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The impact of immunotherapy, specifically immune checkpoint inhibitors, in advanced and metastatic cancer quickly led to interest in using the therapy in earlier-stage disease. Most recently, the momentum has reached the .

Currently, neoadjuvant immunotherapy has only two approved indications: and . Ongoing studies are seeking to expand the indications to other types of cancer. A highlighted evidence suggesting that neoadjuvant immunotherapy "can expand and transcriptionally modify tumor-specific T-cell clones to enhance both intratumoral and systemic anti-tumor immunity." The effects could have applicability to numerous cancers.

"We consider this approach to cancer immunotherapy to be a gold mine for advancing our scientific knowledge of how an immune checkpoint blockade is working, to define better biomarkers that predict clinical outcomes, and to help us design the next generation of more effective treatments with combination therapies," said Suzanne Topalian, MD, of Johns Hopkins' Bloomberg-Kimmel Institute for Cancer Immunotherapy in Baltimore, lead author of the review article.

Topalian and co-authors identified several themes in their review of immune checkpoint inhibitor clinical trials:

• Immunotherapy regimens that prove effective against advanced cancers also tend to be effective in the neoadjuvant setting
• The extent of pathologic response after neoadjuvant therapy predicts the relapse-free interval after surgery
• Besides priming the immune system's anti-tumor activity, immunotherapy may also improve surgical outcomes by shrinking tumors, potentially making surgery unnecessary in some cases
• Pathology specimens after neoadjuvant immunotherapy provide a unique resource to learn more about how immune checkpoint inhibitors work

Melanoma: Where It All Began

Melanoma led the way with clinical proof of immunotherapy's potential for improving outcomes in cancer. Today, melanoma is one of the most active areas of investigation into neoadjuvant immunotherapy. For patients with clinical stage III disease, standard of care consists of surgical resection, lymph node dissection and/or resection of in-transit disease, and consideration for adjuvant systemic therapy. The condition is a high-risk clinical situation associated with high rates of regional recurrence and metastatic progression after surgery.

Neoadjuvant immunotherapy offers the potential to improve outcomes for those patients. However, clinical stage III disease accounts for only about 15% of all new melanoma diagnoses. Investigation into neoadjuvant immunotherapy is limited to that fraction of patients, said Rodabe Amaria, MD, of the University of Texas MD Anderson Cancer Center in Houston.

"Those patients, by definition, have a much higher risk than your average stage III melanoma that has microscopically involved nodal disease," Amaria told 番茄社区app. "The approach of upfront surgery and adjuvant therapy is completely appropriate for that patient population."

Though emphasizing that her expertise is in melanoma, she said that the application of neoadjuvant immunotherapy in other cancers might also be limited to high-risk subgroups.

Neoadjuvant immunotherapy is not without potential downsides, Amaria and co-authors noted in a about the melanoma experience. Disease progression during neoadjuvant treatment could delay or even preclude surgery. Additionally, treatment-related adverse events could delay or complicate surgery. Even so, neoadjuvant immunotherapy for high-risk stage III melanoma "is an exciting paradigm shift supported by an increasing body of clinical data."

Immunotherapy has demonstrated superior survival versus targeted therapy for advanced melanoma and can be used as initial therapy in patients whose disease has targetable mutations. No targeted agents have approval for neoadjuvant treatment of melanoma, but the superiority of immunotherapy likely extends to the neoadjuvant setting.

"We don't have any randomized trials of neoadjuvant BRAF-targeted therapy versus immunotherapy, but in our observation of different trials and data, I can say that, unfortunately, we are seeing a lot more recurrences with neoadjuvant targeted therapy compared with immunotherapy," said Amaria.

Anticipation Builds

With approved indications in breast and lung cancer, oncologists have already begun applying neoadjuvant therapy to clinical practice. Additional approvals are expected in the near future, so oncologists who treat other types of cancer would not be premature in thinking about patient selection and other aspects of neoadjuvant therapy.

"The recommendation is still for clinical trials, if at all possible, but absolutely, I think people are already thinking that way in the community," said Amaria.

Results with neoadjuvant immunotherapy have been particularly encouraging for melanoma and cutaneous squamous-cell carcinoma, said Ravindra Uppaluri, MD, PhD, of Dana-Farber Cancer Institute and Brigham and Women's Hospital in Boston.

In a recent , neoadjuvant plus adjuvant pembrolizumab (Keytruda) led to better event-free survival in resectable stage III-IV melanoma as compared with adjuvant pembrolizumab. Another showed a high rate of pathologic complete response with neoadjuvant cemiplimab (Libtayo) in patients with resectable stage II-IV cutaneous squamous-cell carcinoma.

"Oncologists are feeling more comfortable to use neoadjuvant immunotherapy, and these tumor types will likely have upcoming approvals," Uppaluri said via email.

"Importantly, while many current studies in different tumor types are highlighting a possible approach for our patients with difficult-to-treat cancers, we need randomized clinical trial supportive data prior to integrating this approach as standard of care," he added.

A that coincided with the 2022 American Society of Clinical Oncology annual meeting included a list of almost 50 ongoing phase III trials of neoadjuvant immunotherapy for various types of cancer. The list comprised trials in muscle-invasive bladder cancer, several types of breast cancer, almost a dozen trials in gastrointestinal cancers, ovarian cancer, kidney cancer, head and neck cancer, and lung cancer.

"Administering immunotherapy preoperatively is a biologically sound approach because it is likely the setting in which such therapy can generate the optimal immune response, leading to high rates of pathologic response as well as improved long-term survival," authors of the review article concluded.

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