In Which Cancers Is Immunotherapy Before Surgery Effective?

In cancer, neoadjuvant (preoperative, tumor-shrinking) treatment approaches have attracted considerable interest in recent years, and the immune checkpoint inhibitor ( ICI) class of immunotherapies is making important advances. Given before surgery in previously untreated patients, these treatments aim both to make the primary tumor more surgically resectable and to trigger or potentially strengthen a systemic antitumor immune response using antigens recognized by the immune system. Neoadjuvant ICI thus aims to reduce the risk of recurrence after surgery. The scientific and clinical advances behind this approach are opening promising new avenues in cancer treatment.

FDA-Approved Neoadjuvant Immunotherapies

Neoadjuvant ICI treatment has received two FDA approvals in the past two years and is being tested extensively across many cancers.

• July 27, 2021: Pembrolizumab (Keytruda) was approved for high-risk, early-stage triple-negative breast cancer (TNBC). A combination of carboplatin and paclitaxel followed by doxorubicin or epirubicin with cyclophosphamide was recommended as neoadjuvant treatment. Pembrolizumab monotherapy was recommended as adjuvant treatment. 
• March 4, 2022: Nivolumab (Opdivo) was approved for early-stage, operable non–small-cell lung cancer (NSCLC) . This was the first FDA approval for neoadjuvant treatment of early-stage NSCLC and the first immunotherapy approval for early-stage lung cancer. It applies to stages IB through IIIA. Pathologic complete response was 24% with nivolumab versus 2.2% with chemotherapy alone.

Pathological Response and Clinical Outcomes:

• The fastest way to measure neoadjuvant treatment efficacy is to assess the pathologic complete response (pCR) rate in the surgical specimen.
• A substantial proportion of patients achieve pathologic complete response (pCR) with some neoadjuvant ICI regimens.
• In the first two trials leading to FDA approvals, patients with TNBC and NSCLC achieved pCR and showed improved survival without disease progression or death from the start of treatment.

Detailed Immunological Analyses and Future Research:

• Neoadjuvant ICI treatment has provided a rich resource for detailed immunological analyses of response and resistance mechanisms.
• High- and ultrahigh-dimensional platforms, such as proteomics, transcriptomics, epigenetics, and B- and T-cell receptor repertoire analysis, enable single-cell analysis of every cell type in treated tumors.
• All these scientific efforts are expected to guide the continued improvement of neoadjuvant immunotherapy combinations.

Key Findings of the Study

• Immune Cells and Cancer: The study analyzes the ability of immune cells, particularly T cells, to recognize and destroy cancer cells. T-cell activation and proliferation are central to successful cancer immunotherapy.
• Immunotherapy Responses: Immunotherapy efficacy is directly proportional to the strength and quality of cellular immune responses. Strong cellular responses have been associated with better treatment outcomes.
• Biomarkers: Using biomarkers to assess cellular immune responses may help predict immunotherapy efficacy and develop personalized treatment strategies.
• Tumor Microenvironment: The tumor microenvironment and its interactions with immune responses are important factors influencing cancer immunotherapy success. Modifying this environment to enhance immunotherapy efficacy should be a focus of future research.

Lung Cancer

1. Pathologic Complete Response (pCR) and Efficacy Rates: In CheckMate 816, neoadjuvant chemotherapy plus nivolumab significantly increased pCR compared with chemotherapy alone (from 2.2% to 24%). The duration of treatment efficacy, event-free survival , differed by almost a year with neoadjuvant chemotherapy plus nivolumab (median 20.8 versus 31.6 months). In addition, the 2-year event-free survival rate was above 90% in patients with pCR, compared with approximately 50% in those without pCR.
2. Treatment Tolerability and Surgical Resection: The first neoadjuvant PD-1 pathway blockade trial was conducted in operable NSCLC. Patients received nivolumab before surgery for approximately 4 weeks, treatment was well tolerated, and all underwent complete surgical resection.
3. Response Rates and Long-Term Outcomes: In phase 2 trials such as NADIM and NADIM-2, patients with operable stage III NSCLC received nivolumab with standard neoadjuvant carboplatin-paclitaxel chemotherapy, achieving a notable pCR rate of 57%. The study's 36-month overall survival rate was 82%.
4. Neoadjuvant and Adjuvant Immunotherapy: AEGEAN is the first phase 3 trial evaluating adjuvant immunotherapy after neoadjuvant chemotherapy. A pCR increase to 17.2% was seen in the durvalumab-containing arm versus 4.3% in the control arm. The likelihood of event-free survival was also 32% higher with durvalumab [HR 0.68 (0.53-0.88; p = 0.003902)].

