Neoadjuvant Immunotherapy: An Evolving Paradigm Shift?

Systemic treatments for curable malignancies are frequently given after definitive surgery, with the goal to eliminate microscopic residual disease and improve survival. In contrast, neoadjuvant treatment aims to downstage cancer, making curative surgery possible or less extensive while eliminating micrometastases. Neoadjuvant treatment also allows for early evaluation of treatment efficacy and delivery of systemic therapy while patients can still tolerate it. Neoadjuvant chemotherapy has been the standard of care for decades: in bone osteosarcomas it allows limb-sparing surgeries (1); in breast cancer it allows for higher rates of breast-conserving therapy (although survival benefit is equivalent to adjuvant therapy) (2); in lung cancer (the benefit is similar to adjuvant therapy) (3) and in bladder cancer (where the role of adjuvant therapy is unclear at present) (4).

In the last decade, immune checkpoint inhibitors (ICIs) have revolutionized the treatment and improved survival of metastatic cancers. The efficacy and acceptable safety profile of ICIs support their use earlier in the disease course. When used as adjuvant therapy, ICIs are extending survival in patients with advanced melanoma (ipilimumab, nivolumab, and pembrolizumab) and non-small cell lung cancer (NSCLC) (durvalumab after definitive chemoradiotherapy). In theory, delivering immunotherapeutic agents before surgery should 1) induce a more robust immune response against the antigens present in the intact tumor (5), 2) enhance tumor-antigen presentation in tumor-draining lymph nodes (6), 3) avoid surgery-mediated immunosuppression caused by postsurgical expansion of M2 macrophages and T regulatory cells (7), 4) help with in-depth scientific evaluations and biomarker development, and 5) avoid unnecessary surgical treatments by providing time to uncover hidden metastases.

In this issue of the Journal, Krishnamoorthy et al. (8) reviewed the literature on administering ICIs before surgical resection in high-risk resectable disease. This neoadjuvant immunotherapy strategy has demonstrated a high pathologic response rate and prolonged relapse-free survival in randomized trials in melanoma, glioblastoma, and colon cancer, albeit in smaller numbers of patients. The authors conclude that neoadjuvant immunotherapy, currently being evaluated in large trials across different tumor types, is a promising and feasible therapeutic approach.

An important goal of neoadjuvant immunotherapy is to study the predictive role of surrogate endpoints such as pathologic complete response (pCR) and immune-related pathologic response criteria, a scoring system developed to evaluate pathologic response to ICIs by analyzing the volume of immune-mediated clearance of the tumor (assessing amount of tissue repair, immune activation, regression bed and cell death) (9) and their impact on overall survival. In preclinical studies, neoadjuvant immunotherapy was superior to adjuvant immunotherapy in prolonging survival and decreasing rates of disease recurrence (10,11). Multiple clinical trials have demonstrated that neoadjuvant immunotherapy is safe and feasible. In a recent neoadjuvant study, the addition of pembrolizumab statistically significantly increased pCRs compared with chemotherapy alone in hormone-positive breast cancer (30% vs 13%) and triple-negative breast cancer (60% vs 22%) (12), leading to several ongoing neoadjuvant phase III trials (MO39875, KEYNOTE-522, IMpassion031, and NeoTRIPaPDL1). In bladder cancer, 2 neoadjuvant phase II trials using atezolizumab and pembrolizumab demonstrated a pCR rate of 31%-40% (13,14), leading to an ongoing phase III study in cisplatin-ineligible patients (KEYNOTE-905). In melanoma, 2 clinical trials have shown a pCR rate of 33%-45% (15,16). Several studies have tested neoadjuvant ICI alone or in combination with chemotherapy in NSCLC. Results of these trials suggest that the combination of ICI plus chemotherapy is very effective; pCRs were as much as 59% and up to 80% of patients underwent planned surgery (17). Several ongoing phase III trials are comparing neoadjuvant chemoimmunotherapy to chemotherapy (KEYNOTE-671, IMpassion030, and CheckMate-816).

Our group recently reported results of a phase II study of neoadjuvant vaccine targeting PSA (PROSTVAC) in patients undergoing radical prostatectomy that demonstrated that this approach can induce both intratumoral and peripheral immune responses (18). At the National Cancer Institute, an ongoing study of neoadjuvant PROSTVAC plus nivolumab (NCT02933255) is evaluating changes in T-cell infiltration into the tumor after neoadjuvant treatment relative to changes seen with PROSTVAC alone.

Neoadjuvant immunotherapy has several advantages over adjuvant immunotherapy, including the ability to generate an immune response against a broader antigen repertoire, lower costs due to fewer doses of treatment drugs, and the ability to study and understand mechanisms of action and develop biomarkers. Although neoadjuvant immunotherapy strategies have reported promising results so far, there are still several challenges, including determining the optimal number and schedule of doses, monotherapy vs combination therapy, early detection of nonresponders, and delay of potentially curative surgery (up to 15% of patients did not undergo surgery in neoadjuvant immunotherapy trials) (19). Currently, more than 270 clinical trials are evaluating neoadjuvant immunotherapy, reflecting the growing interest in this treatment approach.

Neoadjuvant studies could accelerate the development of new therapeutic approaches using surrogate endpoints such as pCR and major pathologic response, defined as 10% or less of residual viable tumor. pCR has correlated with overall survival in patients who were treated with neoadjuvant chemotherapy for NSCLC and bladder, gastric, and breast cancers. However, additional studies are needed to determine whether major pathologic response or pCR after neoadjuvant ICI are valid surrogate endpoints that can predict survival similar to neoadjuvant chemotherapy. Neoadjuvant immunotherapy studies are also evaluating new treatment combinations with the goal of increasing accumulation of immune cells within the tumor, such as combinations of cancer vaccines, chemotherapies, and tyrosine kinase inhibitors. The idea that surgery could be forgone in patients with radiographically and clinically documented complete response after neoadjuvant immunotherapy is enticing but needs clinical validation. Novel imaging technologies (immuno-guided positron emission tomography scans) (20) and analysis of circulating tumor DNA (21) could address some concerns, but data from appropriately designed randomized trials are needed before neoadjuvant immunotherapy can be adopted as the new gold standard for cancer treatment. With longer follow-up, long-term outcomes and delayed toxicities can be evaluated, and biomarker discovery is crucial in selecting the best patients for this approach. Finally, results of ongoing studies should elucidate mechanisms and pathways that may lead to new treatment combinations.

Can we be more successful if immunotherapy is used earlier, as neoadjuvant therapy? We hope that answer is yes.

Funding

None.

Notes

Role of the funder: Not applicable.

Disclosures: The authors have no conflicts of interest to disclose.

Author contributions: Bilusic and Gulley—conceptualization (equal), writing (original draft preparation) (MB), and writing (review and editing) (equal). Gulley—Administration.

Data Availability

Not applicable.