center study of single-agent anti-PD-1 neoadjuvant therapy for any solid tumor type,” according to the researchers.
Unanswered Questions
Physicians (and patients) are excited about the potential of neoadjuvant immunotherapy to decrease treatment morbidity and, perhaps, improve survival. But before neoadjuvant immunotherapy can be widely adopted, some unanswered questions must be answered, including:
What impact does neoadjuvant therapy have on survival rates? This question is key to wider adoption of neoadjuvant immunotherapy, according to Kevin S. Emerick, MD, division chief of head and neck surgical oncology and co-director of the Non-Melanoma Skin Cancer Multidisciplinary Clinic and Program at Mass Eye and Ear in Boston.
“We have to make sure we’re thinking like surgical oncologists,” Dr. Emerick said. “Does neoadjuvant immunotherapy followed by surgery actually improve our overall cure rates for these patients compared to immunotherapy alone, surgery alone, or the historical approach of surgery followed by radiation?”
Additional clinical trials, including a phase 3 randomized controlled trial comparing neoadjuvant immunotherapy plus surgery and radiation, if indicated, to the current standard of care, will be necessary to answer this question. Dr. Gross said he’s currently in the process of designing a phase 3, multicenter trial.
Is it possible to predict who will respond well to neoadjuvant immunotherapy? Clearly, some patients do exceedingly well with immunotherapy. Other patients’ disease progresses despite neoadjuvant therapy. Additional research may uncover physiological differences between responders and non-responders.
“Can we predict who will respond with biomarkers?” said Vasu Divi, MD, associate professor of otolaryngology–head and neck surgery at Stanford University in Stanford, Calif. Right now, the answer is no. Identification of biomarkers could help physicians personalize treatment and avoid delaying surgery in patients whose disease is likely to progress despite immunotherapy.
What is the optimal timing and dosage of neoadjuvant immunotherapy? The initial pilot study of neoadjuvant immunotherapy for locally advanced resectable cutaneous squamous cell carcinoma used two doses of cemiplimab. The subsequent phase 2 trial allowed up to four doses. The phase 3 trial may use “a set three doses for everybody,” Dr. Gross said.
No one yet knows the optimal timing or dosage of neoadjuvant immunotherapy. To date, researchers have studied only single drug neoadjuvant therapy. Would escalating patients’ doses, administering additional doses, or adding other drugs in combination improve response, particularly in patients who experience a partial response?
Is radiation necessary after neoadjuvant immunotherapy? Most patients who participated in the initial pilot study of neoadjuvant immunotherapy did not undergo radiation therapy after surgery due to their “dramatic pathologic responses.” To date, these patients seem to be doing well, but additional data are needed to determine the long-term impact of skipping adjuvant radiotherapy.
Current evidence suggests that response to neoadjuvant immunotherapy can be used to personalize adjuvant treatment. “If there is a very good response to neoadjuvant immunotherapy, adjuvant treatment can be de-escalated,” said Dr. Sadeghi. “On the other hand, a poor response would indicate that adjuvant treatment should be escalated.”
If there is a very good response to neoadjuvant immunotherapy, adjuvant treatment can be de-escalated. —Nader Sadeghi, MD
The adjuvant treatment plan was left to the discretion of each site in the phase 2 trial, and it “wasn’t studied systematically,” Dr. Divi said. “I think it really deserves a systematic study to determine if we need to be as aggressive with subsequent local treatment in patients who have a really good response to neoadjuvant therapy as compared to patients who do not.”
The PRADO trial, which assessed the impact of personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in patients with high-risk stage III melanoma, reported good outcomes after personalized response-directed treatment. Sixty-one percent of enrolled patients experienced a major pathologic response (MPR) with combination neoadjuvant immunotherapy, and 59 of the 60 patients with an MPR did not undergo therapeutic lymph node dissection, “resulting in significantly lower surgical morbidity and better quality of life.” The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with an MPR (Nature Med. 2022;28:1178-1188).
Similar trials must eventually be conducted with patients who have locally advanced resectable squamous cell carcinoma before altering the standard of care.
“One of my concerns is that neoadjuvant immunotherapy could become a bit like the Wild West, with folks trying different things because they want to help patients,” Dr. Gross said. “That’s one of the reasons why I’m committed to developing a phase 3 trial.”
Is neoadjuvant immunotherapy a safe option for immune-suppressed patients with advanced cutaneous squamous cell carcinoma? Because immunotherapy revs up the immune system, immunosuppressed patients (including those who have undergone solid organ transplantation and are taking medication to ward off organ rejection and those who have autoimmune diseases) have traditionally been excluded from immunotherapy trials.
“We may find that there’s a group of those patients who should be considered for neoadjuvant immunotherapy,” Dr. Divi said. “For example, some of them may be able to tolerate the drugs without a significant flare of their autoimmune disease and may have a positive response.”
Additional research is needed to determine which immunosuppressed patients may be candidates for neoadjuvant immunotherapy and what doses are safest and most effective.
What Otolaryngologists Need to Know Now
Although more work needs to be done to determine precisely how and when to offer neoadjuvant immunotherapy for the greatest advantage, the availability and largely positive outcomes of this novel approach to advanced resectable cutaneous squamous cell carcinoma means that physicians who see these patients should pause before launching into the traditional standard of care.
“Our previous instinct of ‘surgery first’ should now be, ‘Does this patient need surgery first, or do we need neoadjuvant therapy first?’” Dr. Emerick said.
The answer to that question, of course, is not always clear. “Not every patient is a good candidate for receiving neoadjuvant therapy first,” Dr. Divi said. “If a tumor is borderline resectable, that’s a challenge, because if we get a big shrinkage with neoadjuvant immunotherapy, that’s a huge win. However, if we don’t get that shrinkage and it grows instead, we can go from a resectable tumor to an unresectable one.”
Despite the risk of tumor advancement, Dr. Gross said it’s reasonable to try neoadjuvant therapy before surgery if surgical treatment will likely damage function. “If you’re contemplating removing someone’s eye, ear, or nose to remove this cancer, there may be a better option,” he said. “Even without a phase 3 trial, I think neoadjuvant immunotherapy should be considered for patients who have disease that’s encroaching on critical structures.”
Jennifer Fink is a freelance medical writer based in Wisconsin.
Needed: Multidisciplinary Squamous Cell Carcinoma Teams
Most cancer centers now have multidisciplinary melanoma teams and fantastic interdisciplinary head and neck cancer teams. But few centers have formal, organized multi-specialty teams to manage the care of patients with advanced cutaneous squamous cell carcinoma. As a result, these patients are often shuttled between dermatology and head and neck cancer practices—and the techniques used to manage advanced head and neck skin cancers are quite different from traditional treatments for localized skin cancer and tongue or tonsil cancers.
“We need multidisciplinary teams that are informed and dedicated to this patient population,” said Kevin Emerick, MD, co-director of the Non-Melanoma Skin Cancer Multidisciplinary Clinic and Program at Mass Eye and Ear in Boston.
If your institution or hospital doesn’t yet have a multidisciplinary team to manage locally advanced skin cancers, build connections with your colleagues in dermatology, plastic surgery, general surgery, surgical oncology, head and neck surgical oncology, and facial plastics. Patient involvement is also crucial; consider soliciting patient input and formally appointing patient representatives to steering committees, as appropriate.