Breast Cancer

KEYNOTE 522 and FDA Approval:

• KEYNOTE 522 is a randomized phase 3 trial evaluating pembrolizumab as neoadjuvant immunotherapy (ICI) in early-stage triple-negative breast cancer (TNBC).
• Neoadjuvant pembrolizumab plus chemotherapy produced higher pathologic complete response (pCR) rates than placebo plus chemotherapy (63% versus 56%).
• At a median follow-up of 36 months, event-free survival was 84.5% with pembrolizumab plus chemotherapy versus 76.8% with placebo plus chemotherapy.

Using pCR as an Indicator of Clinical Benefit:

• KEYNOTE 522 showed that pCR provides prognostic information about long-term clinical outcomes.
• GeparNuevo showed a 3-year overall survival rate of 100% in patients with pCR after neoadjuvant durvalumab plus chemotherapy, compared with 3-year overall survival of 91.1% in patients receiving chemotherapy alone. Patients receiving neoadjuvant durvalumab plus chemotherapy were 50% less likely to develop metastases than those receiving neoadjuvant chemotherapy alone.

Neoadjuvant Chemotherapy and ICI Combinations:

• KEYNOTE 522 demonstrated the efficacy of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab monotherapy in high-risk, early-stage TNBC.
• NeoTRIPaPDL1 Michelangelo and NeoPACT showed improved pCR with the addition of anti-PD-(L)1 agents (atezolizumab, pembrolizumab, or durvalumab) to standard neoadjuvant chemotherapy.

I-SPY2 and Innovative Neoadjuvant ICB Regimens:

• I-SPY2 is an adaptive, randomized phase 2 neoadjuvant platform trial comparing multiple experimental drugs with standard neoadjuvant chemotherapy.
• Pembrolizumab efficacy was assessed through estimated pCR rates of 30% versus 13% in HR+ breast cancer and 60% versus 22% in TNBC.
• I-SPY2 also evaluated innovative neoadjuvant ICI regimens, including pembrolizumab with SD-101 (a TLR9 agonist), cemiplimab (anti-PD-1) with paclitaxel, and cemiplimab with REGN376 (anti-LAG-3).

Skin Cancers

Melanoma and Neoadjuvant Immunotherapy:

• Melanoma was an early testing ground for immunotherapy and one of the first platforms for neoadjuvant anti-PD-1-based treatment.
• Four trials published in 2018-2019 found lower-than-expected maximum pathological response (MPR) rates (25-30%) with neoadjuvant anti-PD-1 monotherapy. Adding an anti-CTLA-4 agent increased pathological response rates, and patients achieving at least 50% "pathological partial response" (pPR) experienced long-term relapse-free survival (RFS), meaning time without disease.

The SWOG S1801 and NADINA Trials:

• SWOG S1801 randomized 313 patients with operable stage III-IV melanoma to anti-PD-1 treatment (pembrolizumab) before and after surgery or only after surgery (standard adjuvant care). Neoadjuvant/adjuvant treatment produced significantly better 2-year event-free survival than adjuvant-only treatment (72% versus 49%).
• NADINA evaluates neoadjuvant anti-PD-1 (nivolumab) plus anti-CTLA-4 (ipilimumab) versus immediate surgery followed by standard adjuvant nivolumab. Initial results are expected in late 2023 or early 2024. 

Merkel Cell Carcinoma (MCC) and Neoadjuvant Immunotherapy:

• After approximately 4 weeks of neoadjuvant nivolumab monotherapy, 47% of 36 patients with resectable MCC achieved pCR. Those with pCR had significantly higher relapse-free survival over 2 years after surgery than those without pCR (88.9% versus 52.2%).

Cutaneous Squamous Cell Carcinoma (cSCC) and Neoadjuvant Immunotherapy:

• Among 79 patients with resectable disease treated in the neoadjuvant setting for approximately 12 weeks, 51% achieved pCR. Whereas neoadjuvant ICI experience in melanoma mainly focused on stage III-IV disease, many MCC or cSCC patients were treated for locally advanced tumors.

Neoadjuvant Immunotherapy in Mismatch Repair-Deficient (MMRd) Cancers:

• MMRd was detected approximately twice as often in nonmetastatic cancers (8%) as in metastatic cancers (4%), corresponding to around 40,000 stage I-III MMRd cancer diagnoses annually in the United States alone.
• Neoadjuvant immunotherapy trials in MMRd tumors have shown few progression events and high pathological response rates, with pCR of approximately 60%.
• In INFINTY, pCR was 89% (8/9) among patients with MMRd and T2-T3 disease, compared with 17% (1/6) in T4 disease.
• Organ Preservation Approaches: In a study by Cercek and colleagues, 100% (12/12) of patients with locally advanced MMRd rectal cancer showed complete radiographic and endoscopic responses after 6 months of anti-PD-1 treatment (dostarlimab), with no residual tumor detected on serial biopsies for ≥6 months.

Hepatocellular Carcinoma (HCC) and Neoadjuvant Immunotherapy:

• Three single-institution studies demonstrated the feasibility of neoadjuvant ICI in HCC. These pilot studies showed maximum pathological response (MPR) rates of 20-33%, with very good survival in the pathological responder subgroup.

Neoadjuvant Immunotherapy in Gastroesophageal Cancers:

• Interim DANTE results showed a modest improvement in pathological response in the atezolizumab-containing arm (49% versus 39%). Benefit was more pronounced in the high-PD-L1-expression subgroup, with pathological response of 67% for FLOT plus atezolizumab versus 39% for FLOT alone.

Pancreatic Cancer and Neoadjuvant Immunotherapy:

• In pancreatic cancer, the phase 2 PIONEER-Panc study uses a Bayesian platform design to evaluate one or more experimental arms simultaneously against a shared chemotherapy control arm in patients with resectable, borderline resectable, or locally advanced disease. This reflects the critical need for new pancreatic cancer treatments and provides a framework for rapid evaluation and development of novel therapeutics across tumor types.

Conclusion

Although neoadjuvant immune checkpoint inhibitor (ICI) trials still have short follow-up, themes are emerging, particularly from trials with median follow-up of 2 years or more. The role of neoadjuvant ICI in cancer treatment offers new perspectives for both clinical practice and scientific research.

Neoadjuvant ICI Efficacy and Pathological Response:

• For a given tumor type, combinations containing neoadjuvant immunotherapy show substantial efficacy against advanced, inoperable disease and increase pathological response rates when given before surgery.
• Pathological Response and EFS/RFS Duration: In trials of neoadjuvant ICI plus chemotherapy, patients achieving pCR had few postoperative recurrences. This indicates that pathological response is a useful surrogate for systemic antitumor immunity and elimination of micrometastases that are radiographically invisible at surgery.

Surgical Resection and Functional Outcomes:

• Neoadjuvant ICI may favorably affect surgery, particularly by substantially improving cosmetic and functional outcomes.
• In conditions such as skin cancers highly responsive to ICI and MMRd rectal cancers, neoadjuvant ICI may reduce or eliminate the need for surgery.

Scientific Analyses and a Forward-Looking Perspective:

• Single-cell and high-dimensional analyses generate detailed tumor profiles after neoadjuvant ICI, providing important information about immunotherapy response.
• Analyzing immune cell types such as CD8+ T cells and Treg cells may reveal how neoadjuvant ICI modifies intratumoral immune responses and how these responses relate to clinical outcomes.

In conclusion, neoadjuvant ICI and combination treatments must be designed carefully to address critical clinical and scientific questions in this new era of cancer immunotherapy. Hundreds of ongoing neoadjuvant ICI trials are producing an explosion of scientific insights and clinical benefits, showing that this field of translational research has only scratched the surface of its possibilities. The future of neoadjuvant ICI will shape clinical applications and scientific research in cancer treatment and offers promising potential for better patient outcomes.